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Mental Illness and Substance Use Disorders: Background

About this Course

 

 

Pharmacists possess the training and skills necessary to administer certain long-acting injectable (LAI) medications used in the management of mental illnesses and substance use disorders. Through collaborative practice agreements, pharmacists can administer Long Acting Injectables in almost every state. In some states, including the state of Connecticut, this occurs via collaborative agreements, and necessary injection and disease state training.  Administration of these medications by pharmacists can increase accessibility of care for patients.

UConn has developed web-based continuing pharmacy education activity to enhance pharmacists’ skills and help them make sound clinical decisions about long acting injectables administration. This course includes eight hours of CPE (or eight hours of credit), required by the State of Connecticut.  Successful completion of these eight hours (with four activities consisting of three hours online pre-requisite work and five hours of LIVE CE) will earn the pharmacist a Certificate in Long-Acting Injectables of Psychotropic Medication.

The three activities below are available separately for $17/hour each, or as pre-requisites for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program at $299 which includes both the prerequisites and the full day of LIVE training.

Target Audience

Pharmacists who are interested in administering long acting injectable psychotropic medications to their patients.

This activity is NOT accredited for technicians.

Pharmacist Learning Objectives

At the end of this application-based continuing education activity, the learner will be able to:

Describe the prevalence, pathophysiology, clinical features, and diagnostic criteria of:

·        Schizophrenia

·        Bipolar disorder

·        Substance use disorders

 

Differentiate between signs and symptoms of these disorders

Release Date

Released:  11/15/2023
Expires:  11/15/2026

Course Fee

$17

ACPE UAN

0009-0000-23-050-H01-P

Accreditation Hours

1.0 hours of CE

Session Code

23LA50-TXJ44

Bundle Options

If desired, pharmacists can register for the entire Long-Acting Injectable Psychotropic Medication Pharmacist Certificate Training Program

or for the individual activities.   The Certificate consists of three activities in our online selection, and a 5 hour LIVE activity.

You may register for individual topics at $17/CE Credit Hour, or for the Entire LAIA Certificate at $299.00 which includes 5 hours of LIVE CE and the 3 online pre-requisites listed below.

You must register for ALL 4 activities to receive the bundled pricing of $299.00

Accreditation Statement

ACPE logo

The University of Connecticut, School of Pharmacy, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit 1.0 hours (or 0.1 CEUS) for the online activity ACPE #0009-0000-23-050-H01-P will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

Grant Funding

There is no grant funding for this activity.

Requirements for Successful Completion

To receive CE Credit go to Blue Button labeled "take Test/Evaluation" at the top of the page.

Type in your NABP ID, DOB and the session code for the activity.  You were sent the session code in your confirmation email.

Faculty

Kristin Waters, PharmD, BCPS, BCPP,
Assistant Clinical Professor
UConn School of Pharmacy
Storrs, CT

Faculty Disclosure

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Dr. Waters is a consultant with Janssen Pharmaceuticals. She will discuss all drugs without bias. All financial interests with ineligible companies (as noted) have been mitigated.

Disclaimer

This activity may contain discussion of off label/unapproved use of drugs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of the University of Connecticut School of Pharmacy. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Program Content

Program Handouts

Post Test Evaluation

View Questions for Mental Illness and Substance Use Disorders: Background

Hour 1: Mental Illness and Substance Use Disorders: Background

1. A 38-year-old patient with an unknown psychiatric history is dropped off at the emergency department by police after being found wandering the streets and knocking on doors at random. The patient admits that they believe they are being monitored by the FBI and that “the mafia” wants to recruit them as a spy. The patient is observed having a conversation with themselves while alone in the examination room.

Which of the following positive symptoms is the patient likely experiencing?
A. Psychosis and auditory hallucinations
B. Auditory hallucinations and delusions
C. Delusions and anhedonia
D. Paranoia and agitation

2. Which of the following is the correct term for fixed, false beliefs that patients with schizophrenia may experience?
A. Delusions
B. Hallucinations
C. Disorganized speech
D. Catatonia

3. A patient with schizophrenia has experienced both positive and negative symptoms for several years. They are now presenting with signs of mania, including pressured speech and grandiosity. Which of the following is true?
A. The patient’s diagnosis will likely change to schizoaffective disorder, bipolar type
B. The patient’s diagnosis will likely change to schizoaffective disorder, depressive type
C. The patient will now be diagnosed with schizophrenia and bipolar disorder
D. The patient will now be diagnosed with schizophrenia and major depressive disorder

4. Which of the following is true about bipolar disorder?
A. The most common time that patients are diagnosed is during childhood
B. Most patients are initially diagnosed with schizophrenia
C. It has a higher mortality rate than major depressive disorder
D. Type II bipolar disorder is associated with more severe episodes of mania than type I

5. Most patients with bipolar disorder spend the majority of their time in which mood phase?
A. Mania
B. Depression
C. Hypomania
D. Euthymia

6. A patient with bipolar disorder presents to their outpatient provider and reports that they believe they are on the verge of a “breakthrough” and will soon become a world-famous author once their manuscript is published. They have recently stopped going to work and have been writing “all day and all night” for the past week. They also report spending thousands of dollars on a new computer so that they have “the best equipment” with which to write their manuscript.
Which of the following symptoms of mania is the patient displaying?
A. Grandiosity, decreased need for sleep, increased goal directed activity
B. Flight of ideas, distractibility, grandiosity
C. Disorganized thoughts, decreased need for sleep, flight of ideas
D. Confusion, excessive spending, distractibility

7. Patient NP was diagnosed with bipolar disorder, type II approximately 5 years ago. They have rarely missed work due to hypomanic symptoms, and are generally able to perform all day-to-day activities without impairment. Following a breakup, NP begins to display signs of grandiosity, flight of ideas, decreased sleep, and increased spending. They also begin to hear the voice of their ex-partner telling them that they are worthless.

Which of the following is most appropriate?
A. NP’s diagnosis should be changed to bipolar disorder type I
B. NP’s diagnosis should remain the same
C. NP’s diagnosis should be changed to schizoaffective disorder
D. NP’s diagnosis should be changed to bipolar disorder, mixed type

8. Which of the following is a risk factor for the development of a substance use disorder?
A. Female gender
B. Age > 65 years
C. Co-occurring psychiatric disorder
D. Parenthood

9. Which type of opioid receptor contributes to the stimulation of the dopamine-related reward system?
A. Mu-opioid receptor
B. Kappa-opioid receptor
C. Delta-opioid receptor
D. Beta-opioid receptors

Additional Courses Available for Long Acting Injectable Training

 

Guideline-Driven Treatment for Mental Illnesses and Substance Abuse Disorders– 1.0 hour

Long-Acting Injectable Medication Products– 1 hour

 

Anticoagulation Management Pearls

About this Course

UConn has developed web-based continuing pharmacy education activities to enhance the practice of pharmacists and assist pharmacists in making sound clinical decisions to affect the outcome of anticoagulation therapy for the patients they serve. There are a total of 12 hours of CPE credit available. Successful completion of these 12 hours (13 activities) or equivalent training will prepare the pharmacist for the Anticoagulation Traineeship, which described below in the Additional Information Box.

The activities below are available separately for $17/hr or as a bundle price of $140 for all 13 activities (12 hours). These are the pre-requisites for the anticoagulation traineeship. Any pharmacist who wishes to increase their knowledge of anticoagulation may take any of the programs below.

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

Target Audience

Pharmacists who are interested in making sound clinical decisions to affect the outcome of anticoagulation therapy for the patients they serve.

This activity is NOT accredited for technicians.

Pharmacist Learning Objectives

At the end of this knowledge-based continuing education activity, the learner will be able to:

  1. Describe effective anticoagulation management strategies.
  2. Describe components of effective anticoagulation education session.
  3. Identify barriers to learning.

Release Date

Released:  06/01/2022
Expires:  05/31/2025

Course Fee

$17

ACPE UAN Code

ACPE #0009-0000-22-026-H04-P

Session Code

22AC26-EXW48

Accreditation Hours

1.0 hours of CE

Bundle Options

If desired, “bundle” pricing can be obtained by registering for the activities in groups. This series consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(12 hours of CE)  $140.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Additional Information

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

The University of Connecticut School of Pharmacy and The UConn Health Center Outpatient Anticoagulation Clinic have developed 2-day practice-based ACPE certificate continuing education activity for registered pharmacists and nurses who are interested in the clinical management of patients on anticoagulant therapy and/or who are looking to expand their practice to involve patient management of outpatient anticoagulation therapy. This traineeship will provide you with both the clinical and administrative aspects of a pharmacist-managed outpatient anticoagulation clinic. The activity features ample time to individualize your learning experience. A “Certificate of Completion” will be awarded upon successful completion of the traineeship.

More Information About Traineeship

Accreditation Statement

ACPE logo

The University of Connecticut, School of Pharmacy, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit 1.0 hours (or 0.1 CEUS) for the online activity ACPE #0009-0000-22-026-H04-P will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

Grant Funding

There is no grant funding for this activity.

Requirements for Successful Completion

To receive CE Credit go to Blue Button labeled "take Test/Evaluation" at the top of the page.

Type in your NABP ID, DOB and the session code for the activity.  You were sent the session code in your confirmation email.

Faculty

Anuja Rizal, Pharm.D., RPh, CACP
Anticoagulation Clinical Coordinator
UConn Health Center
Farmington, CT

Faculty Disclosure

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Dr. Rizal has no relationship with an ineligible company and therefore has nothing to disclose.

Disclaimer

This activity may contain discussion of off label/unapproved use of drugs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of the University of Connecticut School of Pharmacy. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Program Content

Program Handouts

Post Test Evaluation

View Questions for Anticoagulation Management Pearls

1. The Joint Commission revised National Patient Safety Goal is intended to:

  1. Ensure all providers are providing same level of care
  2. Set standards on provider’s level of knowledge of anticoagulant medications
  3. Reduce the likelihood of patient harm associated with the use of anticoagulant therapy
  4. Provide guidance on how to deal with providers who do not adhere to the standards
  5. None of the above

 

2. Which of the following are important Anticoagulation Management Considerations?

  1. Assessing pt’s fall risk
  2. Patient Education and Adherence
  3. Selecting appropriate drug
  4. All of the above
  5. None of the above

 

3. Staff education should consist of:

  1. Professionalism in the workplace
  2. Strategies to manage difficult coworkers
  3. Diversity training
  4. Effective time management strategies
  5. How to delegate

 

4. Which of the strategies is best when managing patients with language barriers?

  1. Ask pt. to bring in family members who can help interpret
  2. Ask pt. to bring in friend who can help interpret
  3. Ask bilingual coworker to help interpret
  4. Use google translate
  5. Use qualified interpreter

 

5. When speaking to deaf patients it is important to:

  1. Make indirect contact to avoid conveying incorrect tone/meaning thru facial expressions
  2. Speak slowly and clearly
  3. Learn ASL
  4. Use Visual Aids
  5. Repeat instructions

 

6. Which of the following statements are false?

  1. Using pamphlets or videos will enhance learning for the Visual learners
  2. A person can only have one learning style
  3. It is important to tailor the education to meet the pt’s learning style
  4. Kinesthetic learners learn best by gaining hands on experience
  5. Asking pt’s to repeat your points back to you by asking questions and calling for audience answers enhances learning for the Auditory learner

 

7. The best strategy to manage the non-compliant patient is to:

  1. Identify and address barriers to adherence
  2. Use motivational interviewing
  3. Minimize polypharmacy
  4. Utilize available family and social support
  5. All of the above

 

8. Select the most appropriate response:

  1. Medicare codes 99495 and 99496 are reimbursable for transitional of care services
  2. Transition of care addresses patients moving from one state to another
  3. Transition of care is handled solely by hospital staff
  4. Provide transition of care assistance to elderly patients who request it
  5. None of the above

 

9. Select the most appropriate response:

  1. Americans have been reported to have high health care literacy
  2. Low health care literacy can be managed by ensuring patients learn how to speak English
  3. Using interpreters can help combat low health care literacy
  4. Low health care literacy indicates cognitive decline
  5. None of the above

 

10. AIDET stands for:

  1. Acknowledge, Introduce, Duration, Explanation, Train
  2. Acknowledge, Inform, Duration, Explanation, Train
  3. Acquaint, Inform, Describe, Extent, Teach
  4. Acknowledge, Introduce, Duration, Explanation, Thank you
  5. Acquaint, Introduce, Describe, Extent, Teach

Challenging Topics in Anticoagulation

About this Course

UConn has developed web-based continuing pharmacy education activities to enhance the practice of pharmacists and assist pharmacists in making sound clinical decisions to affect the outcome of anticoagulation therapy for the patients they serve. There are a total of 12 hours of CPE credit available. Successful completion of these 12 hours (13 activities) or equivalent training will prepare the pharmacist for the Anticoagulation Traineeship, which described below in the Additional Information Box.

The activities below are available separately for $17/hr or as a bundle price of $140 for all 13 activities (12 hours). These are the pre-requisites for the anticoagulation traineeship. Any pharmacist who wishes to increase their knowledge of anticoagulation may take any of the programs below.

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

Target Audience

Pharmacists who are interested in making sound clinical decisions to affect the outcome of anticoagulation therapy for the patients they serve.

This activity is NOT accredited for technicians.

Pharmacist Learning Objectives

At the end of this application-based continuing education activity, the pharmacist will be able to:

  • Discuss managing techniques for challenging patient types including alcoholism, pregnancy, and patients with Antiphospholipid Antibodies Syndrome
  • Describe the discrepancy between POC testing and laboratory measurement of INR
  • Discuss the evidence for 12 week follow up visits and how to determine which patients are  appropriate
  • Evaluate anticoagulation therapy for selected challenging cases

Release Date

Released:  06/01/2022
Expires:  05/31/2025

Course Fee

$17

ACPE UAN Code

0009-0000-22-038-H01-P

Session Code

22AC38-PFX62

Accreditation Hours

1.0 hours of CE

Bundle Options

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(12 hours of CE)  $140.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Additional Information

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

The University of Connecticut School of Pharmacy and The UConn Health Center Outpatient Anticoagulation Clinic have developed 2-day practice-based ACPE certificate continuing education activity for registered pharmacists and nurses who are interested in the clinical management of patients on anticoagulant therapy and/or who are looking to expand their practice to involve patient management of outpatient anticoagulation therapy. This traineeship will provide you with both the clinical and administrative aspects of a pharmacist-managed outpatient anticoagulation clinic. The activity features ample time to individualize your learning experience. A “Certificate of Completion” will be awarded upon successful completion of the traineeship.

More Information About Traineeship

Accreditation Statement

ACPE logo

The University of Connecticut, School of Pharmacy, is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ADD ACPE UAN 0009-0000-22-038-H01-P will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

Grant Funding

There is no grant funding for this activity.

Requirements for Successful Completion

To receive CE Credit go to Blue Button labeled "take Test/Evaluation" at the top of the page.

Type in your NABP ID, DOB and the session code for the activity.  You were sent the session code in your confirmation email.

Faculty

Michael Smith, PharmD, CACP, BCPS
East Region Clinical Manager, Pharmacy
Hartford Healthcare
William W. Backus Hospital
Norwich, CT

Faculty Disclosure

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Dr. Smith has no relationship with an ineligible company and therefore has nothing to disclose.

Disclaimer

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Program Content

Program Handouts

Post Test Evaluation

View Questions for Challenging Topics in Anticoagulation

  1. Alcohol interacts with warfarin through

A             CYP450 1A2

B             Alcohol dehydrogenase

C             Interaction has not been clearly defined

D            p-Glycoprotein

 

  1. The greatest risk of fetal abnormalities related to warfarin use occurs during

A             The first trimester

B             The second trimester

C             The third trimester

D            stable throughout pregnancy

 

  1. The optimal duration of follow-up for patients receiving warfarin is:

A             Weekly

B             Monthly

C             Every 12 weeks

D            Not clearly defined in the literature

 

  1. When using enoxaparin during pregnancy for the prevention of VTE in patients who have been receiving long term warfarin therapy:

A             Use near therapeutic treatment level doses adjusted for body weight

B             Use standard prophylactic doses

 

  1. Antiphospholipid antibody syndrome:

A             Decreases the levels of Factor II and X

B             is associated with an Increase in the risk of hemorrhagic complications

C             is a viral disease

D            May interfere with the INR measurement of patients receiving warfarin

 

  1. Alcohol

A             Should be avoided at any level in all patients receiving warfarin

B             Can be managed similar to other drug interactions

C             Multiple studies on the interaction between binge drinking and warfarin have been published

D            Alcoholism is a FDA labeled contraindication to the use of warfarin

 

  1. The risk of thrombosis in pregnant women with mechanical heart valves is

A             Lowest in patients being treated with warfarin

B             Lowest in patients being treated with a LMWH

 

  1. No major group of international experts have supported the notion testing the INR in a patient receiving warfarin as little as once every 3 months

A             True

B             False

 

  1. A clinically appropriate way to monitor a patient receiving warfarin with antiphospholipid antibody syndrome is:

A             Factor II activity level

B             Factor X activity level

C             Activated Clotting Time (ACT)

D            Both A and B

 

  1. Binge drinking of alcohol in an anti-coagulated patient increase the risk of

A             Falls

B             Gastrointestinal bleeding

C             Non-compliance

D            All of the above

 

 

LAW: Science says “NO!” but social media says “GO!”

Learning Objectives

 

After completing this application-based continuing education activity, pharmacists and pharmacy technicians will be able to

  1. Discuss the effect of health misinformation on public health
  2. Review the controversy over ivermectin as a treatment for COVID-19
  3. Characterize the basis for lawsuits seeking to compel specific treatments during a pandemic
  4. Describe the role of regulatory bodies in disciplinary actions for misinformation

4 dice spelling fact and fake

Release Date:

Release Date: February 15, 2022

Expiration Date: February 15, 2025

Course Fee

Pharmacist:  $7

Pharmacy Technician: $4

ACPE UANs

Pharmacist: 0009-0000-22-002-H03-P

Pharmacy Technician: 0009-0000-22-002-H03-T

Session Codes

Pharmacist: 22YC02-ABC28

Pharmacy Technician: 22YC02-XYZ43

Accreditation Hours

2.0 hours of CE

Accreditation Statements

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-002-H03-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

 

Disclosure of Discussions of Off-label and Investigational Drug Use

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Faculty

Gerald Gianutsos, PhD, JD
Emeritus Associate Professor of Pharmacology
University of Connecticut School of Pharmacy
Storrs, CT

Faculty Disclosure

In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

Gerald Gianutsos, PhD, JD has no relationship with an ineligible company and therefore has nothing to disclose.

ABSTRACT

The continuing public health crisis has spurred an increase in the demand for unauthorized remedies. Many approaches are of dubious value and the appeal often has been driven by misinformation and uncertainty, frequently with endorsement from health care providers. This continuing education activity will examine the controversial promotion of unauthorized medications for the treatment for COVID-19, with an emphasis on the antiparasitic drug, ivermectin. Its focus is the efforts by patients to use the legal system to obtain the drug against the advice of mainstream medical practitioners and the efforts by some regulatory and professional organizations to restrict the dissemination of debatably distorted information about ivermectin.

CONTENT

Content

INTRODUCTION

People of the Middle Ages largely believed that bad air (caused by misaligned planets) was the cause of the bubonic plague. They tragically took medical precautions based on misinformation, such as wearing perfume satchels around their nose and mouth, when it was really infected fleas who were the perpetrators.1

The ongoing COVID-19 pandemic has brought forth many experiences including overcrowded emergency rooms, masking, social isolation, lockdowns, “warp speed” vaccine development --- and health misinformation. Disagreements over appropriate treatment of infected patients are numerous and heated and often spill into the political arena. Alternative treatments arising from desperation and inconsistent, everchanging advisories are highly sought, fueled by social media and other Internet resources. In many cases, health care professionals are sources of dubious information.

Pharmacists and pharmacy technicians, of course, also have responsibilities during a health care crisis and can be either another source of misinformation or a resource to clarify and refute poor advice. This continuing education activity examines some recent instances of conflicting health information. It focuses on lawsuits by patients requesting access to unproven or unconventional therapies for COVID-19 against mainstream medical advice and the sanctioning (or lack thereof) of health care providers for encouraging such therapies.

Disclaimer: Please be advised that the author chose the examples referred to in this continuing education activity based upon their high-profile and impact. Learners should not interpret these choices as representing any political commentary, agenda, or endorsement by the author or the University of Connecticut Office of Pharmacy Professional Development. We acknowledge that “misinformation” is hard to characterize, and a consensus can shift as more data are developed. Learners should also not infer that the examples used represent a deliberate intent to deceive by their advocates.

MISINFORMATION

Misinformation was chosen by Dictionary.com as its word of the year in 2018 and has maintained a strong presence during the COVID-19 pandemic.2 Misinformation has been defined as “false information that is spread, regardless of whether there is intent to mislead.”2 Hence, misinformation can be provided in good faith or be malicious and motivated by personal gain; malicious misinformation is sometimes also referred to as disinformation.3 This continuing education activity uses the term misinformation without regard to intent.

Health misinformation has been defined as information that is false, inaccurate, or misleading according to the best available evidence at the time (emphasis added).3 The trustworthiness of information, therefore, can change with time. Misinformation can arrive in many ways, but social media is a major contributor.2-4 A study of information spread over Twitter found that false news reached more people and diffused faster than truthful news.4 There are many possible reasons for this including novelty of the information, the recipient’s emotional reaction and heightened anxiety, cognitive biases, social media platforms that incentivize sharing, and algorithms that prioritize content based on its popularity.3,4

Health misinformation can be problematic and can influence political, economic, and social well-being.4 Health misinformation can be harmful. U.S. Surgeon General Vivek Murthy has stated that “misinformation takes away our freedom to make informed decisions about our health and the health of our loved ones. Simply put, health misinformation has cost us lives.”3 Additionally, people can become confused and anxious when faced with contradictory information, and this is especially harmful during a public health crisis.3,5 It can expose patients to wasteful and harmful products and procedures, delay the discovery of effective treatments, delay treatment with a more scientifically-based therapy, and divide families and communities.5 As we have seen, it can also erode trust in health care personnel, scientists, and public health agencies.

Spreading dangerous health misinformation is not a new phenomenon, especially during a global health crisis. One example occurred during the bubonic plague pandemic during the Middle Ages and is described above. During the 1918 flu pandemic, the U.S. Surgeon General supported the use of high doses of aspirin (1 to 1.3 g every one to three hours) and an epidemiologic analysis concluded that a significant number of fatalities were due to aspirin poisoning.6 More recently, learners may recall the indiscriminate use of chloroquine and hydroxychloroquine during the COVID-19 pandemic resulting in numerous fatal adverse events and a drug shortage.6

PAUSE AND PONDER: A patient approaches you and asks you about a rumor she saw on the Internet stating that cocaine would counteract the virus responsible for COVID-19 (yes, this is a real event5,7). How do you respond?

TURNING TO THE COURTS FOR MEDICAL TREATMENT

It should not be surprising, given the large number of hospitalizations and deaths from COVID-19 infections, that patients would go to great lengths to obtain unconventional but highly promoted, treatments, even if they are not approved or authorized by the U.S. Food and Drug Administration (FDA).8 This is especially true if health care professionals or social media “influencers” endorse the drugs.

Ivermectin is an example of a drug that has been extensively sought by people seeking to treat or prevent COVID. Ivermectin has generated a great deal of controversy, with strong validation from advocates while public health agencies generally expressed disapproval. Ivermectin will be used as a model of a drug that is an unapproved COVID-19 therapy, but highly popularized by non-mainstream sources. The intent is not to resolve issues about its efficacy but to illustrate patient efforts to bypass conventional treatment pathways and seek a remedy via legal challenges.

Ivermectin

Ivermectin is an established, inexpensive FDA-approved drug introduced for medical use in 1982. It is used in humans, but more extensively in animals. It is effective against various types of nematodes and helminths (parasitic worms), and ectoparasites such as mites and lice.9 It is used to treat parasitic tropical diseases such as onchocerciasis (River Blindness) and intestinal strongyloidiasis and is used in high dose concentrated topical and injectable formulations for parasitic infestations in animals, including treating heartworm.8,9,10 It is also approved for human use to treat parasitic worms and in topical formulations for head lice and rosacea.8 Ivermectin is also being evaluated to kill mosquitoes responsible for transmitting malaria.9 Ivermectin’s proposed mechanism of action is by binding to specific cell membrane channels that only reside in invertebrates.10 Activation of these channels leads to chloride‐induced hyperpolarization and inhibition of cell signal transmission which results in paralysis and, ultimately, death of the parasites. However, it is not FDA-approved for the treatment of any viral infection and the FDA has not authorized or approved it for treating or preventing COVID-19.8

Interest in ivermectin as a COVID treatment stems from in vitro (meaning the research was conducted in culture dishes, not live animals or humans) research on the virus responsible for human immunodeficiency virus (HIV). Studies reported that the drug can inhibit the transport of protein to the nucleus by cargo proteins and inhibit viral replication. Similar in vitro investigations have been extended to other viruses.8,10,11 It has also been proposed that ivermectin may interfere with the binding of the coronavirus spike protein to human cells and some studies have reported potential anti-inflammatory properties.9 These would support the notion of a possibly favorable effect in COVID-19.

However, pharmacokinetic and pharmacodynamic analyses suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans,9 although it has been proposed that intravenous and aerosol preparations may achieve higher tissue levels than those attainable by the oral route.11

Despite promising in vitro activity, clinical reports have generally not provided evidence of a clinical benefit for ivermectin in patients with viruses.9 Public health agencies, including the FDA, World Health Organization (WHO), and Centers for Disease Control and Prevention (CDC) recommend against using ivermectin to treat COVID-19, citing a lack of data from large, randomized controlled trials confirming its effectiveness.12 The National Institutes of Health’s COVID-19 Treatment Guidelines Panel has also determined that there are currently insufficient data to recommend ivermectin for treatment of COVID-19.13 The FDA has warned against self-medicating with ivermectin preparations intended for livestock citing multiple reports of patients requiring medical attention, including hospitalization.8 Adverse effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea and more severe overdoses associated with hypotension and neurologic effects such as decreased consciousness, ataxia, confusion, hallucinations, seizures, coma, and death.8,13,14 Ivermectin may also interact with anticoagulants and potentiate the effects of CNS depressants such as benzodiazepines and barbiturates.8,13

Supporters of using ivermectin cite multiple smaller studies and firsthand experience with the drug. They claim ivermectin can work to prevent patients from developing COVID-19 symptoms and can shorten recovery time for those already infected.14,15 Detractors point out that, generally, these studies were incomplete, had no control group, or had other methodological limitations such as small sample sizes or patients receiving additional treatments along with ivermectin.14,15

A recent meta-analysis concluded that, “There is limited evidence for the benefit of ivermectin for COVID-19 treatment and prophylaxis, and most of this evidence is of low quality.” The researchers urged further investigation to provide support for optimal treatment protocols.15 The analysis found some evidence of decreasing mortality and disease progression in patients with severe disease (but not in mild or moderate disease) and an increase in the rate of patients with a negative RT-PCR test, but with low quality of evidence due to factors such as risk of bias, inconsistency, and lack of precision.15

The WHO guidelines also recommend against using ivermectin in patients with COVID-19 except in a clinical trial.16 WHO updated the guidelines in September 2021 and included newer, relatively small trials published since an earlier recommendation and noted that one key trial was retracted due to concerns about research fraud. In a joint statement, the American Medical Association, American Pharmacists Association, and American Society of Health-System Pharmacists strongly opposed the ordering, prescribing, or dispensing of ivermectin to prevent or treat COVID-19 outside of a clinical trial.

Furthermore, one of ivermectin’s largest manufacturers does not support the use of the drug stating that it finds “(n)o meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease” and a “concerning lack of safety data in the majority of studies.”14

The high level of attention focused on ivermectin has resulted in increased demand. A recent study examining trends in ivermectin dispensing from U.S. retail pharmacies during the COVID-19 pandemic showed an increase in the number of prescriptions to 39,000 per week by January 2021, compared with a weekly average of 3,600 prescriptions per week prior to the pandemic.13 More than 88,000 prescriptions were dispensed by August 2021, representing a 24-fold increase from the pre-pandemic baseline.

Adverse effects associated with ivermectin misuse and overdose are also on the rise. Calls to poison control centers report more overdoses and more people experiencing adverse events.13 The National Poison Data System, which collects information from the nation's 55 poison control centers, reported 1,143 ivermectin exposure cases between January 1 and August 31, 2021, many from the use of high dose veterinary products. This is a 163% increase compared with the same period in the previous year. There was a 245% increase in reported cases (133 to 459) between July and August alone.17 In Mississippi, 70% of recent calls to the state poison control centers were due to ivermectin ingestion.17

Australia’s drug regulatory administration, responding to a three-to-four-fold increase in prescriptions, banned medical practitioners from off-label prescribing of ivermectin, including treatment of COVID-19. It took this action because of reported drug shortages, concerns that patients would self-medicate with the drug instead of seeking treatment or vaccination, and the risk of using unsafe doses.18 Prior to the ban, social media encouraged the rise in prescribing with posters sharing the names of sympathetic doctors who were willing to prescribe the drug.

Lawsuits

Despite the large increase in the number of prescriptions for ivermectin, a growing number of patients with COVID have been unable to receive treatment with the drug. Subsequently, some of them have filed lawsuits trying to compel health care providers and organizations to supply it as a therapeutic alternative.19,20 Typically, a case is brought by a guardian or representative of a patient who is severely ill and is believed to have no remaining treatment options. The plaintiff usually raises the argument that the defendant (hospital, practitioner) must comply with the patient’s prescription order as an appropriate standard of care, or that the patient has a constitutional right to receive treatment with ivermectin.21

The family of an 80-year-old patient who was on a ventilator and was given a 20% chance of surviving a COVID-19 infection filed the first ivermectin lawsuit in 2021 against a hospital near Buffalo, NY.22 The family (who did not consult a healthcare provider external to the hospital) pressured an intensive care unit (ICU) physician to give the woman ivermectin, which he agreed to do. After she was transferred to another wing in the hospital, physicians there refused to give her additional doses and her condition deteriorated. The family sued to reinstate the treatment. The hospital argued that physicians, and not the courts, should make decisions about medical care. However, the judge ordered the hospital to immediately provide ivermectin if the patient’s family physician would prescribe it, which he did. The patient’s condition subsequently improved.22 The ability of the court to override clinician treatment decisions in this case helped spur additional suits.

In another case, a 68-year-old woman in Illinois was admitted to intensive care at a hospital in early April 2021 and after about a month, was placed on a ventilator.23 Her daughter searched the Internet and discovered a news report about the Buffalo lawsuit; she asked the hospital to administer ivermectin to her mother, which it refused to do. At the hearing, the hospital claimed that none of its physicians would agree to administer ivermectin for COVID-19. Moreover, its internal ethics panel concluded that the use of ivermectin could not be justified.23 The hospital’s lawyer argued that judges should not overrule medical decisions made by health care personnel. The lawyer stated that a court “doesn’t have the authority to order a medical corporation to use particular medications, particularly when it’s an off-label use, particularly when the federal government has said it could be dangerous.”23 The judge hearing the case countered by saying “If someone has been in the ICU for a month and not improving, why would the hospital not consider another medication?”23 He ordered the hospital to administer the drug.

PAUSE AND PONDER: Who should decide whether a patient should receive a particular therapy?

The hospital responded that no health care professional on staff (including pharmacists) would agree to give the drug. The court ordered the hospital to locate an outside practitioner. The hospital found a local physician who administered ivermectin. He testified at a subsequent court hearing that the patient was taken off the ventilator and discharged from the hospital after receiving the drug for 20 consecutive days.24

In another case in suburban Chicago, a 68-year-old woman was being treated for COVID-19. When the hospital refused to supply ivermectin, her daughter transferred her to another hospital. When the second hospital also refused, the daughter sued the hospital and a judge ordered that the drug be given.25 After receiving a few doses, the patient’s heart rate dropped dramatically (in one instance to 28 beats per minute; normal varies by age, but is generally considered 60 or 75 to 100 bpm) and the hospital went back to court arguing that further treatment would be dangerous.25 The family decided to withdraw the treatment.20,25 However, in an interview, the family’s lawyer stated that the ivermectin was showing benefit and that the bradycardia was due to a different medication that was being used to control her blood pressure.26

In addition to judicial action, hospitals face public backlash over refusal to administer ivermectin.20,27 One Chicago area hospital reported receiving hundreds of phone calls and emails and an in-person protest supporting a hospitalized patient who was seeking treatment with ivermectin.20,27 Prominent advocates (aligned with popular conspiracy movements) shared the hospital’s contact information and encouraged followers to support the movement.20

PAUSE AND PONDER: How would you handle a public demonstration outside the pharmacy by a group protesting a refusal to fill a prescription?

Not all lawsuits have resulted in a victory for the patient.20 In one case, an Ohio man tested positive for COVID-19 and was hospitalized and admitted to the ICU. He was intubated and placed on a ventilator a few weeks later.28 His wife discovered information about ivermectin and connected with a physician known to use the drug who prescribed it, but the hospital refused to administer it. The hospital was sued, and a judge ordered the hospital to provide the man with 30 mg of Ivermectin daily for three weeks.28

In an interview, the prescribing physician said the science behind the use of ivermectin in COVID-19 patients is “irrefutable” and that the CDC and FDA are engaged in a “conspiracy” to block its use to protect the FDA’s emergency use authorization for COVID-19 vaccines.28,29 He further maintained that the mainstream media and social media have engaged in “censorship” regarding ivermectin’s benefits, and that the U.S. government’s refusal to acknowledge the drug’s value amounts to “genocide.” 28 The physician allegedly wrote the prescription without reviewing the patient’s clinical information or consulting with any of the patient’s treating physicians.29

The hospital appealed the order, and the court reversed it.29 The first paragraph of the court’s decision captures the dilemma posed by these cases: “It is impossible not to feel sympathetic to the Plaintiff in the case at bar. The Plaintiff wants her husband to get better. She has sought out a doctor who prescribed ivermectin with the hopes that it could help. The Defendant Hospital wants to follow what it believes are appropriate medical standards and make the husband get better using those protocols.”30

In overturning the previous decision, the judge noted that “based upon the evidence, it (ivermectin) has not been shown to be effective at this juncture” and criticized some of the studies used to support its use.30 He went on to say that “While this court is sympathetic to the Plaintiff and understands the idea of wanting to do anything to help her loved one, public policy should not and does not support allowing a physician to try ‘any’ type of treatment on human beings.”30 In general, healthcare professionals are expected to adhere to the prevailing standard of care.

The ivermectin cases generally revolve around the concepts of bodily integrity, patient autonomy, and informed consent. It is a long-standing legal principle that all competent adults have the right to choose what can be done to their own body and refuse unwanted medical treatment, even if the person may die as a result.31,32 (Some exceptions exist, such as suicide prevention,32 but these are not relevant to this continuing education activity.)

One of many significant Supreme Court rulings addressing this issue is Cruzan v. Director, Missouri Department of Health which was decided in 1990.33 Nancy Cruzan was involved in an auto accident that left her in a vegetative state. Her parents sought a court order to terminate their daughter's artificial feeding and hydration equipment after it became apparent that she had virtually no chance of recovering her cognitive faculties. The hospital refused the request without a court order and the parents filed a suit. The Supreme Court turned down the parent’s request and in so doing held that there must be clear and convincing evidence of a patient’s wishes, in this case to withdraw life support, and that it must be the patient who expresses these wishes. The Court concluded that "Every human being of adult years and sound mind has a right to determine what shall be done with his own body ... The logical corollary of the doctrine of informed consent is that the patient generally possesses the right not to consent, that is, to refuse treatment.”33 The right to refuse medical treatment has been incorporated into many state laws on informed consent.32

While patients clearly have a right to refuse a treatment, most courts have long held that patients, including the terminally ill, do not have a fundamental right to access a particular type of treatment, even if it is legally available.21,34

A recent case from Delaware examined this legal issue when it denied a request to compel a healthcare provider to treat a patient hospitalized with COVID-19 with ivermectin.35 In this case, a patient with COVID-19 was admitted to the hospital and, as his health declined, his wife sought and obtained a prescription for ivermectin from a doctor who never met the patient, and who was unaffiliated with the hospital. Consistent with its guidelines, the hospital refused to administer the drug and the lawsuit followed.

The court held that the health care provider “does not have an enforceable duty” to treat the patient with ivermectin, nor does the patient have “an enforceable legal right to that treatment.”35 The hospital’s duty to the patient did not extend beyond the standard of care according to the judge. Since ivermectin is not part of the standard for treating COVID-19, and its effectiveness is disputed, a physician who refuses to administer the drug is not deviating from the applicable standard of care. Healthcare providers do not have a duty to administer ivermectin to a patient with COVID-19. The court reiterated the concept that the plaintiff’s right of healthcare self-determination is limited to “the right to refuse medical or surgical treatment if such refusal is not contrary to existing public health laws.”35 Applying that limit, courts have held that a patient does not have a constitutional right to obtain a particular type of treatment nor to obtain treatment from a particular provider. Granting the patient’s request, the Court said, would risk harm to the patient and would be detrimental to public policy that expects a healthcare provider to deliver a standard of care based on “prevailing scientific and ethical norms.”35 Since ivermectin lacks proven efficacy, the patient could not legally demonstrate that any irreparable harm would ensue by refusing the request. The Court also warned that “compelling a provider to operate outside the standard of care would improperly and imprudently move health care treatment decision making from the patient’s bedside to a judge’s bench.”35

In a different twist on this issue, a physician, rather than a patient, is suing a hospital over its ban of certain treatments, including ivermectin, for COVID-19.36 According to the complaint, patients will be “denied their right to choose life-saving medicines their attending physician considers appropriate for them.”36 The physician describes himself as “a world-leading authority on the pathophysiology and treatment of COVID”36 and has authored several papers on clinical treatment of COVID, including one that was retracted by the journal that published it on the day the suit was filed. In contrast to suits filed by patients seeking treatment, he asserts that he is not asking the court to practice medicine or make a medical determination, only that the hospital respect his and his critically ill patients’ right to “discuss and decide to use FDA-approved, potentially life-saving medicines.”36 He also argues that double blind, randomized controlled clinical trials are not superior to observational studies, which he has conducted. “Physicians are free to disagree” he states, but “a prudent, knowledgeable physician with COVD clinical experience” such as him, can make a “reasonable professionally sound judgement” that ivermectin is medically appropriate for treating COVID.36 The SIDEBAR discusses issues related to prescribing and provides background on off-label prescribing.

 

SIDEBAR: PRESCRIPTIVE AUTHORITY

Traditionally, American prescribers were physicians. Today, many types of healthcare provider can prescribe medication. During the drug approval process, the FDA works with the sponsoring pharmaceutical company to

• Evaluate the medications’ benefits and risks for a specific use(s) carefully
• Ensure any decision to approve the drug is supported by strong scientific data.
• Approve drug labeling for healthcare providers specifying how to use the drug safely and effectively for the intended use(s)

The sponsoring pharmaceutical company must provide supporting data for each individual indication it proposes.

However, once the FDA approves and markets a medication, clinicians with prescriptive authority have the right to prescribe FDA-approved therapies for diseases and disorders outside of their FDA-approved indications. Healthcare providers may prescribe the drug for an unapproved use when they judge that it is medically appropriate for their patient. This is called off-label use, and it is generally employed when the prescriber wants to use the medication

• For disease or medical condition not listed in the FDA-approved labeling
• In a different way, such as when the FDA has approved a capsule or tablet, but the prescriber has it made into an oral solution or a topical
• In a different dose than that approved by the FDA

But, under some conditions, off-label prescribing is not allowed—not disallowed by the FDA, but by other organizations that pull the prescribing strings. For example, Pharmacy and Therapeutic Committees, which are composed of health professionals, have the authority to prevent the use of a therapy or to limit the conditions under which it can be prescribed to patients treated in its healthcare system. And, payors (insurers or whoever is paying for the prescription) have the right to impose restrictions, too. Even if a prescriber chooses a medication off-label and a patients agree to take it, payors have the right to refuse to pay.

Off-label use is common in a few situations. In children, many drugs lack data on safety and efficacy and are only approved for adults. Pediatricians may rely on available evidence to use medication off-label. Another area in which off-label use is common is cancer. Good references often include lists of off-label indications and refer the reader to the data supporting the use, even if it is limited. The most important thing to remember is that off-label drug use has risks.

SANCTIONS FOR MISINFORMATION?

Patients declining vaccinations or seeking unapproved treatments for COVID may be following advice posted on news outlets or social media, sometimes by health care practitioners who reject mainstream guidance from public health agencies. Is there a risk of disciplinary action against these practitioners for disseminating this information?

Some medical boards have declared that physicians may be subject to disciplinary action if they engage in conduct which is “unethical or unprofessional” related to COVID-19.37 (Note: this applies to all COVID-19-related information including vaccines, masking, and drug treatments.) As with all things associated with the pandemic, outlooks are widely divergent.

The Federation of State Medical Boards (FSMB) took note of the “dramatic increase in the dissemination of COVID-19 vaccine misinformation and disinformation by physicians and other health care professionals on social media platforms, online, and in the media.” It issued a warning to physicians that they risk suspension or revocation of their medical licenses by state medical boards if they generate and spread COVID-19 vaccine misinformation or disinformation.38 The FSMB commented that, “Due to their specialized knowledge and training, licensed physicians possess a high degree of public trust and therefore have a powerful platform in society, whether they recognize it or not. They also have an ethical and professional responsibility to practice medicine in the best interests of their patients and must share information that is factual, scientifically grounded, and consensus-driven for the betterment of public health.” Although the statement focused on vaccination, it could apply to all health information. Spreading inaccurate information undermines that responsibility and “threatens to further erode public trust in the medical profession and puts all patients at risk.”38 Of course, the same comments could also apply to pharmacists. At least five state medical boards (Illinois, Maine, Mississippi, New Mexico, Washington) and numerous certifying and professional organizations have expressed support for the FSMB statement.39

It is not clear how frequently physicians are sanctioned for spreading misinformation, but it appears to be uncommon.40,41 The president of the FSMB has said that medical license renewals are designed to be simple for doctors and it is usually an automatic procedural step. He added that medical boards do not have the capacity to review the large number of renewals that occur each year.41 The license suspension process is long and slow with procedural barriers and investigations, and will ordinarily begin only if someone makes a complaint.42 Moreover, both non-renewals and suspensions require protections to comply with due process.41 Investigations can take months or years to complete and many proceedings are conducted in private.39 Licensing boards are primarily concerned with medical malpractice, patient abuse, and illegal activity, so that the potential that misinformation disseminated by a physician could impact public health takes a relatively low priority.42 In addition, it can be difficult to evaluate whether a comment is sufficiently outside the range of scientific and medical consensus and boards are reluctant to take action on a “fringe” opinion.42

A survey by the FSMB found that 67% of medical boards have seen an increase in complaints about physicians disseminating false COVID-19 information and 21% of respondents had instituted some type of disciplinary action.39,41 However, one report investigating the “20 most vocal physicians spreading COVID falsehoods” found that as of January 2022, none of them had been disciplined.40 Similarly, a recent analysis by NPR of 16 physicians who are known to promote misinformation about COVID-19 found that 15 were still licensed to practice; the sole exception apparently voluntarily did not renew his license.41

Nevertheless. some states have taken action. Boards in at least a dozen states, including Oregon, Rhode Island, Maine, and Texas have issued sanctions against physicians.39

In September 2021, the Oregon Medical Board revoked a physician’s license and fined him $10,000, viewing him as a serious and immediate danger to the public for refusing to follow COVID-19 guidelines in his office.43,44 The physician refused to wear a mask and did not ensure that his staff was masked. In addition to not following guidelines, the Board said he advised patients not to wear masks (unless highly symptomatic) and spread misinformation about masking. According to the Board’s complaint, the physician told patients in person and through fliers in his office that masks were ineffective against COVID-19 and could cause serious unproven health issues, including carbon dioxide poisoning.43,44 He also spoke at a political rally where he made anti-masking statements.43 The Board accused him of “gross negligence” and the order described his conduct as “contrary to medical ethics” and said it “does or might constitute a danger to the health or safety of the public.”44

The physician filed a lawsuit against the Oregon Medical Board after his license was suspended (prior to being revoked). He alleged that the board violated his constitutional rights to due process and free speech, due to a “mere difference in medical opinion.”44,45 He further contends that the Board’s opinions “have been largely disputed by reputable studies and medical experts.”44,45

In a similar action, the Rhode Island Board of Medical Licensure and Discipline investigated a physician who made multiple assertions to his patients that were “misinformed” or “patently false.”46 The physician sent a letter advising his patients not to receive a vaccine for COVID-19. The letter claimed that the vaccine would produce “unpredictable long-term health consequences” including sterilization and disruption of the recipient’s DNA. He also told his patients that government authorities were promoting “a poorly and inadequately tested product” (vaccine) and claimed that treatment with vitamins C and D is safer and more effective than a vaccine. The physician stated that he receives his information from multiple media sources, which do not include mainstream media, and also admitted he did not attend any of the state’s accredited COVID update programs.46 He agreed to a consent order reprimanding him and agreed to complete an ethics course and pay administrative costs of $1100.47

The Texas Medical Board levied a $500 fine against a physician for promoting the use of hydroxychloroquine and ordered her to improve her procedures for obtaining consent. She had prescribed hydroxychloroquine to a COVID-19 patient without adequate explanation of the potential health risks.39 In Idaho, the state’s medical association took the highly unusual step of filing a complaint with the state medical board against a physician for promoting ivermectin.39

However, not all states are supportive of legal sanctions against physicians for disseminating information. The Tennessee Board of Medical Examiners issued a statement supporting the FSMB position but removed the policy form their website due to pressure from the state legislature, although they claim that the policy has not been rescinded.48 Moreover, two bills were introduced in the Tennessee legislature that would forbid state licensing officials from disciplining doctors for how they treat COVID-19 or what they express about vaccines. One bill would protect any recommendation made by a physician so long as the physician has exercised independent medical judgement in the best interest of the patient. The other would prohibit disciplining a physician on the sole basis of to their “prescription, recommendation, use, or opinion relative to a treatment for COVID-19.”49 Although the bills are worded to protect opinions, it may permit physicians to assert that false claims are legally protected opinions.49

A Georgia physician made a number of controversial statements about the pandemic including saying that vaccines have not been studied sufficiently, are not worth the risk, and might result in a more serious disease.50 He also said that hydroxychloroquine and ivermectin are effective in preventing a COVID-19 infection. Other physicians in the state have made similar statements including physicians stating on television that “there is a lot of evidence” that ivermectin “works well” against the COVID-19 virus and rejecting vaccines. Despite receiving numerous complaints from other practitioners about these practices, the Georgia medical board has not taken any action and in at least one instance the Board determined that there was no violation and closed the case.50

It's critical to note that prevailing medical opinion is not always correct. All entities need to be careful when restricting prescribers’ ability to personalize treatment outside standards of care because between the black and the white of science, numerous shades of grey exist.

PAUSE AND PONDER: Should a pharmacist who makes negative comments about vaccinations during a counseling session with a patient be disciplined?

In addition to licensing sanctions, health care practitioners can face other penalties. A Mississippi emergency room physician and noted anti-vaccine spokesperson claims he was fired by a hospital for discontinuing remdesivir, an FDA-approved treatment for COVID, in patients with COVID and replacing it with ivermectin.51 In Texas, a physician who frequently posted criticisms of vaccine mandates and praised the use of ivermectin on social media had her medical staff privileges suspended by the hospital where she worked over the posted misinformation.52

SUMMARY AND CONCLUDING REMARKS

Misinformation often arises when there are information gaps or unsettled science.”53

The severity of the coronavirus pandemic and rapidly evolving scientific knowledge and public health recommendations has created confusion and reliance on unsubstantiated and unconventional advice, often from social media. Misinformation can be harmful, leading patients to favor unreliable therapies and delaying or avoiding more scientifically substantiated treatments.

One approach to addressing health misinformation is to sanction health care practitioners who spread it. Some regulatory bodies and organizations have threatened physicians with penalties for promoting misinformation, but others have given this issue a low priority or even opposed it. The current regulatory environment makes disciplinary actions cumbersome and slow; it’s difficult to determine when an alternative medical opinion crosses the line and becomes unethical or unprofessional, especially when public health guidelines are in flux during a crisis. Pharmacists who promote inaccurate or misleading information may also run the risk of finding themselves subject to disciplinary actions.

Another approach is to try to counteract misinformation.3 The CDC recommends the strategies of communicating accurate information, responding to information gaps, and confronting misinformation with evidence-based messaging from credible sources.53 Dr. Murthy has remarked that “without sufficient communication that provides clarity and context, many people have had trouble figuring out what to believe, which sources to trust, and how to keep up with changing knowledge and guidance.”3

Who will provide the clarity and context? This is an opportunity, and, arguably, a responsibility, for pharmacists. Pharmacists are ideally positioned to begin a dialog with patients as trusted, knowledgeable, and accessible health care professionals.54,55

The popular perception that unproven medications for COVID-19, such as ivermectin, are an alternative form of treatment has led to numerous lawsuits attempting to compel physicians and hospitals to provide the drug. The results of these suits have been mixed, with some courts ruling in favor of patients and ordering that they be made available, even when mainstream public health and medical organizations have issued safety and efficacy warnings. Others have supported practitioners who adhere to the prevailing standard of care, even in life-threatening circumstances. These rulings often distinguish between a well-accepted right to refuse treatment and a more nebulous privilege to demand treatment.

On a final note, a pharmacy in Minnesota is facing a possible lawsuit for failure to fill a prescription for ivermectin to treat COVID-19. The patient and his wife were both infected and obtained prescriptions for ivermectin, but the pharmacist refused to fill the prescriptions. The wife stated that the pharmacist “did not have the right to stand between our physician's prescription and the patient,” but the pharmacist disagreed.56 An attorney called the pharmacist’s position “abhorrent” and accused the pharmacists of “play(ing) God” with the patients’ lives at stake. The patient allegedly obtained a veterinary formulation of ivermectin instead and claimed that he felt relief after eight hours.56 It is likely that these kinds of legal actions against pharmacists will become more frequent, and pharmacists and pharmacies need to evaluate how they will develop policies to respond to demands for an unconventional treatment whether it is for COVID or the next public health c

Pharmacist & Pharmacy Technician Post Test (for viewing only)

This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

 

     
    1. The U.S. Surgeon General issued a statement about misinformation that said:
    A. A lower standard of proof is acceptable during a public health crisis
    B. Health misinformation has been deadly in the U.S.
    C. Government guidelines are a “best guess,” and licensed physicians should use their own judgment

    2. What misinformation contributed to deaths during the 1918 Flu pandemic?
    A. Cautions against using a flu vaccine by prominent physicians
    B. Encouragement from the Surgeon General for the use of high doses of aspirin
    C. Research in medical journals endorsing the use of opioids to reduce fever

    3. How did the prescribing of ivermectin change during the pandemic?
    A. There was a brief, initial surge but it returned to pre-pandemic levels after the FDA issued warnings
    B. Prescribing doubled during the first year of the pandemic
    C. Prescribing increased 24-fold during 2021

    4. The best evidence supporting the potential use of ivermectin as a treatment for COVID-19 is:
    A. It has shown anti-viral activity in vitro
    B. There have been encouraging results from most randomized, controlled clinical studies
    C. The World Health Organization supports its use

    5. Which of the following is an adverse effect associated with ivermectin?
    A. Ataxia and confusion
    B. Constipation
    C. Hypertensive crisis

    6. In the first case of its kind, a lawsuit was brought in Buffalo by a family seeking treatment with ivermectin for a relative. Which of the following occurred in this case?
    A. The patient recovered and the suit was dropped before the trial could be concluded.
    B. The family wanted treatment with ivermectin based on information found on the internet
    C. The hospital reversed their decision to deny ivermectin when the suit was filed

    7. Which of the following is correct about a recent legal case in Illinois?
    A. The patient died from COVID complications before the court could render a decision, leaving the issue unresolved
    B. A pharmacist at the hospital agreed to administer the drug
    C. The judge ordered the hospital to find a certified physician who would administer the drug

    8. A physician is suing a hospital for refusal to administer ivermectin. How does this differ from cases being brought by patients?
    A. He is not expecting the court to make a medical judgment
    B. He asserts that the hospital does not have the authority to prevent him from using an FDA approved drug for any reason
    C. He is using the drug as part of a research study

    9. In the Cruzan case, the Supreme Court said that:
    A. Terminally ill patients have a right to receive unapproved drugs
    B. Patients have a right to refuse a treatment even if it may result in their death
    C. If a patient refuses treatment, a close family member may intercede on their behalf and approve the treatment in a life-threatening situation

    10. What action did Oregon’s state medical board towards a physician who failed to follow accepted risk reduction procedures when dealing with patients with COVDI-19?
    A. They revoked his medical license as an immediate danger to the public
    B. They reprimanded him but took no further action
    C. They refused to take action against the physician stating that he was protected by the First Amendment (freedom of speech)

    11. Tennessee’s legislature is considering legislation that would:
    A. Prohibit prescribing ivermectin for COVID-19
    B. Prohibit disciplining a physician for prescribing or recommending an unauthorized treatment for COVID-19
    C. Require hospitals to approve the use of hydroxychloroquine or ivermectin for COVID-19 patients in the ICU.

    12. Why do state medical boards sanction few physicians who post misinformation on social media?
    A. Misinformation is a relatively low priority for regulatory actions
    B. They rarely receive complaints about these activities
    C. Information posted on social media is beyond the scope of activities that medical boards can impose sanctions for.

    13. A recent legal action involving ivermectin was brought against a pharmacist. The complaint alleged that:
    A. A pharmacist encouraged patients asking about ways to prevent COVID-19 to seek out ivermectin
    B. A pharmacist was stockpiling veterinary formulations of ivermectin and making them available to consumers for COVID-19
    C. A pharmacist refused to fill prescriptions for ivermectin for a couple infected with COVID-19.

    References

    Full List of References

    References

       

      1. SCL Health. 6 Examples of pseudo medicine – and how far we’ve come! Accessed January 21, 2022.
      https://www.sclhealth.org/blog/2018/08/6-examples-of-pseudo-medicine/
      2. Italie L. Dictionary.com chooses ‘misinformation’ as word of the year. AP News. November 26, 2018. Accessed January 21, 2022.
      https://apnews.com/article/entertainment-north-america-ap-top-news-religion-fake-news-e4b3b7b395644d019d1a0a0ed5868b10
      3. Murthy VH. Confronting Health Misinformation: The U.S. Surgeon General’s Advisory on Building a Healthy Information Environment. U.S. Public Health Service. 2021. Accessed January 21, 2022.
      https://www.hhs.gov/sites/default/files/surgeon-general-misinformation-advisory.pdf
      4. Vosoughi S, Roy D, Aral S. The Spread of True and False News Online. Science. 2018;359:1146-1151.
      5. Caulfield T. Misinformation, Alternative Medicine and the Coronavirus. Policy Options. March 12, 2020. Accessed January 21, 2022.

      Misinformation, alternative medicine and the coronavirus


      6. Love JS, Blumenberg A, Horowitz Z. The parallel pandemic: Medical misinformation and COVID-19: Primum non nocere. J Gen Intern Med. 2020;35(8):2435-2436. doi:10.1007/s11606-020-05897-w
      7. CBS News. Snorting cocaine, drinking bleach cannot cure coronavirus. March 9, 2020. Accessed January 21, 2022.
      https://www.news9.com/story/5ec5a0602ac80d591f260ee4/snorting-cocaine-drinking-bleach-cannot-cure-coronavirus
      8. U.S. Food and Drug Administration. Why you should not use ivermectin to treat or prevent COVID-19. December 10, 2021. Accessed January 21, 2022.
      https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19
      9. National Institutes of Health. Ivermectin. February 11, 2021. Accessed January 21, 2022.
      https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ivermectin/
      10. Popp M, Stegermann M, Metzendorf MI, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database of Systemic Reviews. July 28, 2021. Accessed January 21, 2022.
      https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015017.pub2/full
      11. Jans DA, Wagstaff KM. The broad spectrum host-directed agent ivermectin as an antiviral for SARS-CoV-2? Biochem Biophys Res Comm. 2021;538:163-172.
      12. Gonzalez O. Ivermectin: Why are there lawsuits over this unproven drug? CNet. October 6, 2021. Accessed January 21, 2022.
      https://www.cnet.com/health/medical/ivermectin-and-covid-19-why-are-there-lawsuit-over-this-unproven-drug/
      13. Centers for Disease Control and Prevention. Rapid increase in ivermectin prescriptions and reports of severe illness associated with use of products containing ivermectin to prevent or treat COVID-19. August 26, 2021. Accessed January 21, 2022.
      https://emergency.cdc.gov/han/2021/han00449.asp
      14. Merck Statement on ivermectin use during the pandemic. Merck. February 4, 2021. Accessed January 21, 2022.

      Merck Statement on Ivermectin use During the COVID-19 Pandemic


      15. Cruciani M, Pati I, Masiello F, Malena M, Pupella S, De Angelis V. Ivermectin for Prophylaxis and Treatment of COVID-19: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2021;11(9):1645. doi:10.3390/diagnostics11091645
      16. World Health Organization. Therapeutics and COVID-19: living guideline. Updated September 24, 2021. Accessed January 21, 2022.
      https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.3
      17. Romo V. Poison control centers are fielding a surge of ivermectin overdose calls. NPR. September 4, 2021. Accessed January 21, 2022.
      https://www.npr.org/sections/coronavirus-live-updates/2021/09/04/1034217306/ivermectin-overdose-exposure-cases-poison-control-centers
      18. Taylor J. Ivermectin: Australian regulator bans drug as COVID treatment after sharp rise in prescriptions. Guardian. September 10, 2021. Accessed January 21, 2022.
      https://www.theguardian.com/australia-news/2021/sep/10/australian-drug-regulator-bans-ivermectin-as-covid-treatment-after-sharp-rise-in-prescriptions
      19. Grant K. Ivermectin’s Days in Court. MedPage Today. December 31, 2021. Accessed January 21, 2022.
      https://www.medpagetoday.com/special-reports/exclusives/96447?xid=nl_mpt_DHE_2022-01-01&eun=g1359385d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Top%20Cat%20HeC%20%202022-01-01&utm_term=NL_Daily_DHE_dual-gmail-definition
      20. Rogers K. Some COVID-19 patients want ivermectin so badly they’re taking hospitals to court. FiveThirtyEight. September 27, 2021. Accessed January 21, 2022.

      Some COVID-19 Patients Want Ivermectin So Badly They’re Taking Hospitals To Court


      21. Nasrallah NP, LaVette DA. COVID-19 and ivermectin lawsuits. American Bar Association. October 28,2021. Accessed January 21, 2022.
      https://www.americanbar.org/groups/litigation/committees/mass-torts/articles/2021/winter2022-covid-19-and-ivermectin-lawsuits/
      22. Herbeck D. After judge orders hospital to use experimental COVID-19 treatment, women recover. Buffalo News. January 15, 2021. Accessed January 21, 2022.
      https://buffalonews.com/news/local/after-judge-orders-hospital-to-use-experimental-covid-19-treatment-woman-recovers/article_a9eb315c-5694-11eb-aac5-53b541448755.html
      23. Keilman J. DuPage county Judge orders Elmhurst Hospital to allow COVID-19 patient to receive controversial drug. Chic Trib. May 3, 2021. Accessed January 21, 2022.
      https://www.chicagotribune.com/coronavirus/ct-elmhurst-hospital-covid-ivermectin-lawsuit-20210503-odktw5zntnarhnyvdemjbr2xfy-story.html
      24. Ponce A. COVID-19 Patient shows ‘improvement’ after receiving ivermectin following legal battle with hospital. Fox32 Chicago. May 4, 2021. Accessed January 21, 2022.
      https://www.fox32chicago.com/news/covid-19-patient-shows-improvement-after-receiving-ivermectin-following-legal-battle-with-hospital
      25. Keilman J. Libertyville hospital that was ordered to let COVID-19 patient receive ivermectin says controversial medication is putting her at risk. Chic Trib. September 21, 2021. Accessed January 21, 2022.
      https://www.chicagotribune.com/news/breaking/ct-libertyville-hospital-covid-lawsuit-patient-ivermectin-20210922-g7tjh2sm3fdablpbzomuv26vvu-story.html
      26. Keilman J. Family drops lawsuit aiming to force libertyville hospital to provide ivermectin treatment for COVID-19 patient. Chic Trib. September 22, 2021. Accessed January 21, 2022.
      https://www.chicagotribune.com/news/breaking/ct-ivermectin-covid-lawsuit-dropped-libertyville-hospital-20210923-lqwfwls5orcqvdxfjk3lgtyale-story.html
      27. Chappell K. AMITA hospital targeted with ‘hundreds' of emails, calls after denying patient controversial drug. NBC Chicago. September 8, 2021. Accessed January 21, 2022.
      https://www.nbcchicago.com/news/local/amita-hospital-targeted-with-hundreds-of-emails-calls-after-denying-patient-controversial-drug/2607957/
      28. Zuckerman J. Judge orders Cinci hospital to treat COVID-19 patient with ivermectin, despite CDC warnings. Ohio Cap J. August 30, 2021. Accessed January 21, 2022.

      Judge orders Cinci hospital to treat COVID-19 patient with Ivermectin, despite CDC warnings


      29. Zuckerman J. Judge reverses order forcing hospital to give ivermectin to COVID-19 patient. Ohio Cap J. September 6, 2021. Accessed January 21, 2022.

      Judge reverses order forcing hospital to give ivermectin to COVID-19 patient


      30. Smith v. West Chester Hospital. Butler County Common Pleas. September 6, 2021. Accessed January 21, 2022.
      https://cdn.arstechnica.net/wp-content/uploads/2021/09/oster-order.pdf
      31. Vermont Ethics Network. Right to refuse treatment. Accessed January 21, 2022. https://vtethicsnetwork.org/medical-ethics/right-to-refuse-treatment
      32. Standler RB. Legal right to refuse medical treatment in the USA. July 29, 2012. Accessed January 21, 2022.
      http://www.rbs2.com/rrmt.pdf
      33. Cruzan v. Director, Missouri Department of Health, 497 U.S. 261 (1990). Accessed January 21, 2022.
      https://www.law.cornell.edu/supct/html/88-1503.ZO.html
      34. Blake V. The terminally ill, access to investigational drugs, and FDA rules. AMA J Ethics. 2013;15(8):687-691.
      35. DeMarco v. Christiana Care Health Servs., Inc., 2021 WL 4343661 (Del. Ch. 2021). Accessed January 21, 2022.
      https://courts.delaware.gov/Opinions/Download.aspx?id=324670
      36. Marik v Sentara Healthcare. Memorandum of law. Norfolk (VA) Circuit Court. November 9, 2021. Accessed January 21, 2022.
      https://covid19criticalcare.com/wp-content/uploads/2021/11/Dr.-P.-Marik-v.-Sentara-Healthcare.pdf
      37. Miller J. Medical boards threaten action against physicians who spread COVID-19 misinformation.
      Healio. October 1, 2021. Accessed January 21, 2022.
      https://www.healio.com/news/primary-care/20211001/medical-boards-threaten-action-against-physicians-who-spread-covid19-misinformation
      38. Federation of State Medical Boards. FSMB: Spreading COVID-19 vaccine misinformation may put medical license at risk. July 29, 2021. Accessed January 21, 2022.
      https://www.fsmb.org/advocacy/news-releases/fsmb-spreading-covid-19-vaccine-misinformation-may-put-medical-license-at-risk/
      39. Hollingsworth H. Pressure builds for medical boards to punish doctors peddling false COVID-19 claims. Mercury News. December 16, 2021. Accessed January 21, 2022.

      Pressure builds for medical boards to punish doctors peddling false COVID-19 claims


      40. Fiore K. Worst COVID liars still have their licenses. MedPage Today. December 28, 2021. Accessed January 21, 2022. https://www.medpagetoday.com/special-reports/exclusives/96408
      41. Brumfiel J. A doctor spread COVID misinformation and renewed her license with a mouse click. NPR. November 21, 2021. Accessed January 21, 2022.
      https://www.npr.org/sections/health-shots/2021/11/04/1051873608/a-doctor-spread-covid-misinformation-and-renewed-her-license-with-a-mouse-click
      42. Knight V. Will doctors who are spreading COVID-19 misinformation ever face penalty? Time. September 20, 2021. Accessed January 21, 2022.
      https://time.com/6099700/covid-doctors-misinformation/
      43. Forrest J. Oregon medical board revokes license of doctor who bucked COVID guidelines, spread misinformation. Oregonian. September 16, 2021. Accessed January 21, 2022.
      https://www.oregonlive.com/coronavirus/2021/09/oregon-medical-board-revokes-license-of-doctor-who-bucked-covid-guidelines-spread-misinformation.html
      44. Oregon Medical Board Final Order. In The Matter Of: Steven Arthur Latulippe, MD. Accessed January 21, 2022. https://omb.oregon.gov/Clients/ORMB/OrderDocuments/6f460081-4771-441c-a5e7-2a4c3c203523.pdf
      45. Latulippe v Harder. Complaint for injunctive and declaratory relief, Oregon District Court. January 21, 2021. Accessed January 21, 2022.

      46. In the Matter of Mark Brody. Rhode Island Board of Medical Licensure and Discipline. April 14, 2021. Accessed January 21, 2022. https://health.ri.gov/discipline/MDMarkBrody.pdf
      47. Gagosz A. R.I. ‘Integrated medicine’ doctor’s license suspended for five years. Boston Globe. August 17, 2021. Accessed January 21, 2022.
      https://www.bostonglobe.com/2021/08/17/metro/ri-integrated-medicine-doctors-license-suspended-5-years/
      48. Wadhwani A. Facing GOP pressure, Tennessee medical board votes to take down COVID misinformation policy. Tennessee Outlook. December 21, 2021. Accessed January 21, 2022.

      Facing GOP pressure, Tennessee medical board votes to take down COVID misinformation policy


      49. Kelman B. New bills may shield tennessee doctors who spread COVID-19 misinformation. Nashville Tennessean. October 27, 2021. Accessed January 21, 2022.
      https://www.tennessean.com/story/news/health/2021/10/27/tennessee-bills-may-protect-doctors-who-spread-covid-misinformation/8558229002/
      50. Edwards J. Georgia’s medical board mum as doctors spread COVID-19 misinformation. Atlanta J Const. October 28, 2021. Accessed January 21, 2022.
      https://www.ajc.com/news/coronavirus/georgias-medical-board-mum-as-doctors-spread-covid-19-misinformation/CRWP7IZFBBEBPFSAVIW7AGD7CM/
      51. Murray I. MS hospital fires doctor, anti-vaccine leader for treating COVID patients with ivermectin. SunHerald. December 6, 2021. Accessed January 21, 2022.
      https://www.sunherald.com/news/coronavirus/article256383777.html
      52. Watts A, Elassar A. Texas doctor suspended for spreading ‘misinformation’ COVID-19 submits resignation letter. CNN. November 16, 2021. Accessed January 21, 2022.
      https://www.cnn.com/2021/11/13/us/houston-doctor-suspended-covid-19/index.html
      53. Centers for Disease Control and Prevention. How to address COVID-19 misinformation. November 3, 2021. Accessed January 21, 2022.
      https://www.cdc.gov/vaccines/covid-19/health-departments/addressing-vaccine-misinformation.html
      54. Erku DA, Belachew SA, Abrha S, et al. When fear and misinformation go viral: Pharmacists' role in deterring medication misinformation during the 'infodemic' surrounding COVID-19. Res Social Adm Pharm. 2021;17(1):1954-1963.
      55. Marwitz KK. The pharmacist's active role in combating COVID-19 medication misinformation. J Am Pharm Assoc (2003). 2021;61(2):e71-e74. doi:10.1016/j.japh.2020.10.022 Accessed January 21, 2022.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640945/
      56. Pandolfo C. Marine veteran wants to sue Walmart after pharmacist denied him access to ivermectin. Blaze Media. October 18, 2021. Accessed January 21, 2022.
      https://www.theblaze.com/news/marine-veteran-sue-walmart-pharmacist-ivermectin Also
      https://then24.com/2021/10/22/usa-walmart-denies-man-drug-against-covid-19-and-is-sued/

      THYROID DISEASE: The Basics and the Latest

      Learning Objectives

       

      After completing this application-based continuing education activity, pharmacists will be able to

      1. Discuss Thyroid Disease and the typical medications used to treat it.
      2. Explain drug-induced hypo/hyperthyroidism, drug interactions and proper administration of thyroid medications
      3. Explain the lab work and the frequency of monitoring needed for patients treated with levothyroxine.
      4. Differentiate hypothyroid disease from subclinical hypothyroid disease and their respective treatment approaches

      After completing this application-based continuing education activity, pharmacy technicians will be able to

      1. Recall and list the common symptoms of thyroid disease.
      2. Identify typical medications used to treat thyroid disease.
      3. Recognize when to refer patients to the pharmacist for further consultation.

      black and white photo of the Mona Lisa with her enigmatic smile

      Release Date:

      Release Date: April 15, 2022

      Expiration Date: April 15, 2025

      Course Fee

      Pharmacist:  $5

      Pharmacy Technician: $2

      ACPE UANs

      Pharmacist: 0009-0000-22-025-H01-P

      Pharmacy Technician: 0009-0000-22-025-H01-T

      Session Codes

      Pharmacist: 22YC25-XYZ35

      Pharmacy Technician: 22YC25-FXT27

      Accreditation Hours

      2.0 hours of CE

      Accreditation Statements

      The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-025-H01-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

       

      Disclosure of Discussions of Off-label and Investigational Drug Use

      The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

      Faculty

      Kathryn M. Colucci, RPh
      Medical Writer
      Newtown, CT

      Faculty Disclosure

      In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

      Kathryn Colucci, RPh has no relationship with an ineligible company and therefore has nothing to disclose.

      ABSTRACT

      Thyroid hormones, produced by the tiny thyroid gland, influence almost every organ in the body. They control the body’s energy production and metabolic rate; imbalances can have profound health consequences. Thyroid disease is classified as hypothyroidism or hyperthyroidism. In the United States, an estimated 20 million people have thyroid disease. Hashimoto’s thyroiditis, an autoimmune disease resulting in hypothyroidism, accounts for most thyroid disease in the U.S. Prescribers treat it with levothyroxine, which is among the most frequently dispensed medications. Many patients have subclinical hypothyroidism and the decision to treat with levothyroxine is based on a patient’s individual circumstances. Hyperthyroid disorders are less common, and most cases are Graves’ disease, an autoimmune disorder. The 2020 approval of teprotumumab marked a major advancement in the treatment of thyroid eye disease. Pharmacologic treatment of thyroid disease is largely safe and effective with proper management. A knowledgeable pharmacy team can have a positive impact on patient care.

      CONTENT

      Content

      INTRODUCTION

      Did the Mona Lisa have hypothyroidism? Discussions around the Mona Lisa’s enigmatic smile have fascinated art lovers for centuries but now some endocrinologists have started a new line of debate. They describe telltale signs, like swollen hands, thinning hair, and a lump in the neck, that point to the famous Mona Lisa exhibiting hypothyroidism. They even suggest that the disease contributed to her mysterious smile. Amusing! When you view the painting do you see the same signs?

       

      Theodor Kocher, a Swiss physician who was award the Nobel Prize in 1909 for his work on the thyroid gland, described the first case of hypothyroidism in the mid-19th century.1 Effective treatment emerged about 100 years ago, so if the 16th century Mona Lisa had hypothyroidism, she might have suffered without knowing the cause. Patients with undiagnosed or inadequately treated hypothyroidism are at risk for cardiovascular problems, osteoporosis, and infertility.2

       

      The thyroid gland’s main hormones are responsible for controlling the body’s energy production and metabolic rate and they affect nearly every organ system in the body. Having too little or too much of these hormones can have profound consequences on health.

       

      Millions of Americans are affected by thyroid disease with most cases classified as hypothyroidism or underactive thyroid. Children, whose cognitive and physical development depends on normal thyroid function, can also be affected.3 Levothyroxine is used to treat hypothyroidism and is consistently among the most frequently prescribed medications in the U.S.4 Although less common, hyperthyroid disease is a serious endocrine disorder with profound health consequences if not properly treated.

      THYROID GLAND AND FUNCTION

      The thyroid gland is a small bow tie shaped endocrine gland that sits at the base of the neck. It produces two main hormones: tetraiodothyronine called thyroxine (T4), and triiodothyronine (T3). T4 and T3 control energy production and metabolic rate and influence nearly every organ system in the body including the brain, bowels, and skin. They regulate protein, carbohydrate, and fat metabolism by stimulating protein production and increasing oxygen needs at the cellular level. They are essential for proper fetal and neonatal development. Thyroid hormones influence body temperature, heart rate, appetite, mood, and digestion.2

       

      Iodine is a constituent of T4 and T3 and sufficient dietary intake of iodine and its adequate uptake by the thyroid gland is necessary for proper thyroid function. The thyroid gland produces mostly inactive hormone in the form of thyroxine, called T4 because it has four iodine atoms. T4 is highly protein bound for transport to the liver where it undergoes deiodination (the removal of one iodine atom) resulting in T3. T3, like T4, is highly protein bound and must be released from its binding protein to be active. Equilibrium is maintained between bound and free T3; as the body demands more biologically active hormone more T3 is released from the binding protein. Free T3 is the main biologically active form of thyroid hormone.2

       

      Hypothalamic-Pituitary-Thyroid Axis

      The hypothalamic-pituitary-thyroid axis governs thyroid hormone production by regulating the synthesis and secretion of thyroid stimulating hormone (TSH), also called thyrotropin. The hypothalamus is the part of the brain responsible for monitoring thyroid hormone levels in the body. When the hypothalamus detects low levels of thyroid hormone in the body, it releases a hormone called thyrotropin-releasing hormone (TRH). TRH stimulates the pituitary gland, the small pea-size gland sitting at the base of the brain, to secrete TSH. TSH, in turn, instructs the thyroid gland to produce more T4 and T3. High levels of T4 in the body inhibit TSH secretion while low levels of T4 stimulate TSH secretion. Disease affecting any part of the hypothalamic-pituitary-thyroid axis can result in thyroid hormone imbalances and disease.2

       

      THYROID DISEASE AND ETIOLOGY

      Thyroid disease is an endocrine disorder. Primary thyroid disease refers to disease of the thyroid gland. Secondary thyroid disease is far less common and refers to disease affecting the hypothalamus or pituitary gland resulting in thyroid dysfunction. Thyroid disease is classified as either hypothyroidism or hyperthyroidism.

       

      Hypothyroid Disease

      Hypothyroid disease occurs when inadequate thyroid hormone is available to the body. It is often referred to as an underactive thyroid and it is the most common form of thyroid disease. Hypothyroid disorders are categorized as either primary hypothyroidism or secondary hypothyroidism. The vast majority of cases are primary hypothyroidism.2

      Hashimoto’s Thyroiditis

      Hashimoto’s thyroiditis (HT) is the most common cause of primary hypothyroidism in the U.S. Japanese physician Hakaru Hashimoto first described the disease in 1912. It wasn’t until decades later that it was recognized as an autoimmune disorder and it is now considered the most prevalent autoimmune disease.5 Many patients do not realize that their hypothyroid condition is caused by this autoimmune disorder.

       

      HT is characterized by infiltration and destruction of thyroid cells by leukocytes (white blood cells). A chronic autoimmune inflammation ensues resulting in atrophy and fibrosis of the thyroid gland that leads to hypothyroidism. Circulating thyroid autoantibodies, anti-thyroperoxidase antibody (anti-TPO Ab), and anti-thyroglobulin antibody (anti-Tg Ab) can be detected but clinicians usually don’t measure them since all treatment of hypothyroidism is similar.6

       

      Women are more likely to develop HT and often have a family history, implicating a genetic component. The presence of other autoimmune disorders is common and prevalence is higher among those with chromosomal disorders like Down syndrome.2

       

      Patients may present with thyroiditis (inflammation of the thyroid gland) and symptoms of hypothyroidism, like weight gain and fatigue, but not always. Symptoms can develop gradually and go unnoticed. Laboratory assessment of thyroid function (discussed below) confirms the diagnosis. Individuals diagnosed with HT require lifelong treatment with the thyroid replacement hormone levothyroxine.6

       

      HT’s complications can manifest particularly in untreated or undertreated individuals including 2:

      • Lipid disorders (elevated total cholesterol, LDL, and triglycerides)
      • Anemia
      • Menstrual abnormalities
      • Infertility
      • Hyponatremia
      • Thyroid associated orbitopathy
      • Increased risk for papillary thyroid carcinoma

       

      Lipid disorders are of particular concern because they can contribute to coronary artery disease. Anemia is observed in 30% to 40% of patients. Recent research has suggested greater risk for recurrent pregnancy loss in patients with HT and an additional autoimmune disorder, but more research is needed to fully understand the link.7

       

      Most complications of HT are rare but prescribers must monitor and treat complications as they arise to optimize patient management.8

       

      Researchers have also noted vitamin D deficiency in HT. A randomized, double blind, clinical trial observed that supplementation with vitamin D reduced circulating thyroid autoantibodies.5 The researchers suggest a possible role for vitamin D in the alleviation of disease activity but acknowledge the need for further studies before introducing this intervention to clinical practice. Despite the need for additional research, treating vitamin D deficiency in patients with HT may be warranted.

       

      Gut microbiota are considered intrinsic regulators of thyroid autoimmunity. Scientists have studied the composition of the microbiota in patients with thyroid autoimmunity and have found it to be altered in HT.9 Clinical implications of this research are not fully understood, but further research may determine the role these findings may have in HT management.

       

      With early diagnosis, prompt treatment, proper follow-up care, and attention to associated complications, HT’s prognosis is excellent, and patients lead a normal life.10

       

      Iodine Deficiency Hypothyroidism

      Although uncommon in America, iodine deficiency is the leading cause of hypothyroidism worldwide. Adequate iodine intake is necessary for the thyroid gland to function properly, and it is critical for normal fetal and neonatal development. The recommended daily allowance (RDA) for adults is 150 mcg and it increases to 250 mcg in pregnancy and to 290 mcg during lactation. Goiter (an abnormal enlargement of the thyroid gland) is common as the thyroid gland enlarges in an attempt to sequester iodine to make thyroid hormone.11,63

       

      Universal salt iodization programs have dramatically reduced iodine deficiency-related thyroid disease.12 Historically, iodine deficient areas in the U.S. included the mountainous regions and the so called “goiter belt” around the Great Lakes. Most Americans now consume adequate amounts of iodine in their diets by using iodized salt and by eating dairy products, eggs, and seafood. However, certain populations may still be at risk, including vegans, pregnant women, and people who don’t use iodized salt.11 Most alternative milk products are low in iodine and processed foods like canned soup and specialty salts–including kosher, Himalayan, and sea salt–rarely provide iodine.13 Healthcare practitioners must be aware of iodine deficiency’s consequences, especially during pregnancy.11,63

       

      Thyroid diets have gained interest among patients and circulate widely on the Internet. These diets promote avoiding particular foods to achieve optimal thyroid function. Certain foods including broccoli, Brussels sprouts, cabbage, cauliflower, and soy contain goitrogens, which are substances that interfere with iodine uptake by the thyroid. For most people in the U.S. who consume adequate amounts of iodine, eating foods containing goitrogens is not a concern. People with iodine deficiency who eat an abundance of these foods may have trouble consuming enough iodine.13,63

       

      Thyroidectomy and Cancer Treatment Resulting in Hypothyroidism

      Thyroidectomy, the surgical removal of the thyroid gland, is sometimes indicated in cancer treatment and in some cases of hyperthyroidism. Thyroidectomy results in hypothyroidism and patients require life-long thyroid hormone replacement with levothyroxine.14

       

      Most thyroid cancers respond well to treatment, but a small percentage can be very aggressive. Treatment of thyroid cancer often results in hypothyroidism and patients require lifelong treatment with thyroid replacement hormone.14

       

      Medication-Induced Hypothyroidism

      The pharmacy team must be aware that certain medications can affect thyroid function. Table 1 lists common medications that can cause hypothyroidism and hyperthyroidism. The medications that cause hypothyroidism decrease synthesis of T4/T3, inhibit T4/T3 secretion, and/or cause thyroiditis.15

       

      Table 1. Medications that May Lead to Thyroid Dysfunction

       

                             Drug class/medications  Hypothyroidism Hyperthyroidism
      Antidysrhythmic:

       

       Amiodarone X X
      Bipolar Disorder Medication:

       

       Lithium X X
      Thyroid Medications:

       

       PTU X
       Methimazole X
       Radioactive Iodine X
      Cancer Medications:

       

       Biological response modifiers:
       Interferon X
       Interleukin-2 X
       Tyrosine kinase inhibitors:
         Sunitinib X
         Sorafenib X
       Checkpoint inhibitors:
         Nivolumab X X
         Pembrolizumab X X
         Ipilimumab X X
      Multiple Sclerosis Medication:

       

         Alemtuzumab X

       

      Medications that cause thyroid disorders are important treatments and, in most cases, they cannot be discontinued; any drug-induced hypothyroidism requires levothyroxine.

       

      Amiodarone structurally resembles thyroid hormone and is often implicated in thyroid dysfunction, mostly hypothyroidism.16 It is comprised of 37% iodine, so a 200 mg dose provides 75 mg of organic iodide, which is 100 times more than required. Researchers estimate thyroid abnormalities occur in 14% to 18% of patients taking long-term amiodarone but a meta-analysis found that with low doses, the incidence is lower (3.7%).17 Lithium can inhibit thyroid hormone release resulting in hypothyroidism; it usually occurs in younger women within the first two years of therapy. Antineoplastic agents may cause thyroid dysfunction in 20% to 50% of patients.18 Pharmacists must educate patients about the need for routine thyroid function assessment when receiving these medications.

       

      Hyperthyroid Disease

      Hyperthyroidism is characterized by excessive metabolism and secretion of thyroid hormones. It is less common than hypothyroid disease. Graves’ disease, thyroiditis, multi-nodular goiter, and toxic nodular goiter (benign growths on the thyroid gland that produce thyroid hormone in excess) can also cause hyperthyroid disease. Ingestion of too much external thyroid hormone is another possible cause of hyperthyroidism.19

       

      Graves’ Disease

      Graves’ disease (GD) accounts for most cases of hyperthyroidism. GD is an autoimmune disorder caused by a stimulatory autoantibody against the thyroid receptor for TSH. Most autoantibodies are inhibitory; in GD, the autoantibody is stimulatory. Overstimulation of the thyroid gland results in the overproduction of T4 and T3 leading to hyperthyroidism.12

       

      Graves’ disease, like HT, appears to have a genetic link and is often comorbid with other autoimmune disorders. Risk factors for GD include smoking and iodine deficiency. In the case of iodine deficiency, multifocal autonomous growth of the thyroid gland can occur and result in thyrotoxicosis (excess levels of thyroid hormone in the body).20 Women are affected at a higher rate and children can also be affected. GD’s clinical presentation may be dramatic or subtle and goiter may or may not be present. Laboratory assessment of thyroid function is used to help diagnose GD.

       

      Researchers have studied the composition of gut microbiota in patients with GD and similar to findings in HT, have found it to be altered. The researchers suggest the findings from this randomized controlled trial may offer an alternative noninvasive diagnostic methodology for GD.21 Further research is needed to elucidate the role microbiota may play in thyroid autoimmunity.

       

      Thyroid Eye Disease

      Thyroid eye disease is a progressive, potentially sight threatening ocular disease that is reported in almost half of patients who have GD. It arises from a separate autoimmune process involving autoantibodies that activate an insulin-like growth factor-1 receptor (IGF-1R) mediated signaling complex on cells within the eye orbit. The most common clinical feature is proptosis (bulging eyes) with edema and erythema of the surrounding eye tissue, but patients may also experience a skin manifestation called thyroid dermopathy (a nodular diffuse thickening of the skin on the legs). Patients with thyroid eye disease often complain of dry and gritty ocular sensation, photophobia, excessive tearing, double vision, and pressure sensation behind the eyes. Severe disease occurs in 3% to 5% of patients causing intense eye pain and inflammation, and threatening sight.22

       

      Recently, the Food and Drug Administration (FDA) approved the monoclonal antibody teprotumumab for treatment of adults with thyroid eye disease, marking a significant advancement in treatment. Prior to this approval, treatment options only included steroids or surgery.23

       

      Medication Induced Hyperthyroidism

      Like medication that can cause hypothyroidism, some medication can cause hyperthyroidism. The pharmacy team must be knowledgeable of the medications that can cause hyperthyroidism that warrant close monitoring of thyroid function (See Table 1). Patients should understand the importance of routine thyroid function assessment when taking medications that can affect thyroid function.

       

      Amiodarone-associated hyperthyroidism is less common than amiodarone-associated hypothyroidism; still, it is estimated to occur in 3% of patients. Onset of amiodarone-induced thyrotoxicosis (elevated levels of free thyroid hormone) can be sudden and require rapid assessment and treatment.16 Pharmacists must educate their patients about the symptoms of hyperthyroidism and instruct them to report them immediately if encountered.

       

      PAUSE and PONDER

      How many of your patients take medications that might cause thyroid dysfunction? Why is it important to tell these patients that some of their medications might influence the thyroid gland?

       

      PREVALENCE

      As many as 20 million Americans are affected by thyroid disease. Clinicians diagnose hypothyroidism in nearly five of 100 Americans aged 12 years and older.24 Thyroid disease affects men, women, and children. Women are disproportionately affected at a 10 to 15 times higher rate, and it’s estimated one in eight women will develop some form of thyroid disease in their lifetime.24

       

      HT is most often diagnosed between the ages of 40 to 60 years. Prevalence increases with age.8 Twenty percent of adults older than 75, most of them women, have insufficient levels of thyroid hormone.24 The Colorado Thyroid Disease Prevalence Study,25 a cross-sectional study conducted more than 20 years ago, reported the prevalence of hypothyroid disease in symptomatic and asymptomatic adults at 9.5%. In people not taking thyroid hormone, prevalence was 8.5% and 0.4% for subclinical and overt disease, respectively.10

       

      Hyperthyroidism is much less common than hypothyroidism. Prevalence of hyperthyroidism in the U.S. is estimated at 1.3%. GD is the most common cause of hyperthyroidism followed by toxic nodular goiter. GD is estimated to affect 1% of the population, mainly women of childbearing age. Incidence increases with age, and it is observed more frequently in Caucasians compared to other races. Mild hyperthyroidism occurs at a higher rate in iodine deficient geographic areas.12

       

      SYMPTOMS

      Because thyroid hormones affect nearly every organ system in the body thyroid disease’s symptoms are wide ranging and numerous. Symptoms vary depending on the type of thyroid disease and patients may experience few or many symptoms.26 Clinicians should routinely monitor patients for symptoms of thyroid disease, especially those at risk for thyroid disease including elderly women (See Table 2).27

       

      Table 2. Thyroid Disease’s Common Symptoms
      Hypothyroidism Hyperthyroidism
      Whole body Fatigue, lethargy,

      cold sensitivity

      Hunger, fatigue, weakness, sweating, increased appetite, heat intolerance, insomnia
      Mood/Behavioral Depression, irritability,

      sluggish, brain fog

      Nervousness, restlessness, hyperactivity, panic attacks
      Cardiac Bradycardia, elevated cholesterol Tachycardia, palpitations
      Weight Weight gain Weight loss
      Hair, skin, nails Hair loss, dry skin/hair, brittle nails Hair loss, warm skin
      Eyes/face Periorbital edema, puffy face Proptosis (abnormal protrusion of eyes)
      Gastrointestinal Constipation Frequent bowel movements
      Menstruation/fertility Heavy or irregular menstrual periods, fertility problems Amenorrhea, lighter or irregular menstrual periods, fertility problems
      Musculoskeletal Joint/muscle pain Osteoporosis
      Thyroid presentation May be enlarged May be enlarged

       

       

      Weight gain is a common and often first symptom of hypothyroidism. Up to 82% of women with HT have excess body weight and a third suffer from obesity.28 Despite achieving euthyroidism (normal thyroid function) with levothyroxine treatment, many women continue to struggle to lose weight. Caloric reducing diets are often unsuccessful and excess body weight increases risk for comorbidities.29

       

      Food sensitivity and the effects of elimination diets on autoimmune disease have gained interest. An interventional/observational study evaluated the effect of an elimination diet in obese women diagnosed with HT. The researchers observed that women eliminating sensitive foods (foods that may cause an IgG antibody reaction)30 in addition to caloric reduction had a greater decrease in body mass index (BMI) when compared to women only reducing caloric intake. Improvement in thyroid function laboratory parameters was also observed in the group eliminating sensitive foods.31

       

       

      LABS TO ASSESS THYROID FUNCTION

      Thyroid function is assessed mainly through readily available laboratory blood tests. Results of basic thyroid function laboratory tests largely differentiate and diagnose thyroid disease (See Table 3).

       

      Table 3. Thyroid Function Tests in Hypothyroidism and Hyperthyroidism 32

       

      TSH (Thyrotropin) FT4 (Thyroxine) T3
      Lab

      Reference range*

       

      0.5-4.8 mIU/L

       

      0.7-1.8 ng/dL

       

      80-220 ng/dL

      Hypothyroidism
      Primary, untreated High Low Low or normal
      Secondary to pituitary disease Low or Normal Low Low or normal
      Hyperthyroidism
      Untreated Low High High
      T3 toxicosis Low Normal High

      *Reference ranges may vary among laboratories.

       

      TSH is the best measurement to assess thyroid function. A normal TSH essentially rules out thyroid disease, except in the less common cases of disease affecting the hypothalamus or pituitary gland. The American Thyroid Association (ATA) recommends routine screening of TSH in adults beginning at age 35 and repeating the test every five years.27

       

      T4 is the primary thyroid hormone circulating in the blood. T4 is found in the body in two forms: free T4 and bound T4. More than 99% of T4 is bound. Because T4 is converted into T3, free T4 is the more important hormone to measure. Any changes show up in T4 first; therefore, free T4 (FT4) reflects thyroid gland function more accurately.33 Assessment of T3 is primarily used to diagnose and manage hyperthyroidism. It is rarely assessed in hypothyroidism since it’s the last test to become abnormal.34

       

      Patients with thyroid autoimmunity disease develop thyroid autoantibodies. Measurement of autoantibodies may help diagnosis, but clinicians need not monitor them routinely for disease management. Physicians typically order TSH with reflex to FT4 to assess thyroid function in disease management. Reflex testing allows the laboratory to automatically add the FT4 test to the blood sample based on an abnormal TSH result.35

       

      Clinicians sometime use radioactive iodine uptake (a non-blood test) to assess thyroid function. Because iodine is a necessary component of thyroid hormone, administering radioactive iodine and calculating its uptake by the thyroid can determine if the gland is functioning properly. Very high uptake is associated with hyperthyroidism while low iodine uptake indicates hypothyroidism.34

       

      TREATMENT APPROACHES

       

      Levothyroxine

      Levothyroxine sodium tablets (Synthroid and many generics) are synthetic T4 and indicated as replacement therapy in all hypothyroidism, regardless of the cause. Thyroid replacement hormone has a narrow therapeutic index and prescribers must individualize each patient’s levothyroxine dose. It is available in 12 different strengths, making it possible for prescribers to titrate doses carefully and avoid under- or over-treatment. Tablets are color-coded and are available from many manufacturers. (See Table 4)

       

      Table 4. Various Strengths and Colors of Levothyroxine Tablets

      Strength Color
      25 mcg Orange
      50 mcg White
      75 mcg Violet
      88 mcg Mint green
      100 mcg Yellow
      112 mcg Rose
      125 mcg Brown
      137 mcg Deep Blue
      150 mcg Light Blue
      175 mcg Lilac
      200 mcg Pink
      300 mcg Green

       

       

      Variability in levothyroxine absorption may exist across manufacturers. A cohort study in the Netherlands evaluated a forced switch of levothyroxine brand. The researchers concluded that a dose-equivalent levothyroxine brand switch might necessitate a dose adjustment.36 The ATA recommends using a consistent manufacturer. If a brand switch is made, the pharmacy team must inform prescribers; it may necessitate a dose adjustment.37

       

      Sidebar: Tech Tasks for Thyroid Medications

       

      • Inform patients about the importance of using a consistent brand of levothyroxine.
      • Note brand of levothyroxine on each patient’s profile.
      • Review levothyroxine shipments when restocking to assure consistent brand use.
      • Tag all bags and inform the patient if a brand switch is made.

       

      Peak therapeutic effect of levothyroxine is seen in four to six weeks. Prescribers often start levothyroxine at low doses and titrate in small increments of 12.5 to 25 mcg every four to six weeks based on TSH testing until achieving euthyroidism.38 Average full replacement dose is 1.6 mcg/kg/day. Current ATA guidelines recommend adjusting the levothyroxine dose to resolve symptoms of hypothyroidism and to keep the TSH level within the range of 0.4 to 4 mIU/L.29 Clinicians should assess thyroid function in patients on stable doses of levothyroxine every six to 12 months and within six to eight weeks of any dose change. Ongoing assessment helps avoid under- or over-replacement.38

       

      Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism and include the following37:

      • Anxiety
      • Diarrhea
      • Fatigue
      • Hair loss
      • Heat intolerance, excessive sweating
      • Increased appetite
      • Increased heart rate
      • Muscle weakness
      • Nervousness
      • Palpitations
      • Weight loss

       

      Over-replacement with levothyroxine can lead to serious consequences and can put elderly patients at risk for cardiac arrhythmias, especially atrial fibrillation.10 Complications of over-replacement include

      • Accelerated bone loss
      • Increased cardiac contractility
      • Increased cardiac wall thickness
      • Increased heart rate
      • Osteoporosis
      • Reduction in bone mineral density

       

      Medications, supplements, food, coffee, and even orange juice can decrease levothyroxine’s absorption.10 Levothyroxine is taken with water one hour before breakfast and any other prescription medications. Calcium, iron, antacids, cholestyramine, and sucralfate can inhibit its absorption and must be separated by at least four hours.37 Individuals with celiac disease or gastric bypass surgery may absorb medication inadequately.40,41

       

      Bedtime dosing of levothyroxine offers an alternative to morning dosing. Randomized controlled trials have found patients taking the medication in the evening had improved thyroid hormone status control.38,42 Patients struggling with morning dosing may find evening dosing easier. The ATA recommends that if levothyroxine is taken at bedtime that it be separated by three hours from the evening meal.43

       

      Because levothyroxine is usually administered for life, dose adjustment is often necessary to optimize therapy throughout a patient’s lifetime.44 Situations that necessitate possible dose adjustment of levothyroxine include

      • Aging (age older than 65)
      • Diagnosis of new medical conditions
      • Pregnancy
      • Start of new medications
      • Weight changes

       

      The Colorado Thyroid Disease Prevalence study assessed thyroid function, symptoms, and corresponding lipid levels in more than 25,000 participants. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest TSH elevations corresponded to changes in lipid levels that may affect cardiovascular health.25 Optimization of levothyroxine therapy requires that the healthcare team recognize the need for dose adjustments throughout a patient’s life.

       

      PAUSE and PONDER

      Among your patients being treated for hypothyroidism, how many also take calcium supplements? How many of these patients know to separate them from levothyroxine by four hours?

       

      Liothyronine

      Liothyronine (Cytomel) is synthetic T3. It is not recommended, either alone or in combination with levothyroxine, as first line treatment for hypothyroidism. Combination therapy hopes to mimic thyroid hormone physiology more closely; however, current guidelines do not suggest routine use of this approach.10 A 2016 randomized, double blind, crossover study evaluated combination therapy in 32 patients and found no clear clinical benefit and observed increased heart rate in patients receiving it.45A trial, however, may be indicated in a small group of patients who remain symptomatic despite adequate levothyroxine monotherapy.46

       

      Iodine

      Patients with iodine deficient hypothyroidism are treated with iodine supplements to correct the deficiency while levothyroxine is used to achieve euthyroidism. When the iodine level has been restored and goiter size has decreased, levothyroxine may be interrupted. Prescribers should reassess thyroid function in four to six weeks.11

       

      Consumption of too much iodine can have a negative impact on thyroid health. The safe upper limit of iodine for adults is 1.1 mg/day.63 Iodine toxicity may lead to thyroiditis, hypothyroidism, hyperthyroidism, and thyroid papillary cancer.47 Pharmacists should be aware that drug interactions with potassium iodine exist. It can interact with antithyroid drugs and when potassium iodide is taken with ACE inhibitors or potassium sparing diuretics, serum potassium can increase.13

       

      Selenium

      Selenium is an important micronutrient in the diet and increases active thyroid hormone production. The RDA for selenium is 55 mcg/day. Selenium supplements are used to treat or prevent selenium deficiency. Doses exceeding 400 mcg/day can be toxic. Signs of toxicity include brittle hair and nails, diarrhea, irritability, and nausea. Extremely high intakes of selenium can cause severe problems, including difficulty breathing, tremors, kidney failure, heart attacks, and heart failure. Most people consume adequate selenium through the diet, which is preferred. Consuming two Brazil nuts daily can provide adequate selenium intake; each nut contains 68 to 91 mcg of selenium, so people should not consume too many. Selenium is also found in oysters, tuna, whole-wheat bread, sunflower seeds, meat, mushrooms, and rye.48

       

      Subclinical Hypothyroid Disease

      Subclinical hypothyroidism is a common condition occurring in about 15% of older women and 10% of older men.2 It is a persistent condition in which TSH levels are elevated but free T4 levels remain normal. Treating subclinical hypothyroidism with levothyroxine results in an improved quality of life for many while others show no benefit and continue to complain of symptoms despite treatment.

       

      The decision to treat subclinical hypothyroidism is being reevaluated after a large European study found no clear benefit with treatment.3 Published in the New England Journal of Medicine in 2017, this double-blind, randomized, placebo-controlled, parallel-group trial concluded levothyroxine provided no apparent benefits in older people with subclinical hypothyroidism.49 Investigators are conducting more research to evaluate the effect of discontinuing levothyroxine in subclinical hypothyroidism.50 They hope to determine if discontinuing levothyroxine in patients with subclinical hypothyroidism is safe or will reduce quality of life.

       

      For now, prescribers should follow current clinical practice guidelines, which state that they should tailor the decision to treat subclinical hypothyroidism to the individual patient when the serum TSH is less than 10 mIU/L. Prescribers should consider the presence of symptoms and how likely the patient will progress to overt hypothyroidism when making the decision to treat.24

       

      Antithyroid Drugs

      The treatment goal for hyperthyroid disease is to lower excessive thyroid hormone levels and achieve euthyroidism. The two antithyroid drugs (ATD) available in the U.S. for the treatment of hyperthyroidism are methimazole (Tapazole) and propylthiouracil (PTU). Hepatotoxicity has been reported with both medications but methimazole has been associated with far fewer cases. Therefore, methimazole is used as first line therapy, except in pregnancy.51

       

      ATDs inhibit T4 and T3 synthesis by blocking oxidation of iodine in the thyroid gland. PTU also partially blocks peripheral conversion of T4 to T3. Beta-blockers can provide symptomatic relief in patients with hyperthyroidism.

       

      Methimazole is available in 5 mg and 10 mg tablets. The starting dose is 5 mg to 20 mg orally every eight hours. Prescribers must titrate the dose over time to the lowest dose needed to maintain euthyroidism. Maintenance doses range from 5 mg to 30 mg/day administered once daily. Once euthyroidism is achieved, patients usually continue the ATD for another 12 to 18 months. The prescriber should check thyroid function four to six weeks after therapy initiation and then every two to three months once the patient is euthyroid.12

       

      PTU’s labeling carries a boxed warning for acute liver failure,52 and it is reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery. It is also recommended for use in the first trimester of pregnancy because birth defects have been associated with methimazole. PTU is available as a 50 mg tablet. The initial starting dose is 50 mg to 150 mg orally every eight hours and the maintenance dose is usually 50 mg every 8 to 12 hours.53

       

      Minor side effects occur in about 5% of patients receiving an ATD. Side effects include53

      • Agranulocytosis (severe drop in white blood cells)
      • Arthralgia
      • Gastrointestinal distress
      • Hepatotoxicity
      • Pruritus
      • Vasculitis (dangerous inflammation of blood vessels)

       

      Serious side effects are less common at lower doses; patients should be maintained at the lowest possible dose needed to achieve euthyroidism. Although rare, hepatotoxicity and agranulocytosis can be life threatening. Pharmacists should educate patients to report signs of agranulocytosis, such as sudden fever, sore throat, or chills, to their prescribers immediately. Prescribers should obtain a baseline serum liver profile and white blood cell count before starting an ATD. Most side effects occur within the first 90 days of therapy. Vasculitis is more common with longer duration of therapy.

       

      A drawback of ATD therapy is the high relapse rate. A longitudinal cohort study concluded that patients initially treated with an ATD had about a 50% relapse rate and 25% felt they had not fully recovered in six to 10 years.54

       

      Recent studies have shown that longer treatment time with an ATD can achieve higher remission rates. A randomized, parallel-group study compared relapse rates in patients receiving longer-term versus conventional-length methimazole therapy in GD. The authors concluded that low-dose methimazole treatment for 60 to 120 months was safe and effective and had a higher remission rate compared to conventional treatment for 18 to 24 months.55

       

      Long-term methimazole therapy was also evaluated in juvenile Graves’ Disease in a randomized parallel trial. Patients receiving short-term methimazole therapy were almost three times more likely to relapse than those on long-term therapy. The researchers found long-term methimazole treatment of 96 to 120 months to be safe and effective with a significantly higher four-year cure rate.56

       

      Teprotumumab

      The FDA’s approval of teprotumumab (TEPEZZA) in January 2020 was the most significant advance in treating thyroid eye disease in decades. Teprotumumab binds to IGF-1R and blocks its activation and signaling. It was shown to improve the course of thyroid eye disease in patients in two separate clinical trials, leading to this monoclonal antibody’s approval.23, 57 Proptosis and diplopia improved, as did eye pain, redness and swelling, and quality of life. Serious adverse events were uncommon. The most common adverse reactions observed were

      • alopecia
      • altered sense of taste
      • diarrhea
      • dry skin
      • fatigue
      • headache
      • hearing loss
      • hyperglycemia
      • muscle spasm
      • nausea

       

      The FDA approved teprotumumab to be given as an infusion every three weeks for a total of eight doses. Patients completing the course of therapy showed significant improvement in symptoms associated with thyroid eye disease. Infusion reactions are reported in about 4% of patients. Dose is based on weight. The first dose is 10 mg/kg, and then the dose is increased to 20 mg/kg for the remaining seven infusions. Teprotumumab is contraindicated in pregnancy. Women of childbearing age must be counseled on pregnancy prevention during treatment and for six months following the last dose.58

       

      PAUSE and PONDER

      Which patients with thyroid disease in your practice might benefit from teprotumumab? What is important to tell them about this new biologic?

       

      Surgery

      Thyroidectomy is not used as a first line approach for treating hyperthyroidism. It is reserved for patients who refuse radioactive iodine after relapsing on an ATD, patients who cannot tolerate an ATD, or patients with very large goiter, multinodular goiter, or toxic adenoma. Thyroidectomy destroys the thyroid gland and if indicated, patients require lifelong levothyroxine therapy.

       

      Radioactive Iodine

      In the U.S., radioactive iodine is the most common treatment for hyperthyroidism.

      Radioiodine therapy, like surgery, destroys the thyroid gland requiring patients to be on lifelong levothyroxine therapy.

       

      In the last 20 years radioiodine has been used less frequently.19 Many patients report a lower quality of life after receiving radioactive iodine than patients receiving ATD or surgical treatment.59 A randomized parallel group trial found that long-term methimazole, when compared to radioiodine, was safe, effective, and not inferior to radioiodine further supporting the use of ATD over radioiodine.60

       

      Pregnancy

      Undiagnosed or inadequately treated hypothyroidism during pregnancy can lead to miscarriage, preterm delivery, or developmental disorders in children. Levothyroxine is safe in pregnancy, but pregnant patients may require a 30% increase in levothyroxine dose to maintain euthyroidism. During pregnancy, attending healthcare providers should titrate levothyroxine doses against TSH, which has trimester-specific ranges. Postpartum TSH levels are similar to preconception levels, so the dose of levothyroxine should return to the preconception dose following delivery.61

       

      Iodine is a critical mineral for proper fetal development and iodine needs increase by at least 50% in pregnancy and lactation. Pregnant women should receive a prenatal vitamin containing 150 mcg of iodine during pregnancy and lactation. Unfortunately, prenatal vitamins contain variable and inconsistent amounts of iodine. Close to 40% of marketed prenatal vitamins in the U.S. contain no iodine and when measured, the actual iodine content varied between 33 and 610 mcg.11 Healthcare practitioners must be vigilant in assuring that iodine requirements are met during pregnancy and lactation when iodine requirements increase. The ATA recommends that women receive 150 mcg of supplemental iodine daily during pregnancy and lactation and that all prenatal vitamin/mineral preparations contain 150 mcg of iodine.11

       

      Hyperthyroidism in pregnancy requires special consideration. Care givers must stabilize women undergoing treatment for Graves’ disease who intend to become pregnant prior to conception. Prescribers should advise women to delay attempts at conception until they achieve a stable euthyroid state, whenever possible.62 Additionally they should treat hyperthyroidism during pregnancy with the lowest possible dose of PTU because methimazole has been associated with cases of congenital malformation.

       

      The majority of patients with thyroid eye disease are women of childbearing age. Physicians must explain treatment limitations to patients who are contemplating pregnancy. Teprotumumab is contraindicated in pregnancy. Care givers must provide contraceptive counseling to women of childbearing age with thyroid eye disease treated with teprotumumab during treatment and for the six months following therapy.23

       

      Pharmacy Team’s Role

       

      The pharmacy team can have a positive impact on the successful management of patients with thyroid disease by educating and screening patients regarding

      • Adverse effects associated with their thyroid medications
      • Importance of medication adherence
      • Laboratory assessment of thyroid function
      • Screening for drug interactions
      • Signs and symptoms of hyperthyroidism and hypothyroidism

       

      Conclusion

       

      Thyroid disease affects millions in the U.S. and most cases are well controlled with pharmacological management. Adherence to thyroid disease medications is important. A knowledgeable pharmacy team can promote good practices and provide patient education, having a positive impact on patient care. Proper management allows most patients to have an excellent prognosis and quality of life.

       

      With your newly gained knowledge, take another look at the Mona Lisa. Did Leonardo da Vinci, a man before his time, notice a thyroid disorder that he captured in his famous painting and did it intentionally contribute to her enigmatic smile?

       

       

       

      Pharmacist Post Test (for viewing only)

      This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

       

         
        Pharmacist Post-test
        1. Which of the following statement accurately describes hypothyroid disorders?
        A) They are all of autoimmune etiology
        B) They require treatment with levothyroxine, regardless of cause
        C) They are caused only from disease directly affecting the thyroid gland

        2. A woman of childbearing age who follows a strict vegan diet and only uses sea salt is contemplating pregnancy. Which of the following is a risk?
        A) Selenium deficiency
        B) Vitamin D deficiency
        C) Iodine deficiency

        3. What is the best laboratory assessment of thyroid function?
        A) TSH
        B) T3
        C) Total T4

        4. How often should patients on stable doses of levothyroxine have lab assessment of thyroid function?
        A) every 6-12 months
        B) every 3-6 months
        C) every 24 months

        5) A patient newly diagnosed with Hashimoto’s Thyroiditis (HT) is very concerned with her new diagnosis. What statement MOST ACCURATELY describes HT?
        A) It is an autoimmune disease that has an excellent prognosis and is treated with lifelong levothyroxine therapy.
        B) It is an autoimmune disease that has an excellent prognosis and is treated with liothyronine and levothyroxine.
        C) It is subclinical hypothyroidism and she may not need treatment with levothyroxine.

        6) A patient stable on methimazole for Graves’ disease remarks that she is considering having a child. Why would you encourage her to speak to her primary care provider?
        A) Pregnancy is contraindicated
        B) Methimazole is contraindicated and she should be switched to PTU
        C) Methimazole is contraindicated and she should be switched to teprotumumab

        7) Which medication carries a boxed warning in its labeling for acute liver failure, requiring baseline liver function assessment prior to its start?
        A) Methimazole
        B) Propylthiouracil
        C) Teprotumumab

        8) A patient starting methimazole for Graves’ disease asks about symptoms that are common to the condition. Which statement MOST ACCURATELY describes possible symptoms of GD?
        A) Symptoms of hyperthyroidism may include rapid heart rate, weight loss, nervousness, hunger, fatigue, and hair loss.
        B) Symptoms of hyperthyroidism may include hair loss, fatigue, swelling, puffiness, and depression.
        C) Symptoms of hyperthyroidism may include proptosis, anxiety, difficulty breathing, and weight gain.

        9) Which statement MOST ACCURATELY reflects symptoms of hypothyroidism?
        A) Patients may exhibit many or few symptoms, including fatigue, weight loss, depression, constipation, and hair loss
        B) Patients may exhibit many or few symptoms, including fatigue, weight gain, depression, constipation, and hair loss
        C) Patients may exhibit many or few symptoms, including insomnia, weight gain, depression, constipation, and hair loss

        10) What statement MOST ACCURATELY describes subclinical hypothyroidism?
        A) It is a common persistent condition in which TSH levels are elevated and free T4 is high.
        B) It is a common persistent condition in which TSH levels are elevated and free T4 is low.
        C) It is a common, persistent condition in which TSH levels are elevated and free T4 is normal.

        Pharmacy Technician Post Test (for viewing only)

        This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

         

           
          Pharmacy Technician Post-test

          1. What are common symptoms of hypothyroid disease?
          A) Hair loss, proptosis, hunger, fatigue
          B) Hair loss, depression, weight gain, fatigue
          C) Hair loss, heat intolerance, weight loss, fatigue

          2. A patient who started on levothyroxine a year ago is picking up her refill; she remarks that she continues to feel sluggish, fatigue and is still overweight. The patient asks why she is still feeling unwell. What do you tell her?
          A) Refer this patient to the pharmacist
          B) Assure the patient nothing is wrong
          C) Suggest she take a dietary supplement

          3. Which medication is used to treat hyperthyroidism?
          A) Liothyronine
          B) Levothyroxine
          C) Methimazole

          4. Which medication is used to treat hypothyroidism?
          A) Propylthiouracil (PTU)
          B) Levothyroxine
          C) Methimazole

          5. What are common symptoms of hyperthyroid disease?
          A) Hunger, weight loss, nervousness, palpitations, frequent bowel movements
          B) Weight gain, heat intolerance, excessive sweating, increased heart rate
          C) Fatigue, depression, decreased heart rate, cold sensitivity, constipation

          6. What are the available dosage strengths for levothyroxine?
          A) 12 different tablet strengths ranging in dose from 25-300 mcg in 12.5-25 mcg increments.
          B) 8 different tablet strengths ranging in dose from 50-300 mcg in 25-50 mcg increments
          C)16 different tablet strengths ranging in dose from 100-300 mcg in 25-50 mcg increments

          7. A patient who recently started methimazole calls the pharmacy complaining that suddenly she is feeling feverish with sore throat and chills. What next steps should a pharmacy technician take?
          A) Indicate that she probably has a cold
          B) Refer her to the pharmacist
          C) Tell her to call back if she isn’t better in two days

          8. Which mineral is important for thyroid health?
          A) Calcium
          B) Iron
          C) Selenium

          9. What medication was recently approved for thyroid eye disease marking a significant advancement in treatment?
          A) Propylthiouracil
          B) Methimazole
          C) Teprotumumab

          10. A patient is picking up her levothyroxine refill and was told by her physician that she is anemic. She is purchasing iron supplements too. What is important to communicate to the patient?
          A) Iron supplements must be separated by four hours from levothyroxine
          B) Iron supplements should not be used with levothyroxine
          C) Iron supplements may cause upset stomach and dark stools

          References

          Full List of References

          References

             
            References

            1. The Nobel Prize in Physiology and Medicine, Theodore Kocher. The Nobel Prize. Accessed October 17, 2021. https://www.nobelprize.org/prizes/medicine/1909/kocher/biographical/
            2. Porter RS, ed. Merck Manual. 20th ed. Rahway, NJ: Merck Publishing; 2018.
            https://www.merckmanuals.com/professional/endocrine-and-metabolic disorders/thyroid-disorders/overview-of-thyroid function?query=Overview%20of%20the%20Thyroid%20Gland.
            3. Brody J. The Subtle Signs of a Thyroid Disorder. The New York Times. July 24, 2017. Accessed August 11, 2021.

            4. The 50 most commonly prescribed drugs in America and their average price. Drugreport. Accessed June 1, 2021. https://www.drugreport.com/50-commonly-prescribed-drugs-in-america/.
            5. Chahardoli R, Saboor-Yaraghi AA, Amouzegar A, Khalili D, Vakili AZ, Azizi F. Can supplementation with vitamin D modify thyroid autoantibodies (anti-TPO Ab, anti-Tg Ab) and thyroid profile (T3, T4, TSH) in Hashimoto's thyroiditis? a double blind, randomized clinical trial. Horm Metab Res. 2019;51(5):296-301. doi:10.1055/a-0856-1044.
            6. Hashimoto’s thyroiditis: the strange-sounding condition you can have without realizing it. Cleveland Clinic. https://health.clevelandclinic.org/hashimotos-thyroiditis-thyroid-disease-condition/ Accessed June 2, 2022.
            7. Cellini M, Santaguida MG, Stramazzo I, et al. Recurrent pregnancy loss in women with Hashimoto's thyroiditis with concurrent non-endocrine autoimmune disorders. Thyroid. 2020;30(3):457-462. doi:10.1089/thy.2019.0456.
            8. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev. 2014;13(4-5):391-397. doi:10.1016/j.autrev.2014.01.007.
            9. Zhao F, Feng J, Li J, et al. Alterations of the gut microbiota in Hashimoto's thyroiditis patients. Thyroid. 2018;28(2):175-186. doi:10.1089/thy.2017.0395.
            10. What is the Incidence of Hashimoto Thyroiditis in the US? Medscape. Accessed August 11, 2021.https://www.medscape.com/answers/120937-122448/what-is-the-incidence-of-hashimoto-thyroiditis-in-the-us.
            11. Niwattisaiwong S, Burman KD, Li-Ng M. Iodine deficiency: clinical implications. Cleve Clin J Med. 2017;84(3):236-244. doi:10.3949/ccjm.84a.15053.
            12. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906-918. doi:10.1016/S0140-6736(16)00278-6.
            13. Iodine Fact Sheet for Consumers. National Institutes of Health Office of Dietary. Accessed August 11, 2021. Supplements. https://ods.od.nih.gov/factsheets/Iodine-Consumer/
            14. Merk Manual Professional Version. Thyroid Cancers. Accessed October 17, 2021. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/thyroid-disorders/thyroid-cancers
            15. Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab. 2009;23(6):793-800. doi:10.1016/j.beem.2009.08.003.
            16. Tsang W, Houlden RL. Amiodarone-induced thyrotoxicosis: a review. Can J Cardiol. 2009;25(7):421-424. doi:10.1016/s0828-282x(09)70512-4.
            17. Trohman RG, Sharma PS, McAninch EA, Bianco AC. Amiodarone and thyroid physiology, pathophysiology, diagnosis and management. Trends Cardiovasc Med. 2019;29(5):285-295. doi:10.1016/j.tcm.2018.09.005
            18. Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents. J Natl Cancer Inst. 2011;103(21):1572-1587. doi:10.1093/jnci/djr373.
            19. Clinical thyroidology for the public. American Thyroid Association. Accessed August 11, 2021. https://www.thyroid.org/patient-thyroid-information/ct-for-patients/november-2016/vol-9-issue-11-p-3-7
            20. Chung HR. Iodine and thyroid function. Ann Pediatr Endocrinol Metab. 2014;19(1):8-12. doi:10.6065/apem.2014.19.1.8
            21. Jiang W, Yu X, Kosik RO, et al. Gut microbiota may play a significant role in the pathogenesis of Graves' disease. Thyroid. 2021;31(5):810-820. doi:10.1089/thy.2020.0193.
            22. Bahn RS. Graves' ophthalmopathy. N Engl J Med. 2010;362(8):726-738. doi:10.1056/NEJMra0905750.
            23. Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382(4):341-352. doi:10.1056/NEJMoa1910434.
            24. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association [published correction appears in Endocr Pract. 2013 Jan-Feb;19(1):175]. Endocr Pract. 2012;18(6):988-1028. doi:10.4158/EP12280.GL.
            25. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526-534. doi:10.1001/archinte.160.4.526.
            26. Hypothyroidism (Underactive Thyroid). National institute of diabetes and digestive and kidney diseases. Accessed August 11, 2021. https://www.niddk.nih.gov/health-information/endocrine-diseases/hypothyroidism.
            27. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction [published correction appears in Arch Intern Med 2001 Jan 22;161(2):284]. Arch Intern Med. 2000;160(11):1573-1575. doi:10.1001/archinte.160.11.1573.
            28. Song RH, Wang B, Yao QM, Li Q, Jia X, Zhang JA. The impact of obesity on thyroid autoimmunity and dysfunction: a systematic review and meta-analysis. Front Immunol. 2019;10:2349. doi:10.3389/fimmu.2019.02349.
            29. Khaodhiar L, McCowen KC, Blackburn GL. Obesity and its comorbid conditions. Clin Cornerstone. 1999;2(3):17-31. doi:10.1016/s1098-3597(99)90002-9.
            30. Gocki J, Bartuzi Z. Role of immunoglobulin G antibodies in diagnosis of food allergy. Postepy Dermatol Alergol. 2016;33(4):253-256. doi:10.5114/ada.2016.61600.
            31. Ostrowska L, Gier D, Zyśk B. The influence of reducing diets on changes in thyroid parameters in women suffering from obesity and Hashimoto's disease. Nutrients. 2021;13(3):862. doi:10.3390/nu13030862.
            32. What are Normal Thyroid Hormone Levels? UCLA Health. Accessed August 11, 2021.https://www.uclahealth.org/endocrine-center/normal-thyroid-hormone-levels
            33. Free and Bound T4. University of Rochester. Accessed October 17, 2021. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=t4_free_and_bound_blood.
            34. Thyroid Function Tests. American Thyroid Association. Accessed August 11, 2021. http://www.thyroid.org/thyroid-function-tests/.
            35. Henze M, Brown SJ, Hadlow NC, Walsh JP. Rationalizing thyroid function testing: which TSH cutoffs are optimal for testing free T4?. J Clin Endocrinol Metab. 2017;102(11):4235-4241. doi:10.1210/jc.2017-01322.
            36. Flinterman LE, Kuiper JG, Korevaar JC, et al. Impact of a forced dose-equivalent levothyroxine brand switch on plasma thyrotropin: a cohort study. Thyroid. 2020;30(6):821-828. doi:10.1089/thy.2019.0414.
            37. Levothyroxine sodium tablets [package insert]. Lloyd, Inc.; 2019.
            38. Srivastava S, Sharma G, Rathore M, et al. A crossover study evaluating effect of timing of levothyroxine on thyroid hormone status in patients of hypothyroidism. J Assoc Physicians India. 2018;66(9):37-40.
            39. Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ. 2019;366:l4892. doi:10.1136/bmj.l4892.
            40. Skelin M, Lucijanić T, Amidžić Klarić D, et al. Factors affecting gastrointestinal absorption of levothyroxine: a review. Clin Ther. 2017;39(2):378-403. doi:10.1016/j.clinthera.2017.01.005.
            41. Gadiraju S, Lee CJ, Cooper DS. Levothyroxine dosing following bariatric surgery. Obes Surg. 2016;26(10):2538-2542. doi:10.1007/s11695-016-2314-x.
            42. Bolk N, Visser TJ, Nijman J, Jongste IJ, Tijssen JG, Berghout A. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med. 2010;170(22):1996-2003. doi:10.1001/archinternmed.2010.436.
            43. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. doi:10.1089/thy.2014.0028
            44. Duntas LH, Jonklaas J. Levothyroxine dose adjustment to optimise therapy throughout a patient's lifetime. Adv Ther. 2019;36(Suppl 2):30-46. doi:10.1007/s12325-019-01078-2.
            45. Kaminski J, Miasaki FY, Paz-Filho G, Graf H, Carvalho GA. Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. Arch Endocrinol Metab. 2016;60(6):562-572. doi:10.1590/2359-3997000000192.
            46. Dayan C, Panicker V. Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance. Thyroid Res. 2018;11:1. Published 2018 Jan 17. doi:10.1186/s13044-018-0045-x.
            47. Southern AP, Jwayyed S. Iodine Toxicity. [Updated 2021 Apr 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Jan. 2021 Accessed August 11, 2021.https://www.ncbi.nlm.nih.gov/books/NBK560770/.
            48. Schomburg L. Dietary selenium and human health. Nutrients. 2016;9(1):22. doi:10.3390/nu9010022.
            49. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534-2544. doi:10.1056/NEJMoa160382.
            50. Discontinuation of levothyroxine therapy for patients with subclinical hypothyroidism. U.S. National Library of Medicine. Accessed August 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04288115?term=underactive+thyroid&recrs=a&cond=hypothyroidism&fund=01&draw=2&rank=1
            51. Kahaly GJ. Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J Clin Endocrinol Metab. 2020;105(12):3704-3720. doi:10.1210/clinem/dgaa646.
            52. U.S. Food and Drug Administration. FDA Drug Safety Communication: New Boxed Warning on severe liver injury with propylthiouracil. Accessed October 17, 2021. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-new-boxed-warning-severe-liver-injury-propylthiouracil.
            53. Propylthiouracil tablets [package insert]. Chartwell Pharmaceuticals; 2015
            54. Sjölin G, Holmberg M, Törring O, et al. The long-term outcome of treatment for Graves' hyperthyroidism. Thyroid. 2019;29(11):1545-1557. doi:10.1089/thy.2019.0085.
            55. Azizi F, Amouzegar A, Tohidi M, et al. Increased remission rates after long-term methimazole therapy in patients with Graves' disease: results of a randomized clinical trial. Thyroid. 2019;29(9):1192-1200. doi:10.1089/thy.2019.0180.
            56. Azizi F, Takyar M, Madreseh E, Amouzegar A. Long-term methimazole therapy in juvenile Graves' disease: a randomized trial. Pediatrics. 2019;143(5):e20183034. doi:10.1542/peds.2018-3034.
            57. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949.
            58. Tepezza (toprotumumab-trbw) [package insert]. Horizon Therapeutics;2021.
            59. Törring O, Watt T, Sjölin G, et al. Impaired quality of life after radioiodine therapy compared to antithyroid drugs or surgical treatment for Graves' hyperthyroidism: a long-term follow-up with the thyroid-related patient-reported outcome questionnaire and 36-item short form health status survey. Thyroid. 2019;29(3):322-331. doi:10.1089/thy.2018.0315.
            60. Azizi F, Takyar M, Madreseh E, Amouzegar A. Treatment of toxic multinodular goiter: comparison of radioiodine and long-term methimazole treatment [published correction appears in Thyroid. 2019 Dec;29(12):1871]. Thyroid. 2019;29(5):625-630. doi:10.1089/thy.2018.0397.
            61. Li SW, Chan SY. Management of overt hypothyroidism during pregnancy. Best Pract Res Clin Endocrinol Metab. 2020;34(4):101439. doi:10.1016/j.beem.2020.101439.
            62. Managing Graves' disease during pregnancy: risks and benefits. Endocrineweb. Accessed August 11, 2021.
            https://www.endocrineweb.com/conditions/graves-disease/managing-graves-disease-during-pregnancy-risks-benefits.
            63. Iodine Fact Sheet for Professionals. National Institutes of Health Office of Dietary Supplements. Accessed August 19, 2021. https://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/.

            SMARTen Up: Asthma Management Guidelines

            Learning Objectives

             

            After completing this application-based continuing education activity, pharmacists will be able to

            1.     Describe the pathophysiology and severity classifications of asthma
            2.     Identify the class, mechanism of action, place in therapy, and potential side effects of asthma therapies
            3.     Recall updates in the 2020 NHLBI Guideline Update
            4.     State what SMART Therapy is, why it was added to the asthma guidelines, and how to apply it to patient cases

            After completing this application-based continuing education activity, pharmacy technicians will be able to

            1.     List the basic symptoms and pathophysiology of asthma
            2.     Recall how patients are diagnosed with asthma and what the severities are.
            3.     Recognize common medications used for asthma
            4.     Explain SMART therapy and the pharmacy technician’s role in SMART

            drawing of lungs with the word ASTHMA ripped in the middle

            Release Date:

            Release Date: April 19, 2022

            Expiration Date: April 19, 2025

            Course Fee

            FREE

            ACPE UANs

            Pharmacist: 0009-0000-22-023-H01-P

            Pharmacy Technician: 0009-0000-22-023-H01-T

            Session Codes

            Pharmacist: 22YC23-ABC35

            Pharmacy Technician: 22YC23-CBA84

            Accreditation Hours

            2.0 hours of CE

            Accreditation Statements

            The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-023-H01-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

             

            Disclosure of Discussions of Off-label and Investigational Drug Use

            The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

            Faculty

            Melanie Collins, MD
            Co-Director, Asthma Center
            Connecticut Children’s Medical Center
            Hartford, CT

            Jessica Hollenbach, PhD, AE-C
            Co-Director, Asthma Center
            Connecticut Children’s Medical Center
            Hartford, CT

            Lindsay Sawtelle, PharmD Candidate 2022
            University of Connecticut School of Pharmacy
            Storrs, CT

            Faculty Disclosure

            In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

            Dr. Collins and Dr. Hollenbach have no relationship with ineligible companies and therefore have nothing to disclose.

            Lindsay Sawtelle acts as a consultant for GSK but there are no conflicts of interest.

            ABSTRACT

            Asthma is one of the most common chronic diseases. Patients with asthma may have respiratory symptoms that affect their ability to breathe, daily activities, and quality of life. Understanding asthma and its pathophysiology, diagnosis, severities, and medications are pertinent to managing the disease.

            This continuing education activity describes the 2020 update to the Asthma Management Guidelines by the National Heart, Lung, and Blood Institute (NHLBI) expert panel recommendations. Single Maintenance and Reliever Therapy (SMART) is a guideline revision that impacts clinical practice significantly. Pharmacy personnel need to familiarize themselves with the guideline updates to navigate transformations in prescribing that will follow.

            CONTENT

            Content

            INTRODUCTION

            Let’s start this continuing education (CE) course with a story. A 13-year-old adolescent, Emily, had asthma exacerbations that were impacting her life. In addition to sitting out at her soccer games, she was having difficulty waking for school because her asthma exacerbations kept her up a few nights a week. Her physician prescribed a budesonide/formoterol (Symbicort) prescription for maintenance and reliever. When she and her mom went to pick up the prescription, their pharmacist told them this prescription was “inappropriate” and “dangerous” at the pick-up counter. This pharmacist likely frightened the patient and her mother. The patient would have been rightfully hesitant to take the prescription as the physician prescribed.

             

            Although the guidelines did not recommend using this combination for reliever and maintenance before 2020, the pharmacist was mistaken. This pharmacist didn’t know about new NHLBI guidelines for SMART therapy. This continuing education activity will explore a recent change to the asthma guidelines that helps aspiring soccer players like our Emily score a goal with their asthma. Staying up to date on guidelines is the only way pharmacists will keep their place as trusted healthcare professionals.

             

            BACKGROUND

            All pharmacy team members need to know about asthma because it is a common chronic disease in both children and adults. The Center for Disease Control (CDC) estimates that around 8% of the population has asthma. As a chronic disease affecting the airway and lungs, asthma is characterized by airway inflammation, bronchospasm, and mucus hypersecretion. These findings cause symptoms of difficulty breathing, wheezing, coughing, and chest tightness.1 Asthma’s symptoms can range from mild to severe and they fluctuate. Symptom worsening is called an asthma attack, flare, or exacerbation.2

             

            Asthma is often diagnosed in childhood but affects people of all ages. It is diagnosed more commonly in males during childhood, but its prevalence is equal in males and females by adulthood.1 Asthma seems to have a hereditary component, although many genes probably contribute to asthma.3 Family history and the presence of eczema are both risk factors for asthma.1 Other risk factors include exposure to environmental tobacco smoke, air pollutants, or allergens, such as pollen, dust, or workplace chemicals (see the SIDEBAR for information about household pests).1 Risk factors for asthma are often present in childhood. For example, exposure to cigarette smoke in the womb increases the probability infants will develop asthma. Young children with allergies or who have respiratory infections are also more likely to develop asthma.1

             

            Asthma Pathophysiology

            The bronchial tree is the branched system of cartilaginous tubes responsible for conducting gas to alveoli, the small air sacs that allow gas exchange, in the lungs. The word “tree” is an apt description because the lungs look like an upside-down tree, where the trachea is the trunk, and the bronchioles are the smallest terminal twigs. The bronchioles are the smallest bronchi and they facilitate gas exchange with alveoli, the air sacs in the lungs that exchange gas with the blood.4 Each layer of the bronchi has a smaller diameter than the one it stems from and has more smooth muscle fibers, just like the branches of a tree.5 Asthma primarily affects airways including the smooth muscle of the bronchi, where inflammation decreases the airway’s size, in turn increasing the work it takes to breathe.3

             

            In allergic asthma, an asthma exacerbation consists of an early phase and a late phase. IgE antibodies are responsible for the first phase.3 Environmental triggers cause plasma cells to release IgE antibodies, which bind to mast cells and basophils. Mast cells release cytokines, histamine, prostaglandins, and leukotrienes.3 Ultimately, smooth muscle contracts and the airway tightens, causing bronchoconstriction.6 Th2 lymphocytes sustain the inflammation by producing additional cytokines and maintaining the communication between cells.3 The late phase occurs over the next few hours as inflammatory cells localize to the lungs and cause bronchoconstriction and inflammation. The cells involved in this second phase include basophils, eosinophils, helper and memory T-cells, and neutrophils.3 These cells cause inflammation and further edema. Mucus worsens airway obstruction and difficulty breathing. Successful management of an asthma exacerbation requires recognition of both phases.

             

            Hyperresponsiveness of the bronchi is another mechanism of asthma’s pathophysiology. Hyperresponsiveness is excessive bronchoconstriction after inhalation of or exposure to triggers.7 Triggers can include smoke, exercise, emotion, cold temperatures, humidity, animals with fur, infections, and non-steroidal anti-inflammatory drugs.8-11 This mechanism of excessive inflammation involves histamine and increased free intracellular calcium that increases smooth muscle contractility.12 Disease severity and therapeutic intervention are related to bronchial hyperresponsiveness.

             

             

            Rodent and Cockroaches Sidebar13-15

            The prevalence of asthma is highest in developed countries, especially in urban areas. In urban areas, up to 1 in 4 children may have asthma. Urban areas increase the risk of exposure to cockroaches and rodents, increasing allergen sensitization in these areas, ultimately leading to asthma. Mouse Mus m 1, mouse urinary protein (MUP), rat N 1, and cockroach (Bla g 1 and Bla g 2) are the responsible allergen proteins. Tests have confirmed high levels of these proteins in houses, schools, and daycares in urban locations.

             

            Multifamily homes, high population density, lower socioeconomic status, and poor physical condition of buildings are all settings that foster cockroach and rodent infestation. Sensitization to cockroaches and rodents is associated with wheezing and severe asthma morbidity. Most research done to date has been in children.

             

            Like people, pests need food, water, and shelter to live. They prefer to live in dark and damp areas. Pest mitigation strategies can decrease the likelihood of exposure to rodent and cockroach proteins:

             

            • Do not leave food containers open or dirty dishes out in the open.
            • Do not leave pet food and water out overnight.
            • Clean regularly. Pick up garbage, crumbs, and clean liquid spills.
            • Use trash cans with lids, bags that resist breaking, and do not allow them to overflow.
            • Check for plumbing leaks and moisture problems and fix any issues right away.
            • Seal cracks and openings around doors, windows, and foundations.
            • Use bait gel in cracks and traps rather than pesticides.

             

            Structural changes occur in the airway due to chronic inflammation and airway muscle hyperreactivity. This is known as airway remodeling. An asthmatic bronchiole is narrower than a normal bronchiole. Increased swelling, chronic inflammation, and mucus buildup from persistent airflow obstruction cause the narrowing.3 The narrowing of the lumen disrupts the normal replication of epithelial cells, compromising the layer’s structure and function.16 The hyperresponsiveness of the bronchioles leads to hypertrophied smooth muscle, disrupting the basement membrane. Irreversible obstruction of airflow is a consequence of airway remodeling.12 Effective treatment of asthma can prevent or delay airway remodeling.

             

            ASTHMA DIAGNOSIS

            The first step in diagnosing asthma is a focused medical history and physical examination. Symptoms consistent with asthma include episodes of cough, wheezing, difficulty breathing, and chest tightness. It is also notable if these symptoms worsen at night and awaken the patient, as they did for our patient Emily.17 The physical exam may show use of accessory muscles when breathing, sounds of wheezing during normal breathing, increased nasal secretion with mucosal swelling, or atopic dermatitis/eczema.17 Noting patient allergies or a family history of asthma helps establish a diagnosis.

             

            Spirometry can be used to evaluate asthma and monitor disease severity; it can also be used to monitor response to therapy in patients aged 5 and older.  Of note, it is not common to find many five-year-olds who are capable of reliably performing the test.17 Spirometry measures the air a patient breathes in and out. Specifically, spirometry measures the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC).18

            • FEV1: maximum amount of air a patient exhales in one second.
            • FVC: maximum amount of air exhaled when blowing out as fast as possible

             

            Comparing results against values normalized by age, height, weight, gender, and race is the only way to interpret them. An easy way to interpret results is based on the percent predicted; however, most pulmonologists now use z-scores to interpret spirometry.19 Physicians may have the patient repeat spirometry after taking a bronchodilator to evaluate for airway reversibility.

             

            Clinicians also use spirometry to evaluate if current therapy is controlling asthma effectively. The results of patients’ spirometry tests while on treatment guides doctors to increase or decrease the dose of asthma medications.18

             

            Airway hyperresponsiveness is measured using a methacholine test. The clinician uses spirometry to find the patient’s FEV1. The patient then uses a nebulizer and inhales increasingly larger doses of methacholine. The physician takes the FEV1 before and after each dose. The test is positive if the FEV1 drops 20% or more from the baseline FEV1. The test is negative if the maximum methacholine dose does not decrease the FEV1 by at least 20%.20 Regardless of asthma control and response to therapy, most people with asthma would have a positive methacholine challenge test.

             

            The 2020 NHLBI guideline update includes the conditional recommendation to use fractional exhaled nitrous oxide (FeNO) as a test to diagnose asthma.21 Nitric oxide (NO) is a gas produced by cells involved in inflammation. The higher the NO level, the more inflammation in the body. This test is plausible to use as an adjunct for patients aged 5 and older whose asthma diagnosis is uncertain using history, clinical course, and spirometry. Our patient in this CE case would not be a candidate for a FeNO test, as her asthma diagnoses are apparent without one. One should also note that most commercial insurances no longer cover this test.

             

            Asthma Severities

            The NHLBI classifies asthma as intermittent, mild persistent, moderate persistent, or severe persistent. Asthma symptoms before treatment determine the classification, but the patient’s classification may change over time. Patients are diagnosed with the asthma classification in which their most severe symptom falls.17 As you look at these classifications, think about Emily and decide where her asthma would fall.

            • Intermittent Asthma
              • Symptoms occur fewer than two days a week and do not interfere with normal activities
              • Nighttime symptoms occur fewer than two days a month
              • Lung function tests are normal when the patient is not having symptoms
            • Mild Persistent
              • Symptoms occur more than two days a week, but not every day. Attacks interfere with daily activities
              • Nighttime symptoms occur three to four times a month
              • Lung function tests are normal when the patient is not having symptoms
            • Moderate Persistent
              • Symptoms occur daily and interfere with daily activities
              • Nighttime symptoms occur more than once a week, but not daily
              • Lung function tests are abnormal
            • Severe Persistent
              • Symptoms occur daily and severely limit daily activities
              • Nighttime symptoms occur multiple times weekly
              • Lung function tests are abnormal

             

            The severity of asthma drives the treatment recommendations. Asthma classification can change over time. From our case, Emily likely has moderate persistent asthma. She is kept up a few times weekly by nighttime symptoms, interfering with her sleep. She also needs to sit out of soccer games and was having trouble in school due to her lack of sleep. Her symptoms limit her daily activities.

             

            Pause and Ponder: How would asthma attacks occurring nightly affect a patient’s quality of life?

             

            TREATMENT

             

            With the revision to the guidelines in 2020, several things have changed, and pharmacy staff need to be aware of the changes.

             

            Medications

            People can manage asthma with appropriate medications. Table 122-26 provides additional detail on the mechanism of action, pharmacology, and adverse events associated with preferred medications used to treat asthma. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy, and this has not changed with the updated guidelines, although use of biologic agents to control asthma is more prominent.23 ICS may be dosed once or twice daily but more often during symptomatic periods.24 Beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, and mometasone are all commonly used ICS.22 When dosed at equipotent doses, all corticosteroids are equally effective, but some individuals respond better to certain ICS than others.24 The dose of ICS can be titrated for symptom relief and spirometry response, but the dose response is relatively flat after moderate doses.25 A flat dose response is like continuing to eat when you are already full. When you are full, you likely have gotten all the calories you need from a meal, and now you are just increasing your chances of bellyache. Increasing the dose of ICS past moderate strengths does not continue to provide additional relief of asthma symptoms as before, and the risk of side effects increases. Some patients with severe asthma do escalate to high dose ICS.

             

            Table 1. Preferred Medications for Asthma Therapy22-26

             

            Medication Class Mechanism of Action Pharmacology  Adverse events
            ICS Inhibit production and release of signals allowing extravasation of immune cells into the airway. Decrease inflammatory response and airway hyperresponsiveness ·       1-2 Weeks of treatment for full effect

            ·       Goal is high pulmonary affinity with low systemic absorption

            ·       MDI vs. DPI may affect absorption

            ·       Metabolism and active metabolites may contribute to systemic effects

            Nasopharyngitis, headache, bronchitis, sinusitis, influenza, respiratory tract infection, back pain, toothache, abdominal pain, cough, oral candidiasis, rhinitis, and throat irritation
            Inhaled SABA

             

            Bind to beta-adrenergic receptors in the bronchiole. Ultimately leads to the relaxation of smooth muscle. The difference between short and long- acting agonists is the half-life. ·       Onset: Within minutes

            ·       Peak: 30 minutes

            ·       Bronchodilation: 4-6 hours

            Tremor, nervousness and insomnia in children, nausea, fever, bronchospasm, vomiting, headache, pain, dizziness, cough, dry mouth, sweating, chills, dyspepsia
            Inhaled LABA ·       Onset: 5-30 minutes

            ·       Peak: 15 minutes- 3 hours

            ·       Bronchodilation >12 hours

            Adverse events are same as short acting, but less likely. LABAs are more B2 selective and lipophilic, concentrating their effects in the lungs
            Inhaled SAMA Antagonize acetylcholine at muscarinic (M3) receptors, leading to decreased bronchoconstriction, mucus secretion and edema ·       Onset: Within 15 minutes

            ·       Peak: 1-2 hours

            ·       Bronchodilation: 6-8 hours

            Adverse events are related to systemic anticholinergic activity at all muscarinic receptors including urinary retention, dry mouth, headache, dizziness, sinusitis, dyspnea, back pain, cough
            Inhaled LAMA

             

            ·       Onset: 30 minutes

            ·       Peak: 3-4 hours

            ·       Bronchodilation: 12 to >24 hours

            B2: Beta-2 receptor, ICS: inhaled corticosteroids, DPI: dry powdered inhaler, LABA: long-acting beta agonist, LAMA: long-acting muscarinic antagonist, MDI: metered-dose inhaler, SABA: short-acting beta agonist, SAMA: short-acting muscarinic antagonist

             

            Patients use oral systemic corticosteroids for severe exacerbations or if they have a history of severe exacerbations or difficult-to-control asthma.21 Oral corticosteroids have many unfavorable adverse events that need to be considered by prescribing physicians.27 An increase in the release of cortisol from the adrenal glands through a negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis causes many of these adverse effects.27

            Systemic corticosteroid adverse events differ by duration of therapy27:

            • Short term: hyperglycemia, leukocytosis, mood alteration, sodium and fluid retention, increased weight gain, nocturnal enuresis
            • Long term: growth retardation, osteoporosis, skin thinning, impaired wound healing, bruising, cataracts, glaucoma, Cushingoid feature, increased weight gain, and immunosuppression

             

            ICS have little systemic absorption and are preferred for asthma control over oral corticosteroids. Patients taking higher doses of ICS have increased risk of systemic absorption and adrenal suppression. It is important to titrate to the lowest effective dose of ICS to avoid systemic absorption and adverse events. Corticosteroids have a dose-response relationship to adverse events.27 Clinicians must monitor for systemic side effects to determine the risk and benefit balance of both oral corticosteroids and ICS.

             

            While corticosteroids treat the inflammatory component of asthma, additional medications are needed to address airway hyperresponsiveness and can be either short or long-acting medications. “Quick-relief” and “relief” medications are common ways to refer to short-acting medications.22 Short-acting beta-agonists (SABAs) and inhaled short-acting muscarinic antagonists (SAMAs) are the two classes of relief medications. Patients use SABAs and SAMAs when experiencing symptoms or before exposure to triggers.

             

            SABAs are highly effective bronchodilators but have short durations of action.22 Typically, all patients with asthma are prescribed SABAs as a “relief” inhaler.22 Albuterol metered-dose inhalers (MDI) are the most used relief inhaler. Albuterol is dosed at one to two puffs every four to six hours as needed to control an asthma exacerbation.28 SABA use is changing in clinical practice. Newer research shows that SABAs are more effective when followed by an ICS.29 Even in patients with infrequent symptoms, a prescription for daily low-dose ICS reduces asthma symptoms and risk. Increased SABA use is associated with worse outcomes. A patient is at risk of severe asthma exacerbations and asthma mortality if they pick up three or more albuterol inhalers a year from the pharmacy, the equivalent of 1.6 puffs per day.29

             

            SAMAs can be used in place of SABAs but are less effective. SAMAs will be used if SABAs are not tolerated as relief therapy. Ipratropium is a commonly used SAMA. Emily, our patient in the CE case, does not have a SAMA prescription because she receives symptom relief when using albuterol. The APPENDIX describes the different types of inhalers and points that technicians can emphasize when patients pick up refills.

             

             

            Long-acting medications include long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). LABAs are never used alone in asthma therapy but are companions to inhaled corticosteroids (ICS).22 Patients should take these medications even when asthma symptoms are not present because they are maintenance therapy. All LABA medications have a boxed warning cautioning about the potential for severe asthma exacerbations. Some severe exacerbations, when using LABA monotherapy, have led to death.22 LABAs do not have the same association with severe exacerbations and death when used in a combination with ICS. Salmeterol and formoterol are the most frequently used LABAs.22 The two LABAs differ in their time of onset. Formoterol and salmeterol have an onset of 15 minutes and 45 minutes, respectively. Patients aged 6 and older can use tiotropium as an add-on LAMA in maintenance therapy.30 Table 228,30-46 gives an overview of the current inhaled therapies available in the US to treat asthma. You will find details about Emily’s long-acting therapy in the section where SMART is explained.

             

             

            Table 2. Asthma Inhalers 28,30-46

            Class Drug Brand Dosage Forms
            ICS Beclomethasone dipropionate QVAR Redihaler MDI
            Budesonide Pulmicort Flexhaler

            Generic

            DPI

            Nebulizer

            Ciclesonide Alvesco MDI
            Fluticasone propionate Flovent HFA

            Flovent Diskus

            Arnuity Ellipta

            Armon Air Digihaler

            MDI

            DPI

            DPI

            DPI

            Mometasone Asmanex HFA

            Asmanex

            MDI

            DPI

            SABA Albuterol ProAir

            Ventolin

            Proventil

            Generic

            DPI, MDI

            MDI

            MDI

            DPI, MDI

            Levalbuterol Xopenex HFA MDI
            LABA Formoterol Perforomist Nebulizer
            Salmeterol Serevent DPI
            SAMA Ipratropium Atrovent HFA

            Generic

            MDI

            Nebulizer

            LAMA Tiotropium Spiriva Respimat DPI

             

             

             

            Many patients require multiple medications for asthma management. Clinicians prescribe combination inhalers—inhalers that have two medications—to increase efficacy, patient adherence and ease of inhaler use. Patients experience less confusion about when and how to use their inhalers when using fewer products. Clinicians can assess patient adherence and correct use of medications when a patient is on combination products. With this information, clinicians can determine if the patient needs education or an increased medication dose. Table 3 47-52 shows the many combination products on the market.

             

            Think back to our case. This patient's prescription was for budesonide/formoterol. This therapy is an ICS and LABA combined therapy. The patient previously used a fluticasone inhaler once daily and albuterol as a relief inhaler. This new therapy would give the patient only one inhaler to control her asthma, avoiding inhaler confusion.  Also, as patients cannot exactly “feel” the inhaled corticosteroid inhaler making a “difference,” but patients can always feel a change with SABA/LABA therapy—the combination inhalers help patients to experience a positive effect while taking chronic medications.

             

             

            Table 3 Combination Products 47-52

             

            Budesonide/formoterol Symbicort MDI
            Fluticasone/salmeterol Advair DPI, MDI
            Fluticasone/vilanterol Breo Ellipta DPI
            Mometasone/formoterol Dulera MDI
            Budesonide/umeclidinium/ vilanterol Trelegy Ellipta MDI

             

             

            The 2020 NHLBI Guidelines for Asthma Management list the following medications as alternatives to the preferred therapies: leukotriene receptor antagonists (LTRA), cromolyn (Intal), theophylline, and immunotherapies. The guidelines list nedocromil (Tilade) as an alternative therapy, although the FDA has discontinued this medication. 21,53

             

            LTRAs include montelukast and zafirlukast. These medications antagonize the effects of pro-inflammatory chemicals called leukotrienes. LTRAs work to decrease the inflammatory component of asthma.22 Montelukast is indicated in patients aged 1 and older, is only dosed once a day, and does not have many drug interactions.54 Montelukast use is discouraged because of side effects and limited efficacy. Montelukast’s labeling includes a boxed warning because of potential neuropsychiatric adverse events.54

             

            Cromolyn is a nebulized solution approved for asthma prophylaxis. The approval is for patients aged 2 and older. It inhibits release of histamine and leukotrienes from mast cells.55

             

            Theophylline is an oral medication rarely used as maintenance therapy for asthma.  It has many side effects and requires titration via blood tests. It is a phosphodiesterase inhibitor and adenosine antagonist. Theophylline ultimately relaxes smooth muscles in the bronchial airway.22

             

            Immunotherapies are injectable monoclonal antibodies reserved for patients with severe and treatment-resistant asthma. Currently, omalizumab (Xolair) is the only biologic approved for asthma in patients as young as 4 years old. 21 The NHLBI 2020 guideline update does not contain specific recommendations for the use of biologics. The systematic reviews the panel examined to update the guidelines did not include the use of biologics. Anti-IgE (omalizumab), anti-IL5 (mepolizumab [Nucala], reslizumab [Cinqair]), anti IL5-R (benralizumab [Fasenra]), and anti-IL4 (dupilumab [Dupixent]) are other biologic treatments for asthma. Insurers typically require prescribers to document the patient’s allergen sensitization and phenotyping before approving immunotherapies. Patients will have to try other therapies and either be unresponsive or intolerant of them before trying biologics. Specialist supervision is needed.22

             

            Step Therapy Rationale

             

            The NHLBI Guidelines recommend a stepwise approach to the treatment of asthma. The recommendation guides initial asthma treatment based on the asthma severity and subsequent therapy if symptoms persist despite changes in asthma therapy.21 Table 4 represents a combination of the stepwise therapy recommendations across all age groups in the NHLBI Guidelines.21 For simplicity, the figure only shows the preferred medication recommendations. The full step therapy recommendations can be found in the full version of the NHLBI 2020 Update to the Asthma Management Guidelines.

            Table 4. Stepwise Approach to the Preferred Treatment of the Management of Asthma 21

             

            Intermittent Asthma Management of Persistent Asthma
            Step 1 Step 2 Step 3 Step 4 Step 5 Step 6
            Individuals Ages 0-4 years
            PRN SABA

            Short daily course of ICS at the start of respiratory tract infection

            Daily low-dose ICS

             

             

             

            PRN SABA

            Daily medium-dose ICS

             

             

            PRN SABA

            Daily medium dose ICS-LABA

             

            PRN SABA

            Daily high-dose ICS-LABA

             

             

            PRN SABA

            Daily high-dose ICS-LABA + oral systemic corticosteroid

             

            PRN SABA

            Individuals Ages 5-11 years
            SABA Daily low-dose ICS

             

             

             

            PRN SABA

            Daily and PRN combination low-dose ICS-formoterol Daily and PRN combination Daily high dose ICS-LABA

             

             

            PRN SABA

            Daily high-dose ICS-LABA + oral systemic corticosteroid

             

            PRN SABA

            Individuals Ages 12+
            SABA Daily low-dose ICS and PRN SABA or PRN concomitant ICS & SABA Daily and PRN combination low-dose ICS-formoterol Daily and PRN combination medium-dose ICS-formoterol Daily high dose ICS-LABA

             

             

             

            PRN SABA

            Daily high-dose ICS-LABA + oral systemic corticosteroid

             

             

            PRN SABA

             

            In Step 1—which addressed patients with intermittent asthma—patients only use a reliever inhaler to control intermittent asthma symptoms, meaning the patients will only use an inhaler when experiencing symptoms or for pre-treatment before exercise. A clinician would initiate ICS therapy in a patient with mild asthma on Step 2.17 A patient with moderate asthma would start therapy on Step 3 or Step 4.17 A patient with severe asthma would start therapy on Step 5 or Step 6.17

             

            Once treatment has started, a clinician should reassess the patient every two to six weeks to ensure control of asthma symptoms.21 If symptoms persist and asthma is uncontrolled, this would be an appropriate time to step-up therapy. Questioning patients about how frequently they use their reliever inhalers, or how many times they forgot to take their inhaler in the past week may help guide clinicians.17 More frequent use of the SABA, including using a reliever inhaler more than two days a week, would favor stepping up therapy. Appropriate use of asthma inhalers is critical to achieving control. Adherence to the regimen and proper technique are required to determine if the patient is using the medication correctly.21 Pharmacists can play an integral role in educating patients in proper inhaler technique.

             

            Objective measures, like spirometry, can also be used to assess control. Improvements in spirometry readings indicate better control of a patient’s asthma.21 Increased healthcare utilization, like emergency room visits for an exacerbation, is another way to determine if a patient’s asthma is under control.17 An increase in patients’ healthcare utilization suggests poorly controlled asthma. Mitigating the risk of severe exacerbations is another goal of achieving good asthma control.17 Any patient on step 3 or higher should consult with an asthma specialist for treatment.21

             

            If a patient has well-controlled asthma after three consecutive months on a medication, the patient also may step down on therapy.21 A patient would always only go down one step of treatment. A clinician would schedule follow-up in the same two-to-six-week timeframe to ensure a patient still has asthma control.17 The benefit of stepping down therapy is to lower the patient’s systemic ICS and LABA dose exposure, decreasing the risk of potential adverse events.

             

             

            2020 NHLBI Asthma Management Guideline Updates

            The 2020 NHLBI Guideline update focused on six select topics: intermittent ICS (e.g. SMART), LAMAs, indoor allergen mitigation, immunotherapy in the treatment of allergic asthma, FeNO testing, and bronchial thermoplasty (BT). A major update to the guideline that is changing clinical practice is SMART.

             

            Time to be SMART

            The 2020 NHLBI Asthma Management Guidelines recommend SMART in patients with moderate persistent asthma ages 4 and older. Keeping a patient's current regimen would be appropriate if asthma symptoms are well controlled. SMART employs a single ICS+formoterol combination inhaler product dosed daily and as needed for asthma exacerbations. This is a significant change, and all pharmacy staff need to be aware of it! SMART medications are FDA-approved in patients 12 and older. SMART is recommended off label in children aged 4 through 11.

             

            Before the 2020 update, patients with moderate persistent asthma would be on Step 3 or Step 4 therapy. Therapy consisted of a daily ICS inhaler for maintenance and a SABA inhaler for relief—two separate inhalers. If a patient was uncontrolled on ICS, a physician added a LABA to the regimen. SMART potentially transitions patients from three inhalers to one inhaler. An ICS+LABA combination has never been a reliever option before; the only option was SABA. The drastic change in recommendations is why the pharmacist in the CE case, unaware of this change, was hesitant to fill the prescription. It is an extreme change in therapy and based on outdated information, and he was understandably uncomfortable.

             

            It would be reasonable to switch patients who are uncontrolled on their current regimens or have had an exacerbation in the past year.21 It is also reasonable to discuss with patients or families who want to streamline their treatment regimens or those with difficulty adhering to their current regimens. Patients with uncontrolled moderate asthma should switch to SMART on the same treatment step they are currently on before moving up. For example, Emily in the CE case was on Step 4 of the 2007 guidelines, a medium-dose ICS and a LABA.17 After being transferred to SMART, her regimen includes a medium-dose ICS-formoterol. This is Step 4 of therapy in the 2020 guidelines.

             

            Along with an ICS, formoterol, a LABA, is being used as the reliever component of the regimen. Using formoterol is entirely different than our previous approaches where SABAs and SAMAs were the reliever medications. Formoterol’s onset is two to three minutes.56 Its duration of action is up to 12 hours, creating quick and durable smooth muscle relaxation.56 Formoterol is also an ideal drug because patients can use it more than twice daily. The maximum dosage of formoterol varies by age. Each inhalation of SMART will deliver 4.5 mcg of formoterol. Patients aged 4 to 11 can use eight puffs of formoterol daily (36 mcg).21 Patients aged 12 and older can use twelve puffs of their inhaler per day (54 mcg).21

             

            The two ICS currently used in SMART inhalers are budesonide and mometasone.57 A patient using a SMART inhaler as needed will also receive the long-term anti-inflammatory effects of an ICS with each use. SMART therapy aims to provide enough long-acting preventive medicine when symptoms occur to prevent them from recurring.57

             

            This treatment will be prescribed as one to two puffs once or twice daily for maintenance with one to two puffs as needed every five to 10 minutes for asthma symptoms. Age, asthma severity, and ICS dose in the inhaler determine the dosage and frequency a clinician prescribes.21 Pharmacists should ensure the maximum puffs on a patient’s prescription do not exceed the limit for their age.

             

            SMART reduces asthma exacerbations and decreases healthcare utilization while increasing quality of life and asthma control.21 SMART therapy also decreases patients’ systemic corticosteroid use. Patients who decrease their use of oral corticosteroids and maintain lower doses of ICS reduce the risk of corticosteroid-associated adverse events.57

             

            SMART may make asthma treatment easier for patients and families. Patients appreciate this one inhaler approach with a single prescription to refill and pickup.57 Having a single inhaler decreases confusion about which inhaler is responsible for maintenance and reliever. It also ensures the patients always have the correct inhaler in their possession. SMART may be especially beneficial for patients who regularly skip their maintenance inhaler when they do not have symptoms.57 These patients rely on their reliever inhalers. With SMART, if patients only take their reliever inhaler, they still receive anti-inflammatory medication.

             

            Costs, insurance formulary considerations, and intolerance are all reasons SMART may not be appropriate for some patients.21 Patients who overuse their SABA reliever inhalers may not be good candidates for SMART. Some patients use their reliever inhalers when they are anxious or feel short of breath, even when this is not asthma related.57 These patients are at risk of receiving ICS doses that are too high. Patients who use ICS-salmeterol as their maintenance should not use it as SMART.21 Patients using both inhalers will expose themselves to higher and potentially dangerous LABA & ICS doses.

             

            Pharmacists are responsible for reminding patients to use only their maximum daily puffs and to contact a physician if their asthma symptoms require them to exceed this maximum. The pharmacist should also consider the supply a patient will need using the medication for both maintenance and relief doses. Patients may need to pick up multiple inhalers monthly for adequate supply.21

             

            Pharmacy technicians will prevent errors if they can recognize SMART. These prescriptions will contain directions for daily use and as-needed use in the same inhaler. An example prescription is budesonide/formoterol 80/4.5, inhale 2 puffs twice daily and 1-2 puffs every 4 hours as needed for asthma exacerbations (maximum 12 puffs daily). Current evidence only recommends formoterol as the LABA in SMART. Knowing this, a technician can be on the lookout for the look-alike sound-alike medication salmeterol in combination inhalers which are not safe to use for SMART. A patient on SMART therapy will likely need all other prescriptions for asthma therapy put on hold. Let’s emphasize this point: Patients with automatic refills of a SABA or other maintenance medication will be at risk of over-treatment if they continue to take their old inhalers with SMART. If a patient with a SMART prescription comes into the pharmacy, it is important for the technician to recognize this to help prevent medication errors.

             

            Pause and ponder: Who makes the ideal candidate for SMART therapy?

             

            Additional Guideline Updates

            Intermittent ICS21

            The NHLBI organized the recommendations for the use of intermittent ICS by age. This update includes SMART.

             

            The guidelines recommend that from birth to age 4, children with recurrent wheezing related to respiratory tract infections (RTI), not currently on asthma therapy and with no symptoms between infections should use a seven-to-ten-day course of daily ICS when the RTI begins.21 It recommends combining ICS with as-needed quick-relief SABA therapy. This recommendation aims to decrease exacerbations, systemic corticosteroid use, and healthcare utilization.21 Healthcare utilization declines when caregivers have clear instructions for initiating ICS.

             

            Individuals aged 4 to 12 with mild to moderate persistent asthma who are currently taking daily ICS should not increase their regular daily ICS dose for short periods.21

             

            Individuals aged 12 and older with mild persistent asthma have two preferred treatments recommended as Step 2 of therapy21: either a daily low-dose ICS and as-needed SABA or an as-needed SABA and ICS delivered concomitantly, one after the other.21 SMART therapy is the preferred treatment in patients with moderate to severe asthma in patients 4 and older.21

             

            LAMAs

            The 2020 NHLBI guideline update changed the recommendation for LAMA use in patients 12 years and older with asthma not controlled by ICS therapy. The next appropriate step is to add a LABA to ICS rather than a LAMA, unless the patient is unable to tolerate, has a contraindication, or has an adherence barrier to a LABA.21 A prescriber may still add a LAMA onto the ICS+LABA combination for improved symptom control and increased quality of life.21 A patient on ICS+LABA and LAMA will require the use of multiple inhalers.

             

            Indoor Allergen Mitigation

            Some patients have an identified allergen component of their asthma. Patients may use mitigation strategies like air purifiers, impermeable pillows, mattress covers, and HEPA filters to reduce their risk of allergen exposure.21 The 2020 NHLBI guideline update recommends patients use multiple mitigation strategies, as one strategy alone likely will not improve outcomes.21 The guideline recommends integrated pest management in patients' homes who are allergic and exposed to rodents and cockroaches.21 If an individual does not have an allergy to indoor substances, the 2020 Update does not recommend home mitigation strategies.21

             

            Immunotherapy in the Treatment of Allergic Asthma

            Immunotherapy includes subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). The 2020 NHLBI guideline update recommends SCIT as an adjunct treatment in patients with demonstrated sensitization to allergens, but not when patients are experiencing asthma symptoms or have severe asthma.21

             

            FeNO Testing

            The 2020 NHLBI guideline update recommends FeNO measurement in patients older than 4 years with an uncertain asthma diagnosis after a medical examination, complete history, and spirometry testing.21

             

            Bronchial Thermoplasty

            BT is a procedure that removes muscle tissue from the airway using heat. The benefits in this procedure are small, the risks are moderate, and long-term outcomes are uncertain.21 The 2020 NHLBI guideline update conditionally recommends against this procedure.21 Patients who may consider BT must have a risk-benefits conversation with their provider.

             

            Conclusion

            The update to the 2020 NHLBI Asthma Management Guidelines offers new guidance to clinicians treating patients with asthma. Patients need to go to the pharmacy and pick up their evidence-based treatment without unnecessary intervention—or incorrect and possibly frightening information—from the pharmacist. Pharmacists should expect to see prescriptions of ICS-formoterol written for SMART. The patient case in this CE is an avoidable situation. Staying up to date with the current guidelines is a pharmacists’ responsibility. Technicians should work with patients and pharmacists to put outdated medication prescriptions on hold to avoid further medication errors.

             

            Pharmacy Technician Sidebar: Education on DPI/ MDI/ Nebulizer

             

            Proper inhaler technique is an essential aspect of asthma control. It may seem like a silly statement, but there are different kinds of inhalers and devices. Each inhaler requires patients to use specific inhalation techniques that deliver medications effectively. Some patients may have multiple inhalers, complicating their regimen and increasing the chance for error. Understanding the different types of inhalers highlights the importance of pharmacist counseling for patients who use inhalers. Below are explanations of the differences between using, cleaning, and storing a metered-dose inhaler (MDI), a dry powder inhaler (DPI), and a nebulizer. Pharmacy technicians can point out that every inhaler has an information sheet where patients can find specific and additional instructions. Technicians should encourage patients to read them.

             

            DPI58

            The DPI contains preset doses of medications in powder form. The medicine is released into the airways with deep, fast breaths. The DPI may be easier than the MDI for patient use.  However, patients with really low lung function or small children may not be able to generate enough inspiratory flow to effectively get the medications. Patients do not need to coordinate breathing and using the inhaler with a DPI .

             

            • Instructions for use:
              • Open the cover. Hold the inhaler as shown on instructions.
              • Load a dose of medicine as shown in your instructions. Do not tip or shake the inhaler.
              • Stand or sit up straight.
              • Holding the inhaler away from your mouth, breathe out completely to empty your lungs.
              • Place the mouthpiece of the inhaler in your mouth. Close your lips around it to form a tight seal.
              • Take a fast, deep, forceful breath in through your mouth. Take as big of a breath as possible.
              • Hold your breath and count to 10.
              • Take the inhaler out of your mouth. Breathe out slowly.
              • If you need more than one puff, wait 1 minute between puffs. Repeat steps 2-8 for each puff.
              • When you finish close the cover. Store in a cool, dry place.
              • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection.
              • Some multi-dose DPI have a built-in counter to tell you how many doses are left. When the counter gets to “0,” throw it away. Arrange your refill pick-up before it gets to 0.
            • Instructions to clean the DPI
              • Wipe the mouthpiece at least once a week with a dry cloth
              • Do not use water to clean to DPI

             

            MDI59

            The MDI is a canister of medication placed into an actuator inhalation mouthpiece. Every use of the MDI delivers the correct amount of medication.

            • Instructions for use:
              • Take off the cap, shake the inhaler. Prime the inhaler (if needed)
              • If a spacer* is used, place the inhaler in the rubber ring on the end of a spacer
              • Stand or sit up straight
              • Breathe out completely to empty your lungs
              • Place the mouthpiece in your mouth and close your lips around it to form a tight seal
              • While breathing in, press down firmly on the top of the canister to release one “puff,” or dose of medication. Take as big of a breath as possible, breathing in slowly for 3-5 seconds.
              • Hold your breath and count to 10.
              • Take the mouthpiece out of your mouth. Release your breath.
              • If you need more than one puff, wait 1 minute between puffs. Repeat steps 3-8 for each puff.
              • Put the cap back on the inhaler.
              • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out.This helps prevent infection.
            • Important cleaning instructions:
              • Do not put the medicine canister in water
              • Do not brush or wipe the inside of the inhaler

            A “spacer” is a tube or chamber that adds distance between the mouth and the canister of medication. The device increases the ease of administering medication.

             

             

            Nebulizers60

            Nebulizers change liquid medication into an aerosol. Nebulizers come in both home and portable sizes. Nebulizers need a power source. They plug into a wall, have chargers, or need batteries replaced. Nebulizers take longer to use than MDI or DPI. They are also more laborious to use and store.

             

            • Instructions for use:
              • Wash hands well.
              • Put together the nebulizer machine, tubing, medicine cup, and mouthpiece or mask as shown in instructions.
              • Put the prescribed amount of medicine into the nebulizer cup.
              • Place the mouthpiece in your mouth and close your lips around it to form a tight seal. If a child wears a mask, make sure it fits in snugly around the child’s face and covers their mouth and nose.
              • Turn on the nebulizer machine. You will be able to see a light mist coming from the back of the tube or from the mask.
              • Take normal breaths through the mouth until the medicine cup is empty or the mist stops. This should take about 10 minutes.
              • Take the mouthpiece out of your mouth (or the child’s mouth) and turn off the machine.
              • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection. If a child uses a mask, wash the face as well.
            • How to clean and store:
              • After each treatment
                • Wash hands well.
                • Wash the medicine cup and mouthpiece/ mask with warm water and mild soap.
                • Do not wash tubing.
                • Rinse well and shake off excess water.
                • Air dry parts on a paper towel.
              • Once a week:
                • Disinfect nebulizer parts to help kill any germs. Use the instructions that come with your device.
                • Do not wash or boil the tubing.
                • Air dry parts on a paper towel.
              • Between uses:
                • Store nebulizer parts in a dry, clean plastic storage bag.
                • If the same machine is used by more than one person, keep each person’s medicine cup, mouthpiece or mask, and tubing in a separate, labeled bag to prevent the spread of germs and medication errors.
                • Wipe surface with a clean, damp cloth as needed.
                • Replace parts as stated in the instructions or when they appear damaged.

             

            Pharmacist Post Test (for viewing only)

            This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

             

               
              1. Which of the following Ig antibodies are responsible for the early phase of allergic asthma?
              a. IgA
              b. IgD
              c. IgE

              2. The mother of a 7-year-old patient takes him to the physician because she is concerned that he has asthma. The patient has attacks of wheezing two to three times a week when at recess or playing in the neighborhood. He sits out and cannot seem to catch his breath. The doctor suspects the patient has mild persistent asthma. When the patient is sitting in the office, he has no symptoms. But the doctor still initiates therapy according to the NHLBI guidelines. What objective measure can the doctor use to monitor his response to ICS therapy?
              a. Total IgE
              b. Spirometry
              c. X-Ray

              3. A patient presents to the pharmacy with a prescription for mometasone/formoterol (Dulera). What is the class combination used in this inhaler?
              a. ICS/LABA
              b. ICS/LAMA
              c. ICS/SABA

              4. A 16-year-old patient presents to the pharmacist complaining of side effects she thinks are related to her tiotropium (Spiriva Respimat inhaler). Her symptoms include extreme dry mouth, headache, and dizziness. The pharmacist asks how she has been using the medication. The patient responds that she uses it twice daily and sometimes when she develops symptoms during the school day. Why is the pharmacist concerned?
              a. The patient is overusing her rescue inhaler.
              b. These side effects are not related to the therapy.
              c. She is using her tiotropium inhaler incorrectly.

              5. Match the drug product with the correct mechanism of action.
              a. Albuterol/agonist of beta-adrenergic receptors in the bronchiole leading to smooth muscle relaxation
              b. Budesonide/agonist of beta-adrenergic receptors in the bronchiole. Ultimately leads to smooth muscle relaxation
              c. Ipratropium/agonist of beta-adrenergic receptors in the bronchiole. Ultimately leads to smooth muscle relaxation

              6. A 14-year-old patient presents to the physician with worsening shortness of breath and night-time awakenings. She has uncontrolled-moderate persistent asthma. She reports adherence to her medications and uses her inhalers properly. The patient is currently on a medium-dose ICS maintenance therapy and a SABA for rescue. What does the 2020 NHLBI Guideline recommend?
              a. Transitioning the patient to SMART therapy
              b. Considering bronchial thermoplasty as an option
              c. Using an FeNO test to confirm the asthma diagnosis

              7. Select the statement that correctly summarizes the 2020 NHLBI Guideline Update for using immunotherapy in the treatment of allergic asthma.
              a. All patients with documented allergic asthma should consider SCIT.
              b. SCIT is recommended as an adjunctive treatment in select patients.
              c. SCIT is recommended in all patients with severe asthma.

              8. Tom is an 8-year-old boy with moderate asthma. Tom also has type 2 diabetes and autism. He has frequent asthma exacerbations at school, requiring inhaler use. Tom presents to the doctor because he has been using his albuterol rescue inhaler multiple times during the week. His physician plans to switch his current regimen to SMART. Which of the following is an advantage the patient will have when switching to SMART?
              a. Tom will not need to have an inhaler at school to control his exacerbations
              b. SMART therapy will help lower Tom’s blood glucose, helping his diabetes
              c. Tom will only need to use one type of inhaler, simplifying administration

              9. Select the best way to describe SMART therapy.
              a. A patient uses a single inhaler made of a SABA/formoterol for asthma maintence and rescue treatment.
              b. A patient uses a single inhaler made of an ICS/formoterol for asthma maintenance and rescue treatment.
              c. A patient only needs to use a single medication for asthma once a day

              10. Lily is 14-year-old girl who has uncontrolled, moderate persistent asthma. She is currently prescribed a medium dose ICS inhaler with a SABA for rescue. When the pharmacist asks how she takes her medications, Lily admits that she forgets to take her ICS most days. In the morning when she wakes up, she doesn’t have symptoms. This leads her to using her SABA around eight times weekly when symptoms occur. Which of the following is a benefit Lily will receive switching to SMART?
              a. When Lily forgets her maintence dose, she still receives the ICS anti-inflammatory benefits when using the rescue dose
              b. Lily will save money switching to SMART
              c. Lily would not benefit from switching to SMART. It would be dangerous for her to switch because she currently overuses her SABA.

              Pharmacy Technician Post Test (for viewing only)

              This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

               

                 
                1. Select the correct symptoms associated with asthma.
                a. Sore throat, cough, burning while running
                b. Wheezing, coughing, chest tightness
                c. Difficulty breathing, sore throat, pain in chest

                2. Which of the following can trigger asthma?
                a. Smoke
                b. Light
                c. Salt Water

                3. Allie has had worsening asthma over the past 15 years. She has not been great at taking her medications and her asthma has never been controlled. Allie has chronic inflammation and hyperreactivity. Allie has structural changes in her lungs that includes the narrowing of her bronchioles. Allie has non-reversible obstruction. What is the term for Allie’s structural changes in her lungs?
                a. Allie has airway remodeling.
                b. Allie has overreactive T-cells.
                c. Allie has overgrown mast cells.

                4. Tyler is a 7-year-old boy presenting to the physician with asthma. When asked about his symptoms, Tyler says they occur every day. Because of his symptoms, Tyler cannot play outside with his friends sometimes. When asked if his symptoms keep him up at night, Tyler guesses once or twice a week, but not every night. What severity of asthma does Tyler have?
                a. Mild Persistent Asthma
                b. Moderate Persistent Asthma
                c. Severe Persistent Asthma

                5. Select the correct test that a physician could consider performing to get objective diagnostic information on cooperative patients 5 and older with asthma.
                a. Chest X-ray
                b. FeNO
                c. Spirometry

                6. A patient is coming into the pharmacy to pick up a medication for her asthma. Which medication is she picking up?
                a. Budesonide/formoterol (Symbicort)
                b. Umeclidinium (Incruse)
                c. Glycopyrrolate (Seebri NeoHaler)

                7. Which of the following represents a preferred asthma medication in the 2020 NHLBI Asthma management Guideline Update?
                a. Montelukast
                b. Theophylline
                c. Budesonide/formoterol

                8. David is a 13-year-old boy presenting to the pharmacy to pick up his new inhaler to begin SMART. Which prescription below is a recommended SMART therapy?
                a. Fluticasone/salmeterol 250/50 mcg: Inhale 2 puffs two times daily and 1-2 puffs as needed (up to 12 puffs daily).
                b. Budesonide/formoterol 80/4.5 mcg: Inhale 2 puffs two times daily and 1-2 puffs as needed (up to 12 puffs daily).
                c. Budesonide/formoterol 80/4.5 mcg: Inhale 2 puffs two times daily

                9. Select the best way to describe SMART therapy.
                a. A patient uses a single inhaler made of a SABA/formoterol for asthma maintenance and rescue treatment.
                b. A patient uses a single inhaler made of an ICS/formoterol for asthma maintenance and rescue treatment.
                c. A patient only needs to use a single medication for asthma once a day

                10. A mom presents with her son with his new prescription for budesonide/formoterol with directions you recognize as SMART. The patient has been picking up his asthma inhalers at your pharmacy for years. What is a step you can take to ensure this patient transitions safely to SMART?
                a. Confirm with the mother if the other asthma inhalers should be put on hold.
                b. Tell the family about a boxed warning in the product labeling
                c. Ask the patient if you can refill the albuterol that appears to be due for a refill.

                References

                Full List of References

                References

                   

                  1. National Heart, Lung and Blood Institute. Asthma. Updated 3 December 2020. Retrieved 9 March 2022, from https://www.nhlbi.nih.gov/health-topics/asthma
                  2. Centers for Disease Control and Prevention (CDC). Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001--2009. MMWR Morb Mortal Wkly Rep. 2011 May 06;60(17):547-52.
                  3. Sinyor B, Concepcion Perez L. Pathophysiology Of Asthma. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551579/
                  4. Chaudhry R, Bordoni B. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 31, 2021. Anatomy, Thorax, Lungs
                  5. Patwa A, Shah A. Anatomy and physiology of respiratory system relevant to anaesthesia. Indian J Anaesth. 2015 Sep;59(9):533-41.
                  6. Liu MC, Hubbard WC, Proud D, Stealey BA, Galli SJ, Kagey-Sobotka A, Bleecker ER, Lichtenstein LM. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes. Am Rev Respir Dis. 1991 Jul;144(1):51-8.
                  7. Sterk PJ, Fabbri LM, Quanjer P, Cockcroft DW, O'Byrne PM, Anderson SD, Juniper EF, Malo JL. Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur Respir J 1993;6(Suppl 16):53–83.
                  8. Grootendorst DC, Rabe KF. Mechanisms of bronchial hyperreactivity in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(2):77-87. doi:10.1513/pats.2306025
                  9. Vucević D, Radosavljević T, Mladenović D, Todorović V. Srp Arh Celok Lek. 2011;139(3-4):209-215. doi:10.2298/sarh1104209v
                  10. D'Amato, M., Molino, A., Calabrese, G., Cecchi, L., Annesi-Maesano, I., & D'Amato, G. (2018). The impact of cold on the respiratory tract and its consequences to respiratory health. Clinical and translational allergy, 8, 20. https://doi.org/10.1186/s13601-018-0208-9
                  11. Sturtevant J. NSAID-induced bronchospasm--a common and serious problem. A report from MEDSAFE, the New Zealand Medicines and Medical Devices Safety Authority. N Z Dent J. 1999;95(421):84.
                  12. Doeing DC, Solway J. Airway smooth muscle in the pathophysiology and treatment of asthma. J Appl Physiol (1985). 2013 Apr;114(7):834-43.
                  13. Lilly CM. Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol. 2005;115 suppl:S526–S531.
                  14. Sheehan, W. J., Rangsithienchai, P. A., Wood, R. A., Rivard, D., Chinratanapisit, S., Perzanowski, M. S., Chew, G. L., Seltzer, J. M., Matsui, E. C., & Phipatanakul, W. (2010). Pest and allergen exposure and abatement in inner-city asthma: a work group report of the American Academy of Allergy, Asthma & Immunology Indoor Allergy/Air Pollution Committee. The Journal of allergy and clinical immunology, 125(3), 575–581. https://doi.org/10.1016/j.jaci.2010.01.023
                  15. Indiana Department of Environmental Management. Integrated Pest Management. [Fact Sheet]. Accessed 28 March 22, https://www.in.gov/idem/files/factsheet_ipm.pdf
                  16. Kudo M, Ishigatsubo Y, Aoki I. Pathology of asthma. Front Microbiol. 2013 Sep 10;4:263.
                  17. National Institutes of Health (2007). National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (NIH Publication No. 08–5846). Available online: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm.
                  18. Irvin CG. Pulmonary function testing in asthma. UpToDate. Available at https://www.uptodate.com/contents/pulmonary-function-testing-in-asthma#H341135837. Accessed 3/9/2022.
                  19. Johnson JD, Theurer WM. A stepwise approach to the interpretation of pulmonary function tests. Am Fam Physician. 2014;89(5):359-366.
                  20. American Academy of Allergy Asthma & Immunology. Methacholine Challenge Test. Accessed 28 March 2022. https://www.aaaai.org/Tools-for-the-Public/Conditions-Library/Asthma/Methacholine-Challenge-Test
                  21. National Heart, Lung and Blood Institute (2020). 2020 Focused updates to the Asthma Management Guidelines. Clinician’s Guide. (NIH Publication No. 20-HL-8141). Washington, DC: U.S. Government Printing Office
                  22. Sharma S, Hashmi MF, Chakraborty RK. Asthma Medications. [Updated 2022 Feb 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531455/
                  23. Williams DM. Clinical Pharmacology of Corticosteroids. Respir Care. 2018;63(6):655-670. doi:10.4187/respcare.06314
                  24. Phillips K, Oborne J, Lewis S, et al. Time course of action of two inhaled corticosteroids, fluticasone propionate and budesonide. Thorax 2004;59:26-30.
                  25. Adams NP, Jones PW. The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. Respir Med. 2006;100(8):1297-1306. doi:10.1016/j.rmed.2006.04.015
                  26. Ejiofor S, Turner AM. Pharmacotherapies for COPD. Clin Med Insights Circ Respir Pulm Med. 2013;7:17-34. Published 2013 Apr 25. doi:10.4137/CCRPM.S7211
                  27. Pandya D, Puttanna A, Balagopal V. Systemic effects of inhaled corticosteroids: an overview. Open Respir Med J. 2014;8:59-65. Published 2014 Dec 31. doi:10.2174/1874306401408010059
                  28. ProAir HFA (albuterol). Package insert. Teva Respiratory, LLC; 2016.
                  29. Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes. Am J Respir Crit Care Med. 2022;205(1):17-35. doi:10.1164/rccm.202109-2205PP
                  30. Spriva Respimat (tiotropium). Package insert Boehringer Ingelheim Pharmaceuticals, Inc; 2017.
                  31. QVAR (beclomethasone dipropionate HFA). Package insert. Teva Respiratory, LLC; 2014.
                  32. Pulmicort Flexhaler (budesonide inhalation powder). Package insert. AstraZeneca; 2010.
                  33. Alvesco (ciclesonide). Package insert. Sunovion Pharmaceuticals, Inc; 2012.
                  34. Flovent HFA (Fluticasone propionate). Package insert. GlaxoSmithKline; 2010.
                  35. Flovent Diskus (fluticasone propionate inhalation powder). Package insert. GlaxoSmithKline; 2014.
                  36. Arnuity ellipta (fluticasone furoate inhalation powder). Package insert. GlaxoSmithKline; 2018.
                  37. Armonair digihaler (fluticasone propionate). Package insert. Teva Pharmaceuticals; 2020.
                  38. Asmanex HFA (mometasone furoate). Package insert. Merck & Co., Inc; 2014.
                  39. Asmanex Twisthaler (mometasone furoate). Package insert. Schering Corporation; 2018.
                  40. ProAir Respiclick (albuteral sulfate) inhalation powder. Package insert. Teva Respiratory, LLC; 2016.
                  41. Ventolin HFA (albuterol sulfate). Package insert. GlaxoSmithKline; 2014.
                  42. Proventil HFA (albuterol sulfate). Package insert. Merck & Co., Inc; 2012
                  43. Xopenex HFA (levalbuterol tartrate) inhalation aerosol. Package insert. Sunovion Pharmaceuticals Inc; 2017.
                  44. Performist (formoterol fumarate). Package Insert. Dey Pharma, L.P.; 2010
                  45. Serevent Diskus (salmeterol xinafoate inhalation powder). Package insert. GlaxoSmithKline; 2006
                  46. Atrovent HFA (ipratropium bromide). Package insert. BoehringerIngleim International GmbH; 2004.
                  47. Symbicort (budesonide and formoterol fumarate dehydrate). Package insert. AstraZenexa; 2017
                  48. Advair Diskus (Fluticasone propionate and salmeterol). Package insert. GlaxoSmithKline; 2008
                  49. Advair HFA (Fluticasone propionate and salmeterol). Package insert. GlaxoSmithKline; 2017.
                  50. Breo Ellipta (fluticasone furoate and vilanterol inhalation powder). Package insert. GlaxoSmithKline. 2019.
                  51. Dulera (mometasone furoate and formoterol fumarate dihydrate). Package insert. Merck & Co., Inc.; 2015.
                  52. Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol inhalation powder). Package insert; 2020.
                  53. Federal Drug Agency. Phase-Out of CFC Metered-Dose Inhalers Containing flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil - Questions and Answers. Available at https://www.fda.gov/drugs/information-drug-class/phase-out-cfc-metered-dose-inhalers-containing-flunisolide-triamcinolone-metaproterenol-pirbuterol-0. Accessed 3/10/22.
                  54. Singulair (Montelukast). Package insert. Merck & co., Inc; 2012
                  55. Intal (cromolyn sodium inhalation solution). Package Insert. King’s Pharmaceuticals, Inc. 2003
                  56. Anderson GP: Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. Life Sci. 1993;52(26):2145-60. doi: 10.1016/0024-3205(93)90729-m.
                  57. Fliesler N. SMART: A New approach to asthma Management. Boston Children’s Hospital. Available at: https://answers.childrenshospital.org/smart-asthma-inhaler. Accessed 12 March 2022.
                  58. U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. (Updated 2021). How to Use a Dry Powder Inhaler. (NIH Publication No. 21-HL-8164). Retrieved from: https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/how-use-dry-powder-inhaler
                  59. U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. (Updated 2021). How to Use a Dry Powder Inhaler. (NIH Publication No. 21-HL-8164). Retrieved from: https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/how-use-dry-powder-inhaler
                  60. U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. (Updated 2021). How to Use a Nebulizer. (NIH Publication No. 21-HL-8163). Retrieved from: https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/how-use-nebulizer.

                  Multiple Sclerosis: Evoking the Pharmacy Team’s Complete Potential

                  Learning Objectives

                   

                  After completing this application-based continuing education activity, pharmacists will be able to

                  ·       List the pathogenesis of MS
                  ·       Describe the first line and second line disease modifying therapies available for MS
                  ·       Personalize individualized treatment plans for the pregnant and pediatric MS patient
                  ·       Describe the pharmacist’s responsibilities for management of side effects associated with DMTs
                  ·       Explain vaccine recommendations for patients with MS

                  After completing this application-based continuing education activity, pharmacy technicians will be able to

                  ·       List MS’s primary signs and symptoms
                  ·       Point out warning signs of adverse reactions and nonadherence in patients taking DMTs for MS
                  ·       Identify patients for vaccinations

                  the letters MS on a background of multicolors

                  Release Date:

                  Release Date: May 15, 2022

                  Expiration Date: May 15, 2025

                  Course Fee

                  FREE

                  GRANT INFORMATION

                  Educational Grant Funding for this CE is provided by:

                  Bristol Meyers Squibb

                  Novartis

                  ACPE UANs

                  Pharmacist: 0009-0000-22-039-H01-P

                  Pharmacy Technician: 0009-0000-22-039-H01-T

                  Session Codes

                  Pharmacist: 22YC39-KXV62

                  Pharmacy Technician: 22YC39-XEB48

                  Accreditation Hours

                  2.0 hours of CE

                  Accreditation Statements

                  The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-039-H01-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

                   

                  Disclosure of Discussions of Off-label and Investigational Drug Use

                  The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

                  Faculty

                  Bisni Narayanan, MS, PharmD
                  Pharmacy Supervisor- Operations
                  Yale New Haven Health Systems
                  Hamden, CT

                  Faculty Disclosure

                  In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

                  Dr. Narayanan has no relationship with ineligible companies and therefore have nothing to disclose.

                   

                  ABSTRACT

                  Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Disease modifying therapies (DMTs) modify the disease’s natural course by reducing relapse and disability progression rates to improve patients’ quality of life. MS’s therapeutic landscape has changed vastly with the recent approval of several new DMTs. Similar to other autoimmune diseases, MS is more common in women than men. Women of childbearing age initiating DMTs need extensive counseling on safety during pregnancy and lactation. Pediatric MS is underdiagnosed and undertreated and coupled with exclusion of patients younger than 18 in clinical trials, therapy initiation can be complicated and delayed in pediatric patients. Pharmacists have a vital responsibility to monitor regular clinical follow up, surveillance of DMTs, and vaccine uptake in this population.

                  CONTENT

                  Content

                  Introduction

                   

                  Until the mid-19th century, people who had the vague symptom constellation now recognized as multiple sclerosis (MS) were diagnosed with “paraplegias” (progressive neurological disorders with elements of motor impairment) or nervous disorders. Until then, the disease was usually diagnosed at autopsy, where “scleroses” (indurations or hardened areas) could be seen in the brain. French physician von Frerichs was the first to identify “scleroses” in living patients, and his colleague physicians Vulpian and Charcot teased MS from the other paraplegias as a separate neurologic entity with an episodic presentation.1 It was Charcot who drew the first macroscopic and microscopic images of MS lesions (see Figure 1), and the first patient he examined was one of his maids who had dysarthria (difficulty articulating words), ataxia (loss of the ability to control body movements), and tremor, now called Charcot's triad. (He initially thought she had syphilis.) Since then, researchers have developed a remarkable knowledge base about MS, but still, we have no cure.

                  FIGURE 1

                  Anatomical drawing of lobes of the brain and MS lesions found by Charcot, one of the physicians mentioned in the article.

                   

                  MS is a chronic, inflammatory, demyelinating, and neurodegenerative central nervous system (CNS) disease. In the United States, its projected prevalence in 2020 was 0.9 million cases and globally, the case count exceeded 2.8 million.2

                  MS in general is more prevalent in northern geographic latitudes, suggesting sunlight or vitamin D may influence its development. Although the life expectancy of people with MS has increased in the past 25 years, the median age of survival for people with MS is now 76 years compared to 83 years for the matched population. The International Advisory Committee on Clinical Trials of MS has defined four basic MS disease courses3:

                  • clinically isolated syndrome (CIS)
                  • relapsing- remitting (RRMS)
                  • secondary progressive (SPMS), and
                  • primary progressive disease (PPMS)

                  Clinicians and patients further describe this disease with the modifiers “activity” and “progression.” Disease activity refers to occurrence of a relapse or new activity on MRI, and progression refers to disability accrual independent of relapse activity during the progressive MS phase. Modifiers help accurately describe the patient’s current disease process.

                  Like the patients Frerichs and Charcot saw so long ago, MS’s initial symptoms may include Charcot’s triad (dysarthria, ataxia, and tremor), fatigue, visual impairment, motor weakness, reduced mobility, sensory loss, pain, impaired genitourinary function, depression, and cognitive impairment. MS is often labeled as a “silent” or “invisible” disease. MS’s presence or impact may not be immediately apparent to others because visual and sensory symptoms are not overtly visible. Silent disease progression can also occur with disability accrual in the absence of relapse activity.

                  Symptoms generally appear in adults between 20 and 50 years of age. RRMS is the most common disease course, affecting about 85% of patients who present with MS. It is characterized by an initial phase of relapses or exacerbations of neurologic episodes followed by periods of partial or complete recovery (remissions). In the secondary phase, neurologic disability accrues progressively.2

                  Returning to the days before MS had a name, physicians tried many nonspecific and dangerous remedies—among them deadly nightshade, arsenic, mercury, and injection of malarial parasites.

                  They tried many treatments that were considered useful for neurosyphilis. This continuing education activity focuses on today’s disease modifying therapies (DMTs). DMTs modify the disease’s natural course by reducing relapse and disability progression rates or inflammation to improve quality of life.

                  Since the approval of intramuscular interferon β-1a (IFNβ-1a) 25 years ago (the first DMT), MS’s therapeutic landscape has changed considerably. Clinicians face several challenges—selecting initial therapy, managing adverse effects, and reaching patients effectively in the pandemic era—while caring for patients with MS.4 MS treatment consumes significant healthcare resources, with treatment cost correlating closely with disease progression. According to a 2019 National MS Society analysis, MS’s estimated total economic burden in the US was $85.3 billion, with direct medical costs at $63.2 billion and indirect and nonmedical costs of $22.1 billion.5

                  Patients who have MS have multiple therapeutic options, from injections to oral therapy. Despite the convenience and autonomy offered by oral therapies, its use is often associated with poor adherence. About 1 in 10 patients with MS discontinued their first oral DMT within 6 months and 1 in 5 patients with MS did so within one year.6 Nonadherence increases MS-related hospitalization, relapse rates, morbidity, mortality, and healthcare costs. Infusion-based treatments administered by physicians have higher adherence rates. An important factor in adherence is many patients’ negative perception of lifelong therapy. Pharmacists can manage side effects, prevent drug interactions, and improve treatment adherence.

                  Pathogenesis

                  MS’s exact etiology and pathogenesis remain unclear.7 Researchers have proposed environmental, genetic, and infectious agents as factors influencing immune-mediated CNS injury. Both adaptive and innate immune responses play a role in MS pathogenesis.

                  • Antigen presentation to CD4+ lymphocytes prompts activation and proliferation of pro-inflammatory T lymphocytes (Th1 and Th17) leading to a downward cascade of pro-inflammatory cytokines.
                  • Up-regulation of adhesion molecules leads to T cell migration across the blood brain barrier in the CNS.
                  • The downstream inflammatory cascade of events includes B cell activation, proliferation and migration into the CNS, and recruitment of other inflammatory cells of CD8+ T cells, B cells, monocytes, macrophages, and microglia in the CNS.

                  These immune-mediated responses cause myelin, oligodendrocyte, and axonal damage—all of which occur in an acute inflammatory lesion. Axons that survive acute attacks may die from metabolic stress, and axonal loss correlates with disability in patients. Axonal damage can be identified by pathological changes and imaging studies.7

                  DISEASE MODIFYING THERAPIES

                  DMTs suppress and modulate the immune system to modify the disease’s course. DMTs act in the relapsing phase of the MS by exerting anti-inflammatory activity to reduce relapses and accumulation of MRI lesions and stabilize and delay disability. DMTs for MS can be grouped into infusion, oral, and injectable drugs.

                   

                  PAUSE AND PONDER: If a recently-diagnosed patient with MS asked you about “first-line” therapies, what would you say?

                   

                  The American Academy of Neurology practice guideline for DMTs in adults with MS recommends8

                  • Prescribing DMT to patients with a single clinical demyelinating event and two or more brain lesions characteristic of MS after discussing DMTs’ benefits and risks with patients
                  • Offering DMTs to patients with relapsing forms of MS with recent clinical relapses or MRI activity
                  • Prescribing alemtuzumab, fingolimod, or natalizumab for people with highly active MS
                  • Directing patients on DMTs to pharmaceutical support programs
                  • Switching DMTs when one of these factors occur: sub-optimal response to therapy, medication-related adverse effects, laboratory abnormalities, inadequate adherence, or when a more appropriate therapy is available

                  In many diseases, research has clearly defined first-, second-, and third-line approaches. For example, in hypertension, prescribers usually start with a diuretic and/or an ACE inhibitor. In cancer, oncologists turn to the National Comprehensive Cancer Network guidelines for specific types of cancer. Treatment is not so clear or structured in MS with one exception: alemtuzumab is never used first. It is used only if two other agents have failed to provide adequate response. Treatment must be tailored to the patient and is influenced by the patient’s presentation and symptoms, the disease’s progression or likelihood of progression, and the patient’s insurance coverage or lack thereof. Pharmacy technicians can be extremely helpful to patients who have financial barriers and help patients find financial assistance (see the SIBEBAR).

                  SIDEBAR: Financial Burden of MS Therapies51 

                  The direct and indirect cost of managing MS is substantial. MS is the second most expensive chronic disease to manage, behind only heart failure. According to a recent study, among commercially insured patients with MS, the estimated direct healthcare cost exceeded $68,000 per year.

                  Drug therapies account for 70% of total healthcare expenditure in MS compared to national figures of 10% to 15% for other diseases. DMTs are the eighth most expensive therapeutic medication class—the national annual DMT spending in 2019 was $18.7 billion. Only 25% to 30% of people with MS are covered under the Medicare D program.

                  High and rising DMT prices translate to higher out of pocket copays, deductibles, and co-insurance for patients. This could lead to poor adherence, which in turn can lead to higher relapse rates, increased hospitalizations, and emergency room visits ultimately resulting in a vicious cycle of higher healthcare dollars. Pharmacy technicians can assist patients with MS in signing up for copay cards and applying for foundation assistance.

                  Since the Food and Drug Administration (FDA) approved the first MS drug almost two decades ago, experts have been unable to come to consensus on which treatment should be initiated first.9 Clinicians use two treatment approaches: escalation and induction therapy.

                  • The escalation approach emphasizes safety. If during prospective monitoring, a patient experiences breakthrough disease (e.g., relapses, MRI changes, or disability), then the prescriber switches the patient’s treatment to a higher efficacy agent. Clinicians employing this approach believe it spares patients potential side effects.
                  • The induction or highly effective early treatment approach rests on the theory that the ability to predict long-term MS outcomes and prospectively determine ongoing nervous system damage is limited. Hence, neurologists prescribe higher-efficacy agents early to alter the disease course, prevent irreversible disease progression, and minimize future disability.9

                   

                  Among the currently approved agents (see Table 1), monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab, and ofatumumab) and cladribine have the highest efficacy. Sphingosine-1 phosphate receptor modulators and fumarates have intermediate efficacy and teriflunomide and platform therapies have the lowest efficacy.10

                  Table 1. Currently Approved Agents for MS10

                   

                  Drug Name (Brand)
                  Recommended Dose
                  Fumarates
                  Dimethyl fumarate (Tecfidera) 120 mg PO BID for 1 week, then 240 mg PO BID
                  Diroximel fumarate (Vumerity) 231 mg PO BID for 7 days, then 462 mg PO BID
                  Monomethyl fumarate (Bafiertam) 95 mg PO BID for 7 days, then 190 mg PO BID
                  Monoclonal Antibodies
                  Alemtuzumab (Lemtrada) Year 1: 12 mg/day IV infusion on 5 consecutive days

                  Year 2: 12 mg/day IV infusion for 3 consecutive days.

                  Year 3&4- no treatment

                  Natalizumab (Tysabri) 300 mg IV infusion every 4 weeks
                  Ocrelizumab (Ocrevus) Start dose: 300 mg IV infusion, followed by 300 mg IV infusion 2 weeks later

                  Subsequent dose: 600 mg IV every 6 months

                  Ofatumumab (Kesimpta) Week 0,1 &2: 20 mg SC

                  Week 4: 20 mg per month starting at week 4

                  Platform therapies
                  Glatiramer acetate (Copaxone, Glatopa) 20 mg SC QD

                  40 mg SC TIW

                  Interferon beta-1b (Avonex) 30 mcg IM once weekly
                  Interferon beta-1b (Betaseron, Extavia) 250 mcg SC every other day
                  Interferon beta-1b (Rebif) 22-44 mcg SC TIW
                  PegINF beta-1b (Plegridy) 125 mcg SC or IM every 14 days
                  Purine analogue
                  Teriflunomide (Aubagio) 7 mg or 14 mg PO QD
                  Pyrimidine synthesis inhibitor
                  Cladribine (Mavenclad) 3.5 mg/kg of body weight divided into two yearly treatment courses. Each treatment course divided is divided into two treatment cycles of 4-5 days separated by 4 weeks
                  Sphingosine-1 phosphate receptor modulators
                  Fingolimod (Gilenya) 0.5 mg PO QD
                  Ozanimod (Zeposia) 0.23 mg PO QD on days 1-4, 0.46 mg PO QD on days 5-7, 0.92 mg PO QD on day 8 and thereafter
                  Ponesimod (Ponvory) 2 mg PO QD, titrated over 15 days to maintenance dose of 20 mg PO QD
                  Siponimod (Mayzent) 0.25 mg PO QD, titrated to 2 mg PO QD over a six-day period

                  ABBREVIATIONS: BID = twice daily; IM = intramuscular; IV = intravenous; PO = oral; QD = once daily; SC = subcutaneous; TIW = three times a week

                   

                  PAUSE AND PONDER: Can you list the generic names of the monoclonal antibodies used in MS? Can you think of good reasons to know the generic and brand names?

                   

                   

                  Platform Therapies

                  The first DMTs approved for MS were IFNβ-1a and glatiramer acetate, both injection therapies.11 Platform therapies were the mainstay of therapy until the FDA approved some oral agents. In patients with relapsing MS, the initial phase 3 trial of IFNβ-1a showed this biologic reduced relapse rates by 18% to 34% compared to placebo.11 These agents have more long-term safety data available than the newer agents. Common adverse effects include injection site reactions, myalgias, and flu-like symptoms. Glatiramer acetate can cause lipoatrophy, vasodilation, and rash in addition to injection site reactions.10

                  Monoclonal Antibodies

                  Many current therapies are monoclonal antibodies, all of which end in the suffix -mab.

                  Anti-CD20 Therapies

                  CD20 is a transmembrane ion channel protein expressed on the surface of B cells. Anti-CD20 therapies deplete circulating CD20+ B-cells through mechanisms of antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDCC), and antibody-triggered apoptosis (programmed cell death).12 Anti-CD20 treatment reduces the proliferation of pro-inflammatory cytokines CD4+ and CD8+ T cells while increasing regulatory T cells. Researchers have studied four anti-CD20 monoclonal antibodies in MS: ocrelizumab, ofatumumab, rituximab, and ublituximab. They differ in structure, binding site, immunogenicity,  degree of ADCC, and CDCC.12 Ublituximab is an investigational anti-CD20 monoclonal antibody and rituximab is commonly prescribed off-label MS treatment and will not be discussed. All monoclonal antibodies are infusion therapies (with the exception of ofatumumab which is available as prefilled syringes and autoinjector pens for subcutaneous use) with a less frequent dosing frequency compared to platform therapies.

                   

                  Ocrelizumab  

                  Ocrelizumab is intravenously administered and selectively targets and binds to the CD20 epitope on B-cells to trigger ADCC.13 Ocrelizumab is approved for the treatment of PPMS, relapsing forms of MS including CIS, RRMS, and active SPMS. Phase 3 randomized controlled trials (OPERA I and OPERA II) compared ocrelizumab’s efficacy (600 mg IV every 24 weeks) with subcutaneous IFNβ-1a (44 mcg three times weekly) for 96 weeks in patients with RRMS. In both studies, the annualized relapse rate (ARR) in ocrelizumab-treated patients decreased significantly compared to IFNβ-1a at 96 weeks. The proportion of ocrelizumab-treated patients had less confirmed disability progression than IFNβ-1a-treated patients at 12 and 24 weeks. The open-label extension phase showed that early initiation and continuous ocrelizumab treatment for up to five years was associated with a reduction of confirmed disability progression compared to switching to ocrelizumab after two years of IFNβ-1a. Patients with PPMS receiving ocrelizumab had lower 12- and 24- week confirmed disability progression compared to placebo. Post hoc analysis of the open-label extension of the phase 3 ONTARIO trial showed ocrelizumab was associated with sustained benefits on measures of disease progression over 6.5 years of follow up.13 

                  Common adverse reactions with ocrelizumab infusion include respiratory and herpes infections and infusion reactions. Clinical staff must observe patients for at least one hour post infusion.13

                  Ofatumumab

                  Ofatumumab is a humanized, IgG1 monoclonal antibody that binds to a distinct site from ocrelizumab.14 Ofatumumab exhibits marked CDCC activity with decreased ADCC. The MIRROR trial assessed the dose-response of subcutaneous ofatumumab on efficacy and safety outcomes in relapsing forms of MS. The researchers randomized patients with RRMS to subcutaneous ofatumumab 3, 30, or 60 mg every 12 weeks, subcutaneous ofatumumab 60 mg every 4 weeks for 24 weeks, or placebo followed by subcutaneous ofatumumab 3 mg at week 12. Imaging studies showed all patients in all ofatumumab groups had 65% fewer cumulative new lesions than patients who received placebo. Dose dependent B-cell depletion was observed, and complete depletion was unnecessary for robust treatment effect.14 In the phase 3 ASCLEPIOS I and II trials, subcutaneous ofatumumab was associated with lower ARR compared to teriflunomide, an oral pyrimidine synthesis inhibitor.15 Despite the advantage of subcutaneous administration, clinicians must monitor patient adherence as closely as they monitor adherence to IV administration.

                  Adverse reactions include injection site reactions, upper respiratory tract infections, and headache.

                   

                  Anti-Integrin Therapy

                  Natalizumab prevents binding of integrins at their endothelial receptors, blocking lymphocyte entry into the CNS.16 In the AFFIRM study, patients with relapsing MS received natalizumab (300 mg IV every four weeks) or placebo.16 At the one-year mark, patients in the treatment arm showed a 68% reduction in ARR compared to placebo.

                   

                  Adverse reactions include headache, fatigue, urinary tract infection, urticaria, vaginitis, depression, and diarrhea. Of note, in February 2005, the manufacturer voluntarily temporarily withdrew the drug following the death of two patients from progressive multifocal leukoencephalopathy (PML) (See SIDEBAR). Because of the risk of PML, natalizumab is now only available through a restricted REMS program called the TOUCH Prescribing Program.16 Only prescribers, pharmacies, and infusion sites enrolled in the program can prescribe, distribute, or infuse natalizumab. Patients must acknowledge the risks of treatment including PML and opportunistic infections by signing the Patient-Prescriber Enrollment Form. 

                  SIDEBAR: What is Progressive Multifocal Leukoencephalopathy?50 

                  Progressive multifocal leukoencephalopathy (PML) is a rare infection caused by the John Cunningham virus (JCV). The virus attacks and damages the myelin sheath (the material that insulates and protects the nerve cells) leading to demyelination. About 85% of the general adult population carries the JCV virus, but it is inactive in healthy individuals.

                   

                  In immunocompromised patients JCV reactivation can lead to deadly consequences. Clinical manifestations of PML can vary. Most patients experience ataxia, gait disturbance, and visual and cognitive dysfunction. There is no specific treatment for PML. The current recommendation for PML is remove the offending agent along with supportive care. Natalizumab is commonly associated with PML, followed by fingolimod, and other DMTs including dimethyl fumarate, ocrelizumab and alemtuzumab. A combination of clinical and imaging findings along with the presence of cerebrospinal JCV by PCR is used for diagnosing PML.

                  Anti-CD52

                  Alemtuzumab is directed towards the CD52 surface antigen on B- and T-lymphocytes, natural killer cells, monocytes, and macrophages.17 Alemtuzumab is indicated for the treatment of relapsing forms of MS. It is usually reserved for patients with inadequate responses to two or more previous MS drugs.

                   

                  In the CARE-MS I study, researchers randomized patients with untreated RRMS to alemtuzumab 12 mg/day intravenous (five consecutive days; 12 months later: three consecutive days) or IFNβ-1a 44 mcg subcutaneous three times a week.18 Alemtuzumab-treated patients experienced an ARR reduction of 54.9% compared to those treated with IFNβ-1a. The CARE MS II trial compared the efficacy and adverse events of alemtuzumab and IFNβ-1a in patients with RRMS who had failed first-line therapies.19 Alemtuzumab reduced the relapse rate by 49.4% compared to IFNβ-1a.

                   

                  Alemtuzumab’s adverse reactions include autoimmune diseases and infusion reactions. Clinicians must monitor patients for two hours after each infusion. Patients should receive acyclovir prophylaxis during the first two months post infusion or until CD4 lymphocytes are less than 200 cells/mcL. Patients usually need acyclovir prophylaxis for the first 24 months, as about 80% of patients may not reach CD4 counts less than 200 cells/mcL until 12 months after infusion.17

                   

                  Alemtuzumab is a restricted distribution drug and is available only via a REMS program due to risk of autoimmunity, infusion reactions, and malignancies.

                  Oral Therapies

                  Fumarates

                  Fumarates are esters or salts of fumaric acid, a compound that is found in nature, has a fruity taste, and is sometimes used as a food additive. It’s an intermediary in the cellular energy-producing cycle (Kreb’s cycle) and a product of the urea cycle. The fumarates’ exact mechanism of action in MS is unknown. Fumarates may activate the nuclear factor (erythroid-derived 2)–like 2 (Nrf2) pathway for anti-inflammatory and cytoprotective effects.20 Dimethyl fumarate, diroximel fumarate, and monomethyl fumarate are oral medications indicated for the treatment of relapsing forms of MS including CIS, RRMS, and active SPMS. Dimethyl fumarate’s common adverse effects include flushing, diarrhea, nausea, and abdominal pain. Patients generally tolerate treatment well but rare cases of PML have been recorded.

                   

                  Diroximel fumarate is a second-generation fumarate, approved in 2019 based on the bioequivalence, safety, and efficacy data for dimethyl fumarate.20 Both dimethyl fumarate and diroximel fumarate are converted into monomethyl fumarate, the pharmacologically active metabolite. In the EVOLVE-MS-2 phase 3 trial, diroximel-treated patients (462 mg PO twice a day) experienced fewer gastrointestinal (GI) side effects and lower discontinuation rates due to GI side effects compared to dimethyl fumarate (240 mg PO twice a day).21

                   

                  The FDA approved monomethyl fumarate in April 2020 for the treatment of relapsing forms of MS. In a randomized, five-week study, patients on monomethyl fumarate (190 mg PO twice a day) showed an improved GI tolerability profile compared to dimethyl fumarate treatment arm (240 mg PO twice a day).22 A distinct feature of fumarate therapy is the gender distribution of GI adverse effects. Females are more likely to experience treatment-related GI adverse effects compared to males.22

                  Teriflunomide

                   

                  Teriflunomide is a once daily oral immunomodulator approved in 2012 for the treatment of RMS, including CIS, RRMS and active SPMS.23 It reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme required for the de novo pyrimidine synthesis. Inhibition of de novo pyrimidine synthesis reduces the number of activated T and B cells available to enter the CNS. Its common adverse effects are headache, diarrhea, nausea, hair thinning, and elevated alanine aminotransferase levels (ALT).

                   

                  Since teriflunomide is an active metabolite of leflunomide, it is contraindicated in patients on current leflunomide treatment. Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis. The TEMSO and TOWER trials demonstrated teriflunomide’s clinical effectiveness. Compared to placebo, it significantly reduced relapse rates and disability progression at the dose of 14 mg daily in adults. Results from clinical trials with direct comparisons to other DMTs vary. Ofatumumab was associated with lower ARR and lower rates of disability worsening compared to teriflunomide, but similar rates of disability improvement and brain volume loss. Ponesimod (discussed in next section) was associated with lower ARR and improvement in fatigue compared with teriflunomide.23

                   

                  Sphingosine-1 Phosphate Receptor Modulators 

                  Sphingosine-1 phosphate receptors (S1PR) are expressed in multiple organs and systems.24 The S1PR axis is implicated in several immune mediated disorders. Lymphocyte cell surfaces express sphingosine-1 phosphate receptor subtype 1 (S1PR1); S1PR modulators bind to the receptor, sequestering lymphocytes within the lymph nodes and preventing their migration to the CNS.24

                   

                  Currently, the FDA has approved four S1PR1 modulators to treat MS: fingolimod, siponimod, ozanimod, and ponesimod.24 Fingolimod has a broad affinity for all S1PR subtypes, and the rest were developed with greater selectivity for the S1PR1 subtype. The second generation S1PR1 modulators have shorter half-lives, which allows rapid reversal of pharmacological effects upon discontinuation. This is beneficial when managing treatment-related complications, serious or opportunistic infections, and drug elimination during pregnancy.25

                   

                  The first dose of fingolimod acts as an agonist activating S1PR1 leading to bradycardia and heart block. Subsequent doses downregulate S1PR1 and cardiac effects resolve.26 Patients initiating fingolimod require first dose observation for at least six hours with electrocardiogram before and at the end of the observation period and pulse and blood pressure monitoring hourly. First dose observation is not required for siponimod and ozanimod in the absence of cardiac history, as patients gradually increase the dose over several days.26

                   

                  Vascular effects of S1PR modulators can produce other adverse effects.24 Prior to S1PR modulator treatment initiation, the manufacturer recommends an ophthalmologic assessment, especially for patients with a history of diabetes, macular edema, or uveitis due to risk of macular edema. CYP2C9 genetic testing is required prior to siponimod treatment initiation to determine the titration and dosing schedule. Siponimod is metabolized through the cytochrome P450 system primarily through CYP2C9 enzyme. Heterozygote individuals (who have a different version of gene from each parent) with the *3 variant of CYP2C9 enzyme exhibit slower siponimod metabolism.46 However, homozygous individuals CYP2C9 *3/*3 (same version of the gene from each parent) will have severely impaired drug metabolism. Heterozygotes will need lower dose titration and lower final dose. Siponimod is contraindicated in CYP2C9 *3/*3 genotype.

                   

                  One death occurred in a phase 3 trial of fingolimod due to disseminated varicella infection. For this reason, patients starting S1PR modulators must undergo testing for varicella zoster virus (VZV) antibodies. If they have no antibodies, the recommendation is to delay treatment until VZV vaccination is complete.24

                   

                  Cladribine

                  Cladribine is a synthetic purine nucleoside analogue that selectively depletes peripheral lymphocytes.27 It was initially developed to treat hematological malignancies. Cladribine is the first short-course DMT approved for MS. Patients take two short courses one year apart followed by 2 years of no treatment. Patients are monitored during the 2-year treatment course and for at least another 2 years of no treatment. The safety and effectiveness of restarting cladribine more than 2 years after completing therapy is unknown. Analysis from CLARITY extension study shows benefits of cladribine tablets sustained for 6 years.49

                   

                  Common adverse effects are upper respiratory tract infections, headache, and lymphopenia. Patients must be screened to exclude malignancies, infections, and pregnancy prior to initial treatment. Clinicians need to obtain a baseline MRI due to risk of PML.27

                  DMTs in Special Populations

                   

                  MS affects women of childbearing age (20 to 40 years) disproportionately and is three times more common in women than men.4 Up to 25% of women have reported planning a pregnancy within two years of diagnosis. About 30% of women with MS will deliver a child after disease onset. Female patients have higher relapse rates and inflammatory lesions than men, but male patients reach SPMS sooner than women.4 People with MS are encouraged to start treatment early to prevent long-term disability accrual. About 20 years ago, the main recommendation was to abandon treatment during pregnancy. With available treatment options, DMT is the first line treatment option for women with MS, due to its effectiveness in lowering MS severity, relapses, and progression of CNS lesions.

                  Preconception Counseling

                  Women of childbearing age with MS (WMS) need preconception counseling.24 Clinicians must consider various drugs’ half-lives and wash out periods, and potential for disease reactivation if they discontinue drugs in WMS contemplating a future pregnancy (see Figures 2 and 3).4

                  Figure 2. Safety and Efficacy of DMTs in Pregnancy28

                  A chart comparing the safety and efficacy of DMTs in MS.

                  Figure 3. Recommended DMT wash out period for pregnancy28

                   

                  Chart showing the recommended wash out period for pregnancy in months by each medication.

                  *Wash out period is the time the body takes to eliminate the administered drug. The risk from the administered drug is eliminated after the wash out period

                  The landmark Pregnancy in Multiple Sclerosis (PRIMS) study examined the effect of pregnancy and postpartum state on MS’s course along with breastfeeding and epidural analgesia.28 The study demonstrated that relapse rates decline in WMS during the third trimester but increase within three to four months postpartum, especially for patients with active preconception MS. For some women the best choice is to achieve disease control/stability with highly effective DMTs prior to conception. For WMS already on DMT, prescribers need to discuss any switch or wash out period in advance to minimize relapse risk and fetal exposure. The overall birth rate is slightly lower in WMS than the general population. This could be attributed to the birth choices by WMS. Clinicians should reassure WMS that the majority of pregnancies result in a healthy baby.28 

                   

                  PAUSE AND PONDER: What are the common adverse effects of DMTs for multiple sclerosis?

                   

                  Pregnancy and Post-Partum

                  In women with relatively mild MS, discontinuing medication during pregnancy is an acceptable risk.28 An appropriate strategy for women with more active disease is to continue the medication during pregnancy, while mitigating risk to the fetus. First-line injectable medications (IFNβ-1a and glatiramer acetate) are generally considered safe during pregnancy as these are large molecules and do not cross the placenta. If women stop medications and restart them post-partum, it may take three months to reach full efficacy. Oral DMTs are small molecules and cross the placenta.28

                  Monoclonal Antibodies

                  The transplacental transfer of IgG in the first trimester is negligible.28 Hence, monoclonal antibodies can be dosed close to conception. In the second or third trimester, the monoclonal antibody will cross the placenta, with active transport in the third trimester increasing fetal exposure.

                   

                  Natalizumab

                  Natalizumab’s biologic duration is short with dosing every four to eight weeks to prevent disease reactivation.28 Discontinuing natalizumab before or during pregnancy can cause disease reactivation and accumulation of permanent irreversible disability. Natalizumab exposure in pregnancy is associated with hematological abnormalities, low birth weight, and increased hospitalizations in the baby’s first year of life. Women with highly active MS receiving natalizumab may switch to an alternative high efficacy agent (ocrelizumab or alemtuzumab) to prevent rebound relapses. Another option is to extend the dosing interval to six to eight weeks during pregnancy with last dose no later than 34 weeks of gestation. Natalizumab should be re-dosed promptly post-partum.28

                   

                  Anti-CD20 Therapies

                  Ocrelizumab’s biannual dosing schedule is conducive to attempting a pregnancy with minimal drug exposure.28 Ocrelizumab is eliminated roughly four months after infusion. Since IgG does not cross the placenta in the first trimester, women with more active MS can attempt to become pregnant one to three months after infusion. If women are unsuccessful by nine months after dosing, another dose can be administered followed by attempts at conception. Use of anti-CD20 antibodies during pregnancy should be reserved for women with aggressive MS due to limited data.28

                   

                  Alemtuzumab

                  Alemtuzumab efficacy on inflammatory MS activity has been demonstrated to extend for more than 12 years following initial treatment.29 Conception can occur four months following treatment with subsequent doses if required delayed to sometime after pregnancy. Clinicians should stress the importance of monitoring thyroid function and complete blood count due to potential risk of unrecognized thyroid disease or thrombocytopenia to both mother and child.28

                  Treatment of Relapses during Pregnancy and Postpartum

                   

                  The first-line treatment option for relapses during pregnancy or breast feeding is short courses of high-dose methylprednisolone.28 Studies have shown a slight increased risk of adverse fetal outcomes including cleft palate and low birth weight from corticosteroid exposure. Prescribers should reserve corticosteroids for clinically significant relapses and avoid first-trimester exposure. Severe or refractory relapses can be treated with plasma exchange with associated risks of thromboembolic events.28

                  Pediatric Multiple Sclerosis

                  Pediatric multiple sclerosis (PMS; MS occurring in children younger than 18 years of age) accounts for 3% to 5% of the MS population.30 PMS has distinctive features with a differing course than that seen in adults. About 98% of PMS presents with RRMS; readers will recall that RRMS accounts for 85% of MS in adults. Children with PMS accumulate more MRI lesions, reach disability milestones at earlier ages, and have more long-term cognitive impairment than adults. Children also exhibit higher relapse rates than adults. However, after the initial period of the disease, children’s high CNS plasticity and regeneration of brain damage usually leads to complete symptom remission. Common symptoms reported in children with PMS include sensory, motor, and brainstem dysfunction. Pediatric and adult-onset diseases have common genetic and environmental risks.30

                   

                  PAUSE AND PONDER:   How does treatment of pediatric and adult MS differ?

                   

                  Treatment 

                  Traditionally, the first-line treatment in children with PMS is IFNβ-1a or glatiramer acetate due to their favorable safety profiles.31 Researchers studied IFNβ-1a’s safety and tolerability in a cohort of 43 children with mean age of 13 years and eight children younger than 10. The most common adverse effects included flu-like symptoms, abnormal liver function tests, and injection site reactions. Another large retrospective study, REPLAY, examined interferon-beta’s safety and efficacy in children, reviewing records of children aged 2 to 17. The ARR was 1.79 before treatment, and 0.47 during treatment.32

                   

                  Fingolimod is the only FDA-approved DMT for affected individuals younger than 18.33 In a randomized, double-blind trial, researchers compared fingolimod to intramuscular IFNβ-1a. They assigned patients aged 10 to 17 with RRMS to receive fingolimod 0.5 mg orally per day (0.25 mg per day for body weight 40 kg or less) or intramuscular IFNβ-1a 30 mcg per week for up to two years. The ARR was 0.12 with fingolimod compared with 0.67 with IFNβ-1a. MS relapses occurred in 88.8% of fingolimod patients versus 95.3% of IFNβ patients. Over two years, fingolimod was associated with lower relapse rates and less accumulation of lesions on MRI than IFNβ. However, the fingolimod-treated population had higher rates of adverse events (infection, leukopenia, and convulsions).33

                   

                  The majority of adult and pediatric patients have a relapsing-remitting course. Hypothetically, treatments proven effective in adults could theoretically be used in children. However, recruiting pediatric patients for clinical trials has several challenges.34 Given the low prevalence of PMS, recruitment into a clinical trial is a prolonged process. A consensus statement from the International Pediatric Multiple Sclerosis Study group mentions placebo-controlled trials of immunomodulatory agents proven effective in adult MS are inappropriate in the pediatric MS population. This reflects the ethical dilemma of enrolling children into a placebo group given the high relapse rate and more rapid accrual of new lesions in the pediatric population relative to the adult-onset disease.34

                  Vaccine Recommendations

                   

                  Clinicians should assess infectious disease history and review previous immunity to vaccine-preventable infections at the time of MS diagnosis. They should offer vaccinations as soon as possible to prevent treatment delays caused by need to complete the vaccination series. Patients with MS experiencing a relapse should delay vaccination until resolution or symptom improvement. In patients on immunosuppressive treatments, attenuated vaccines are contraindicated due to the risk of developing vaccine-transmitted disease (see Table 2).35 DMTs may also modulate the effectiveness of inactivated vaccine by lowering the immune system’s capacity to mount an effective response. However, patients with MS should receive the seasonal influenza vaccine to reduce vaccine-preventable hospitalization and mortality.35

                  Table 2. Live Vaccine Considerations for Patients with MS on DMTs27,39-47

                  Drug name Special considerations
                  Alemtuzumab Complete necessary immunizations at least 6 weeks prior to treatment. Prior to treatment, check for varicella history or vaccination. If antibody negative, consider vaccination
                  Cladribine Complete live or live attenuated vaccines within 4-6 weeks preceding treatment
                  Fingolimod Avoid the use of live attenuated vaccines during and for 2 months after treatment because of the risk of infection
                  Fumarates, platform therapies, natalizumab No special considerations
                  Ocrelizumab Complete live or live-attenuated vaccinations at least 4 weeks and non-live vaccinations at least 2 weeks prior to initiation
                  Ofatumumab Complete live or live-attenuated vaccinations at least 4 weeks and non-live vaccinations at least 2 weeks prior to initiation
                  Ozanimod Complete live vaccinations at least 1 month prior to treatment initiation. Avoid live vaccines during and for 3 months after treatment cessation. Prior to treatment, check for varicella history or vaccination. If antibody negative complete VZV vaccination, postpone ozanimod treatment for 4 weeks.
                  Ponesimod Avoid live attenuated vaccines during and for up to 1-2 weeks after treatment. Complete live attenuated vaccine at least 1 month prior to initiation. If antibody negative complete VZV vaccination, postpone ponesimod treatment for 4 weeks
                  Spinomod Avoid live attenuated vaccines during and for 4 weeks after treatment cessation. Discontinue treatment 1 week prior and until 4 weeks after a planned vaccination. Prior to treatment check for varicella history or vaccination. If antibody negative complete VZV vaccination, postpone spinomod treatment for 4 weeks

                   

                  A number of immune mediated processes are involved in mounting a defense against infection after a vaccination. Vaccination leads to a downward cascade of immune reactions, with the final step involving B-cell transformation into plasma cells and production of antigen-specific antibodies. B-cell depleting therapies are a major concern due to their direct impact on humoral response. Researchers studied the effect of B-cell depleting therapy, ocrelizumab, on vaccine responses in patients with MS.36 In patients receiving ocrelizumab, seroconversion frequency and antibody titer was reduced after the 23-valent pneumococcal polysaccharide vaccine (23-PPV). Boosting with the 13-valent conjugate pneumococcal vaccine (13-PCV) four weeks after the first dose did not enhance response to pneumococcal serotypes 13-PCV has in common with 23-PPV. Despite the blunted vaccine response with the anti-CD20 antibodies, vaccinations can be expected to be protective.36

                   

                  With the ongoing COVID-19 pandemic, appropriate immune response against the SARS-CoV-2 virus is vital especially in patients with MS receiving DMTs (see Table 3). In a recent study, patients with MS demonstrated protective response six months following PfizerBNT162b2 vaccination.37 Positive humoral IgG response was demonstrated in 9.5% of fingolimod treated patients, 22.8% of ocrelizumab treated patients, and 86.4% of alemtuzumab treated patients. All patients treated with cladribine, dimethyl fumarate, natalizumab, and teriflunomide exhibited positive humoral response which was comparable to untreated patients with MS. The Centers for Disease Control now recommends a third booster dose for the COVID-19 vaccination series. The third COVID-19 booster dose is safe in patients with MS, with no increased risk of relapse activity.38

                  Table 3. MS Society Guidelines for COVID-19 Vaccine Series48

                  Drug Class/Drug Name Guidance
                  Alemtuzumab Receive vaccine 4 weeks prior to treatment initiation. If patient is already on the infusion, vaccinate 24 weeks or more after the last dose. If patient is due for next dose, resume infusion 4 weeks or more after full vaccination of 2 doses.
                  Beta interferons, glatiramer acetate, fumarates, natalizumab, teriflunomide Can receive vaccine, no DMT adjustment required
                  Cladribine Receive vaccine 2 weeks prior to treatment initiation. Limited data exists for vaccination while on cladribine.
                  Ocrelizumab Receive vaccine 2 weeks prior to infusion. If patient is already on infusions, can complete vaccination 12 weeks or more after last ocrelizumab dose. Resume 4 weeks or more after getting fully vaccinated
                  Ofatumumab Receive vaccine 2 weeks prior to infusion. Limited data exists for vaccination while on infusion. Patients may consider getting vaccinated 4 weeks after last dose of ofatumumab. Resume 4 weeks after getting fully vaccinated
                  S1PR modulators Receive vaccine 2 weeks prior to treatment initiation. If patient is already on the medication, vaccinate as soon as possible.

                  Pharmacist Responsibilities in MS Patient Management

                   

                  Pharmacists have vital responsibilities in regular clinical follow up and surveillance with the expanding arsenal of DMTs. Patients with MS need extensive education about the possible side effects and disease management (see Table 4).49 Due to the effects on the immune system, most DMTs are associated with an increased risk of infections, typically urinary tract or upper respiratory tract infections and pneumonias. In addition, pharmacists must monitor for laboratory abnormalities, opportunistic infections, autoimmune diseases, and malignancies with DMTs (see Table 5).48

                  Table 4. Monitoring Strategies for Adverse Effect Management49

                  Drug Name Potential adverse effect Adverse effect management
                  Fumarates ·       Gastrointestinal symptoms

                  ·       Flushing

                  ·       Slow dose titration, from 120 mg twice daily to 240 mg twice daily over 4 weeks (instead of 7-day uptitration schedule)

                  ·       Administration with high-fat, high-protein, and low-starch food

                  ·       If symptoms persist, temporary dose reduction and symptomatic treatment with antacids, promethazine may be required

                  ·       Non-enteric coated aspirin up to 325 mg administered 30 minutes prior to dosing reduces the incidence or severity of flushing

                  Infusion therapies ·       Infusion associated reactions (chills, flushing, fever, nausea, hives, dyspnea, and itching) and allergic reactions ·       For alemtuzumab and ocrelizumab, appropriate premedication with corticosteroids, antihistamines, and antipyretics.

                  ·       Blood pressure monitoring is important, especially for alemtuzumab.

                  Interferon-beta and glatiramer acetate ·       Injection site reactions ·       Cold compress, premedication with NSAIDs
                  S1PR modulators (spingolimod) ·       Bradycardia, atrioventricular block ·       Monitor patients for six hours after initial dose, with pulse and blood pressure assessment hourly

                   

                  Table 5. Laboratory Monitoring for DMTs 27,39-47

                  Medication Required baseline Required monitoring Recommended additional monitoring
                  Fumarates
                  Dimethyl fumarate, Diroximel fumarate

                  Monomethyl fumarate

                  CBC with differential, LFTs CBC with differential every 6 months. Annual LFTs
                  Monoclonal Antibodies
                  Natalizumab CBC with differential, LFTs, JCV serology, brain MRI JCV serology every 3-6 months, brain MRI every 6-12 months for JCV-seronegative patients. CBC with differential, LFTs every 6 months. anti-natalizumab neutralizing antibodies at 3 months
                  Ocrelizumab CBC with differential, LFTs, hepatitis panel, serum immunoglobulins None PPD or QFT at baseline, CBC with differential, LFTs annually, and serum immunoglobulins periodically during treatment
                  Ofatumumab Hepatitis panel, serum immunoglobulins None PPD or QFT at baseline, CBC with differential, LFTs annually, and serum immunoglobulins periodically during treatment
                  Alemtuzumab CBC with differential, creatinine, thyrotropin, ALT, AST, hepatitis panel, VZV antibodies, PPD or QFT, urinalysis, baseline skin exam, ECG CBC with differential, creatinine, LFTs, and urinalysis every month until 48 months after last dose. Thyrotropin every 3 months until 48 months after last dose, annual skin exam. HIV at baseline, liver function, gynecologic exam/HPV screen annually
                  Platform therapies
                  Interferons CBC with differential, LFTs CBC with differential, LFTs every 6 months None
                  Glatiramer acetate None None CBC with differential and LFTs
                  Purine analogue
                  Cladribine CBC with differential, LFTs, PPD and QFT, VZV antibodies, HIV, hepatitis panel, cancer screening. Baseline MRI CBC with differential 2 and 6 months after initiation, if lymphocyte count <200/mcL, test monthly for 6 months. Age-appropriate cancer screening. None
                  Pyrimidine synthesis inhibitor
                  Teriflunomide CBC with differential, LFTs, PPD or QFT, blood pressure Liver function monthly for first 6 months, then every 6 months. CBC with differential every 6 months
                  Sphingosine-1 receptor modulator
                  Fingolimod CBC with differential , LFTs, ECG, VZV antibodies, fundus exam CBC with differential, LFTs every 6 months. Fundus exam 3-4 months after initiation. Skin exam
                  Siponimod CYP29 genotype, CBC with differential , VZV antibodies, LFTs, ECG, fundus exam None CBC with differential, LFTs every 6 months
                  Ozanimod CBC with differential , VZV antibodies, LFTs, ECG, fundus exam None CBC with differential and LFTs every 6 months

                  ABBREVIATIONS: JCV = John Cunningham Virus (to detect PML); LFT = Liver function test; PPD = purified protein derivative (TB test); QFT = QuantiFERON-TB Gold (TB Test); VZV = varicella zoster virus

                  CONCLUSION

                  Patients with MS need lifelong therapy with DMTs. With the available medications, patients now have the convenience of oral therapies. Prevention of relapses and disability progression are the primary treatment goals. Clinicians must tailor their treatment to individual treatment needs. Women of childbearing age need extensive counseling during the prenatal, pregnancy and post-partum phase. Treatment challenges remain with a differential disease presentation in the pediatric population. Patient education and drug monitoring are profound opportunities for pharmacists.

                   

                  Pharmacist Post Test (for viewing only)

                  This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

                   

                     
                    1. Which of the following are the three proposed immune responses that may contribute to the development of MS?
                    A. Antigen presentation to CD4+ lymphocytes, up-regulation of adhesion molecules, and a downstream inflammatory cascade of events.
                    B. Antigen presentation to CD4+ lymphocytes, up-regulation of axonal apoptosis, and an upstream inflammatory cascade of events.
                    C. Antigen presentation to CD4+ lymphocytes, up-regulation of adhesion molecules, and a downstream inflammatory cascade of events.

                    2. Researchers propose three factors influence the immune-mediated CNS injury associated with MS. What are they?
                    A. Environmental, genetic, and hormonal agents
                    B. Environmental, genetic, and infectious agents
                    C. Genetic, and infectious agents and inactivity

                    3. Among medications used for patients with MS, which of the following statements would describe alemtuzumab?
                    A. First line agent for high induction therapy
                    B. Second line after poor response to > 2 therapies
                    C. Only approved for inactive SPMS therapy

                    4. What are dimethyl fumarate’s common adverse effects?
                    A. Flushing and GI adverse effects
                    B. First-dose bradycardia and heart block
                    C. Progressive multifocal leukoencephalopathy

                    5. A patient CB calls the pharmacy and asks to speak to the pharmacist. Her pregnancy test is positive, and she has active RRMS and takes fingolimod. What should the pharmacist advise the patient?
                    A. Stop fingolimod for three months, then resume the fingolimod
                    B. Continue on fingolimod throughout the pregnancy
                    C. Inform her to call the provider’s office immediately.

                    6. The patient CB delivers a healthy baby, what would you tell her about MS in the post-partum phase?
                    A. In patients with active pre-pregnancy MS, relapse usually occurs within 4 months
                    B. In patients with active pre-pregnancy MS, relapse rates decrease in the 3 months post-partum
                    C. In patients with active pre-pregnancy MS, relapse rates are unpredictable and extreme

                    7. Which of the following is the only FDA approved agent for the treatment of pediatric MS?
                    A. Glatiramer acetate
                    B. Fingolimod
                    C. Interferon-beta

                    8. Patient AB is a newly diagnosed patient with MS. He is very anxious about his disease prognosis. His provider wants him to start ofatumumab injections. He is at the pharmacy to receive his shingles vaccine, and he tells you he plans to start the injections 7 days from vaccine administration. What should you tell him?
                    A. He can start ofatumumab treatment regardless of when he receives non-live vaccinations
                    B. He can start ofatumumab injections 7 days after vaccine administration as he planned
                    C. He must wait to start ofatumumab injections for 14 days from vaccine administration

                    9. Which of the following monoclonal antibodies has the highest risk of PML
                    A. Natalizumab
                    B. Ocrelizumab
                    C. Ofatumumab

                    10. While conducting routine follow up with a patient who takes teriflunomide, you notice she has not received her COVID booster shot. What will you tell the patient?
                    A. She has to stop teriflunomide for 2 weeks post vaccine administration
                    B. She cannot receive her booster shot while on teriflunomide
                    C. She can (and should) receive her booster shot while on teriflunomide

                    Pharmacy Technician Post Test (for viewing only)

                    This test is for viewing purposes only. If you would like to submit the test, go to the blue button at the top of the page or  Test/Evaluation Site.

                     

                       
                      1. Which of the following accurately describes “scleroses”:?
                      A. Antigen presentation to CD4+ lymphocytes, up-regulation of adhesion molecules, and a downstream inflammatory cascade of events.
                      B. indurations or hardened areas in the brain
                      C. Antigen presentation to CD4+ lymphocytes, up-regulation of adhesion molecules, and a downstream inflammatory cascade of events.

                      2. What symptoms does Charcot’s triad include?
                      A. Fatigue, visual impairment, and pain
                      B. Dysarthria, ataxia, and tremor
                      C. Motor weakness, reduced mobility, and sensory loss

                      3. Which of the following is a problem with MS as a “silent disease”?
                      A. Others often notice the signs and symptoms before the affected patient does
                      B. The disease lays dormant for many years, and then—BOOM!—it turns deadly
                      C. Progression can occur with disability accrual without relapse activity

                      4. A patient comes in to pick up her prescription and she is visibly flushed. You ask if she rushed in or has been exercising, and she says, “No, I’ve been flushed like this since I started my new MS treatment.” Which oral drug is most likely to cause this adverse reaction?
                      A. dimethyl fumarate
                      B. glatiramer acetate
                      C. ocrelizumab

                      5. A patient CB calls the pharmacy and asks to speak to the pharmacist. Her pregnancy test is positive, and she has active RRMS and takes fingolimod. It’s very busy and the pharmacist has a backlog of prescriptions. How important is this call?
                      A. Not important; take a message and tell the patient to expect a call from the pharmacist within 48 hours
                      B. Moderately important; ask the pharmacist if you can tell the patient to keep taking the fingolimod
                      C. Very important; this drug is contraindicated in pregnancy, so ask the pharmacist to take the call immediately.

                      6. A patient has been on an injectable platform biologic for MS for several years and brings a new prescription for an oral medication. Looking forward, what are the chances that she will be nonadherent in one year?
                      A. 10% (1 in 10)
                      B. 20% (1 in 5)
                      C. 80% (4 in 5)

                      7. Which of the following is the only FDA approved agent for the treatment of pediatric MS?
                      A. Glatiramer acetate
                      B. Fingolimod
                      C. Interferon-beta

                      8. Patient AB is a newly diagnosed with MS. He is very anxious about his disease prognosis. His provider wants him to start ofatumumab injections. He is at the pharmacy to receive his shingles vaccine, and he tells you he plans to start the injections 7 days from vaccine administration. What should you tell him?
                      A. He can start ofatumumab treatment regardless of when he receives non-live vaccinations
                      B. He can start ofatumumab injections 7 days after vaccine administration as he planned
                      C. He must wait to start ofatumumab injections for 14 days from vaccine administration

                      9. Which of the following monoclonal antibodies has the highest risk of PML
                      A. Natalizumab
                      B. Ocrelizumab
                      C. Ofatumumab

                      10. While conducting routine follow up with a patient who takes teriflunomide, you notice she has not received her COVID booster shot. What will you tell the patient?
                      A. She has to stop teriflunomide for 2 weeks post vaccine administration
                      B. She cannot receiver her booster shot while on teriflunomide
                      C. She can (and should) receive her booster shot while on teriflunomide

                      References

                      Full List of References

                      References

                         

                        1. Zalc B. One hundred and fifty years ago Charcot reported multiple sclerosis as a new neurological dis-ease. Brain. 2018;141(12):3482-3488.
                        2. Cohan SL, Hendin BA, Reder AT, et al. Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex). CNS Drugs. 2021;35(7):743-767
                        3. What is MS? National Multiple Sclerosis Society 2022. Accessed on April 16, 2022. What is MS? | National Multiple Sclerosis Society (nationalmssociety.org)
                        4. Villaverde-González R. Updated Perspectives on the Challenges of Managing Multiple Sclerosis During Preg-nancy. Degener Neurol Neuromuscul Dis. 2022;12:1-21. Published 2022
                        5. Bebo B, Cintina I, Yang W, et al. Economic burden of multiple sclerosis in 2019. Presented at ACTRIMS Forum 2022; February 24-26; West Palm Beach, FL and Virtual. Session CE3.1
                        6. Setayeshgar S, Kingwell E, Zhu F, et al. Persistence and adherence to the new oral disease-modifying therapies for multiple sclerosis: A population-based study. Mult Scler Relat Disord. 2019;27:364-369.
                        7. Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol. 2011;9(3):409-416.
                        8. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implemen-tation Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2019 Jan 8;92(2):112]. Neurology. 2018;90(17):777-788
                        9. Stankiewicz JM, Weiner HL. An argument for broad use of high efficacy treatments in early multiple sclero-sis. Neurol Neuroimmunol Neuroinflamm. 2019;7(1):e636. Published 2019 Nov 22.
                        10. Olek JM, Mowry E. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. In: Dashe FJ, UpToDate. UpToDate; 2020. Accessed April 12, 2022. www.uptodate.com
                        11. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet. 1998;352(9139):1491-1497.
                        12. Milo R. Therapies for multiple sclerosis targeting B cells. Croat Med J. 2019;60(2):87-98
                        13. Mancinelli CR, Rossi N, Capra R. Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology. Ther Clin Risk Manag. 2021;17:765-776. Published 2021 Jul 30.
                        14. Bar-Or A, Grove RA, Austin DJ, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study [published correction appears in Neurology. 2018 Sep 11;91(11):538]. Neurology. 2018;90(20):e1805-e1814
                        15. Gärtner J, Hauser SL, Bar-Or A, et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II [published online ahead of print, 2022 Mar 10]. Mult Scler. 2022;13524585221078825
                        16. Rudick R, Polman C, Clifford D, et al. Natalizumab: bench to bedside and beyond. JAMA Neurol. 2013;70(2):172-182.
                        17. Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Be-yond. Int J Mol Sci. 2015;16(7):16414-16439. Published 2015 Jul 20
                        18. Cohen JA, Coles AJ, Arnold DL, et al. CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 tri-al. Lancet. 2012;380(9856):1819–1828
                        19. Coles AJ, Twyman CL, Arnold DL, et al. CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 tri-al. Lancet. 2012;380(9856):1829–1839
                        20. Piehl F. Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis. J In-tern Med. 2021;289(6):771-791
                        21. Naismith RT, Wundes A, Ziemssen T, et al. Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study. CNS Drugs. 2020;34(2):185-196
                        22. Wynn D, Lategan TW, Sprague TN, Rousseau FS, Fox EJ. Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate. Mult Scler Relat Disord. 2020;45:102335
                        23. Miller AE. An updated review of teriflunomide's use in multiple sclerosis. Neurodegener Dis Manag. 2021;11(5):387-409
                        24. McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other condi-tions [published correction appears in Lancet. 2021 Sep 25;398(10306):1132]. Lancet. 2021;398(10306):1184-1194
                        25. Roy R, Alotaibi AA, Freedman MS. Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclero-sis. CNS Drugs. 2021;35(4):385-402
                        26. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuro-pharmacol. 2010;33(2):91-101
                        27. Mavenclad[package insert] Merck KGaA; 2012
                        28. Dobson R, Hellwig K. Use of disease-modifying drugs during pregnancy and breastfeeding. Curr Opin Neurol. 2021;34(3):303-311
                        29. Steingo B, Al Malik Y, Bass AD, et al. Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223. J Neurol 2020; 267:3343–3353.
                        30. Brola W, Steinborn B. Pediatric multiple sclerosis - current status of epidemiology, diagnosis and treat-ment. Neurol Neurochir Pol. 2020;54(6):508-517.
                        31.Banwell B, Reder AT, Krupp L, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclero-sis. Neurology. 2006;66(4):472-476.
                        32. Tenembaum SN, Banwell B, Pohl D, et al. Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study. J Child Neurol. 2013;28(7):849-856.
                        33. Chitnis T, Arnold DL, Banwell B, et al. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018;379(11):1017-1027
                        34. Waubant E, Banwell B, Wassmer E, et al. Clinical trials of disease-modifying agents in pediatric MS: Oppor-tunities, challenges, and recommendations from the IPMSSG [published correction appears in Neurology. 2019 Oct 1;93(14):647]. Neurology. 2019;92(22):e2538-e2549.
                        35.Otero-Romero S, Ascherio A, Lebrun-Frénay C. Vaccinations in multiple sclerosis patients receiving disease-modifying drugs. Curr Opin Neurol. 2021;34(3):322-328.
                        36. Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology. 2020;95(14):e1999-e2008
                        37. Achiron A, Mandel M, Dreyer-Alster S, et al. Humoral immune response in multiple sclerosis patients follow-ing PfizerBNT162b2 COVID19 vaccination: Up to 6 months cross-sectional study. J Neuroimmunol. 2021;361:577746
                        38. Dreyer-Alster S, Menascu S, Mandel M, et al. COVID-19 vaccination in patients with multiple sclerosis: Safe-ty and humoral efficacy of the third booster dose. J Neurol Sci. 2022;434:120155.
                        39.Adakveo [package insert]. Novartis Pharmaceuticals Corporation;2019
                        40. Ocrevus[package insert]. Genentech Inc;2017
                        41. Kesimpta[package insert]. Novartis Pharmaceuticals Corporation; 2020
                        42. Lemtrada[package insert]. Genzyme Corporation; 2017
                        43. Gilenya[package insert]. Novartis Pharmaceuticals Corporation; 2012
                        44. Zeposia[package insert]. Celgene Corporation; 2020
                        45. Ponvory[package insert] Janssen Pharmaceutical Companies; 2021
                        46. Mayzent[package insert] Novartis Pharmaceuticals Corporation;2019
                        47. Ponvory [package insert] Janssen Pharmaceuticals Inc; 2021
                        47. COVID-19 VACCINE GUIDANCE FOR PEOPLE LIVING WITH MS. National Multiple Sclerosis Society. 2022. Accessed on April 16, 2022. COVID-19 Vaccine Guidance for People Living with MS | National MS Society | National Multiple Sclerosis Society.
                        48. Moiola L, Rommer PS, Zettl UK. Prevention and management of adverse effects of disease modifying treat-ments in multiple sclerosis. Curr Opin Neurol. 2020;33(3):286-294.
                        49. Fyfe I. More CLARITY on long-term benefits of cladribine. Nat Rev Neurol. 2021;17(12):726.
                        50. Sriwastava S, Kataria S, Srivastava S, et al. Disease-modifying therapies and progressive multifocal leu-koencephalopathy in multiple sclerosis: A systematic review and meta-analysis. J Neuroimmunol. 2021;360:577721.
                        51. Hartung DM. Economics of Multiple Sclerosis Disease-Modifying Therapies in the USA. Curr Neurol Neuro-sci Rep. 2021;21(7):28

                        Cannabidiol: When is Similar Different?

                        Learning Objectives

                         

                        After completing this application-based continuing education activity, pharmacists will be able to

                        ·       Discuss cannabidiol and its known pharmacologic profile
                        ·       Identify FDA-approved indications for prescription cannabidiol and other indications in which research is promising
                        ·       Distinguish the FDA-approved cannabidiol from various nonprescription products in terms of quality and risk/benefit profile
                        ·       Maximize the pharmacist’s role in helping patients who are good candidates for prescription cannabidiol or use nonprescription cannabidiol products either with or without other prescription drug therapies.

                        After completing this application-based continuing education activity, pharmacy technicians will be able to

                        ·       Discuss the basic facts about cannabidiol products
                        ·       Acquire reputable sources for patients who have an interest in cannabidiol to find information
                        ·       Distinguish between nonprescription and prescription cannabidiols
                        ·       Infer when to refer patients to the pharmacist for recommendations or referral

                        Multicolored pastel photo of marijuana leaves

                        Release Date:

                        Release Date: June 15, 2022

                        Expiration Date: June 15, 2025

                        Course Fee

                        FREE

                        An Educational Grant has been provided by:

                        Jazz Pharmaceuticals

                        ACPE UANs

                        Pharmacist: 0009-0000-22-043-H01-P

                        Pharmacy Technician: 0009-0000-22-043-H01-T

                        Session Codes

                        Pharmacist: 22YC43-XYZ92

                        Pharmacy Technician: 22YC43-CBA84

                        Accreditation Hours

                        2.0 hours of CE

                        Accreditation Statements

                        The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-043-H01-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

                         

                        Disclosure of Discussions of Off-label and Investigational Drug Use

                        The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

                        Faculty

                        C. Michael White, Pharm.D., FCP, FCCP
                        Professor and Chair, Pharmacy Practice
                        University of Connecticut School of Pharmacy
                        Storrs, CT

                        Faculty Disclosure

                        In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

                        Dr. White has no relationship with ineligible companies and therefore has nothing to disclose.

                         

                        ABSTRACT

                        The U.S. Food and Drug Administration (FDA) approved a highly purified cannabidiol (CBD) product called Epidiolex (hereafter referred to as CBD-Rx) for the treatment of seizure disorders in Dravet and Lennox-Gastaut syndromes and for patients with tuberous sclerosis complex (an indication that was FDA-approved in August 2020). Patients with epilepsy are sensitive to small changes in antiepileptic drug concentrations. Due to CBD products’ tendency to deviate from the dose on the label with the dose actually delivered, the medical evidence highly discourages use of non-FDA-approved CBD products in people with epilepsy. CBD is well tolerated but like all drugs, poses risks to the consumer. CBD has benefits, adverse events, and drug interactions that the pharmacy team must assess; careful counseling is critical for optimal use. While the lay press and various sites on the Internet tout CBD to treat or alleviate many ailments, the evidence for benefit is limited. The pharmacy team, with their high accessibility and deep respect in the community, should be an unbiased information source on the possible benefits and risks of CBD for various ailments.

                        CONTENT

                        Content

                        Introduction

                        Sales of Epidiolex, the prescription oral solution version of cannabadiol (CBD) and known hereafter as CBD-Rx, grew from $296 million in 2019 to $464 million by the end of 2021 in the U.S.1,2 Nonprescription CBD products, hereafter known simply as CBD, also grew from $0.8 billion in 2018 to $1.6 by the end of 2021.3 Continuing robust sales growth is expected for both CBD-Rx and CBD through at least the year 2025.3 Both types of CBD products took very different legal routes from a Drug Enforcement Agency (DEA) Schedule I designation to allowing legal sales in the U.S. These legal differences yield important clinical differences. What are prescription and nonprescription CBD products’ similarities and differences? How should they impact the pharmacy team’s advice to health professionals and consumers?

                         

                        This continuing education activity will help pharmacists and pharmacy technicians understand the different legal frameworks for CBD-Rx and other CBD products while elucidating the patient care implications. It will explore the evidence supporting the benefits and safety of CBD-Rx and CBD products in important diseases from seizures and anxiety to sleep disorders and pain, inflammation and other diseases. To start, the SIDEBAR dispels some common myths.

                         

                        SIDEBAR: Common Misperceptions

                        • Myth: CBD has all medical cannabis’s beneficial effects except the tetrahydrocannabinol high.

                        Reality: CBD provides one of cannabis’ many constituents only. No one should assume it will work the same as medical cannabis. Before people can treat medical disorders with CBD confidently, researchers must prove it’s effective and safe for each indication.

                        • Myth: CBD has been proven effective for many diseases and disorders.

                        Reality: CBD has been proven effective for seizure control in Lennox-Gestaut and Dravet syndromes and tuberous sclerosis complex, but there is insufficient human efficacy data for other uses. Although promising for patients with stage fright, schizophrenia, pain, inflammation, and Parkinson’s disease, much more research needs to be done before the balance of benefits to harm is known.

                        • Myth: CBD has no adverse effects or drug interactions.

                        Reality: In clearly defined and controlled doses, CBD is generally safe and well tolerated. But CBD has potential to cause adverse events, including severe adverse events. It also has many potentially serious drug interactions requiring oversight from a trained health professional for safe use.

                        • Myth: All CBD products are the same.

                        Reality: Nonprescription CBD products (which are not FDA-approved) could be adulterated or contaminated and have CBD concentrations that frequently differ from the dose listed on the label. These variations can change the benefits to harm balance.

                        • Myth: All CBD products are now legal to sell, possess, and use in the United States.

                        Reality: CBD products that intentionally or inadvertently contain more than 0.3% THC are illegal according to federal law, but some states have legalized recreational marijuana and do not prosecute. However, transporting any product with more than 0.3% THC over state lines remains illegal. If patients use non-FDA-approved CBD forms and don’t have test results confirming an acceptable THC level, they could be in legal jeopardy.

                         

                        Legal Status of CBD-Rx and Unapproved CBD Products

                        Epidiolex (CBD-Rx) was Food and Drug Administration (FDA)-approved in 2018 and remains the only approved form of CBD. It is indicated for the treatment of seizures associated with Lennox-Gastaut and Dravet syndromes or tuberous sclerosis complex in patients 1 year of age and older. It consistently delivers 100 mg/mL of CBD to patients with THC concentrations below 0.1%. The DEA placed CBD-Rx in Schedule V (drugs with a relatively low risk of abuse).4,5

                         

                        Health professionals and consumers see CBD products in beer, oil, coffee, creams and ointments, gummies, lip balm, and seltzer on store shelves across the country. These CBD products are not FDA approved—they are over the counter products and do not meet the definition of dietary supplements either. As stipulated in the 2018 U.S. Farm Bill, the Department of Agriculture regulates some hemp-derived CBD products that have THC concentrations of less than 0.3%, and are not DEA Schedule I (high risk of abuse or harm, limited or no medicinal value, illegal to possess).6 Manufacturers of these CBD products can sell them to consumers if they made no health claims that would place their products under the FDA’s jurisdiction. If CBD products have a THC concentration at or exceeding 0.3%, whether known to the proprietor or consumer, they are considered marijuana-derived CBD, classified as DEA Schedule I, and illegal to sell or possess according to federal law.6

                         

                        Comparing Products: Quality and Purity Differences, Dosage Fluctuations

                        The CBD-Rx product provides the CBD concentration specified on the label with little variation over time. That is, patients can trust that the product contains and delivers the labeled dose, and people who take the same dose consistently will have predictable blood levels. However, this may not occur with non-FDA-approved CBD products. In 2016, investigators purchased 84 non-FDA-approved CBD products from 31 different Internet-based companies. A commercial laboratory tested them in triplicate using high-performance liquid chromatography (HPLC; an analytical chemistry technique used to separate, identify, and quantify each component in a mixture).7 The laboratory averaged and reported triplicate test results by product weight. If the average detected concentration was 90% to 110% of the labeled value, it was considered accurately labeled. With respect to CBD, manufacturers had labeled only 31% of products correctly, with most products under-labeled. The frequency of accurate labeling for CBD vaporization liquids, tinctures, and oils was 12.5%, 25%, and 45%, respectively. Products contained unlabeled THC at a mean concentration of 0.45 mg/mL (range 0 to 6.4) in 21% of samples, which would place people selling, possessing, or using these products at risk of arrest and prosecution.7 People have failed THC drug tests despite reporting use of CBD products only.8,9

                         

                        These quality issues persist. In 2020 the FDA assessed 102 products that indicated a specific amount of CBD.10 Only 45% of products had dosages within 20% of that specified on the label with 18% having less than 80% of the specified amount; 37% had more than 120% of the amount of CBD indicated on the label. Additionally, 49% of products tested positive for tetrahydrocannabinol (THC, cannabis’s principal psychoactive constituent and one of at least 113 cannabinoids [CB] in the plant). The U.S. is not the only country with concerns.

                         

                        In the Netherlands, for example, a laboratory assessed eight CBD products. Four were labeled correctly (less than 10% variability), two had 18% or 35% higher concentrations, and two had 74% or 98% lower CBD concentrations than the label stated, respectively.10 ConsumerLabs is a third-party laboratory that differs from most labs. Instead of being paid to do their analysis by product manufacturers, it conducts its testing without the manufacturers consent and then charges consumers to see the results. They assessed multiple CBD products for CBD content and found the labeled CBD dosages had little correlation with the products’ actual CBD concentrations.11 It is simply impossible to know the exact CBD dose patients take if they buy products that are not FDA approved or independently tested by outside laboratories.

                         

                        Inaccurately labeled CBD concentration or variability in CBD concentrations create potentially dangerous implications.12 For example, in a systematic review of non-CBD antiepileptic drugs, the University of Connecticut Evidence-Based Practice Center found that small changes in drug concentration impacted seizure control. While brand and generic antiepileptic drugs were equally effective when started de novo, risk of emergency medical services or hospitalization increased when patients switched from a brand to a generic or vice versa.12 This suggests that for seizure control, using CBD products with differing CBD content or products in which CBD concentrations vary over time could harm patients. This is especially risky since the FDA-approved indications for CBD-Rx include use in children as young as 1 year old.

                         

                        Adulteration and Contamination

                        Adulteration and contamination pose additional risks to patients using non-FDA-approved CBD products. In 2017, five patients in Utah who used CBD reported adverse events (e.g., seizures, confusion, unconsciousness, and hallucinations).13 An in-depth investigation found that a CBD product included a synthetic CB. From 2017 to May 2018, the specific product’s contamination harmed 52 people in that region.13

                         

                        The International Cannabis and Cannabinoid Institute in the Czech Republic assessed 29 CBD products and found 69% of them exceeded recommended levels of polycyclic aromatic hydrocarbons. The International Agency for Research on Cancer classifies polycyclic aromatic hydrocarbons as class IIa carcinogens and genotoxic mutagens.10,14

                         

                        Additionally, pesticide or heavy metal contamination in unregulated CBD products is possible.10 The Florida Department of Agriculture and Consumer Services tested a random sample of a CBD product and found lead levels at 4.7 ppm. When informed, the manufacturer conducted an internal investigation and instituted a recall of one batch of their product.15 Another assessment of CBD oil and hemp oil products found detectable levels of arsenic, cadmium, and lead. A large assessment of 240 CBD products was conducted by Ellipse Analytics, an independent laboratory.16 It found that 70% of CBD products tested positive for heavy metals like lead and arsenic, concentrated chemical pesticides, or toxic mold.17 Without independent third-party laboratory testing, there is no way to know if any product is adulterated or contaminated. See the Tech Talk SIDEBAR for some product verification tips and tricks.

                         

                        CBD Alone or CBD + Other Cannabis Constituents

                        CBD isolate products, including CBD-Rx, contain virtually no cannabinoids, terpenes, or other compounds in cannabis sativa except for CBD. In contrast, broad or full-spectrum CBD contains the cannabis plant’s naturally available compounds and differ only in the amount of THC. Broad-spectrum products have very low THC concentrations, while hemp-based full-spectrum products contain between 0.1% and 0.29% THC.17 Other constituents in the cannabis sativa plant may accentuate or attenuate the effects of CBD alone through the “entourage effect.” For each disease or disorder, researchers need to determine whether broader administration of the other cannabis sativa constituents impacts efficacy or safety.

                         

                        Pharmacokinetic Profile Comparison of CBD-Rx and Unapproved CBD Products

                        The CBD-Rx product demonstrates a less than dose-proportional increase in concentration over the range of 5 to 20 mg/kg/day doses in patients. At steady state, the time to maximal concentration (Tmax) is 2.5 to 5 hours, the volume of distribution is high at 20963 to 42849 liters (showing very high penetration into fat and other body tissues like the brain), and the elimination half-life is long at 56 to 61 hours. High fat/high calorie meals dramatically increase the maximum concentration (Cmax) and the area under the curve (AUC) by 5- and 4-fold, respectively, but the prescribing information does not address timing with food.17 However, the labeling recommends taking CBD-Rx consistently with regards to food. Following a single CBD 1500 mg dose (1.1 times the maximum recommended daily dosage), plasma clearance is 1111 L/hour.4

                         

                        Unapproved CBD products lack similar pharmacokinetic data and could differ from that of the CBD-Rx product as the formulation changes. For instance, topical application of one CBD product may penetrate the skin and enter the bloodstream very differently than another. Additionally, edible products with CBD might not be absorbed as readily as other oral delivery methods, and vaporized CBD could have faster onsets of action.

                         

                        CBD, when given as the CBD-Rx product or not, has many potential drug interactions as a substrate and as an inhibitor and inducer of metabolic enzymes. CBD is primarily metabolized by hepatic cytochrome P450 (CYP2C19 and CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT1A7, UGT1A9, and UGT2B7).4 Researchers have explored the impact of CYP3A4 and CYP2C19 inducers and inhibitors on CBD for a combined CBD/THC product.20 The Cmax and AUC decreased 52% and 59% with concomitant rifampin (CYP enzyme inducer), increased 89% and 165% with concomitant ketoconazole (CYP3A4 inhibitor), and was unchanged with omeprazole (CYP2C19 inhibitor).20

                         

                        CBD’s main metabolite is 7-OH-CBD which subsequently converts into the 7-COOH-CBD metabolite, both of which may have anticonvulsant properties. After repeat dosing, the 7-OH-CBD and 7-COOH-CBD metabolites’ AUCs are 38% lower and 40-fold higher respectively than CBD’s AUC.4,21 Protein binding of CBD and its metabolites was found to be 94% in vitro.4

                         

                        CBD inactivates some CYP enzymes in the short term but like other anticonvulsants, induces them with chronic dosing.21 Upregulation of CYP3A4 and CYP2B10 mRNA have occurred in mice and induction of CYP1A1 occurred in vivo.21 In contrast, CBD seems to inhibit UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19 metabolism.4

                         

                        To test CBD’s enzyme inhibition and induction effects, researchers assessed CBD-Rx’s impact on clobazam and its N‐desmethylclobazam metabolite in 13 subjects (age range 4 to 19 years) with refractory epilepsy. The mean increase in clobazam and N-desmethylclobazam levels was 60% and 500% after four weeks of concomitant therapy. CBD-Rx was determined to be a CYP2C19 inhibitor.22 The prescribing information suggests clinicians consider reducing the dose of sensitive CYP2C19 substrates such as diazepam and clobazam, as clinically appropriate, when coadministered with CBD-Rx.4

                         

                        Taken together, the pharmacokinetic and drug interaction data suggests a strong risk of drug interactions with many CYP and UGT substrates (especially CYP2C19 substrates), CYP inducers, and CYP 3A4 inhibitors.4,21 Much more research is needed to determine how to manage patients—especially those with refractory seizures—who take multiple drugs that impact the CYP enzyme system. The potential for multiple drug interactions makes patient CBD use without input from a health care professional risky.

                         

                        PAUSE AND PONDER: How can the pharmacist proactively ensure that CBD products are not interacting with a patient’s prescribed therapy if patients purchase CBD products from a smoke shop or over the Internet?

                         

                        CBD-Rx’s Efficacy in Refractory Rare Seizure Disorders

                        Five major randomized trials were instrumental to the FDA’s decision to approve CBD-Rx, involving patients with rare seizure disorders – for more information about these conditions, see the SIDEBAR.

                         

                        SIDEBAR: What are Lennox-Gestaut and Dravet Syndromes and Tuberous Sclerosis Complex? 23-25

                        Lennox-Gestaut syndrome affects roughly one in 3,800 people, making it rare. Its many different causes include inflammation of the brain or brain covering, brain malformations, decreased blood and oxygen to the brain, injuries to the brain’s frontal lobes that create a constellation of childhood epilepsy disorders. In 25% of cases, clinicians can’t find a cause. On electroencephalogram when the person is awake, patients with Lennox-Gestaut syndrome have similar presentations characterized by slow spike and wave epileptiform activity. Multiple seizure types can occur (tonic, atonic or drop attacks, atypical absence, myoclonic, and generalized tonic-clonic) and Lennox-Gestaut syndrome is associated with cognitive impairment. Although rare, Lennox-Gestaut syndrome comprises 10% of children with epilepsy appearing before 5 years of age.

                        Dravet syndrome is a rare genetic defect (affecting 1 in 20,000 to 40,000 children) arising from new genetic polymorphisms rather than genetic heritage. It usually begins in the first year of life in an otherwise healthy infant and causes seizures throughout life. Infants have normal development when the seizures begin but as seizures continue, most children develop some level of developmental disability.

                        Tuberous sclerosis complex, also a rare genetic disorder, affects 1 in 6,000 children. Mutations in the tuberous sclerosis complex 1 or 2 gene cause benign tumors in different parts (e.g., brain, skin, lung, kidney, heart, and eye). When the tumors impinge on the brain, seizures can result. Tumors in other organs can cause respiratory, kidney, heart, or vision disorders.

                         

                        In the first study, researchers randomized 120 children and young adults with Dravet syndrome and drug-resistant seizures to receive adjunctive CBD-Rx oral solution (20 mg/kg CBD per day) or placebo.26 The median frequency of convulsive seizures per month decreased from 12 to six with CBD-Rx versus a decrease from 15 to 14 with placebo (p = 0.01). The CBD-Rx patients’ overall condition improved by at least one category on the 7-category Caregiver Global Impression of Change scale (62% versus 34%, p = 0.02) with CBD-Rx versus placebo. The trends toward at least a 50% reduction in seizure frequency (43% versus 27%, p = 0.08) and being entirely seizure free (5% versus 0%, p = 0.08) with CBD-Rx versus placebo were strong.26

                         

                        Adverse events occurred more frequently in the CBD-Rx group than in the placebo group including somnolence (36% versus 10%), diarrhea (31% versus 10%), fatigue (20% versus 3%), vomiting (15% versus 5%), pyrexia (15% versus 8%), and lethargy (13% versus 5%).26 A drug interaction between CBD and clobazam likely accentuated the somnolence since 18 of the 22 sleepy patients in the CBD-Rx group took both drugs. More patients had increased aminotransferase levels with CBD than placebo (12 versus 1) and more patients in the CBD-Rx group withdrew from the trial (8 versus 1).26

                         

                        Since the FDA approved CBD-Rx, a randomized, double-blind, placebo-controlled trial of 199 patients compared CBD-Rx 10 mg/kg/day and 20 mg/kg/day to placebo.27 Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least four convulsive seizures during the 4-week baseline period while receiving at least one antiepileptic drug. The percentage reduction compared to placebo was 29.8% (p = 0.01) for CBD-Rx-10 group and 25.7% (p = 0.03) for the CBD-Rx-20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD-Rx-20 group discontinued treatment owing to adverse events but no patients in other groups discontinued treatment. Three patients in the CBD-Rx-10 and 13 in the CBD-Rx-20 groups experienced elevated liver transaminase levels, with all affected patients on concomitant valproate sodium. Overall, this trial found similar efficacy and better potential safety with a lower initial CBD dosage.27

                         

                        A multicenter, double-blind, placebo-controlled trial conducted in patients with Lennox-Gastaut syndrome enrolled 225 patients (aged 2 to 55 years) who were resistant to other therapy and experienced two or more seizures per week.28 Researchers randomized them to receive CBD-Rx oral solution at a dose of either 10 mg/kg CBD twice daily (high dose CBD), 5 mg/kg twice daily (low dose CBD), or matching placebo for 14 weeks. The median percent reduction from baseline in drop-seizure frequency with CBD-Rx was 41.9% in the CBD-Rx-10 group (p = 0.005) and 37.2% in the CBD-Rx-5 group (p = 0.002) compared with 17.2% in the placebo group. Most common CBD-Rx-related adverse events (occurring more frequently in the higher-dose group) were somnolence, decreased appetite, and diarrhea. Six patients in the high-dose CBD group and one patient in the low-dose CBD group discontinued therapy because of adverse events. Fourteen patients who received CBD (9%) had elevated liver aminotransferase concentrations.28

                         

                        In a second randomized, double-blind, placebo-controlled trial in patients (N = 171) with treatment-resistant Lennox-Gastaut syndrome, researchers investigated CBD-Rx’s efficacy as add-on therapy.29 Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, at least two drop seizures per week during the 4-week baseline period and had not responded to treatment with at least two antiepileptic drugs. Patients randomly received CBD-Rx 20 mg/kg/day or matched placebo for 14 weeks.29

                         

                        The median percentage reduction in seizure frequency from baseline was 43.9% (IQR -69.6 to -1.9) in the CBD-Rx group and 21.8% (IQR -45.7 to 1.7) in the placebo group for an estimated median difference between the groups of -17.21 (95% CI -30.32 to -4.09; p=0.0135) over 14 weeks.29 Adverse events occurred in 86% of patients (n = 86) in the cannabidiol group and 69% of patients in the placebo group (n = 85). The most common treatment-related adverse events were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Fourteen percent of patients in the cannabidiol group and 1% of patients in the placebo group withdrew because of adverse events.29

                         

                        In a recent randomized, double-blind, placebo-controlled trial of 224 patients with tuberous sclerosis complex, researchers compared the efficacy and safety of CBD-Rx oral solution (CBD-Rx-25: 25-mg/kg/day and CBD-Rx 50: 50-mg/kg/day) to placebo over 16 weeks.30 Eligible patients were aged 1 to 65 years with medication-resistant epilepsy and had experienced at least 8 seizures during the 4-week baseline period. The percentage of seizure reduction versus placebo was 30.1% (p < 0.001) for the CBD-Rx-25 group and 28.5% (p = 0.002) for the CBD-Rx-50 group. The most common adverse events were diarrhea (25%, 31%, and 56%) and somnolence (9%, 13%, and 26%) in the placebo, CBD-Rx-25 and CBD-Rx-50 groups, respectively. Two, 8, and 10 patients in the placebo, CBD-Rx-25, and CBD-Rx-50 groups discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels compared to none taking placebo.30

                         

                        Since CBD-Rx is an effective anti-convulsant therapy, the FDA is concerned that it might cause suicidal ideation.4 Currently, long-term data is insufficient, or study populations have been too small to fully assess for suicidal ideation or suicides.4 The literature and the FDA have not reported suicide or suicidal ideation associated specifically with the use of CBD-Rx. Counseling patients and/or their parents/caregivers on the risk of suicidal ideation so they can seek early intervention if problems arise is critical.

                         

                        Properly Using CBD-Rx in Seizure Disorders

                        The recommended starting dosage of CBD-Rx for Lennox-Gastaut or Dravet Syndrome is 2.5 mg/kg twice daily (5 mg/kg/day).4 After one week, the dosage can be increased to the usual maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day). If the individual clinical response is insufficient and tolerated, CBD-Rx can be increased in 2.5mg/kg increments each week up to a maximum maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day).4

                         

                        The recommended starting dosage for tuberous sclerosis complex is 2.5 mg/kg twice daily (5 mg/kg/day).4 Prescribers can increase the dose weekly by 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated, to a usual maintenance dosage of 12.5 mg/kg twice daily (25 mg/kg/day).4

                         

                        Using the highest recommended maintenance dose of 10 mg/kg twice daily or 12.5mg/kg twice daily can provide better seizure protection but increases the severity of adverse effects, including the risk of liver damage.4 Food may affect CBD-Rx levels, so consistent dosing with respect to meals is recommended to reduce variability in response. That means if a patient chooses to take (or a caregiver administers) CBD-Rx  with food in the morning or the evening, the patient should always take or receive the drug with food. Pharmacists should be mindful that children grow quickly and CBD-Rx doses may require adjustment to maintain effectiveness and prevent breakthrough seizures. Prescribers should monitor patients’ weights; weight gain of four kilograms of body weight or more requires administration of an additional 10 mg of CBD-Rx.4

                         

                        If patients wish to discontinue CBD-Rx therapy, patients should step down the dosage in weekly intervals to prevent breakthrough seizures. Patients or their families should always consult with their prescribers before stopping therapy.

                        Patients with moderate hepatic impairment should receive half of the normal starting, maintenance, and maximum maintenance doses.4 In patients with severe hepatic impairment, prescribers should start all patients at 0.5 mg/kg twice daily with a normal maintenance dose of 1 mg/kg twice daily for Dravet and Lennox-Gestaut syndromes and 2.5 mg twice daily for tuberous sclerosis complex. The maximum CBD-Rx dose should be 2 mg/kg twice daily for Dravet and Lennox-Gestaut syndromes and 2.5 mg twice daily for tuberous sclerosis complex.4

                         

                        CBD-Rx’s manufacturer provides a calibrated 5 mL or 1 mL oral syringe for accurate dosing.4 Patients with calculated CBD-Rx doses of 100 mg or less should receive the 1 mL syringe because the product contains 100 mg of CBD per mL. Household teaspoons or tablespoons are not proper measuring devices and patients should not use them. Patients should discard any unused CBD product remaining 12 weeks after first opening the bottle. Again, small changes in anticonvulsant drug concentrations can result in breakthrough seizures.4

                         

                        Counseling for CBD-Rx

                        CBD-Rx comes with oral syringes.4 Pharmacy staff should show patients or caregivers the oral syringe and demonstrate how to affix the syringe to the bottle and withdraw the plunger to the correct line (or mark) to achieve a proper dose.4

                        Pharmacists should remind patients with seizure disorders who are prescribed CBD-Rx to avoid  non-FDA-approved CBD products due to

                        • risks from dosing variability inducing breakthrough seizures or adverse events
                        • exposure to unneeded THC, and
                        • complications from adulteration and contamination.

                        This is an area where technicians can be very helpful, especially in stores that sell CBD products over the counter; technicians who see patients purchasing nonprescription CBD products should invite discussion with the customer, especially if the customer or a family member is using CBD-Rx.

                        Pharmacists should inquire whether the prescriber has ordered liver function testing before the patient starts therapy and when follow-up monitoring of the liver is planned. Pharmacists should also counsel patients to alert their prescribers if they develop new unexplained nausea and vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice, and/or dark urine. These signs of liver injury indicate patients should have their liver function tested. Clinicians should routinely assess liver function before therapy and one, three, and six months after patients start therapy. Therapy should be discontinued if the AST or ALT rises more than three times the upper limit of normal or bilirubin is increased more than 2 times the upper limit of normal.

                        CBD-Rx can sedate patients. Sedation is usually more intense for several days after therapy initiation or a dosage increase. People should avoid driving or operating heavy machinery until they know that they can function adequately while taking the CBD-Rx. They should also avoid concomitant use of other sedating over the counter products such as alcohol, sedating antihistamines, kava, or valerian.

                        Pharmacists should screen patients for drug interactions and monitor patients when it’s impossible to avoid the risk of adverse drug interactions. They should be vigilant, especially when patients are prescribed diazepam and clobazam.

                        While we do not know if CBD-Rx enhances the risk of suicidal ideation like other antiepileptic medications, patients receiving CBD-Rx almost always take other antiepileptic medications. As such, patients need to be aware that any antiepileptic medication could cause this effect. Counseling that they should monitor themselves or their children for signs of depression or suicidal ideation while taking antiepileptic medication including CBD-Rx is critical.

                         

                        CBD-Rx or Unapproved CBD in Other Diseases and Disorders

                        Researchers have studied both CBD-Rx and unapproved CBD products in many other diseases and disorders. While Internet sources hype CBD’s curative effects in many diseases and disorders, Table 1. summarizes the available—and much weaker—evidence. Confused by the statistical terms in this section? Check out the SIDEBAR.

                        Table 1. Relative Strength of Evidence Base for CBD

                        Condition Evidence Base
                        Anxiety

                        THC Induced or Opioid Withdrawal

                        Public Speaking

                        Stressor Prophylaxis

                        Chronic Anxiety

                         

                        ++

                        ++

                        +

                        0

                        Psychosis/Schizophrenia

                        THC Induced

                        Other

                         

                        ++

                        +

                        Pain and/or Spasticity +
                        Parkinson’s Disease

                        Movement disorders

                        Sleep

                         

                        +

                        +

                        Acne

                        Sebum production

                        Fewer Breakouts

                         

                        +

                        0

                        Rosacea, Eczema, Psoriasis 0
                        Crohn’s Disease 0
                        Cancer 0

                        Legend: 0 No Evidence or no evidence of benefit, + Very weak evidence of benefit, ++ Weak evidence of benefit, +++ Moderate evidence of benefit, ++++ Strong evidence of benefit

                         

                        SIDEBAR: What do these statistical terms mean?

                        Strength of Evidence – The strength of evidence indicates how certain you are that the intervention you are assessing will deliver desired or feared results when used in patients. The best way to improve the strength of evidence is to use strong study methods and adequate numbers of participants; they minimize the chance that study weaknesses will cause the results. If the study methods are weak or researchers enroll too few patients, the results may be caused by chance rather than an actual difference caused by the intervention. In studies discussed in this activity, CBD is the intervention.

                        Extrapolation – Extrapolation means taking data from one setting or circumstance and making a guess about what would happen in another setting or circumstance. For example, when researchers breed animals to have extremely high cholesterol and treat them with lipid-lowering drugs, the animals’ cholesterol levels fall, and they live longer than animals that do not receive lipid-lowering drugs. Researchers might assume that it would also provide these benefits in humans. In another example, a drug reduces blood pressure and in general, higher blood pressure increases the risk of heart attack or stroke. So, researchers might extrapolate the blood pressure reductions and assume that this means that the drug also reduces heart attack and stroke risk.

                        Underpowered – Sometimes an intervention seems to provide benefits or harms, but the researchers haven’t enrolled enough people to be able to say with 95% confidence that the results are not due to chance. For example, a study of four people per group found that no people died in group A died (0% mortality) but 1 person in group B died (25% mortality). It may be that intervention in group A prevented the death, but it could also be that the participant’s death (although unfortunate) had nothing to do with the intervention. If the study had 800 people and the mortality rate was 0% vs. 25% in the two groups, you would have much more confidence that the intervention in group A could protect people from death.

                         

                        Anxiety

                        Multiple studies have assessed CBD’s impact on anxiety.31-43 All studies except one used single dose CBD so the efficacy or safety of chronic therapy is unknown. Most studies enrolled normal volunteers, so their response might be different than responses in people with social anxiety or generalized anxiety disorders.31-43 The studies used a range of CBD doses from multiple manufacturers.

                         

                        In several trials, single dose CBD was given to counteract anxiety induced by single dose THC.31-34 While concurrent CBD use seemed beneficial as assessed using two validated anxiety scales, this result cannot be used as evidence of anti-anxiety effects arising from things other than THC agonism of the CB1 receptor. 31-34 However, in one study, researchers assessed people who were prone to paranoia unrelated to THC use in an anxiety-provoking virtual reality session.44 Participants were randomized to receive a single dose of oral cannabidiol (600 mg) or placebo 130 minutes before entering virtual-reality. Immersion in the virtual-reality session elicited anxiety as indexed by the Beck’s anxiety inventory (p < 0.005), and increased cortisol concentrations (p = 0.05), heart rate (p < 0.05) and systolic blood pressure (p < 0.05). Not only did CBD fail to provide any benefits on these parameters, but the researchers also noted a trend toward increasing anxiety (p=0.09).44

                         

                        Other trials assessed CBD use a couple of hours before public speaking.35-37 Overall, CBD provided positive anti-anxiety effects compared with the control. While underpowered, the 300 mg dose might provide greater benefits than smaller or larger doses, but this requires further investigation. CBD’s benefits were less robust than the benzodiazepine clonazepam’s in one study, but the latter induced significant sedation whereas the former did not.35-37

                         

                        Researchers also assessed the acute use of CBD before stressful or anxiety-provoking situations other than public speaking.38-43 Unfortunately, the results were inconsistent and it is unclear whether patients taking CBD before non-public speaking anxiety-provoking events is an effective strategy.38-43 However, in 2021, the impact of the placebo effect on CBD anxiolysis was explored.45 Researchers gave 43 people a CBD-free hemp oil but told them in one phase that they were receiving CBD oil and in another phase that they were not receiving CBD oil. Those with the strongest beliefs that CBD was an effective anxiolytic had the most profound anxiety reductions when they were given placebo compared with when they had the same acute stressor but were told they were not receiving CBD.45 As such, given the current dataset, it is hard to discern whether CBD’s innate pharmacology helps calm anxiety or the expectation of anxiolysis provides the benefit.

                         

                        The final study in this section assessed short term anxiety caused by withdrawal symptoms.46 In a randomized, double-blind, placebo-controlled trial, researchers enrolled drug-abstinent individuals with heroin use disorder. They assessed the acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 mg or 800 mg, once daily for 3 consecutive days) on drug cue-induced craving (exposure to stimuli associated with drug use that often causes craving and subsequent anxiety and drug-seeking behavior). Acute CBD administration reduced both craving and anxiety induced by the presentation of salient drug cues significantly more than placebo. Three days of CBD also showed significant protracted effects on these measures seven days after exposure.46

                         

                        Taken together, short term use of CBD may provide anti-anxiety benefits to those ingesting THC who are at risk of anxiety from paranoid thoughts but those prone to paranoia not due to THC might not accrue these benefits. Researchers have been unable to determine the extent to which this CBD helps people with stage fright; such reductions could be due to its pharmacology or might be placebo effect. And while anxiety due to opioid withdrawal was reduced in one study, researchers need to repeat these studies and enroll larger numbers of participants. No data suggest that CBD is a safe, effective chronic medication for those with anxiety disorders.

                         

                        Psychosis and Schizophrenia

                        THC is known to induce paranoia and psychosis in some individuals. Two double-blind trials assessed the impact of single doses of CBD on attenuating the acute psychotic-like effects of THC in normal volunteers.39,47 The first trial found CBD had no impact on the Positive and Negative Syndrome Scale (PANNS) score without THC use when compared to placebo. It did find suppression of THC-induced changes at 30 minutes.39 The second trial compared CBD to placebo 210 minutes before the researchers administered intravenous THC 1.5 mg.47 Post-THC administration, the CBD group had lower PANSS positive scores, but the difference was statistically insignificant. However, clinically significant positive psychotic symptoms were less frequent in the CBD group compared with the placebo group. Post-THC paranoia and episodic memory, as rated with the State Social Paranoia Scale (SSPS) and the Hopkins Verbal Learning Task-revised (HVLT-R), were lower in the CBD group compared with the placebo group.47

                         

                        Two randomized, placebo-controlled trials assessed the impact of moderate length CBD therapy on patients with schizophrenia.48-50 The first trial found significantly greater reductions in PANNS positive scores in the CBD group versus placebo but not for the other PANNS scores (PANNS negative, total, or general).48 The second trial found CBD therapy conferred no significant benefits for PANNS total, general, positive, or negative scores compared to placebo. The first trial allowed only one antipsychotic to be used for baseline therapy while the second trial allowed a sizeable portion of patients to receive more than one antipsychotic agent.49

                         

                        In a double-blind, randomized, actively controlled trial, CBD was directly compared to the atypical antipsychotic amisulpride in patients (n = 39) with acute schizophrenia.50 After three antipsychotic-free days (or greater than three months after a depot injection), the researchers randomized patients to 200 mg of CBD or amisulpride daily, which could be increased by 200 mg daily for a total of four administrations daily (total 800 mg per day) within the first week. The PANNS total, general, positive, and negative scores and the Brief Psychiatric Rating Scales scores improved significantly in both groups at 14 and 28 days but there were no significant differences between the two groups at any point. As compared to amisulpride-treated patients, CBD-treated patients had fewer extrapyramidal symptoms, approximately three kilograms (6.6 pounds) less weight gain at 28 days of therapy, and less prolactin release at both 14 and 28 days.50 This improved safety profile could be an important advantage for CBD either as monotherapy or as an adjunctive therapy if it provides reasonable efficacy.50

                         

                        Pain and Spasticity

                        Studies assessing CBD alone for pain relief are scant and two of three use methodologies with very weak strength of evidence.51,52 The first two trials were open label single arm studies assessing pain relief from human papillomavirus (HPV) vaccine or renal transplant. While study participants had qualitatively lower pain scores over time after CBD use, researchers could not determine whether benefits seen in these trials were due to CBD, natural alleviation of symptoms over time, or placebo. A lack of intention-to-treat methodology with a high withdrawal rate may have confounded the first trial.51,52 Similarly, the first trial used CBD-enriched hemp oil; hemp oil constituents (other than CBD) might have provided some of the benefits.51

                         

                        One randomized, double-blind, multi-group crossover trial assessed pain and spasticity. This trial enrolled patients (N = 24) with multiple pain and spasticity disorders.53 Only 12 patients, 16 patients, and eight patients completed the pain, spasm, and spasticity assessments, respectively, creating a weak dataset without the use of intention to treat analysis. The CBD group had significantly better but modest pain control (54.8 + 22.6 versus 44.5 + 22.7, P < 0.05) but no significant improvements in spasm (54.6+19.1 versus 47.3+22.6), spasticity (47.8 + 18.5 versus 42.3 + 18.1), bladder function (60.5 + 28.4 versus 54.9 + 28.8), or coordination (38.3 + 22.9 versus 40.6 + 21.1) compared with placebo.53

                         

                        In one study, 29 patients with symptomatic peripheral neuropathy were randomized to a topical whole-plant-extracted CBD (250 mg CBD/3 fluid ounces) group or a matching placebo group with therapy applied up to four times daily.54 The researchers administered the Neuropathic Pain Scale biweekly to assess the mean change from baseline to the end of the treatment period. The change from baseline was -5.55 + 2.81 points in the CBD group and -3.33 + 2.02 in the placebo group for a significant mean difference of −2.22 (95% CI −4.07 to −0.37). No adverse events were reported.53

                         

                        Parkinson’s Disease

                        One available trial examined CBD in Parkinson’s disease.55,56 Twenty-one patients with Parkinson’s disease without dementia or comorbid psychiatric conditions were assigned placebo, CBD 75 mg/day, or CBD 300 mg/day for six weeks.55 The researchers found no differences in or between any group for the Unified Parkinson Disease Rating Scale, concentrations of Brain-Derived Neurotrophic Factor, or in Proton Magnetic Resonance Spectroscopy indices. The group receiving CBD 300 mg/day had significant improvements compared with placebo in the Parkinson’s Disease Questionnaire-39 (p = 0.05).55 Four of the subjects had Parkinson’s disease-associated rapid eye movement (REM) sleep behavior disorder, which is characterized by nightmares and loss of muscle tone or strength during REM sleep.56 All REM sleep behavior disorder-affected patients received CBD (75mg/day in one patient and 300mg/day in three patients). At baseline patients had between two to four episodes of REM sleep behavior disorder per week but during the six-week study, three patients had no events, and the other patient (receiving 300mg/day CBD) had a reduction to one episode per week.56

                         

                        In an open-label study of 13 patients with Parkinson’s disease and substantial rest tremor, CBD-Rx was titrated from 5 mg/kg/day to 20 to 25 mg/kg/day and maintained for 10 to 15 days.57 All participants reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none were serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20-25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. The 10 people who completed the study had 18% improvements (p=0.012) in their total and 25% improvements (p=0.004) in their motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores. Nighttime sleep and emotional/behavioral scores also improved significantly.57

                         

                        Finally, investigators in one study used the public speaking methodology employed in the anxiety study section above and studied CBD’s impact in patients with Parkinson’s disease.58 Participants in this randomized, double-blinded, placebo-controlled, crossover clinical trial (N = 24) underwent two experimental sessions within a 15-day interval. CBD attenuated experimentally-induced anxiety assessed by the Visual Analog Mood Scales anxiety factor and reduced anxiety provoked tremor amplitude as recorded by the accelerometer.58

                         

                        Topical CBD for Skin Related Disorders

                        Despite the hype around CBD use for acne, rosacea, eczema, and other skin disorders, the data is poor. To date, only two studies have explored CBD’s role in acne. In the first study, researchers administered CBD to cultured human sebocytes and human skin organ culture, which inhibited the lipogenic actions of various compounds (arachidonic acid, linoleic acid, and testosterone) and suppressed sebocyte proliferation and lipogenesis through TRPV4 activation.59-61

                         

                        In a second study, male volunteers applied a 3% cannabis seed extract in a vehicle to one cheek or vehicle alone to the other cheek for 12 weeks. Using a sebumeter, the researchers found a significant reduction in sebum production with cannabis extract versus vehicle alone (p < 0.05). CBD’s contribution apart from the contribution from other cannabis constituents’ contribution in this study is unknown and researchers have not adequately explored its role in reducing pimples or pustules. Other CBs have potential anti-acne potential with similar effects on human sebocytes, so whether CBD alone or the CB mixture in hemp extract is more effective is unknown.59-61

                         

                        Theoretically, CBD could impact inflammatory skin conditions. However, human data on CBD’s impact on rosacea, eczema, or psoriasis is nonexistent in the biomedical literature.

                         

                        PAUSE AND PONDER: Aside from possible adverse effects, what are some other risks of trying to self-medicate with CBD for inflammatory diseases like rheumatoid arthritis, colitis, and psoriasis?

                         

                        Crohn’s Disease

                        CBD is an anti-inflammatory cannabinoid shown to be beneficial in an animal model of inflammatory bowel disease. It has only been studied in one human trial. The study randomized 20 patients with refractory Crohn's disease to receive oral CBD 10 mg twice daily or placebo. After eight weeks of treatment, no differences in CBD signs and symptoms occurred. It is possible that refractory patients were not amenable to benefits, the dose was too low, or that CBD is just ineffective for this inflammatory disorder.62

                         

                        To understand this next study, readers need to know that episodes of inflammation like those seen in inflammatory bowel disease and septic shock compromise the gut’s barrier function (increase its permeability), allowing noxious material to transfer into the systemic circulation. In an initial randomized, double-blinded, placebo-controlled trial, 30 normal volunteers who had no gastrointestinal diseases received aspirin 600 mg to increase gut permeability.63 Researchers administered oral CBD 600 mg or placebo to participants and then compared their lactulose/mannitol ratios over six hours; a larger ratio suggests greater gut permeability. The lactulose/mannitol ratio across the experimental period was increased after both CBD and placebo (P < 0.001 for both compared with their respective baselines) but compared with the placebo and aspirin group, the lactulose/mannitol ratio was lower in the CBD and aspirin group (p < 0.0001). While this is a model for inflammatory bowel dis- eases, whether these effects will translate to clinical benefits in patients with Crohn’s disease remains to be seen.

                         

                        Cancer

                        Some in vitro and animal models suggest CBD has cancer preventive or treatment effect.64 A few case reports suggest efficacy.65,66 However, no human trials have evaluated CBD’s anticancer effects and cancer patients may be at appreciable risk due to CBD drug interactions if they self-treat without coordinating with their treatment teams.

                         

                        Counseling for Unapproved CBD Products

                        All healthcare providers should caution people interested in oral CBD for non-FDA-approved indications that no human studies exist for most diseases. While preliminary trials in anxiety, local pain, psychosis or schizophrenia, and Parkinson’s disease are promising, patients should not use nonprescription CBD to replace FDA-approved therapies. Patients should disclose CBD use to all healthcare clinicians so trained clinicians can assess the impact and potential adverse events. Pharmacists and pharmacy technicians can remind patients to only buy CBD products with independent laboratory verification of the CBD dosage, THC percentage, and lack of contamination and adulteration. Using substandard products in which the active ingredient varies from batch to batch for diseases or disorders is dangerous.

                         

                        For all oral CBD products, instructing patients about the main risks of therapy including sedation and gastrointestinal distress is essential. Due to possible sedation, patients should not operate heavy machinery until they know how CBD impacts them specifically and even then, only if they can do so safely. Patients using oral CBD should not start new over the counter drugs or dietary supplements without checking with their pharmacists to avoid drug interaction-induced adverse events. Here, again, the pharmacy technician’s role is to watch for purchases of these products.

                         

                        Patients with chronic liver disease should not use CBD products as they might worsen the degree of damage. Pharmacists should warn patients that if they develop tender upper quadrant abdominal pain, yellowing of the skin and eyes, or light-tan colored stools, they should call the doctor right away as this can indicate liver damage. Finally, pharmacists should tell patients and/or their caregivers about the risk of suicidal ideation, that this warning is not specific to oral CBD products, and it has been reported with other anticonvulsants as a class. Pharmacists should remind patients that if they notice feeling more down than usual or are thinking about harming themselves, they should consult their doctors immediately.

                         

                        If patients ask about topical CBD products for acne, pharmacists can tell them limited weak data suggests a potential benefit. Whether pure CBD is better or worse than products with all of hemp extract’s components is unknown. For rosacea, psoriasis, and other inflammatory skin disorders, no human studies suggest a benefit from topical CBD products.

                         

                        Finally, CBD is a drug, not a trendy food or beverage additive. Pharmacists should recommend against using CBD products without healthcare provider input, especially if the patient takes other CBD products or other drugs that could interact.

                         

                        Conclusion

                        If patients use non-FDA-approved forms of CBD, they risk exposure to variable CBD and THC dosages, adulteration, and contamination. If not FDA-approved, products tested by an independent laboratory are safer. CBD is an effective option for the adjunctive treatment of refractory seizures in Dravet and Lennox-Gastaut syndromes and holds promise in the treatment of other refractory seizures, but more data is needed to determine its role. Additionally, CBD is promising but not proven for pre-medicating before anxiety-inducing events such as public speaking and chronic treatment of patients with schizophrenia. CBD has not been assessed for chronic treatment of anxiety. Data in pain, spasticity, and Parkinson’s disease is limited and weak. CBD is not risk free since it has both drug interaction and adverse event potential. Somnolence and fatigue coupled with gastrointestinal disturbances are not uncommon and rarer but serious events such as elevated liver function tests have been observed. CBD’s impact on suicidal ideation must be explored as this is a serious but rare adverse event associated with other anti-convulsant drugs. Longer-term safety data is needed to weigh CBD’s possible benefits against possible harms.

                        Pharmacist Post Test (for viewing only)

                        Pharmacists Post-test

                        After completing this continuing education activity, pharmacists will be able to
                        1. Discuss cannabidiol’s known pharmacologic profile
                        2. Identify FDA-approved indications for prescription cannabidiol and other indications in which research is promising
                        3. Distinguish the FDA-approved cannabidiol from various nonprescription products in terms of quality and risk/benefit profile
                        4. Maximize the pharmacist's role in helping patients who are good candidates for prescription cannabidiol or use nonprescription cannabidiol products either with or without other prescription drug therapies

                        1. What is the difference between CBD-Rx and unapproved CBD products in terms of their pharmacologic profiles?
                        A. For both products, high fat/high calorie meals dramatically increase the Cmax and the AUC by 5- and 4-fold, and both products are labeled, “Take with a low-fat meal.”
                        B. For both products, high fat/high calorie meals dramatically increase the Cmax and the AUC by 5- and 4-fold, and both products are labeled, “Take with the biggest meal of the day.”
                        C. At doses of 5 to 20 mg/kg/day, CDB-Rx’s increase in concentration is less than dose-proportional; similar data is mostly unavailable for unapproved CBD products

                        2. When thinking about any CBD product and potential drug interactions, what should pharmacists remember?
                        A. CBD is primarily metabolized by CYP2C19 and CYP3A4 and UGT1A7, UGT1A9, and UGT2B7
                        B. CBD is primarily metabolized by CYP1A2 and CYP2D64 and UGT1A7, UGT1A9, and UGT2B7
                        C. CBD is primarily metabolized by CYP2C19 and CYP3A4 and UGT1A1*6, UGT1A1*28, and UGT2B7

                        3. Which of the following are FDA-approved indications for Rx-CBD?
                        A. Lennox-Gestaut and Dragnet’s Syndromes and tuberous sclerosis complex
                        B. Lennox-Gestaut and Dravet’s Syndromes and tuberous breast syndrome
                        C. Lennox-Gestaut and Dravet’s Syndromes and tuberous sclerosis complex

                        4. When thinking about unapproved CBD products and available evidence, which of the following uses has the LEAST scientific evidence to support it?
                        A. Acute anxiety
                        B. Chronic anxiety
                        C. Sebum production

                        5. A parent whose child has been taking Rx-CBD for a seizure disorder comes to the pharmacy and indicates she can no longer afford the copay. She has visited a local shop and asked about using unapproved CBD instead; the cost would be much lower. What is the BEST advice you can give her?
                        A. This is a cost-saving idea, and she should ask for a CoA and bring it to you so you can guide dosing, and monitor the children for signs of depression or suicidal ideation after the switch
                        B. This is a bad idea; trained clinicians need to be able assess the impact and potential adverse events, and unapproved products can vary in their CBD concentration and entourage content
                        C. This is a bad idea, but it’s an understandable problem; she should make sure the product she selects complies with standards set by the Association of Official Agricultural Chemists

                        6. A patient recently started on Rx-CBD. His father says he has had fewer seizures and his condition is much more manageable. The father says, “We are going to continue the Rx-CBD for another three months, and then we will think about using a product we can buy without a prescription. They are so much less expensive.” What is the BEST counseling advice you can provide in support of continuing with the Rx-CBD product?
                        A. It’s always important to do your own research. Would you like me to provide some links to websites that can explain unapproved CBD?
                        B. The Rx-CBD product has been associated with “hot lots” that were contaminated with a synthetic cannabidiol, but those issues have been resolved.
                        C. The Rx-CBD product contains and delivers the labeled dose, and people who take the same dose consistently will have predictable blood levels. Small reductions in blood levels of other antiseizure drugs can cause breakthrough seizures.

                        7. Several health agencies around the world have investigated unapproved CBD products. What have they found?
                        A. Non-FDA approved products have remarkable purity, with heavy metal contamination rare
                        B. Some products contain polycyclic aromatic hydrocarbons, but these compounds are harmless
                        C. Pesticide or heavy metal contamination has been identified in up to 70% of batches

                        8. A young adult who has moderate to severe acne has responded to benzoyl peroxide and other OTC products poorly. She asks you if you think a CBD product would help, and why? What is the BEST answer?
                        A. Two studies in human volunteers indicates that well-formulated products can reduce the frequency and magnitude of breakouts.
                        B. You may not have fewer breakouts; to date, only two studies have been conducted and they are of poor quality.
                        C. Maybe it would help. The best bet is to enroll in one of the many clinical trials that are looking at CDB’s effects on sebocytes.

                        9. A mother tells you that her son’s neurologist has suggested a trial of CBD-Rx. The child has Dravet’s syndrome. She said that he explained why he would like to try it. She said she would think about it but is concerned about the possibility of addiction. What should you tell her?
                        A. CBD-Rx has virtually no THC, the chemical that causes the high. The DEA placed CBD-Rx in Schedule V (drugs with a relatively low risk of abuse). If using it as directed, she need not worry.
                        B. Although CBD-Rx is classified as Schedule V, her concern is valid. Cases of addiction and abuse have been reported.
                        C. Although CBD-Rx is not a Scheduled medication, so during review, the DEA found no potential concerns with this product.
                        10. Parents of a young child who has a serious seizure disorder present with their first prescription for CBD-Rx. With the prescription, the physician has provided a prescription that tapers the patient’s clobazam dose down. The mom is very concerned. What do you say?
                        A. CBD-Rx is so effective, your daughter won’t need the clobazam anymore. The prescriber is tapering the dose because she won’t need it at all.
                        B. This is a prescribing error. I need to call the prescriber and notify him that your daughter will need a higher dose of clobazam going forward.
                        C. CBD-Rx interacts with some drugs that are processed by a specific enzyme. Clobazam is one of those drugs. By tapering the dose, the prescriber is preventing a drug interaction.

                        Pharmacy Technician Post Test (for viewing only)

                        Pharmacy Technician Post-test

                        After completing this continuing education activity, pharmacy technicians will be able to
                        1. Discuss the basic facts about cannabidiol products
                        2. Acquire reputable sources for patients who have an interest in cannabidiol to find information
                        3. Distinguish between nonprescription and prescription cannabidiols
                        4. Infer when to refer patients to the pharmacist for recommendations or referral

                        1. How does Rx-CBD differ from CBD products that people can purchase at the gas station, grocery store, or CBD vendor shops?
                        A. CBD has all of medical cannabis’s beneficial effects except the tetrahydrocannabinol high.
                        B. Nonprescription CBD products may have CBD concentrations that differ from labeled dose.
                        C. Both types of CBD products are now legal to sell, possess, and use in all U.S. states.

                        2. Match the Drug Enforcement Agency schedule with the product.
                        A. CBD-Rx products are schedule V; unapproved CBD products with THC concentrations greater than 0.3%, are schedule I.
                        B. CBD-Rx products are schedule 1; unapproved CBD products with THC concentrations greater than 0.3% are schedule V.
                        C. CBD-Rx products and unapproved CBD products unapproved CBD products with THC concentrations greater than 0.3% are schedule I.

                        3. What did the 2018 U.S. Farm Bill stipulate?
                        A. The Food and Drug Administration regulates some hemp-derived CBD products that have THC concentrations of less than 0.3%.
                        B. The Department of Agriculture regulates all hemp-derived CBD products that have THC concentrations exceeding 0.3%.
                        C. The Department of Agriculture regulates some hemp-derived CBD products that have THC concentrations of less than 0.3%.

                        4. A patient starts a discussion about OTC CBD products and implies that he thinks they are all the same. You know better and contribute what you know to the conversation. He asks if there is a way to determine a product’s quality and actual content. What do you tell him?
                        A. Consumers can request CBD products’ Certificate of Analysis (CoA) from the FDA or Department of Agriculture.
                        B. Consumers can request CBD products’ Certificate of Analysis (CoA) from the manufacturer.
                        C. Consumers need to look for the Quick Response code on the products’ labeling and call the phone number that appears when they scan it.

                        5. What information can consumers find on the CoA?
                        A. Information about the company’s good manufacturing compliance
                        B. Information about the growing conditions for the hemp used in the product
                        C. Information about testing for contaminants and THC and CBD levels

                        6. Which product would be MOST APPROPRIATE for a patient who has tuberous sclerosis complex?
                        A. CBD-Rx oral solution (25 mg/kg CBD per day)
                        B. CBD-Rx oral solution (120 mg/kg CBD per day)
                        C. And CBD product that has a certificate of analysis

                        7. Which auxiliary label is appropriate for CBD-RX?
                        A. Avoid milk, cheese, and antacids for one hour before and two hours after taking this medication.
                        B. May discolor the urine or feces.
                        C. Take with food at the same time every day.

                        8. A mom comes into the pharmacy with her child who is 4 years old and has Lennox-Gestaut syndrome. She is picking up the fifth refill of a prescription for CBD-Rx. The child is in a wheelchair, and a woman who knows them approaches saying, “Gosh! Is that Lilly? She looks great!” The mom replies, “She does! She is doing much better on this new medication and has only had two seizures in the last month. She’s gained so much weight, we’ve had to switch her from a stroller to a wheelchair!” Why should you get the pharmacist?
                        A. CBD-Rx is dosed by weight. These comments suggest she may have gained more than 4 kg (8.8 lbs) and her dose may need adjustment.
                        B. CBD-Rx should eliminate all seizures. The fact that she has had two seizures in the last month is something the pharmacist needs to know.
                        C. Weight gain is a serious adverse effect associated with CBD-Rx. It may indicate that the child is retaining fluid and the pharmacist needs to know.

                        9. Which of the following patients would you refer to the pharmacist?
                        A. A patient who is on CBD-Rx and says she’s picking up her CBD-Rx refill later than she expected because she had liver function tests drawn that morning.
                        B. A patient who is purchasing an unapproved CBD product and who has a family member who is on CBD-Rx.
                        C. A patient who asks if the bag contains the FDA-approved Medication Guide because she spilled something on her old one and likes to have it handy.

                        10. Parents of a young child who has a serious seizure disorder present with their first prescription for CBD-Rx. With the prescription, the physician has provided a prescription that tapers the patient’s clobazam dose down. The mom is very concerned. What do you say?
                        A. CBD-Rx is so effective, your daughter won’t need the clobazam anymore. The prescriber is tapering the dose because she won’t need it at all.
                        B. This is a prescribing error. I need to call the prescriber and notify him that your daughter will need a higher dose of clobazam going forward.
                        C. CBD-Rx interacts with some drugs that are processed by a specific enzyme. Clobazam is one of those drugs. By tapering the dose, the prescriber is preventing a drug interaction.

                        References

                        Full List of References

                        References

                           
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                          55. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28:1088-1098.
                          56. Chagas MH, Eckeli AL, Zuardi AW, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series. J Clin Pharm Ther. 2014 Oct;39(5):564-566.
                          57. Leehey MA, Liu Y, Hart F, et al. Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study. Cannabis Cannabinoid Res. 2020;5(4):326-336. Published 2020 Dec 15. Doi:10.1089/can.2019.0068
                          58. de Faria SM, de Morais Fabrício D, Tumas V, et al. Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease. J Psychopharmacol. 2020;34(2):189-196. Doi:10.1177/0269881119895536
                          59. Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and nti-inflammatory effects on human sebocytes. J Clin Invest. 2014;124:3713-3724.
                          60. Ali A, Akhtar N. The safety and efficacy of 3% cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content. Pak J Pharm Sci. 2015;28:1389-1395.
                          61. Oláh A, Markovics A, Szabó-Papp J, et al. Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrheic skin and acne treatment. Exp Dermatol. 2016 Sep;25(9):701-707.
                          62. Naftali T, Mechulam R, Marii A, et al. Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial. Dig Dis Sci. 2017;62:1615-1620.
                          63. Couch DG, Cook H, Ortori C, Barrett D, Lund JN, O’Sullivan SE. Palmitoylethanolamide and cannabidiol prevent inflammation-induced hyperpermeability of the human gut in vitro and in vivo-a randomized, placebo-controlled, double-blind controlled trial. Inflamm Bowel Dis. 2019;25(6):1006-1018. Doi:10.1093/ibd/izz017
                          64. Hande K. Cannabidiol: The need for more information about its potential benefits and side effects. Clin J Oncol Nurs. 2019;23:131-134.
                          65. Sulé-Suso J, Watson NA, van Pittius DG, et al. Striking lung cancer response to self-administration of cannabidiol: A case report and literature review. SAGE Open Med Case Rep. 2019;7:2050313X19832160.
                          66. Dall’Stella PB1, Docema MFL1, Maldaun MVC1, et al. Case Report: Clinical Outcome and Image Response of Two Patients With Secondary High-Grade Glioma Treated With Chemoradiation, PCV, and Cannabidiol. Front Oncol. 2019;8:643. Doi: 10.3389/fonc.2018.00643.

                          Go Bananas: Peel Away the Unknowns of Monkeypox

                          Learning Objectives

                           

                          After completing this application-based continuing education activity, pharmacists and pharmacy techicians will be able to

                          ·       Describe emerging information about monkeypox
                          ·       Use this information to answer patients’ questions

                           

                          Cartoon image of a virus with the face of a monkey.

                          Release Date:

                          Release Date: June 18, 2022

                          Expiration Date: June 18, 2025

                          Course Fee

                          FREE

                          ACPE UANs

                          Pharmacist: 0009-0000-22-046-H01-P

                          Pharmacy Technician: 0009-0000-22-046-H01-T

                          Session Codes

                          Pharmacist: 22YC46-PXK36

                          Pharmacy Technician: 22YC46-KPX88

                          Accreditation Hours

                          1.0 hours of CE

                          Accreditation Statements

                          The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.  Statements of credit for the online activity ACPE UAN 0009-0000-22-046-H01-P/T  will be awarded when the post test and evaluation have been completed and passed with a 70% or better. Your CE credits will be uploaded to your CPE monitor profile within 2 weeks of completion of the program.

                           

                          Disclosure of Discussions of Off-label and Investigational Drug Use

                          The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

                          Faculty

                          Pamela Sardo, PharmD
                          Sardo Solutions
                          Josephine, TX

                          Faculty Disclosure

                          In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

                          Dr. Sardo has worked for Rhythm Pharmaceuticals.  All potential conflicts of interest have been mitigated.

                           

                          ABSTRACT

                          Pharmacy professionals and paraprofessionals are receiving questions about monkeypox. Monkeypox is caused by the monkeypox virus, a member of the Orthopoxvirus genus. It is a viral disease that usually occurs in tropical rainforest areas of central and west Africa, but recently clinicians are diagnosing cases in other regions around the globe. Monkeypox is less contagious than smallpox and generally causes less severe illness. Monkeypox is transmitted to humans through close contact with an infected person or animal, or with material contaminated with the virus. The virus is transmitted from one person to another by contact with lesions, body fluids, respiratory droplets, and contaminated materials such as bedding. Usually, it presents clinically with fever, rash, and swollen lymph nodes and may lead to a range of medical complications. Monkeypox is typically a self-limiting disease with the symptoms lasting from two to four weeks. Severe and atypical cases can occur. Guidance from the Centers for Disease Control and Prevention and other health agencies is evolving. Treatment options for monkeypox may include smallpox vaccine, cidofovir, tecovirimat, and vaccinia immune globulin (VIG), among others.

                          CONTENT

                          Content

                          Introduction

                          Monkeypox is a rare virus believed to be transmitted to humans from animals and is endemic to Central and West Africa, typically near tropical rainforests.1 There are two clades (groups that share a common biological ancestor) of monkeypox virus: the West African clade and Congo Basin clade. More severe illness has been reported from the Congo Basin clade. Monkeypox is caused by monkeypox virus, a member of the Orthopoxvirus genus.2

                          The U.S. Centers for Disease Control and Prevention (CDC), in coordination with state and local officials, have initiated an emergency response to identify, monitor, and investigate monkeypox. This response includes a Health Alert Network (HAN), which is developing public health and clinical recommendations by developing protocols, medical guidance, and facilitating delivery of vaccine postexposure prophylaxis (PEP). The HAN also provides evolving education regarding antivirals that the U.S. government has stockpiled for preparedness and response purposes.2 Antivirals are discussed later in this continuing education activity.

                           

                          Exposure to Monkeypox

                          Much like how we peel a banana to see what is underneath, let’s peel away the mystery of monkeypox exposure. Transmission of the monkeypox virus to humans can occur via animal bite or direct contact with the blood, meat, bodily fluids, cutaneous, or mucosal lesions of an infected animal. Human-to-human transmission by close direct contact and via exhaled large droplets is rare but can occur.3

                           

                          Historically, human to-human transmission has been reported among household contacts and in other shared living quarters (e.g., in prisons). Transmission has also been reported in health care providers who have had close, sustained contact with a patient, objects, or materials that are likely to carry infection, such as bedding, clothes, utensils, and furniture. Touching and being face-to-face with someone who has symptoms are risk factors for exposure.2

                           

                          Monkeypox can spread through close skin-to-skin contact during sex, including kissing, touching, and oral and penetrative sex with someone who has symptoms. Monkeypox rashes are sometimes found on genitals and in the mouth. Mouth-to-skin contact could cause transmission where skin or mouth lesions are present. It is currently unknown whether monkeypox can be spread through semen or vaginal fluids. People who have symptoms should avoid sexual contact with others. Until more is known, individuals should continue using condoms after they recover, and continue using condoms until we know more about this virus’s transmission.4

                           

                          Although the evidence is limited and the risk of human-to-human transmission appears to be low, researchers report that infants and young children appear to be at the greatest risk of severe disease.5 The World Health Organization (WHO) reports that transmission from the mother to the fetus can occur via the placenta (which can lead to congenital monkeypox) or by close contact during and after birth.1

                           

                          Symptom Presentation

                          Just like a variety of recipes include bananas, patients with monkeypox can experience a variety of symptoms. Patients with monkeypox typically experience a febrile prodrome five to 13 days after exposure (range = four to 17 days), which often includes lymphadenopathy (abnormal enlargement of the lymph nodes), malaise, headache, and muscle aches. The prodrome might vary depending on the nature of exposure. The onset of a characteristic skin rash generally occurs one to four days following the prodrome. The lesions are well defined and progress over time to scabs. The rash can be disseminated.2

                          The monkeypox rash progresses through sequential stages6:

                          • Macules—small spots, different in color from the surrounding tissue
                          • Papules—small circumscribed solid elevations on the skin
                          • Vesicles—small, circumscribed elevations on the skin containing fluid
                          • Pustules—small, circumscribed elevations of the skin containing purulent material
                          • Scabs—crust formed by coagulation of blood, pus, serum, or a combination

                          The rash can last up to a month.1 The rash can also be confused with other diseases that are more commonly encountered in clinical practice (e.g., secondary syphilis, herpes, and varicella zoster). Researchers report some patients are co-infected with monkeypox virus and other infectious agents (e.g., varicella zoster or syphilis). Patients with a characteristic rash should be advised to receive testing.2

                          Monkeypox’s clinical presentation is occasionally inconsistent. Some cases present classically, while other cases are atypical. Common symptoms include genital and peri-anal lesions, fever, swollen lymph nodes, and pain when swallowing. Oral sores remain a common feature in combination with fever and swollen lymph nodes. In some cases, pustules appear before classical symptoms (e.g., fever) and lesions appear at different stages. Anogenital rash (with vesicular, pustular, or ulcerated lesions) sometimes appears first without spreading to other parts of the body. This initial presentation of a genital or peri-anal rash suggests close physical contact as the likely route of transmission, such as during sexual contact.7

                           

                          Pause and Ponder Question: How often should you ask patients with fever if they have also had close contact with someone with similar symptoms or a rash or headache?

                           

                          Avoiding Monkeypox                                        

                          Some learners may avoid eating bananas. Let’s avoid monkeypox. As of June 2022, clinicians in Europe, North America, South America, Africa, Asia, and Australia have reported monkeypox cases. Public health officials are cautioning travelers to avoid close contact with dead or live wild animals such as small rodents and monkeys. Travelers should avoid eating prepared meat from wild game or using products such as creams and lotions derived from wild animals in Africa, where cases of monkeypox are mainly found.8

                          Health care professionals should continue to watch for updates and evolving guidance as more information becomes known. The CDC raised its alert level for monkeypox to level 2. (see Figure 1) An example of evolving guidance is that, initially, the CDC recommended that people wear masks when traveling. A few days later, the advice regarding mask-wearing is no longer present on the CDC web sites. Thus, their advice evolved.2 Travel watch alert level 2 continues to encourage people to practice enhanced precaution measures, such as avoiding contact with visibly sick people and regularly washing hands.9

                           

                          Chart showing the three levels of travel watches, with travel watch level 3 recommending avoiding all non-essential travel to that area.

                          Figure 1. Centers for Disease Control and Prevention Travel Health Notices9

                           

                          Researchers recommend the following measures to prevent infection with monkeypox2:

                          • Isolate ill people from uninfected people
                          • Practice good hand hygiene and use appropriate personal protective equipment to protect household members if ill or caring for ill persons at home (e.g., long sleeves and pants, and disposable gloves)
                          • Use an Environmental Protection Agency–registered disinfectant with emerging viral pathogens claim that is found on its List Q for disinfection of surfaces. Examples include hydrogen peroxide, isopropyl alcohol and citric acid among others.10 This list is available at https://www.epa.gov/pesticide-registration/disinfectants-emerging-viral-pathogens-evps-list-q
                          • Patients should also avoid contact with pets and other animals while infectious, because some mammals might be susceptible to monkeypox
                          • A person is considered infectious from the onset of illness until all lesions have crusted over, those crusts have separated, and a fresh layer of healthy skin has formed under the crust

                          Pause and Ponder Question: How can you make individuals in your practice setting more comfortable about the U.S. monkeypox outbreak?

                          Potential Health Impact

                          The WHO communicates that monkeypox is less contagious than smallpox and causes less severe illness. Monkeypox is usually a  self-limiting condition with the symptoms lasting from two to four weeks.1

                          For individuals with monkeypox, isolation precautions should continue until all lesions have resolved, the scabs have fallen off, and a fresh layer of intact skin has formed. Patients who do not require hospitalization but remain potentially infectious should isolate at home. Clinicians should discontinue isolation only after consultation with the local or state health department.10

                          Beyond self-limiting cases, severe cases can occur and may lead to a range of medical complications.1 Conditions leading to hospitalization have included the need to provide adequate pain management and the need to treat secondary infections.7 Agencies are communicating monkeypox updates quickly, so many unknowns remain. Data reports of mortality are widely inconsistent so are not discussed in this manuscript.

                          Learners should refer to their states’ public health departments to determine if and how they should report suspected or confirmed monkeypox.

                          Pause and Ponder Question: The WHO is considering a name change for monkeypox.  What do you believe would be a clinically accurate name?

                           

                          APPROACH TO TREATMENT

                          Scientists say the risk of monkeypox becoming established in non-endemic countries is real. The WHO urges affected countries to make every effort to identify all cases and contacts to control this outbreak and prevent further spread. The FDA has approved a vaccine and has allowed expanded access for additional treatments for monkeypox, but these are in limited supply.11

                          The WHO is developing a coordination mechanism for the distribution of supplies based on public health need. The WHO does not recommend mass vaccination against monkeypox. In the few places where vaccines are available, they are being used to protect those who may be exposed, such as health workers and laboratory personnel.11

                          In general, some countries may consider post-exposure vaccination, ideally within four days of exposure, for higher-risk close contacts such as sexual partners, family members in the same household, and health workers.11 The CDC facilitates the availability of vaccine post-exposure prophylaxis (PEP) to contacts with high-risk exposures (e.g., unprotected contact with a patient’s skin or mucous membranes, lesion, or body fluids).10

                          PEP is not recommended for people with low or uncertain risk (e.g., health care providers entering a patient’s room without eye protection). Eligible intermediate- and high-risk contacts are offered PEP with2,12,13

                          • smallpox (vaccinia) vaccine, live (ACAM2000) or
                          • smallpox and monkeypox vaccine, live, nonreplicating (Jynneos) vaccines.

                          Researchers and regulatory authorities have not communicated whether optimal doses of expanded access investigational new drug (EA-IND) therapeutics for patients presenting with monkeypox will be consistently the same or different from doses for other indications. Clinicians should consult the full prescribing information for each therapeutic for comprehensive information, and pharmacy technicians should use the approved prescribing information to find information on storage conditions if necessary. Table 1 lists FDA-approved treatments for people presenting with monkeypox. It also describes therapeutics with EA-IND protocols for monkeypox or treatments undergoing further research.

                           

                          Table 1. Approved and Investigational Therapeutics for Monkeypox12-17

                          Generic Name (Brand Name; Manufacturer) Current FDA approved indication
                          Smallpox (Vaccinia) Vaccine, Live (ACAM2000) Vaccine indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection
                          Smallpox and Monkeypox Vaccine, Live, Non-replicating (Jynneos) Vaccine indicated for prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection
                          Tecovirimat (TPOXX)

                           

                          Capsules and injection indicated for the treatment of human smallpox disease in adults and pediatric patients weighing ≥ 3 kg
                          Cidofovir (Vistide) Infusion indicated for CMV retinitis in patients with acquired immunodeficiency syndrome
                          Brincidofovir (Tembexa) Tablets and oral solution indicated for the treatment of human smallpox disease in adult and pediatric patients, including neonates
                          Vaccinia immune globulin (human) (Vigiv) Intravenous immune globulin indicated for the treatment of complications due to vaccinia vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, vaccinia infections in individuals who have skin conditions, aberrant infections induced by vaccinia virus

                           

                          Smallpox Vaccine

                          The smallpox live vaccine listed in Table 1 is licensed for immunization in people who are at least 18 years old and at high risk for smallpox infection. It is contraindicated in individuals with severe immunodeficiency. Select warnings include myocarditis, encephalitis, ocular vaccinia, infants younger than 12 months, and pregnancy. Common adverse events include injection site reactions, malaise, fatigue, fever and headache.12 It can be used in people exposed to monkeypox if it is used under an EA-IND protocol. The smallpox vaccine is not currently available to the general public. In the event of another outbreak of monkeypox in the U.S., CDC will establish guidelines explaining who should be vaccinated.18

                          Smallpox and Monkeypox Vaccine

                          The FDA has licensed smallpox and monkeypox vaccine to prevent infection with smallpox and monkeypox viruses. Anaphylactic reactions after dosing are possible. In smallpox vaccine-naïve healthy adults, the most common injection site reactions were pain, redness, swelling, induration, and itching. The most common systemic adverse reactions were muscle pain, headache, fatigue, nausea and chills.13

                           

                          Data from Africa suggests that this vaccine is at least 85% effective in preventing monkeypox. Effectiveness against monkeypox was concluded from a clinical study on the immunogenicity and efficacy data from animal studies. Researchers believe that vaccination after a monkeypox exposure may help prevent the disease or make it less severe.18

                           

                          Tecovirimat

                          The U.S. government stockpiles tecovirimat.18 Tecovirimat reduces the production and release of enveloped orthopoxvirus in vitro for seven monkeypox virus strains.19 Tecovirimat use for monkeypox is not FDA approved, but the CDC holds a non-research expanded access EA-IND protocol that allows its use for primary or early empiric treatment of monkeypox in adults and children of all ages. Clinical trials demonstrate the drug is safe with only minor side effects.18 The injection is contraindicated in severe renal impairment. Clinicians should monitor for hypoglycemic symptoms. Both the capsules and injection may cause headache.14

                          Cidofovir and Brincidofovir

                          Data is not available on the effectiveness of cidofovir or brincidofovir in treating human cases of monkeypox. Both have proven activity against poxviruses in in vitro and animal studies. It is unknown whether a person with severe monkeypox infection will benefit from treatment with either antiviral, although their use may be considered in such instances.18 The CDC holds an expanded access protocol for both products that allows use of stockpiled cidofovir for the treatment of orthopoxviruses (including monkeypox) in an outbreak. Brincidofovir may have a better safety profile than cidofovir. Serious renal toxicity or other adverse events have not been observed during treatment of cytomegalovirus infections with brincidofovir compared to treatment using cidofovir.18

                          Vaccinia Immune Globulin

                          Data is unavailable on the effectiveness of vaccinia immune globulin (VIG) in treatment of monkeypox virus infection. Use of this immune globulin is under an EA-IND. Proven benefit in the treatment of monkeypox is currently undetermined; however, healthcare providers may consider its use in severe cases. VIG can be considered for prophylactic use in an exposed person with severe immunodeficiency in T-cell function for which smallpox vaccination following exposure to monkeypox virus is contraindicated.18 A boxed warning indicates maltose in immune globulin products may give falsely high blood glucose levels in certain types of blood glucose testing systems. Additional warnings include renal dysfunction, thrombotic events, and infusion rate precautions. The most common adverse drug reactions are headache and nausea.

                           

                          Pause and Ponder Question: What side effects have your patients reported after receiving a vaccine? 

                          Ancillary Treatment Options, Supportive Care

                          Bananas are considered comfort food by many people. What comfort care can be recommended for patients suffering with monkeypox? Monkeypox can impact multiple systems and co-infections are possible. Soap and water, povidone-iodine, silver sulfadiazine and moist occlusive bandages promote healing at lesions sites. Adequate hydration and nutrition and protecting vulnerable anatomical sites such as the eyes and genitals are critical. Treatment for pain is recommended but specific analgesics have not been specified.20

                          Antipyretics can be used for fever. Antiemetics can be used for nausea. For ocular infection, topical application of trifluridine has been used to resolve symptoms and to attempt to prevent possible ocular scarring. Topical or oral antibiotics have also been used in combination either to treat bacterial infection or as prophylactic therapy. Bronchodilation, nebulizer, or suctioning is recommended if the respiratory tract is affected.20

                          CONCLUSION

                          Pharmacists are knowledgeable about many viruses and now are engaged in conversations involving monkeypox. The CDC urges health care providers in the United States to be alert for patients who have rash or illnesses consistent with monkeypox, regardless of a patient’s gender, sexual orientation, history of international travel, or specific risk factors for monkeypox. All health care providers should contact their local or state health department if they suspect a case of monkeypox.

                          Pharmacist Post Test (for viewing only)

                          Pharmacist Post-test

                          EDUCATIONAL OBJECTIVES
                          After participating in this activity pharmacists and pharmacy technicians will be able to:
                          ● Describe emerging information about monkeypox
                          ● Use this information to answer patients’ questions

                          1.Which of the following is TRUE about monkeypox?

                          A. Monkeypox is more contagious than smallpox
                          B. Monkeypox transmission by bodily fluids can occur
                          C. Monkeypox is only contagious for four days

                          2. Which of the following is important regarding transmission of monkeypox?

                          A. The population at greatest risk for severe disease are infants and young children
                          B. Sexually active monkeypox infected individuals can stop using a condom after six days
                          C. Monkeypox transmission by exhaled droplets is the most common method of spread

                          3. When Tom Smith is requesting a refill, he tells you that he recently heard that monkeypox evolves into syphilis. What is your reply?
                          A. Yes, monkeypox evolves to primary syphilis but not secondary syphilis
                          B. Testing is not required for genital rashes because the evolution occurs
                          C. They are separate conditions but some people may be co-infected

                          4. Sally Williams comes to you for her travel vaccines before travel to Africa to hunt. She shares that she loves feeding the monkeys there and asks about monkeypox risk.

                          A. Tell her to get vaccinated with cidofovir and take insect repellant
                          B. She should avoid contact with monkeys, hunting and eating game meat
                          C. Tell her PEP is recommended in uncertain risk when she returns

                          5. What is one monkeypox potential impact on health?

                          A. Patients not requiring hospitalization but who are potentially infectious should home isolate
                          B. Conditions leading to hospitalization have included the need to provide behavioral consult
                          C. Discontinuation of isolation should be determined in consultation with respiratory therapist

                          6. A second year medical school fellow asks you whether to include recommendations for monkeypox vaccination routinely for clinic patients for whom she is caring. What do you say?
                          A. Tell the fellow “yes” because WHO does recommend mass vaccination against monkeypox
                          B. Tell the fellow you can provide information on CDC post-exposure prophylaxis criteria for individuals with high-risk exposure
                          C. Tell the fellow “no,” but post-exposure vaccination, ideally within four weeks of exposure, may be considered

                          7. Which vaccine is indicated for prevention of monkeypox in adults 18 years of age or older who are determined to be at high risk for infection?

                          A. TPOXX
                          B. VIGIV
                          C. JYNNEOS

                          Links to LO#1; answer found in Table 1 discussion of prevention
                          Rationale: Answer A is incorrect because TPOXX is indicated for smallpox. Answer B is incorrect because VIGIV is an infused immune globulin for complications. Answer C is CORRECT as Jynneos is indicated for both smallpox and monkeypox.

                          8. Which pharmaceutical can be used in people exposed to monkeypox, if it is used under an expanded access investigational new drug protocol?

                          A. Smallpox vaccine
                          B. Pfizer/BioNTech vaccine
                          C. Afluria Quadrivalent

                          9. Which therapeutic is stockpiled by the U. S. government, has an EA-IND and was found to have in vitro activity against seven monkeypox strains?
                          A. Vaccinia immune globulin
                          B. Tecovirimat
                          C. Cidofovir

                          10. What is a fact about the smallpox and monkeypox vaccine (JYNNEOS)?
                          A. Anaphylactic reactions after dosing are possible
                          B. Africa data suggests only 50% effectiveness
                          C. A common adverse reaction was afibrillation

                          Pharmacy Technician Post Test (for viewing only)

                          Go Bananas: Peel Away the Unknowns of Monkeypox

                          Pharmacy Technician Post-test

                          EDUCATIONAL OBJECTIVES
                          After participating in this activity pharmacists and pharmacy technicians will be able to:
                          ● Describe emerging information about monkeypox
                          ● Use this information to answer patients’ questions

                          1. Which of the following is TRUE about monkeypox?
                          A. Monkeypox is more contagious than smallpox
                          B. Monkeypox transmission by bodily fluids can occur
                          C. Monkeypox is only contagious for four days

                          2. Which of the following is important regarding transmission of monkeypox?
                          A. The population at greatest risk for severe disease are infants and young children
                          B. Sexually active monkeypox infected individuals can stop using a condom after six days
                          C. Monkeypox transmission by exhaled droplets is the most common method of spread

                          3. When Tom Smith is requesting a refill, he tells you that he recently heard that monkeypox evolves into syphilis. What is your reply?
                          A. Yes, monkeypox evolves to primary syphilis but not secondary syphilis
                          B. Testing is not required for genital rashes because the evolution occurs
                          C. They are separate conditions but some people may be co-infected

                          4. Sally Williams comes to you for her travel vaccines before travel to Africa to hunt. She shares that she loves feeding the monkeys there and asks about monkeypox risk.
                          A. Tell her to get vaccinated with cidofovir and take insect repellant
                          B. She should avoid contact with monkeys, hunting and eating game meat
                          C. Tell her PEP is recommended in uncertain risk when she returns

                          5. What is one monkeypox potential impact on health?
                          A. Patients not requiring hospitalization but who are potentially infectious should home isolate
                          B. Conditions leading to hospitalization have included the need to provide behavioral consult
                          C. Discontinuation of isolation should be determined in consultation with respiratory therapist

                          6. A nurse from a physician’s office in the building next door stops by and asks you about storage conditions for three vaccines they plan to order for their clinic patients. What is the BEST answer?
                          A. Tell her that none of the vaccines used for monkeypox are commercially available
                          B. Pull the complete prescribing information for the vaccines in question
                          C. Say that you need to consult with the pharmacist and you will call her later

                          7. Which vaccine is indicated for prevention of monkeypox in adults 18 years of age or older who are determined to be at high risk for infection?

                          A. TPOXX
                          B. VIGIV
                          C. JYNNEOS

                          8. Which pharmaceutical can be used in people exposed to monkeypox if it is used under an expanded access investigational new drug protocol?

                          A. Smallpox vaccine
                          B. Pfizer/BioNTech vaccine
                          C. Afluria Quadrivalent

                          9. Which therapeutic is stockpiled by the U. S. government, has an EA-IND and was found to have in vitro activity against seven monkeypox strains?

                          A. Vaccinia immune globulin
                          B. Tecovirimat
                          C. Cidofovir

                          10. What is a fact about the smallpox and monkeypox vaccine (JYNNEOS)?
                          A. Anaphylactic reactions after dosing are possible
                          B. Africa data suggests only 50% effectiveness
                          C. A common adverse reaction was afibrillation

                          References

                          Full List of References

                          References

                             
                            References
                            1. Monkeypox. World Health Organization. Updated May 2022. Accessed June 8, 2022. https://www.who.int/news-room/fact-sheets/detail/monkeypox
                            2. Minhaj F, Ogale Y, Whitehall F, et al. Monkeypox outbreak-nine states, May 2022. MMWR Morb Mortal Wkly Rep. 2022 Jun 10;71(23):764-769. doi: 10.15585/mmwr.mm7123e1
                            3. Monkeypox. Transmission. Centers for Disease Control and Prevention. Updated May 29, 2022. Accessed June 12, 2022. https://www.cdc.gov/poxvirus/monkeypox/transmission.html
                            4. Public health advice for gay, bisexual and other men who have sex with men on the recent outbreak of monkeypox. World Health Organization. May 2022. Accessed June 8, 2022. public-health-advice-for-msm-on-monkeypox-22-may-2022.pdf (who.int)
                            5. Khalil A, Samara A, O'Brien P, Morris E, Draycott T, Lees C, et al. Monkeypox and pregnancy: what do obstetricians need to know? Ultrasound Obstet Gynecol. 2022 Jun 2. doi: 10.1002/uog.24968. Epub ahead of print
                            6. Dirckx, J, ed. Stedman’s concise medical dictionary for the health professions.3rd edition. Williams and Wilkins; 1997
                            7. Multi-country monkeypox update. World Health Organization. Updated June 4, 2022. Accessed June 8, 2022 Multi-country monkeypox outbreak: situation update (who.int)
                            8. Travel Health Notices. Centers for Disease Control and Prevention. Updated June 8, 2022. Accessed June 8, 2022. https://wwwnc.cdc.gov/travel/notices
                            9. Disinfectants for emerging viral pathogens. US Environmental Protection Agency. Updated June 2, 2022. Accessed June 12, 2022. https://www.epa.gov/pesticide-registration/disinfectants-emergingviral-pathogens-evps-list-q
                            10. Monkeypox. Duration of isolation procedures. Centers for Disease Control and Prevention. Updated May 31, 2022. Accessed June 12, 2022. https://www.cdc.gov/poxvirus/monkeypox/clinicians/isolation-procedures.html
                            11. WHO Director-General’s opening remarks at the COVID-19 media briefing-8 June 2022. World Health Organization. June 8, 2022. Accessed June 12, 2022. WHO Director-General's opening remarks at the COVID-19 media briefing – 8 June 2022
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                            18. Monkeypox. Treatment. Centers for Disease Control and Prevention. Updated June 9, 2022. Accessed June 9, 2022. https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.html
                            19. Smith S, Olson V, Karem K, et al. In vitro efficacy of ST246 against smallpox and monkeypox. Antimicrob Agents Chemother. 2009;53(3):1007–1012
                            20 Reynolds M, McCollum A, Nguete B, Shongo Lushima R, Peterson B. Improving the carand treatment of monkeypox patients in low resource settings: applying evidence from contemporary biomedical and smallpox biodefense research. Viruses. 2017; 9(12):380 doi: 10.3390/v9120380

                            Cartoon image of a virus with the face of a monkey.

                            Law: Off-Label Drug Use and The Pharmacist’s Role

                            About this Course

                            This course is a recorded (home study version) of the CE Finale Encore Webinars.

                             

                            Learning Objectives

                            Upon completion of this application based CE Activity, a pharmacist will be able to:

                            ·       Differentiate critical state and federal personnel law
                            ·       Explain common personnel laws and issues with their implementation
                            ·       List pharmacy-related laws most likely to be violated
                            ·       Identify ways to improve adherence to laws

                            Release and Expiration Dates

                            Released:  December 21, 2021
                            Expires:  December 17, 2024

                            Course Fee

                            $15 Pharmacist

                            ACPE UAN

                            0009-0000-21-055-H03-P

                            Session Code

                            21RW55-JXT85

                            Accreditation Hours

                            1.0 hours of CE

                            Additional Information

                             

                            How to Complete Evaluation:  When you are ready to submit quiz answers, go to the BLUE take test/evaluation button.

                            Accreditation Statement

                            The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

                            Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs)  for completing the activity ACPE UAN 0009-0000-21-055-H03-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

                            Grant Funding

                            There is no grant funding for this activity.

                            Faculty

                            Jeannette Y. Wick, RPh, MBA, FASCP
                            Asst. Director OPPD
                            University of Connecticut School of Pharmacy
                            Storrs, CT

                            Faculty Disclosure

                            In accordance with the Accreditation Council for Pharmacy Education (ACPE) Criteria for Quality and Interpretive Guidelines, The University of Connecticut School of Pharmacy requires that faculty disclose any relationship that the faculty may have with commercial entities whose products or services may be mentioned in the activity.

                            • Jeannette  Wick has no relationships with ineligible companies

                            Disclaimer

                            The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

                            CONTENT

                            POST TEST

                            1. How do federal and state law compare?
                            A. Most states use a model that mimics federal system
                            B. State law trumps any federal law in explicit conflict
                            C. The law that affords the fewest rights always prevails

                            2. An employee believes she has a discrimination case against her employer. She does her research and learns she is unlikely to win. What type of discrimination has she alleged?
                            A. Retaliation
                            B. Color
                            C. Race

                            3. Why is the OSHA “look-back” period important once a pharmacy is cited for a violation?
                            A. Repeat citations for the same violation during the next five years can cost up to $70,000 each
                            B. OSHA can fine employers if employees allege violations in previous five years without proof
                            C. Should an employee death or injury occur within five years, OSHA will shutter the business.

                            4. Which of the following questions can reduce risk and increase employee satisfaction in your workplace when an employee files a complaint or grievance?
                            A. Did you complain about this at your last job?
                            B. What exactly is your problem?
                            C. What relief are you seeking?

                            5. What can an employer use as an affirmative defense if an employee files a discrimination complaint?
                            A. Demonstrate the plaintiff’s performance was better than other employees’
                            B. Provide detailed records of complaint filed by clients/patients/customers
                            C. Show documentation that the plaintiff was an acceptable team player

                            Handouts

                            VIDEO