INTRODUCTION

A woman is anxiously waiting at the pharmacy counter and asks to see the pharmacist. She hands you a container and says, “I picked up this prescription for my father yesterday and I noticed this big black box on the patient information.” There is indeed a visible big black box that surrounds a message saying “WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.” “What should I do?” she asks, “and why didn’t someone talk to me about this when I picked up the prescription?” You think back and remember that this is called a “boxed warning”…

THE BOXED WARNING

The Food and Drug Administration (FDA) has several means of providing information on drug risks to healthcare practitioners and patients.¹ One example is the boxed warning (BW, formerly and colloquially referred to as a “black box warning”). The FDA requires a BW for certain medications and reserves them for the most serious risks associated with a drug.¹ It is intended “to identify and describe a discrete set of adverse reactions and other potential safety hazards that are serious or are otherwise clinically significant because they have implications for prescribing decisions or for patient management.”² A BW is designed to alert healthcare providers and patients to potentially fatal or serious life threatening or disabling adverse effects that may occur with the use of that drug.³

A BW is ordinarily used in situations where¹

• an adverse reaction is so serious in proportion to the potential benefits that it is essential that prescribers consider the risk/benefit before prescribing
• there is a serious adverse reaction that can be prevented or reduced in severity by appropriate use of the drug
• the FDA has concluded that the drug can be safely used only if its distribution or use is restricted.

Appropriate use of the drug in this context includes patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug, or managing patients in a specific manner.¹

A BW provides a brief, concise summary of the information that is critical for prescribers to consider before providing it to a patient and includes any restriction on distribution or use.¹ Typically, a more detailed description of the risk is included elsewhere in the labeling (e.g., in contraindications or warnings and precautions sections), that must be identified by a cross-reference.¹

BWs have a required format. The information within the box must not exceed 20 lines, must be arranged in bullet points, and must be preceded with a bold, uppercase header containing the word “WARNING” and identify the subject of the warning.² The bolded heading and summary must be contained within the box and must be followed by the statement “See full prescribing information for complete boxed warning.”² The standardization of the BW results in a uniform, easily recognizable warning, ensuring that safety information is easily accessible for its intended audience without confusion.⁴

The FDA's Center for Drug Evaluation and Research (CDER) ordinarily determines whether to require a drug to carry a BW. The decision is usually based on clinical data, but serious animal toxicity may also be the basis of a BW in the absence of sufficient clinical data.⁴ CDER usually seeks the advice of an advisory committee before issuing a warning. CDER is not bound by the committee’s recommendation but usually defers to their advice.⁴

Approval of a new drug by the FDA may be contingent upon the addition of a BW. Alternatively, the manufacturer may add the warning after marketing if post-marketing surveillance detects a serious adverse effect.⁵ The FDA continuously monitors data from post-marketing surveillance, such as MedWatch, and may modify the warning if it is warranted.³

While the FDA mandates the warning, the drug manufacturer often drafts and incorporates it into the product's labeling subject to FDA approval.⁶ Typically, the sponsor submits initial labeling which the FDA reviews and is subject to negotiation; there is a 30-day period during which the agency and the drug sponsor can exchange viewpoints and suggest alternative language.⁶ The FDA may request edits and clarification or additional studies. The FDA may also insist on narrowing the approved indications for the drug or limit it to severe cases of the approved indication. If the FDA and the manufacturer cannot reach an agreement, the FDA has the authority to make the final determination.⁶ Moreover, the manufacturer may not issue a BW without prior FDA approval.⁷

Healthcare professionals should recognize that the BW is the result of a regulatory judgment and emerges from consideration of factors such as clinical trial data, post-market surveillance, mechanistic plausibility, expert opinions, and other subjective factors; it is not based on an objective or systematic standard or threshold.^8,9 The determination about a warning may be based on observed harms or anticipated harms, such as risks associated with pharmacologically similar drugs or plausible risks that have not yet been substantiated with current use.⁸

Drug manufacturers have an incentive to resist labeling their product with a BW since a BW may affect the prescribing of a drug, especially if alternatives exist that do not have a prominent warning.^9,10 One example is the use of atypical antipsychotic drugs (such as the one our patient above inquired about). One study examined the prescribing of atypical antipsychotic drugs before and after an FDA advisory leading to a subsequent BW in 2005. The BW warned of an increased risk of mortality associated with the use of atypical antipsychotics among elderly patients with dementia.¹⁰ Use of atypical drugs had increased at an annual rate of 34% during the two years prior to the BW. The advisory and BW were associated with a decrease in the use of these drugs beginning within one month of the advisory and continuing at least through 2008.¹⁰

Similar declining sales were observed for droperidol and antidepressants in children.⁹ A mail survey of 2,400 pediatricians in Canada conducted after a warning was required for selective serotonin reuptake inhibitor antidepressants found that about three-quarters of prescribers were aware of the warning and 80% of those changed their prescribing habits.¹¹ About one-third of prescribers aware of the warning followed their patients more closely and 7% stopped treatment with these drugs in at least one patient.¹¹

An interesting tale of the effect of a boxed warning occurred with droperidol.¹² The FDA approved droperidol in 1970 as an antiemetic and tranquilizer and prescribers used it effectively to prevent and treat postoperative nausea and vomiting. In the late 1990s, reports indicated the drug had the potential to produce cardiac complications, including QT interval prolongation, ventricular arrhythmias, and Torsades de Pointes. The FDA mandated a BW in 2001 because of the heart complications.¹²

The warning label stated that patients should be given droperidol only after failing other treatment options and also stated that prescribers should use electrocardiography prior to drug administration and continue for two to three hours afterwards to monitor cardiac arrhythmias.¹²

Following this decision, droperidol use dropped as hospitals and clinicians switched to safer alternatives that required less monitoring. The drug virtually vanished from hospital pharmacies and formularies.¹² This resulted in strong reaction from the medical community. Critics pointed out that the scientific evidence to support the BW consisted of a few hundred patients receiving varying doses of droperidol, with the vast majority of patients far exceeding the usual antiemetic dosing by as much as two orders of magnitude.¹² Most patients who suffered fatal complications had received droperidol doses of 25 to 250 mg, compared with the lower standard intravenous antiemetic dose of 0.625 to 1.25 mg. Moreover, many of the patients who received droperidol doses of 1.25 mg or less and experienced cardiac complications had confounding factors present, which were not accounted for by the FDA.¹²

Independent reviews of the FDA’s data concluded that droperidol’s safety and efficacy at lower doses was comparable to alternatives, but the FDA refused to drop the warning label.^12,13 In 2003, the FDA noted that it had asked the manufacturer to undertake additional safety studies or submit an extensive literature review.¹² The drug manufacturer rejected this request, citing financial constraints. However, the FDA provided further clarification that the BW was only meant to apply to droperidol doses specified in the package insert, which was an initial dose of 2.5 mg, since that was the only data available to the agency.¹² The FDA could not assess the safety and efficacy of the lower antiemetic dose and considered this to be an off-label use.¹² The FDA reasserted that it does not regulate off-label drug use as deemed appropriate by a clinician's professional judgement. Subsequently, the drug regained some use in emergency departments.¹²

PAUSE AND PONDER: How can you balance providing important risk information while not instilling reluctance to use a medication when counseling?

The BW is not permanent. Warnings can be removed or modified (see below) if new, robust scientific evidence shows the risks are overstated or don't apply to current patient populations.^3,8 Some circumstances that would justify removal of a BW include conclusions based on outdated or flawed original studies; better follow-up studies that show a more favorable risk/benefit relationship; warnings that overstate the risk and result in patients avoiding needed treatments; or advocacy from medical organizations.³

BACKGROUND

The boxed warning was first implemented in 1979 and currently, more than 400 products carry the warning.^5,9 One analysis determined that the estimated probability of acquiring a new boxed warning or being withdrawn from the market over 25 years was 20%.¹⁴ Many serious adverse drug reactions are not identified until after FDA approval, and a drug’s safety profile often remains uncertain for several years on the market.¹⁴

A study of 222 drugs approved between 2001 and 2010 found that 123 resulted in postmarket safety events sufficient to trigger a regulatory response; 61 of these were BW, 59 were safety communications, and three drugs were withdrawn from the market.¹⁵ The median time from approval to first postmarket safety event was 4.2 years.¹⁵ Eight of the BWs were preceded by a safety communication but only four of these safety communications described the safety risk that triggered the subsequent BW.¹⁵ Biologics and psychiatric medications were the most likely to receive a warning.

Drugs that were given FDA fast-track approval status were more likely to receive a boxed warning.^15,16 One study found that fast-tracked drugs were 3.5 times more likely to receive a BW after already being prescribed to patients.¹⁶ The study, looking at 200 approved drugs, found that 30 received a BW and 11 were eventually withdrawn due to safety concerns.¹⁶

Familiar examples of drugs requiring a BW include atypical antipsychotics (such as the one the woman asked the pharmacist about), antidepressants, opioids, benzodiazepines, anticoagulants, non-steroidal anti-inflammatory drugs, isotretinoin, certain antibiotics, and biologics.³

An early example is the antibiotic, chloramphenicol. Chloramphenicol received a black box-like warning in 1961 before the 1979 regulations were enacted due to concerns over an adverse effect: fatal aplastic anemia (a rare life-threatening hematologic condition marked by bone marrow failure and subsequent low levels of red and white blood cells and platelets in the blood).¹⁷ The FDA first warned prescribers through other types of label modifications, but inappropriate use of the drug continued, prompting the FDA to issue its first box-like warning.¹⁷ The warning was directed to prescribers and appeared in the Physician’s Desk Reference, without direct communication to patients.¹⁸

When a BW is warranted, the FDA usually requires it for all members of a drug class.³ The rationale is that the characteristics necessitating the warning are usually shared by different pharmacologically similar therapeutic agents.  However, there are also circumstances where a BW is not universal for all drugs in a category; for example, two pharmacologically similar drugs may have different pharmacokinetic profiles.⁹

A boxed warning can also be applied when a drug poses risk-benefit considerations that are unique among drugs in a class.¹ It is important to identify when a drug is uniquely associated with a particular risk and is therefore designated as a second‑line therapy for that reason.

Although the BW is intended to warn prescribers, pharmacists, and patients, many researchers and clinicians question this labeling approach’s effectiveness.⁵ One study of hospital residents and attending physicians found that they had a limited knowledge of which medications carried BWs and the content of the warnings.^5, Needless to say, this may put patients at risk.

Another study investigated how frequently physicians prescribe BW drugs and whether they do so in compliance with the warnings. The study used automated claims data from almost one million U.S. patients from 10 geographically diverse health plans.¹⁹ They found that over a 30-month period, the range of compliance with BWs among prescribers varied from 0.3% to 49.6%.^19,20 More than 40% of health plan enrollees received at least one medication that carried a BW that could potentially apply to them. Most prescriber non-compliance occurred with recommendations for baseline laboratory monitoring. The authors speculated that the lack of consensus regarding the value of laboratory monitoring, for example of liver function testing in preventing drug‑induced liver failure, may explain why some physicians choose not to monitor some laboratory results, given the limited evidence supporting their effectiveness.²⁰ In contrast, they found few instances of prescribing BW drugs to pregnant women that were absolutely contraindicated in pregnancy.^19,20 The authors commented that evidence shows that BWs may not adequately function as risk communication tools so consequently, the FDA and manufacturers increasingly implement strengthened risk management programs for certain drugs.²⁰

OTHER RISK MANAGEMENT PROGRAMS

The FDA has other risk management programs in addition to BWs.²¹ The Durham-Humphrey Act of 1951 may be considered the first risk management program, since it established the requirement that certain prescription drugs could only be used under the supervision of a licensed healthcare practitioner.²¹ (Prior to the act, the manufacturer decided if its drug would be prescription or OTC.) In the 1980s, the FDA occasionally asked companies to develop special safety programs called Risk Management Programs (RMPs) or Risk Minimization Action Plans (RiskMAPs) to mitigate serious risks for a limited number of drug products that offered substantial therapeutic benefits.²¹ These programs consisted of education for patients and providers and distribution restrictions.^21,22

Some other current risk management programs include Patient Package Inserts (PPIs), the Risk Evaluation and Mitigation Strategy (REMS), and Medication Guides (MGs). FDA’s primary risk management tool is communication through FDA-approved product labeling for healthcare providers and patients.²¹ The FDA considers labeling to be sufficient to ensure that benefits outweigh the risks for most drugs. However, the FDA may determine that additional precautions, such as REMS, are needed in a limited number of cases.²¹

Patient Package Inserts

The forerunner to the boxed warning was the now-familiar PPI which was first put into place in 1970 for oral contraceptives (OC) and expanded in 1977 to include estrogen-containing drugs.^23,24 The PPI includes a warning regarding the most serious adverse effects of drugs and is required to be placed in or accompany each package dispensed to the patient.²³ The FDA's rationale for mandating direct information to patients was based on the elective nature of OC use by otherwise healthy women and the potential for serious (sometimes fatal) adverse effects.²⁵ The inclusion of a warning to patients also provided an opportunity for patients to participate with physicians in making a decision about their therapy.²⁵ The agency's action came as a result of several studies published in 1970s that indicated an association between the use of conjugated estrogens and an increased risk of endometrial cancer in women. A recommendation by the FDA’s Obstetrics and Gynecology Advisory Committee also contributed to the decision.²⁶

The institution of the PPI prompted litigation.²⁶ The Pharmaceutical Manufacturers Association and others, including the National Association of Chain Drug Stores, sued the FDA alleging that the Food Drug and Cosmetic Act (FDCA) did not grant the authority to make these types of requirements and that the PPI interferes with the physician-patient relationship.²⁶

The court rejected these arguments. The judge ruled that the FDCA does provide the FDA with authority to require these warnings and concluded that when the FDA “determines that the possible side effects of a drug when used as customarily prescribed are sufficiently serious as to be material to the patient's decision on use of the drug, he or she may require disclosure of those side effects on the labeling.”²⁶ Moreover, the court agreed with the FDA’s point that new studies showing that estrogen may be "unsafe for use" under the conditions explained in the labeling justified the development of the PPI since labeling that did not disclose the risks involved would be misleading.²⁶

The manufacturers asserted that, “requiring the physician to communicate information emanating from Washington without regard to his or her professional judgment concerning the accuracy of the advice or the desirability of the patient being exposed to it” interfered with the physician-patient relationship.²⁶ The court reasoned that the requirement does not preclude a physicians from exercising their judgement since they are “free to discuss the matter fully with the patient, noting his own disagreement and views” and that the labeling requirement actually encourages this behavior. The court stated that the manufacturers “urge recognition not of a right to exercise judgment in prescribing treatment, but rather of a right to control patient access to information.”²⁶

It is also worth noting the messages submitted to the FDA during the public comment period prior to the enactment of the PPI.²⁵ The agency received more than 1,000 comments with consumer groups supporting the development of warning labels.²⁵ The comments revealed that patients often do not understand the language healthcare professionals use. Further, patients exposed to oral information usually are not attentive to it, often do not remember it, and are unwilling to ask for clarification.²⁵

PAUSE AND PONDER: How do you think these findings from 1975 would be applied today? In what ways are they (or aren’t they) still relevant?

The FDA initially proposed requiring PPIs for 50 to 75 drug classes during a pilot phase, with plans to expand the requirement to nearly all prescription drugs afterward.²⁵ Obviously, this has not yet occurred.

Risk Evaluation and Mitigation Strategies

Another warning that the FDA uses to alter patient behavior impact pharmacists and technicians: the REMS.  REMS are designed to help reduce the occurrence or severity of a particular serious adverse event produced by a drug and may go beyond mere communication.²⁷ FDA can require a REMS for prescription drugs and biologics if the agency determines a warning is necessary to ensure that the benefits of the medication outweigh the risks. These medications would not be approved—or would be withdrawn—without a REMS due to their known or potential serious risks.²⁷

The FDA’s authority to require REMS was established by the passage of the Food and Drug Administration Amendments Act of 2007 (FDAAA).²⁸ The FDAAA expanded the FDA’s authority to manage risks. The FDA’s practice already included most of the REMS elements, but the new law created the authority to utilize risk evaluation and mitigation strategies and provided for structure, enforcement, and dispute resolution.²² Prior to FDAAA (before 2007), 16 drugs were approved with restrictive risk management programs, including clozapine (the "No Blood, No Drug" program) and thalidomide (the "System for Thalidomide Education and Prescribing Safety" program, or S.T.E.P.S.).²²

In determining whether REMS is necessary, the law requires consideration of the following factors²⁹:

• the estimated size of the population likely to use the drug involved
• the seriousness of the disease or condition that is to be treated with the drug
• the expected benefit of the drug with respect to such disease or condition
• the expected or actual duration of treatment with the drug
• the seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug
• whether the drug is a new molecular entity

A REMS is a required risk management plan that can include one or more elements to ensure that the benefits of a drug outweigh its risks.²⁹ If the FDA determines that a REMS is necessary, it may require additional resources describing the risks including a PPI or a MG (see below).²⁹ They may also require “elements to assure safe use” (ETASU) as part of a REMS if the documentation is not adequate to mitigate a serious risk.²⁹

ETASU may include one or a combination of the restrictions described in Table 1.²⁹

FDA’s determination as to whether a REMS is necessary for a particular drug is a drug-specific inquiry, reflecting an analysis of multiple, interrelated factors and of how each component applies in a particular case.²⁹ In conducting this analysis, FDA evaluates whether “any drug‑specific risks outweigh the drug’s benefits and whether additional interventions beyond FDA‑approved labeling are needed to ensure that its benefits continue to outweigh its risks.”²⁸ FDA relies on both premarketing and postmarketing risk assessments in making the determination. Pharmacy employees can consult FDA’s website (https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm ) to view which drugs currently require a REMS.

While FDA determines that a REMS is necessary, specifies the requirements, and approves the specific programs, the drug’s manufacturer is responsible for developing and implementing the program.²⁷ Some manufacturers develop these programs themselves while other manufacturers hire vendors or other companies to develop and implement the programs on their behalf.

The law requires that when a drug has a REMS, any generic equivalents for these drugs must also have a REMS.²⁷ Sometimes, the brand name manufacturer and the generic version’s manufacturer jointly develop and implement a REMS (referred to as a “shared system REMS”). At other times, the brand name drug and the generic have different REMS, but both must meet the same goal(s) and requirements.

The law permits waiving REMS distribution or use restrictions for certain medical countermeasures during a declared public health emergency and establishes a pathway to ensure access to REMS restricted drugs for off-label use in serious or life-threatening conditions.²⁹ It does not appear that the FDA has ever exercised this option.

REMS can affect healthcare practitioners and patients in many ways.³⁰ Some medications with a REMS can only be dispensed in specific healthcare settings, such as hospitals or infusion centers. Many REMS do not require pharmacists to do anything outside of their normal dispensing activities. However, for certain REMS, pharmacists and other dispensers may need to complete certain requirements in order to dispense the drug. These may include completing training, verifying safe use conditions (e.g., verifying required laboratory monitoring or that a patient or healthcare provider is enrolled in the REMS), counseling patients, and/or providing the patient with educational materials or a MG prior to dispensing a medication with a REMS.³⁰ Certain REMS may require the pharmacies to become certified. For example, the anticonvulsant vigabatrin is only available in an inpatient setting or from pharmacies that are able to comply with the REMS’ requirements. Another example is mifepristone, discussed below.

Some drugs require both a BW and a REMS. Pharmacists and technicians have probably encountered the dual warnings for isotretinoin. The FDA approved isotretinoin for the treatment of severe acne in 1982.²² Isotretinoin is highly teratogenic and the FDA issued multiple warnings against the use of the product during pregnancy: in three sections of the package insert (warnings, precautions, and contraindications) and also in a patient information brochure and in information to prescribers.²² Shortly after approval, reports of human malformations emerged in patients taking the drug. As a result, health communication letters were sent to 500,000 prescribers and 60,000 pharmacists reminding them about the warnings on the package insert. The 1982 warning was sufficient to inform users of the dangers from the drug and also provided protection for the manufacturer to avoid liability, at least according to the Florida Supreme Court.³¹

In 1988, following a meeting of the Dermatologic Advisory Committee, warnings were upgraded and an isotretinoin Pregnancy Prevention Program (PPP) was implemented; this was the first risk management program introduced by a pharmaceutical company.^22,31 The program included several elements: a boxed warning; informed consent for female patients; a PPP kit for physicians containing patient information brochures and pregnancy counseling materials for the prescriber; a prescriber tracking survey; and annual and quarterly meetings with FDA.²²

Pharmacy personnel are aware that isotretinoin also has a REMS designation, the iPLEDGE program.³² The iPLEDGE Program was originally implemented in early 2005 and approved as the iPLEDGE REMS in 2010. The goal of the REMS was to inform prescribers, pharmacists, and patients about isotretinoin’s serious risks and safe-use conditions and prevent fetal exposure to the drug. One of the REMS requirements is that prescribers must be enrolled, and the dispensing pharmacist must receive a Risk Management Authorization (RMA) before filling and dispensing prescriptions.³²

Isotretinoin has also been associated with an increased risk of neuropsychiatric adverse events including depression, anxiety, and increased suicidality.³³ These risks prompted the FDA to issue a BW in 2005, but these observations have been refuted.³³

Another example of a drug that carried both a boxed warning and a REMS is the atypical antipsychotic drug, clozapine. The FDA approved clozapine for treatment-resistant schizophrenia in 1989 and its labeling included a warning due to a risk of producing severe neutropenia.³⁴ The initial requirement called for weekly white blood cell monitoring. The requirement was revised in 2005 to weekly monitoring for the first six months of therapy, biweekly monitoring for months six to 12 months, and monthly monitoring therafter.³⁴ The monitoring protocol formally became a REMS in 2015.³⁵ The REMS was lifted in 2025 as a result of evidence suggesting that the risk is no greater than for other antipsychotics and a decision by FDA to decrease the burden on the healthcare delivery system and improve access to clozapine.^35,35

Clozapine and most other second-generation antipsychotic drugs also carry a BW warning of increased risk of death related to psychosis and behavioral problems in elderly patients with dementia.³⁵ (Where have we seen this lately?)

A REMS that generated considerable controversy is the one for the abortion drug mifepristone. The FDA approved mifepristone but concluded that certain restrictions were necessary to ensure its safe use. It received both a BW for rare, but potentially fatal, bleeding episodes, and a REMS.³⁶ The initial REMS in 2011 required prescribers to be certified. They also needed to demonstrate necessary qualifications to assess whether patients are appropriate candidates for the drug and provide intervention in case of complications. It also restricted dispensing to in-person in a clinic, medical office, or hospital visit. (Notably, the so called “in-person dispensing requirement” was temporarily lifted during the COVID-19 public health emergency, permitting telehealth prescribing.) The FDA determined in 2021 that the REMS should be modified to reduce the burden on the healthcare delivery system and improve access to this time-sensitive medication. The modifications removed the in-person requirement and also permitted pharmacies to become certified to dispense the drug. These changes spawned numerous lawsuits by states and healthcare providers on both sides of this highly contentious issue: one side wanting to reinstate the in-person requirement and the other to eliminate the REMS. Some of these suits are still ongoing.³⁷

REMS have also created another controversy. The FDA, the Federal Trade Commission, generic drug manufacturers, and some members of Congress have expressed concern that brand-name manufacturers are using REMS to prevent or delay generic drugs from entering the market. The Director of the CDER, for example, has testified that some brand pharmaceutical companies have used REMS and distribution restrictions to impede competition by withholding or refusing to sell samples of the branded drug to the generic company for purposes of bioequivalence testing and prolonging negotiations related to developing a single, shared system of REMS.²²

MEDICATION GUIDES

Another means of alerting patients to potential risks is the MG.³⁸ An MG is part of the FDA-approved prescription drug labeling for certain prescription drugs when the FDA determines that³⁸

• Patient labeling could help prevent serious adverse reactions
• The drug has serious risk(s) relative to benefits of which patients should be made aware because information concerning the risk(s) could affect patients' decision to use, or to continue to use, the product, or
• Patient adherence to directions for use is crucial to the drug’s effectiveness

The medication’s manufacturer develops MGs, but the FDA must approve them. They are required to be distributed to the patient or the patient’s agent at the time of dispensing in paper form although the patient may request electronic delivery instead.³⁸

The MG contains information on proper use of the drug product, such as contraindications, how to use the drug properly (e.g., adhering to dosing instructions and what to do in case of an overdose), adverse reactions reasonably likely to be caused by the drug product that are serious or occur frequently, activities to be avoided while taking the drug, risk to special populations, or risk of dependence.³⁹

It is important to appreciate that while MGs may be required for drugs with a BW, not every BW triggers an MG.⁸ Consequently, many high-risk discussions may not take place. BWs are primarily intended as signals to healthcare providers providing guidance on what clinicians prescribe and how pharmacists should dispense and function, not as direct patient alerts.⁸ Their effectiveness in changing behavior has been questioned.⁸ Moreover, even the MGs may not achieve their desired result.

A recent study utilizing 449 patients seeking primary care services (18 to 85 years old) analyzed 185 patient Medication Guides.⁴⁰ The authors found that the guides averaged almost 2000 words with a mean reading level of 10-11^th grade. Only one guide was deemed suitable for readability. None provided summaries or reviews. Moreover, comprehension of the guides was poor, especially among patients with low or marginal literacy. The authors concluded that current MGs are of little value to patients, as they are too complex and difficult to understand especially for individuals with limited literacy.⁴⁰ The SIDEBAR describes “plain language” communication tips that manufacturers should use to simplify such patient communications.

SIDEBAR: What is Plain Language?
The U.S. Department of Health and Human Services (DHSS) designed Plain Language Guidelines to help communicators present information so that readers can find, understand, and use information quickly. The guidelines emphasize clarity, organization, and audience awareness—principles that are especially important in healthcare, where misunderstanding can have serious consequences.

A central tenet of plain language is writing for the intended audience. This means identifying who the readers are, what they already know, and what they need to do with the information. For example, materials written for patients should avoid technical jargon or, when technical terms are necessary, define them clearly. The guidelines encourage writers to anticipate readers’ questions and structure content so that answers are easy to locate.

Organization is another key principle. The DHHS recommends placing the most important information first—often referred to as “front-loading.” Readers should not have to work through dense paragraphs to find critical instructions or key messages. Effective use of headings, subheadings, and logical flow allows readers to scan documents and quickly identify relevant sections. Bulleted or numbered lists are encouraged when presenting steps, recommendations, or multiple items, as they improve readability and reduce cognitive load.

Word choice plays a significant role in plain language. The guidelines advocate for using common, everyday words instead of complex or unfamiliar terminology. For instance, “use” is preferred over “utilize,” and “help” over “facilitate.” Writers should keep sentences relatively short and direct. Active voice—sentence structure that clearly identifies who is responsible for an action—makes instructions more actionable and less ambiguous.

Design and formatting are integral to comprehension. Adequate white space, readable fonts, and consistent formatting make documents more approachable. The guidelines suggest avoiding large blocks of text and instead breaking content into manageable chunks. Visual aids—such as tables, charts, or icons—can enhance understanding when used appropriately, but they should complement, not replace, clear writing.

Another important aspect of the DHHS Plain Language Guidelines is testing and revision. Reviewing materials with real users whenever possible ensures the content is understandable and useful. Feedback can reveal gaps in clarity or assumptions about reader knowledge that may not be true. Revising based on this input is an essential step in producing effective communication.

Ultimately, the DHHS Plain Language Guidelines are not about “dumbing down” content but about making it accessible and usable. In healthcare and public health contexts, this approach supports better decision-making, improves patient outcomes, and promotes equity by ensuring that information is understandable to people with varying levels of literacy and background knowledge.

In May 2023, the FDA published a proposed rule about a new type of FDA-approved patient labeling, known as Patient Medication Information (PMI).³⁹ The intent of the PMI is to highlight essential information that patients need to know about the prescription drug product, including basic directions on how to use the product.

PAUSE AND PONDER: What information do you think a PMI should contain to successfully provide adequate warnings to patients?

RECENT DEVELOPMENTS

As noted above, the inclusion of a BW is not necessarily permanent. An important example is the smoking cessation drug varenicline. The drug was approved in 2006. Shortly after its approval, anecdotal reports from popular press and internet sites, post‐marketing case reports, and reports to the FDA's Adverse Event Reporting System suggested that some patients prescribed varenicline had experienced suicidal thoughts and aggressive and erratic behavior.⁴¹ The FDA initiated safety reviews in response to these reports and concluded that the drug was associated with adverse psychiatric events.⁴¹ The agency issued a public health advisory in 2008 and mandated a boxed warning in 2009.⁴³ Subsequently, a large clinical trial of patients with and without psychiatric illness found that the drug was not associated with an increased incidence of clinically significant neuropsychiatric adverse events. The FDA removed the boxed warning in 2016.⁴²

FDA has recently lifted the boxed warning on hormone replacement therapy (HRT) drugs, which are commonly used to treat menopause symptoms.⁴⁴ The warning was mandated in 2003 based a study of more than 16,000 post-menopausal women receiving conjugated equine estrogens plus medroxyprogesterone.^3,44 The study found an increased risk of breast and endometrial cancers, stroke, blood clots, heart attacks, and dementia associated with the use of the hormone therapy.^3,44 Following the implementation of the label, the use of these treatments among postmenopausal women decreased from 30% to 5% over the next two decades.³

FDA removed the BW in November 2025, citing “fear and misinformation surrounding hormone replacement therapy.”⁴⁴ The FDA justified the change by noting problems in the initial research, including “the average age of women in the study was 63 years—over a decade past the average age of a woman experiencing menopause—and study participants were given a hormone formulation no longer in common use.”⁴⁴ Moreover, randomized studies showed that women who initiate HRT within 10 years of the onset of menopause (generally before age 60) have a reduction in all-cause mortality and bone fractures, and may reduce the risk of cardiovascular disease and Alzheimer’s disease.⁴⁵ The FDA’s actions further illustrate the effect that a BW has on prescribing and use and also the dynamic nature of the warnings. Of note, an epidemiologist pointed out that these changes in labeling were not the result of new information but rather a reconsideration and reassessment of the risk-benefit for these drugs.³ However, FDA is not seeking to remove the boxed warning for endometrial cancer for systemic estrogen-alone products.

PAUSE AND PONDER: How would you have handled the situation presented at the beginning of this activity?

SUMMARY

The FDA has a number of tools that can be used to communicate drug risks to healthcare providers and patients. These include boxed warnings, REMS, and MGs. Pharmacy personnel should be aware of these different tools and how they are developed to manage the risk-benefit of drugs. In addition, pharmacy personnel should recognize that the warnings are subject to change and need to remain aware of the evolving judgment on how risks should be managed. They also need to be ready to answer questions from patients receiving these warnings.

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INTRODUCTION

Meet Charlie. Charlie is a newly licensed pharmacist who is excited to start his new job at a busy community pharmacy. During his training, a more experienced coworker, Hazel, instructs Charlie to override insurance claim rejections. She shows him the prior authorization override code to submit claims. She tells him, “You don’t actually need to contact the prescriber and have them obtain prior authorization for it to work. It’s just a workaround everyone does.”

The next day, the insurance program rejects a prescription for Reimbursitol because it requires prior authorization. Its cash price is more than $1,000, and Charlie dreads informing the patient. Hazel tells Charlie to enter the override code, even though they have not contacted the provider and the insurer has not approved the prior authorization. The claim goes through, and the pharmacy receives payment for Reimbursitol. Charlie is eager to fit in and lacks experience, and this workaround streamlines his workflow, so he follows this process for several prescriptions over the next few weeks.

Healthcare fraud imposes an enormous burden on the healthcare system. Experts estimate that fraud accounts for 3% to 10% of healthcare expenses annually, resulting in billions of dollars lost each year.¹ In 2024, the United States (U.S.) spent $5.3 trillion on healthcare, or about $15,474 per person. A large share of this spending was divided among the following²

• Medicare: $1.118 billion (21%)
• Medicaid: $932 billion (18%)
• Private health insurance: $1.645 billion (31%)
• Out-of-pocket spending: $557 billion (11%)

Based on these figures, fraud could account for losses of $159 billion to $530 billion in just one year.

Not only does fraud affect healthcare on a national level, but it directly impacts pharmacies. For example, in 2019, an independent pharmacy chain allegedly submitted false claims to Medicare and Medicaid for prescription medications by switching from a lower cost to a higher cost product without a medical need or prescription. Investigators allege that pharmacy staff switched patients from an inexpensive to an expensive medication and billed federal healthcare programs for reimbursement of the high-cost item. This change in therapy inflated the complexity of the product dispensed, which was not medically necessary and resulted in larger reimbursement payments, In some cases, the pharmacy dispensed the expensive item and billed federal payors without a valid prescription. The case resolved in 2022 with the pharmacy paying $2.05 million and implementing training programs regarding fraud and compliance.^3,4

The water can sometimes seem muddy when it comes to billing practices and legal regulations. Understanding the laws and regulations that govern healthcare can enable pharmacy team members to identify, report, and prevent fraud and abuse, rather than falling victim to unsavory practices.

FRAUD, ABUSE, AND WASTE: WHAT'S THE DIFFERENCE?

Although fraud, waste, and abuse are often grouped together, each carries a distinct definition, intent standard, and regulatory implication.

Fraud is an intentional deception or misrepresentation that could result in an unauthorized benefit. It is intentionally wrongful and considered criminal.^5,6 An example of fraud is billing for services that were not provided.⁷

Abuse is provider practices that are inconsistent with accepted practices, resulting in an unnecessary cost to the health care system. There is usually not criminal intent, but it still leads to financial loss by the payor.^5,6 An example of abuse is billing for medically unnecessary services.⁷

Waste is misuse or inappropriate use of resources that results in unnecessary costs to the healthcare system. It is not associated with deceptive intentions.⁶ An example of waste is ordering excessive or unnecessary tests or services.

See the SIDEBAR for a quick overview of additional law terminology.

SIDEBAR: A (Very) Brief Law Terminology Refresher^8,9

Law: A broad term for all rules that govern conduct, such as statutes, ordinances, and regulations. For example, the Controlled Substance Act is a federal law regulating agents with potential for abuse.

Act or statute: Both refer to a specific type of law. An act is a formal, written law passed by a legislative body, such as Congress or state legislature. A statute refers to the written law itself, typically as it is codified in the U.S. Code. For example, the False Claims Act began as a bill in January 1863. When President Lincoln signed it in March 1863, it became law. It is currently published in the official U.S. federal code as 31 U.S.C. §§ 3729–3733.

Ordinance: A local law in place to ensure public safety, health, and general welfare. Ordinances often regulate fire and safety regulations, housing standards, parking regulations, snow removal, littering, public streets and sidewalks, and zoning. Examples of ordinances pertaining to pharmacy include zoning, signage, and operating hours.

Regulation: A rule issued by administrative agencies that have legislative authority over a specific area to enforce rules or statutes. For example, the state board of pharmacy may regulate how many CE hours pharmacists and technicians must complete each year, or for how many years documentation must remain on the pharmacy premises.

Table 1 offers a brief side-by-side look at civil versus criminal law.

Table 1. Overview of Criminal Law vs. Civil Law^10-12

*Burden of proof is the responsibility to present enough evidence to win the case and meet the applicable legal standard. It usually lies with the party initiating the case. In other words, the prosecutor or plaintiff must find the defendant guilty rather than the defendant proving their innocence.

COMPLIANCE IN ACTION: FEDERAL LAWS AND REGULATIONS

Several federal laws and regulations are in place to prevent and address fraud. The False Claims Act (FCA), Anti-Kickback Statute (AKS), Physician Self-Referral Law (Stark Law), and HIPAA establish important compliance requirements for healthcare.

False Claims Act (FCA)

The False Claims Act (FCA; 31 U.S.C. §§ 3729–3733) is a civil federal statute dating back to 1863 in response to contractor fraud during the American Civil War.¹³ Still in effect today, the FCA allows the federal government to recover losses through civil lawsuits for false or fraudulent claims, seek financial penalties, and pursue criminal charges for that conduct.¹⁴

Knowingly submitting false claims or conspiring to submit false claims violates the FCA.¹³ In the healthcare setting, the FCA applies whenever a federal payor is involved, such as Medicare or Medicaid. Examples of healthcare-related FCA violations include submitting false or fraudulent claims for payment, billing for services not rendered, and upcoding (billing for a more expensive service than was actually obtained by the patient).¹⁵

Civil liability under the FCA does not require a specific intent to defraud. In its definition, the FCA uses the term “knowingly” to include individuals who knew the claim was false, deliberately ignored that it was false, or ignored signs that it was false. Violations carrying civil liability consist of recklessness or deliberate ignorance and do not require intent. In other words, an individual who “looks the other way” or “should have known” may be violating the FCA.¹⁶

Civil penalties under the FCA are up to three times the government’s loss plus inflation-related fines ($11,000 for Medicare or Medicaid fraud) per claim. Because each item or service billed counts as a claim, losses and fines can accumulate quickly.¹⁶ The FCA includes a whistleblower provision (“qui tam”), which allows private citizens to submit a claim on the government's behalf for a share of recoveries, usually between 15% to 30%.³ Whistleblowers can be business partners (current or former), hospital or office staff, patients, or competitors.^13,16

In addition to seeking civil penalties under the FCA, the government may also bring criminal charges where appropriate. More severe cases—those with intentional fraud—may face criminal prosecution. Criminal penalties include imprisonment and criminal fines.¹⁶

Anti-Kickback Statute (AKS)

The Anti-Kickback Statute (AKS; 42 U.S.C. § 1320a-7b(b)) ensures that healthcare providers make clinical decisions objectively and appropriately based on patient need, not financial incentive. This federal criminal law prohibits knowingly and willfully offering, paying, soliciting, or receiving remuneration to entice or reward referrals. It also prohibits creating federal healthcare business involving items or services that are reimbursable by programs like Medicare, Medicaid, or other federal health programs. Remuneration is considered anything of value, and in this instance, it covers a wide range. Examples include–but are not limited to–free rent, hotel stays, meals, bribes, rebates, and excessive compensation.¹⁶

The AKS applies to both the party offering the kickback and the party receiving it. This means that it is illegal to accept payment for referring patients, and it is illegal to pay to have patients referred.¹⁶

AKS violations carry both criminal and civil penalties that can be extensive and overlapping. Violations of the AKS are classified as felony crimes under federal law and can result in jail time.¹⁶ Criminal penalties can include fines up to $25,000 per violation and/or up to a 5-year prison term. Civil penalties fall under the Civil Monetary Penalties Law and carry penalties of up to $50,000 per kickback plus up to three times the remuneration value.

Furthermore, AKS violations may also create liability under the FCA and incur the penalties associated with FCA violations. In addition to the criminal and civil penalties, AKS violations can result in ineligibility to participate in federal health care programs.^14,16

Physician Self-Referral Law (Stark Law)

The Physician Self-Referral Law (42 U.S.C. § 1395nn), often called the Stark Law, is a civil law that prohibits physicians from referring Medicare or Medicaid patients for designated health services (DHS) to parties with which the physician or an immediate family member has a financial relationship, unless an exception applies. Simply put, physicians should not profit by referring patients to services in which they have a financial stake.¹⁶ See Table 2 for a list of DHS.

Table 2. Stark Law Designated Health Services (DHS)¹⁷

The Stark Law is a strict liability statute, meaning that a violation can exist even without specific intent to break the law. Any violation—even an accidental one—is a violation of the Stark Law.¹⁶

Civil penalties include fines and ineligibility to participate in federal healthcare programs.¹⁶ Although the Stark Law addresses physician referrals, pharmacists and technicians may be indirectly affected. For example, if a physical refers Medicare or Medicaid patients to a pharmacy which he or she has a financial interest, it may violate the Stark Law, unless an exception applies. A complete list of regulatory exceptions to the Stark Law is beyond the scope of this activity; however, exceptions that may apply to a pharmacy setting include the in-office ancillary services exception, bona fide employment relationships, and fair market value compensation arrangements.^18,19 Pharmacy team members can contact their legal or compliance departments if concern exists regarding Stark Law and/or its exceptions.

Health Insurance Portability and Accountability Act (HIPAA)

While HIPAA is often perceived as primarily protecting patient privacy, it includes fraud provisions. It is a crime to knowingly use, obtain, or disclose protected health information (PHI). Criminal penalties for HIPAA violations, addressed under 42 U.S.C. § 1320d–6, can be substantial and vary depending on the nature and extent of the violation. A basic violation can result in fines up to $50,000 and/or up to 1 year in prison. When committed under false pretenses, the fines increase to no more than $100,000 and/or up to 5 years in prison. The intent to sell, transfer, or use PHI for personal gain increases the fines even further to a maximum of $250,000 and/or 10 years in prison.^20,21

Understanding the functions of key regulatory bodies can illustrate the many moving parts involved in governing healthcare. The SIDEBAR summarizes these organizations briefly.

SIDEBAR: Regulatory and Enforcement Agencies ^7,22-27

The U.S. Department of Justice (DOJ) is the federal agency responsible for ensuring justice. It enforces federal laws, prosecutes cases, oversees federal law enforcement agencies such as the Federal Bureau of Investigation (FBI) and Drug Enforcement Agency (DEA), and manages prisons. The DOJ is headed by the Attorney General.

The Federal Bureau of Investigation (FBI) reports to the DOJ. It enforces federal criminal law and conducts investigations, and can investigate corruption, fraud, and organized crime.

The U.S. Drug Enforcement Administration (DEA) enforces controlled substance laws and regulations, including the manufacture and distribution of controlled prescription drugs.

The Office of the Inspector General (OIG) is a federal agency that aims to counteract fraud, abuse, and waste while maximizing efficiency and accountability in the Department of Health and Human Services programs. The OIG can audit, investigate, and inspect federal programs, especially Medicare and Medicaid programs, which comprise a large portion of the federal budget.

The Centers for Medicare and Medicaid Services (CMS) is a federal agency within the U.S. Department of Health and Human Services. CMS oversees and regulates federal healthcare programs such as Medicare, Medicaid, and State Children’s Health Insurance Program (SCHIP). CMS collaborates with individuals, groups, and law enforcement organizations to prevent and determine fraud and abuse.

State boards regulate healthcare professions by overseeing licensing and renewals, enforcing professional standards, and inspecting facilities. They may also take disciplinary action when standards are not met. There are many state healthcare boards, but only the following disciplines have prescribing authority or direct access to medications: pharmacy, nursing, medical, osteopathic, dentistry, optometry, podiatry, and veterinary.

From Laws to Practice: Examples of Pharmacy Fraud and Abuse 

Remember Charlie? A month into his new job, he takes this CE program, reviews the earlier claims, and realizes that he entered override codes even though prior approval was never obtained. Charlie becomes worried that he might have followed bad advice.

PAUSE AND PONDER: Did Charlie knowingly commit fraud, or did he make a mistake after receiving misleading guidance? What responsibilities does Charlie have to correct past claims or disclose potential issues?

Fraud in healthcare can be committed by an individual, group, or organization.⁷ In the pharmacy setting, fraudulent activity often involves improper billing or reimbursement practices.

Pharmacy Billing and Reimbursement Fraud

Several types of billing fraud can occur in the pharmacy, such as billing for prescriptions that were never dispensed (“phantom claims”), dispensing a different quantity than prescribed without documentation, or refilling prescriptions without authorization. Additional fraudulent billing practices include billing for a brand-name drug while dispensing a generic (or billing for a more expensive generic than what was dispensed), adding medications to prescriptions without dispensing them, and submitting claims without an invoice to document purchase.²⁸

What does this look like in pharmacy practice? Here are two real-life examples involving mismatched quantities coming in versus quantities going out: A pharmacy did not have documentation supporting the medication quantities billed to Medicaid as compared to the quantities purchased from vendors over four years. The case settled for $1,333,660. Another pharmacy had similar documentation gaps; the case settled for $42,521.²⁸

See the SIDEBAR for more real-world examples of fraudulent healthcare schemes and consequences.

SIDEBAR: From the Headlines: Health Care Fraud Cases Involving Pharmacists^29-36

Between 2017 and 2022, a pharmacist submitted fraudulent claims to Medicare for medications that were never dispensed in violation of the FCA. He created fake patient profiles and fraudulent prescription entries, resulting in more than $1 million in Medicare payments to the pharmacy. In 2023, the pharmacist plead guilty to one count of healthcare fraud and was sentenced to 2 years in federal prison (after facing a maximum of 10 years). He was also ordered to pay $1.138 million in fines and restitution, and the state board of pharmacy ordered that he surrender his license.

From June 2014 to June 2020, a pharmacist defrauded Medicare and Kentucky Medicaid by billing for prescriptions that patients never received in violation of the FCA. The pharmacist also submitted inflated reimbursement claims by billing for expensive diabetic test strips while dispensing a less expensive item. The pharmacy collected $627,614 from the healthcare payors for the fraudulent prescriptions and $102,441 for the fraudulent test strip claims. She was sentenced to 20 months in prison with 2 years’ probation after release. She was also ordered to pay $730,056 in restitution, and she surrendered her license.

A pharmacist who owned a pharmacy and served as the pharmacist-in-charge coordinated a healthcare fraud scheme with two co-schemers, resulting in more than $300 million in fraudulent Medi-Cal (California’s version of Medicaid) claims. In early 2022, Medi-Cal suspended its prior authorization requirements while transitioning to a new payment system. From May 2022 to March 2023, the pharmacy billed Medi-Cal $306,521,392 for high-reimbursement, non-contracted generic drugs that normally would have required prior authorization and received approximately $204,032,151 in payments. Investigators allege that these medications were not medically indicated, often weren’t dispensed, and involved kickbacks to the two co-schemers. The co-schemers allegedly received more than $36 million in kickbacks, which the pharmacist referred to as “consulting services.” One co-schemer was a nurse practitioner who received kickbacks for writing the fraudulent prescriptions without evaluating patients, medical records, or medical necessity. The state charged her with two counts of healthcare fraud. The other co-schemer was involved in laundering money from the fraudulent payments and has been charged with one count of healthcare fraud. In August 2024, the pharmacist pleaded guilty to two counts of healthcare fraud. At the time of this writing, he is awaiting sentencing and facing a maximum of 10 years in jail for each count of healthcare fraud. This conduct not only violated the FCA by submitting claims for services not performed but also violated the AKS.

Medical Provider Healthcare Fraud

Healthcare providers may also commit fraud. Examples can include double billing (submitting multiple claims for the same service), phantom billing (billing for a service, visit, or supplies that was never received), unbundling (billing components of a service separately), or upcoding.²²

Patient or Individual Fraud

Although not the focus of this activity, pharmacy staff should be aware of fraudulent schemes involving patients or individuals. Examples include forged or altered prescriptions, doctor shopping (seeing multiple providers to obtain prescriptions for controlled substances), diversion (selling one’s prescription medication), health care provider impersonation (billing for services or supplies without a license to do so), and benefit card abuse (using someone else’s health care card or allowing someone else to use it).²² Awareness of these patterns may help pharmacy staff recognize fraudulent activities.

Speak Up! Don’t Look Away: Addressing Fraud and Abuse

Prompt reporting of suspected fraud is critical to maintain compliance with laws and regulations, and to maintain the financial viability of the healthcare system. There are several ways to report suspected fraud or abuse.⁷

In some cases, self-reporting may result in less severe penalties.²⁸ If one realizes the billing process was questionable, the very first step is to stop submitting problematic claims. Next, individuals should consider obtaining legal counsel specializing in healthcare fraud to evaluate legal practices or risks. Individuals should determine how much money was collected in error and return overpayments. If an investment or suspicious relationship is involved, end it! If appropriate, individuals should consider self-disclosure to CMS or OIG.⁷

So, what does Charlie do? He reports his concern to the pharmacy manager, who audits the claims and corrects the errors. Charlie and the pharmacy team receive additional training to prevent future mistakes. Hazel’s intent and the extent of her use of override codes—and those she influenced—were evaluated during the internal audit. No legal action is taken because the issue was caught early, reported internally, and corrected. Additionally, there was not intent to defraud—it appears to be negligent error.

The pharmacy manager uses the incident as a choose-your-own misadventure learning example. She discusses the following potential outcomes with Charlie:

• If Charlie had continued billing incorrectly even though he knew or suspected it was wrong, he could have been subject to consequences including criminal charges, civil charges, or license suspension/revocation.
• If the manager ignored Charlie’s concerns, the pharmacy and/or manager could have faced a federal investigation and penalties. Charlie could have been protected by whistleblower protection laws if he chose to file a file a qui tam case.
• If the miscoding practices were discovered during a third-party audit, consequences could have included civil penalties and a criminal investigation (to determine intent) for the individuals involved and the pharmacy.
• If Charlie had recognized and reported the miscoding right away, it would have triggered an internal investigation with possible disciplinary action for Hazel. It also would have eliminated Charlie’s liability.

Contact Information: How to Report Suspected Fraud or Abuse

If a beneficiary (patient) wants to report:

CMS Hotline: 1-800-MEDICARE (1-800-633-4227)

OIG Hotline: 1-800-HHS-TIPS (1-800-447-8477)

https://oig.hhs.gov/fraud/report-fraud/index.asp

U.S. Department of Health and Human Services

Office of Inspector General

ATTN: OIG Hotline Operations

PO Box 23489

Washington, DC 20026

Complaints specific to Medicare Part C or Part D: 1-877-7SafeRx (1-877-772-3379)

If a Medicare or Medicaid provider wants to report:

OIG Hotline: 1-800-HHS-TIPS (1-800-447-8477)

https://oig.hhs.gov/fraud/report-fraud/index.asp

U.S. Department of Health and Human Services

Office of Inspector General

ATTN: OIG Hotline Operations

PO Box 23489

Washington, DC 20026

Contact MAC (Medicare Administrative Claiming) (https://www.cms.gov/mac-info) or Medicaid State Agency

MAC can also address billing procedures, errors, or questionable practices

The OIG hotline is anonymous; however, providing contact information is preferred so that follow up can occur.⁷

DIVERSION AWARENESS FOR PHARMACY STAFF

Diversion is the unauthorized acquisition, use, or distribution of drugs.³⁸  It can occur with medications that fall under the Controlled Substance Act, such as opioids, benzodiazepines, and/or stimulants, and non-controlled medications.³⁹ Diversion can happen at any point in the supply chain and by either healthcare workers or patients.⁴⁰ This activity will focus on diversion by healthcare workers.

Diversion of Controlled Substances

Addiction often drives controlled substance diversion in healthcare environments, with opioids identified as the most frequently diverted medications.³⁸ Table 3 lists commonly diverted controlled substances. Diversion of controlled substances can cause significant harm to the patient, healthcare worker, and healthcare facility.

Table 3. Commonly Diverted Controlled Substances^38,40

Diversion of controlled medications by a healthcare worker can result in patient harm in several ways. Consider a hypothetical situation in which a healthcare worker tampers with a vial of an injectable controlled substance. The worker removes half of the contents for her own use and replaces the remainder with another clear liquid, which may or may not be sterile, using a technique that is definitely not sterile. Patient harm can result due to^41-43

• An inadequate control of pain or anxiety from a subtherapeutic dose.
• Risk of infection if the product administered is contaminated due to the addition of a nonsterile diluent or needle sharing. For example, two outbreaks occurred in 2018 due to contamination:
  • An emergency department nurse in Washington diverted a medication and it resulted in 12 cases of hepatitis C
  • A cancer center nurse diverted medication in New York leading to 6 cases of Sphingomonas paucimobilis bacteremia.
• Risk of allergy or intolerance if the patient receives a drug other than the one prescribed due to diversion of the prescribed agent.
• Potential for adverse outcomes, such as errors and complications, if a patient receives direct care from a healthcare worker who is actively and acutely impaired, as this impairment will significantly compromise clinical judgement.

Diversion also poses personal and professional harm to the healthcare worker, including the risk of overdose. Diversion and administration of injectable agents present the potential for infection due to unsterile or unsanitary self-injection techniques or contamination, along with transmission of bloodborne illnesses. Professional risks include felony prosecution, civil charges, and license suspension or revocation. The worker is also liable for fraudulent documentation in the medical record and fraudulent billing if the patient or insurance provider was billed for a medication that the patient did not receive.⁴²

Additionally, the risks associated with the diversion of controlled substances extend to the employer or healthcare organization. Regulatory and legal consequences include the ramifications of fraudulent billing, liability for damages, and diminished community confidence in the healthcare system.⁴¹

Behavioral patterns of healthcare workers may be associated with potential medication diversion. Red flags include^38,44

• Unexpected absences or late arrivals
• Disappearance from the worksite (frequent extended bathroom breaks or excessive time in the medication storeroom)
• Extra time at work (appearance on scheduled days off, seeking overtime, early arrivals, staying late)
• Consistently removing controlled substances towards the end of a shift
• Erratic productivity
• Errors with insufficient explanation
• Poor relationships with colleagues, including isolation or avoidance
• Insistence upon personal administration of injected medications to patients
• Trends with waste: too much or too little, delaying waste documentation procedures until the end of shift, or documenting waste with a variety of healthcare colleagues
• Trends with work areas: offering to work in non-assigned areas, preferring patients with controlled medications, or prioritizing work alongside new employees or orientees
• Creating false orders or “prefill” orders

Diversion of Non-Controlled Substances

Let’s check in on Charlie. A few weeks go by, and Charlie is settling into his job. He has become more comfortable with the skills and responsibilities required in his position and is adapting to the workplace culture. He notices that Hazel likes to do things her way and on her own. When Charlie tries to unpack the refrigerated delivery one morning, she takes over, telling him “I always do this. It’s too hot to leave the refrigerated items out, and I’m the fastest at putting them away.” He also notices that she’s frequently on the closing shift. When he offers to stay late so she can go home on time, Hazel says “I’ve got it. My roommate borrowed my car and is picking me up late anyway, so I might as well be the one who stays.”

Recently, Charlie has had trouble filling prescriptions for a popular injectable GLP-1 receptor agonist medication. It seems that the pharmacy can’t keep it in stock, even though the ordering system shows several recent deliveries. Hazel often tells patients the medication is on backorder.

When reviewing two GLP-1 receptor agonist prescriptions marked as “returned to stock,” Charlie can’t find the product in the refrigerator. Hazel says they were restocked earlier, adding that she will adjust the inventory herself. Charlie also notices documentation that two additional boxes were “damaged due to temperature excursion,” but he doesn’t remember a recent refrigerator breakdown.

PAUSE AND PONDER: Does Hazel’s behavior demonstrate red flags? Why are discrepancies with non-controlled, high-cost medications concerning?

The incidence of non-controlled diversion has been rising. Because non-controlled medications may not be as tightly regulated as controlled medications, they may be easier to acquire through illegal means. Individuals may divert non-controlled medications, especially high-cost products, for their own use, resale, or to supply friends or family members who can’t afford the cost.³⁹

High-cost medications that are commonly diverted include antiretrovirals and oncology medications. Other agents often diverted are performance-enhancing agents (such as erythropoietin) and psychoactive medications (such as cyclobenzaprine, quetiapine, and trazodone).³⁹ The sedative and anxiolytic effects of atypical antipsychotics have increased their desirability for misuse or diversion. These medications can be used alone for insomnia or anxiety or in combination with other illicit substances for either calming or enhancing effects.⁴⁵

Another potential area for diversion involves medications used in the management of opioid use disorder, including diphenhydramine (for histamine-induced pruritus), ondansetron (for withdrawal-related nausea and vomiting), and naloxone (for overdose reversal).³⁹

Picking up the Pieces: Prevention and Reporting

In a perfect world, medications would make their way to patients without illegal interception by an intermediary. But this world—the real world—isn’t a perfect one, and diversion happens. How should the pharmacy team handle it?

At the end of the month, Charlie is reviewing a routine inventory variance report for high-cost medications. When he completes a physical count of the items in stock, Charlie finds that the pharmacy is short four boxes of the GLP-1 receptor agonist medication. The system shows two prescriptions that were billed and later reversed to “never picked up,” and two boxes that were documented as “temperature excursion — product damaged.” However, the refrigerator logs do not show temperature fluctuations for that time.

PAUSE AND PONDER: How should Charlie address this discrepancy?

The strongest defense is a good offense. Some strategies for preventing and detecting diversion include³⁸

• Establishing a diversion program. This is a big task, and it can be challenging to find the time, energy, and resources when it is simply tacked on as an additional responsibility to an existing job description. Ideally, a position (or positions) would be dedicated solely to this role.
• Establishing to whom the program reports internally—compliance, risk management, legal, pharmacy, nursing, and so on. This will vary depending on the size and structure of the organization.
• If appropriate, including members across all disciplines in the organization, such as pharmacy, nursing, anesthesiology, medical directors, security, risk management, compliance, legal, human resources, occupational health, and employee assistance programs. Organizations can consider creating a subset Response Team for initial investigations.
• Having policies for diversion monitoring, investigation, and events.
• Conducting audits to identify and investigate discrepancies sooner rather than later. Early action may minimize risk to patients, employees, and the organization.

Monitoring for diversion of non-controlled medications may require a more nuanced strategy. Because these medications aren’t regulated as stringently as their controlled counterparts, they may be more easily diverted. The above recommendations apply for assessing non-controlled diversion, along with a few additional points³⁹

• Identify non-controlled medications at risk for diversion and consider storing them like controls—locked and routinely inventoried.
• Monitor inventory, especially noting excessive restocking and unexpected unavailability.
• If appropriate and/or feasible, utilize diversion analytics software programs to identify access, dispensing, and behavior patterns.
• For facilities with automated dispensing cabinets, review reports for overrides (who and what), canceled transactions, inventories, and discrepancies. Investigate any outliers.
• Establish a confidential reporting system for employees.
• Investigate and respond to all suspicious findings.
• Educate employees about commonly diverted non-controlled medications and the steps provided by the facility to prevent, identify, and report suspected diversion.
• Use staff feedback and facility data to evaluate and adjust the process as needed.

Charlie brings the discrepancy to the pharmacy manager, who begins an official internal audit. The audit shows that the claim reversals and inventory adjustments for the missing GLP-1 receptor agonist medications were completed with Hazel’s credentials. Security footage from two closing shifts shows Hazel placing small, boxed items from the refrigerator into her personal bag after other staff had left during times that correspond with the claim reversal.

PAUSE AND PONDER: How does reporting differ for controlled versus non-controlled discrepancies? What consequences could one expect for Hazel’s actions?

Controlled diversion requires reporting at local, state, and federal levels. Local law enforcement should be contacted, and the appropriate state licensing boards should be notified.^38,40,46 The state health department should be notified if patient risk occurs, such as tampering or product contamination.⁴³ If the diversion occurred after the prescription was filled and dispensed, it should be reported to the state Medicaid agency–even if it was filled using private insurance or cash. Incidents with diversion are often linked to other acts of fraud, waste, or abuse involving Medicaid, and reporting each occurrence may help to identify other activities.⁴⁰

Under federal regulations, DEA registrants (such as pharmacies) must notify the appropriate DEA field division office within one business day after discovery of significant loss of a controlled substance, and DEA Form 106 must be filed within 45 days.⁴⁷ Additionally, the FDA Office of Criminal Investigations (FDA-OCI) holds federal jurisdiction and can assist facilities when drug tampering of a controlled substance is involved.³⁸

Although controlled diversion carries stricter federal regulations, noncontrolled diversion is unethical, unprofessional, and can lead to significant legal and financial consequences, including license suspension. Incidents of non-controlled diversion usually are addressed by an internal investigation and documentation, state board notification, and local law enforcement notification.⁴⁶ Staff should correct insurance claims if applicable. Notification to the DEA is not required for non-controlled diversion.

How is the loss addressed at Charlie’s pharmacy? The pharmacy manager places Hazel on administrative leave and begins an investigation. Law enforcement is contacted regarding suspected internal theft of prescription medications. The compliance and legal departments are notified, the loss is documented, and the affected insurance claims are reviewed.

CONCLUSION

Where does this leave Charlie?

The next Saturday night, Charlie closes the pharmacy and meets with his new friend, Harry, who also works at the pharmacy.

“Well, this has been…” Charlie pauses to find the right words.

“Interesting,” volunteers Harry.

The two colleagues reflect on the past several weeks. They agree that they have both learned a lot in a short amount of time. They now understand the importance of accurate billing practices and prompt reporting of miscoding errors, and they appreciate that management implemented training to prevent future errors. They are also aware of medications with potential for diversion, along with behavioral red flags that may suggest suspicious activity. Charlie has even volunteered to spearhead a diversion program that encompasses both controlled and non-controlled products, including inventory assessment and staff education.

Together, they can look forward to stronger pharmacy practices related to billing accuracy, diversion prevention, and regulatory compliance.

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INTRODUCTION

In modern pharmacy practice, the concept of generic drug interchangeability is crucial for patient care, medication accessibility, and healthcare expenses. Since pharmacists fill approximately 90% of prescriptions with generic drugs and biosimilars, they are essential in handling substitution challenges and ensuring therapeutic equivalence.¹ Cost savings remain a primary motivation for switching to generics, which are among the few ways the United States (U.S.) healthcare system reduces overall spending.¹ Nevertheless, safety must never be sacrificed for savings. Pharmacy employees and healthcare providers must understand the regulations, bioequivalence criteria, and clinical considerations related to interchangeable drugs, particularly when managing medications with narrow therapeutic indices.

THE GENERIC DRUG TIMELINE

The history of the generic drug industry is marked by challenges and controversies from its inception to the present day. Over the years, scrutiny and doubt have shaped what we recognize as generic drugs now.

So, what is a generic drug?

The Food and Drug Administration (FDA) defines a generic drug as a medication that is identical to a previously marketed brand-name drug in terms of dosage form, intended use, performance, quality, route of administration, safety, and strength. It functions exactly like the brand-name drug and offers the same clinical benefits, making it an equivalent substitute.² However, brand-name and generic drugs have minor differences, discussed later.

In 1888, the American Pharmaceutical Association (now called the American Pharmacists Association, or APhA) published the first National Formulary (NF) to support the U.S. Pharmacopoeia (USP). The NF sets official standards for commonly used pharmaceutical preparations to help prevent counterfeit branded products.³ While not initially a legally recognized official document, it laid the foundation for the Roosevelt administration's passage of the Federal Pure Food and Drugs Act in 1906.⁴ This law banned adulterated or misbranded food and drugs for humans or animals, and allowed the government to hold companies accountable if a product caused serious harm. It also required drugs to meet standards of purity, quality, and potency established by the USP or NF—standards maintained by the FDA, formerly known as the Bureau of Chemistry.⁵

By the 1930s, the significant flaws in the Pure Food and Drug Act had become increasingly evident. Ingredient lists on products were optional, drug factory inspections lacked standardization, and there were no laws preventing unsafe products from reaching consumers. At that point, manufacturers could market and advertise drugs without substantial evidence of safety or effectiveness.⁵ Desperate to inform the public, the FDA compiled a collection of dangerous products legally available at the time. This exhibit, later called “The Chamber of Horrors,” debuted at the 1933 World’s Fair in Chicago and featured^5,6

• Lash Lure, a popular cosmetic eyelash and eyebrow enhancer for women sold in many beauty salons, resulting in permanent blindness and disfigurement
• X-rays of children’s esophagi after ingesting candy with embedded trinkets, including coins, rings, or small lead toys*
• The Diana Ideal Womb Supporter, which could puncture the uterus if inserted incorrectly

*Table 1 describes the FDA’s stance on popular global treats.

Table 1. Surprise! FDA Cracks Down on Popular Treats⁷

**In 2017, the U.S. version of Kinder Surprise, Kinder Joy, hit the market, consisting of an egg-shaped package that splits into two halves–one with chocolate, one with a small toy.

The critical watershed event occurred in October 1937.⁸ Earlier that year, scientists at the Pasteur Institute in France recognized sulfanilamide as a miracle drug for the treatment of streptococcal infections. Since the antibiotic was originally synthesized in 1908 and was no longer under patent (the legal right to be the sole producer or seller of a product), multiple pharmaceutical companies rushed to market it. One such company was S.E. Massengill. Their sales team noticed that sore throats, especially in children, were a common symptom of streptococcal infections. Seeing an opportunity, the company developed the first liquid form of the antibiotic, Elixir Sulfanilamide. They distributed 240 gallons of this mixture, containing 10% sulfanilamide, 16% water, and 72% diethylene glycol, across the U.S. without conducting toxicity tests. Of the 353 patients who used it, 105 died from acute kidney failure caused by diethylene glycol-induced proximal tubular necrosis.⁸ The FDA initiated a nationwide recall of any remaining Elixir Sulfanilamide. The government charged S.E. Massengill with selling a misbranded drug in interstate commerce. The elixir, not because of its toxic constituents, but because it lacked the required alcohol vehicle, was classified as illegal under current laws.⁵

Following arguably the most impactful mass poisonings of the 20th Century, Congress enacted the Food, Drug, and Cosmetic Act (FDCA) in June 1938. This law was a significant step forward in consumer protection and laid the groundwork for many of the public health improvements we see today. Under the FDCA, the FDA is tasked with several responsibilities⁹:

• Mandating drug manufacturers to submit safety data before marketing
• Setting quality standards for food, drugs, medical devices, and cosmetics
• Inspecting manufacturing and storage facilities
• Regulating labeling and claims for foods and dietary supplements
• Approving new drugs, medical devices, food, or color additives

While the FDCA significantly strengthened drug regulation in the U.S., it also created a new issue. Once a patent on a pioneering or brand-name drug expired, other companies could produce identical versions without needing to undergo the FDA’s strict safety and efficacy testing. These derivative (or generic) products, which vary in quality, then entered the market.⁴

Table 2 describes two significant amendments to the FDCA. Both continued the push towards stricter manufacturing expectations and categorical designations to achieve safe and effective administration of pharmaceuticals.^10,11

Table 2. Amendments to the Food, Drug, and Cosmetic Act^4,10,11

Under the Kefauver-Harris Amendments, the requirements for new drug applications (NDA) diminished incentives to develop new generics. Generic manufacturers became frustrated because they had to invest considerable time and money in safety and efficacy studies that had already been completed for the brand-name drugs they sought to replicate. By 1983, only 35% of the top-selling branded medications with expired patents faced generic competition. Furthermore, pharmacists could only dispense a generic drug if it was explicitly prescribed.¹¹

The Generic Drug Boom

The Drug Price Competition and Patent Term Restoration Act of 1984, known as the Hatch-Waxman Act (H-WA), transformed the generic drug industry.¹² It sped up the approval process for generic drugs, establishing an Abbreviated NDA (ANDA) based solely on bioequivalence to the reference listed drug (brand-name). Once the FDA recognizes these generics as therapeutically equivalent, healthcare providers can regularly substitute them for prescriptions. It also allowed manufacturers to start testing before the brand’s patent expired, and the first successful ANDA filing would receive 180 days of market exclusivity after patent expiration. The H-WA also benefited and continues to help brand manufacturers by restoring patent time lost due to FDA testing, with a maximum extension of five years. Additionally, brand-name firms received three years of exclusivity for improvements resulting from clinical trials, such as new dosage forms, drug release methods, or dosage regimens. For example, Ambien CR (zolpidem tartrate extended-release tablets), was a widely used medication for insomnia. Its manufacturer updated Ambien’s immediate release mechanism by designing a dual-layered tablet where 50% of the drug releases immediately to help induce sleep, and the other 50% releases slowly to help maintain sleep.¹²

The H-WA immediately led to high financial risks, intense competition, and, unfortunately, widespread fraud.¹² On the day the H-WA took effect, regulatory affairs members from Bolar Pharmaceuticals drove to the FDA headquarters and hand-delivered 40 ANDAs in an effort to secure the 180-day market exclusivity granted to the first successful generic drug applicant. Upon reviewing the submissions, the FDA discovered that all of Bolar’s submissions were fraudulent, having been fabricated solely to be the first company to file.¹²

The five years following the enactment of the H-WA became known as the "Generic Drug Scandal." An investigation by a government subcommittee revealed widespread bribery and numerous instances of fraudulent data submissions to the FDA. Only about six of 39 generic drug companies investigated avoided criminal or regulatory penalties.¹² Public confidence in generic drugs dropped sharply, with a 1989 Gallup poll showing 51% of Americans doubted that generics met the same manufacturing standards as brand-name drugs. Recognizing the need for decisive action, the FDA responded with a series of reforms, including¹²

• Enactment of the Generic Drug Enforcement Act, allowing the FDA to take legal action against individuals or companies that violate FDA regulations
• Release of a comprehensive product analysis report reviewing 2500 samples from the 30 most prescribed generic drugs; less than 1% failed to meet standards
• Development of a strong application queue system within the Office of Generic Drugs, which included a pre-approval inspection process to verify the accuracy of data submitted with applications
• Requirement for all ANDAs to be complete upon submission. Drug manufacturers can no longer modify incomplete applications with additional data after they are filed

In the 21st Century, generic medications have remained a key part of the U.S. healthcare system. Congress has enacted several acts and amendments over the past 25 years to support and sustain the generic drug pathway (see Table 3). The FDA continues to promote the development of generic drugs by releasing a biannual list of drugs that have been off-patent for more than a year and have no generic competitors, and by establishing an expedited pathway for drugs designated as competitive generic therapies. This list can be found on the FDA’s website under “List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic.”¹³

Table 3. Notable Updates to Generic Drug Regulations in the 21^st Century^13,14,15

PAUSE AND PONDER: Given the historical context of drug regulation, how do you think public perception and trust in generic drugs today are influenced by past events like the Elixir Sulfanilamide tragedy or the Generic Drug Scandal, even with robust current regulations?

Approval Pathway of Drugs

Transforming a molecular compound into a well-known drug involves an extensive, expensive, and risky process. Usually, it takes 10 to 15 years and costs about $1 to $2 billion to approve a new drug, depending on the therapeutic area. Between 2010 and 2017, clinical trial data indicated a 90% failure rate among drug candidates that progressed to phase 1 testing. Including failed candidates in preclinical stages, the failure rate would be even higher.¹⁶

The initial stage of drug development is the preclinical phase. During this stage, a pharmaceutical company or research institution must demonstrate to the FDA that the drug candidate is reasonably safe for human trials.¹⁷ This involves a combination of in vitro (within a test tube or glass) and in vivo (within a living organism) studies that must establish six essential components¹⁸:

1. Creation of drug substance/active pharmaceutical ingredient
2. Dosage design (formulation)
3. Analytical and bioanalytical method development and validation
4. Metabolism and pharmacokinetics (PK)
5. Toxicology and pharmacologic safety
6. Current Good Manufacturing Practice (cGMP) and documentation of the drug candidate for use in clinical trials

At this point, a drug developer can submit an Investigational New Drug (IND) application to the FDA, which includes data from preclinical animal tests and the plan for human trials. The FDA and a local institutional review board (IRB)—comprising scientists and healthcare professionals from different institutions and hospitals involved in clinical research—review the application.¹⁷ An IRB must also approve a clinical trial protocol that includes¹⁷

• The study’s objectives and length
• Description of eligible trial participants
• Schedule of tests and procedures
• Medications and dosages used
• Participant consent

The clinical studies portion of drug development consists of four phases.¹⁹

Phase 1 focuses on the pharmacology and toxicity of the drug candidate. Absorption, distribution, metabolism, and excretion data help determine a safe and tolerable dose range for later trials. These trials typically involve small groups of subjects, often fewer than 20 healthy volunteers. Phase 1 is usually the shortest, lasting between nine and 18 months.¹⁹

Phase 2 evaluates the safety and effectiveness of the investigational drug. The clinical trials aim to determine how well the drug treats the target condition, helping to establish dosing regimens or parameters for future research. During this phase, the participant pool expands to hundreds of individuals with the condition under study, enabling the identification of other target populations and potential drug interactions. Typical studies at this stage are often blinded, randomized, controlled trials with specific inclusion and exclusion criteria. These studies usually last from one to three years.¹⁹

Phase 3 studies aim to confirm the drug’s therapeutic efficacy and benefit. Common questions considered in Phase 3 studies include¹⁹

• Can a dose-response relationship be established?
• Can the target population be increased?
• Can the drug be used at different stages of the disease?
• Can common side effects and food or drug interactions be identified?

Phase 3 also includes developing a product label with clear administration instructions. The study sample increases to about 1,000 subjects with the relevant condition, with minimal inclusion or exclusion criteria. This phase can last up to five years.¹⁹ Once finished, the drug company can formally submit its NDA to the FDA for approval. The FDA then has 60 days to either file the application for review or mark it incomplete if required data is missing. The Center for Drug Evaluation and Research (CDER) conducts the final NDA review. Under the Prescription Drug User Fee Act, CDER is expected to review and decide on at least 90% of NDAs for standard drugs within 10 months.¹⁷ The patent term of the brand drug is 20 years from the date the FDA files the NDA.²⁰

Phase 4 trials are a post-marketing requirement of the FDA.¹⁷ These studies often highlight the difference between efficacy (which is a clinical trial’s construct) and effectiveness (which is how the drug performs in the real world). An investigational drug may be efficacious in the controlled environment of a Phase 2 trial, where strict inclusion criteria, constant monitoring, and perfect adherence are maintained. An effective drug performs without all of those guarantees.²¹ Real-world data collection for a newly approved drug often focuses on¹⁹

• Monitoring the drug safety profile, especially in populations not previously studied
• Identifying long-term adverse events
• Optimizing the application of the drug
• Determining potential contraindications in combination with other drugs or diseases

Post-approval trials may last up to three years or longer, as determined by the FDA.

After the brand-name patent expires and before a generic drug reaches pharmacy shelves, the FDA must conduct a comprehensive review of the product. Generic manufacturers must adhere to the same cGMP regulations as brand-name drug manufacturers, ensuring consistency, purity, and quality comparable to those of brand-name products across batches. These cGMP guidelines also enforce strict oversight of all manufacturing facilities.²² According to H-WA, approval of generics depends on demonstrating bioequivalence and pharmaceutical equivalence to the brand-name drug. Since generic developers do not need to repeat safety and effectiveness studies already conducted for the original drug, the ANDA was introduced.¹² This simplified process means manufacturers only need to scientifically show that their drug performs similarly to the brand-name, without submitting new preclinical and clinical data.²³ Table 4  provides a list of the data submission requirements for brand-name and generic drugs.

Table 4. Brand-Name Versus Generic Drug Data Submission Requirements²³

SIDEBAR: “Can you tell me where my medication is from?”

If you've ever worked in a community pharmacy, chances are a customer asked about the source of their medication at least once. Although it might seem like a minor or unnecessary question, important reasons may prompt such inquiries.

Katherine Eban’s “Bottle of Lies: The Inside Story of the Generic Drug Boom,” a 2019 New York Times bestseller, reveals the dark side of some overseas generic medication manufacturing practices.

The story follows the journey of an ex-Ranbaxy (a generic drug company in India) employee turned whistleblower as he helps the FDA expose the poor operating standards of his former company. The protagonist witnessed multiple levels of deception and fraud, including²⁴

• Intentional data falsification and manipulation
• Using a brand-name product to perform bioequivalence testing and publishing the results as data for the generic drug
• Unreported variations in generic drug effectiveness between batches
• Shipping drugs that did not meet the standards of one country to another country with less strict market standards.

Ranbaxy was not the only culprit; this was just the tip of the iceberg. Because the manufacturing sites of these generic drug companies were located on the opposite side of the world, the FDA couldn't investigate and monitor practices as frequently as it would for a company in the U.S. Additionally, the FDA would notify these companies weeks or even months in advance of a visit, giving the companies ample time to conceal their fabricated data and prepare their workers to provide the right lies to the FDA.²⁴

Over time, evidence began to accumulate in the U.S.²⁴ Many pharmacologists, doctors, and healthcare providers began noticing patterns in their patients’ reactions to certain generic drugs. Adverse reactions to generic narrow therapeutic index (NTI) drugs like levothyroxine and phenytoin started to rise. Doctors would try to switch patients to the generic version of their maintenance medication needed for managing chronic conditions, only to see those patients develop hyperthyroidism or experience an immediate uptick in seizures. Drugs with specially designed release profiles also came under scrutiny. Several patient complaints led Ted Cooperman, president of the independent laboratory ConsumerLab, to test Teva’s generic Budeprion XL against GSK’s brand-name Wellbutrin XL. The results were shocking – the generic drug released four times as much active ingredient in the first two hours as the brand-name did.²⁴

Although some justice was achieved when Ranbaxy agreed to pay a $500 million settlement, the largest settlement to date with a generic drug manufacturer, the broader issue was fully revealed.²⁴ When produced properly and in compliance with regulations, generic drugs positively impact medicine worldwide. Unfortunately, a certain level of vigilance is necessary, and pharmacy teams need to consider and report patient concerns when relevant. To stay informed, sign up on the FDA website to receive alerts about recalls, market withdrawals, and safety notices.

For a generic drug to be recognized as an adequate and appropriate substitution for a brand-name drug, the FDA formulated a simple equation²⁵:

Pharmaceutical Equivalence (PE) + Bioequivalence (BE) = Therapeutic Equivalence (TE)

PE is demonstrated between two drug products if all of the following characteristics are identical²⁵

• Dosage form
• Route(s) of administration
• Amount of active drug ingredient
• Amount of active drug ingredient delivered over a dosing period
• USP standard of drug identity, strength, quality, and purity

BE is entirely determined by what happens to a drug after it enters the body.²⁶ There is a common misconception that a generic drug must contain 80% to 125% of the active ingredient present in the branded product to be considered bioequivalent. Equal doses of the active ingredient in both the generic and reference drugs must become available at the site of drug action at rates and extents that are not significantly different. The entire 90% confidence interval of PK measures, including area under the curve and peak concentration, must be between 0.80 and 1.25 to achieve BE. Determining BE through PK performance explains why differences in excipient content, color, or shape can occur between the generic and the reference listed drug.²⁶

Only after demonstrating both PE and BE can a generic drug attain TE. As a TE product, the generic drug can then be included in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations list, commonly known as the "Orange Book." The generic drug now enjoys complete interchangeability with its brand-name counterpart.^{25, 27}

Fun Fact: The FDA chose an orange cover for the first annual edition of the Approved Drug Products with Therapeutic Equivalence Evaluations List because it was published on Halloween in 1980. This festive choice led to the colloquial name, the "Orange Book," which has remained ever since.²⁸

Authorized Generics

Imagine this situation: You are the CEO of PharmaZen Labs, a successful (fictitious) pharmaceutical company. Your flagship drug, ZenoLog, a fast-acting insulin, is about to lose its patent. Veta Pharmaceuticals, a generic drug producer, is eagerly waiting for the new year because the FDA has approved its ANDA for insulin-fastpart, the first generic version of ZenoLog. Veta plans to sell insulin-fastpart at a price 10 times lower than ZenoLog during the 180-day exclusivity period. The expected losses for ZenoLog in the upcoming year, due to competition from insulin-fastpart and other anticipated generics entering the market later, are considerable. You call for an urgent all-hands meeting to brainstorm ways to counter the bleak projections from the finance team. The room falls silent, tense and expectant. You glance around, hoping someone will have a solution. Suddenly, a tentative hand rises from a woman in the legal department. She quietly suggests, “What if we made our own generic?”

Congress was unprepared for a loophole in the H-WA: Authorized Generic (AG) drugs. In 1984, the idea that a brand-name company would produce a generic drug to compete with its own brand and first-market generic was unlikely.²⁹ AGs refer to generic medications made by the same manufacturer as the brand-name product. They are identical in composition, shape, and size to the brand-name drug. Oftentimes, AGs and brand-name products are manufactured in the same facility.

In some cases, the AG may have a different marking or color. Standard generic drugs, however, often differ from the brand version in terms of shape, color, size, and inactive ingredients. AGs are a separate category of generics, and the FDA does not require their manufacturers to seek approval through the ANDA pathway because they are marketed under the brand-name NDA.³⁰ Two significant distinctions evolved from this categorical differentiation of generic medicines^29,30:

1. AGs are excluded from the "Orange Book" because they fall under the proprietary NDA.
2. An AG can directly compete with a standard generic during the 180-day exclusivity period because the law only prohibits other ANDA submissions. There is no restriction on launching identical versions of branded products through NDA supplementation.

In a community pharmacy setting, pharmacists and pharmacy technicians may dispense AGs frequently without realizing it. For example, Pfizer, a leading name in the pharmaceutical industry, developed Viagra in 1998. In 2003, Pfizer acquired Greenstone LLC, making it its generic subsidiary. The Viagra patent expired on December 11, 2017. On that day, Pfizer announced that Greenstone’s AG sildenafil was available alongside generic sildenafil from Teva Pharmaceuticals.^31,32

AGs have recently ignited significant debate. In 2013, the Supreme Court recognized the financial significance of the 180-day exclusivity period for generic drug manufacturers, valuing it at hundreds of millions of dollars.³³ From a consumer standpoint, the faster a drug's price drops substantially, the better, regardless of the manufacturer. A recent notable example of an AG is Mylan’s epinephrine auto-injector, the first generic of any kind for the EpiPen.³³ Public and political outrage over Mylan’s 400% price hike for EpiPen accelerated the company’s decision to bring an affordable alternative to market. Other generic versions soon followed, helping to reduce costs and address supply chain issues often associated with the EpiPen.³⁴

PAUSE AND PONDER: Considering the strategic move by brand-name companies to launch AGs to compete with their own products, what are the potential long-term implications for both generic manufacturers (especially smaller ones) and for overall drug pricing and patient access?

Narrow Therapeutic Index Drugs

Effective generic drugs have undoubtedly enhanced global healthcare by reducing costs, boosting competition, and increasing access to affordable medicines, thereby improving health outcomes.³⁵ In most cases, TE products achieve their intended clinical effect even with minor variations in PK parameters compared to the brand-name versions. The FDA’s recommended BE range of 80% to 125% is suitable for most drugs, as the gap between the minimum therapeutic concentration and toxic levels is sufficiently large. This ensures the drug remains safe and clinically effective.³⁶

The FDA defines NTIs as drugs with slight differences in dose or measured blood level that may result in therapeutic failure and/or potentially fatal adverse reactions. While the FDA does not maintain a formal list of NTIs, as of January 2024, it has updated the product-specific considerations for 14 active ingredients for prospective generic drug manufacturers (see Table 5).³⁷

Table 5. Examples of Drugs with Narrow Therapeutic Indexes^37,38

*FDA indicated the product as NTI in product-specific consideration provided to generic drug manufacturers

PAUSE AND PONDER: For NTIs, where subtle variations can have significant clinical consequences, how might pharmacists and healthcare providers best navigate the balance between cost savings through generic substitution and ensuring optimal patient safety and efficacy?

BE studies in healthy individuals often show similar average exposure between generic and brand-name drugs, but this does not ensure TE for every patient, especially with sensitive drug classes like antiepileptics or cardiovascular medications. This is crucial because average BE studies, which measure mean differences, may not account for individual patient variability in PK, risking underdosing or overdosing in some cases.³⁹ PK variability within the same patient, rather than the quality of generics themselves, has been identified as a key factor in adverse drug reactions after switching medications.⁴⁰

Although two generics may be bioequivalent to the brand-name drug, the FDA does not explicitly approve them as interchangeable. For example, variations in excipients—often considered inert—can significantly impact drug bioavailability and cause substantial differences in BE, as seen with alendronate, where certain excipients of a generic product increased bioavailability by 5-fold compared to Fosamax.⁴¹ The American Academy of Neurology has also expressed concern about generic substitution in antiepileptic therapy. The organization has recommended prioritizing brand-name treatments and opposing a generic switch without prescriber approval.⁴² A recent study also pointed out that the nocebo effect (adverse effects that occur just because the patient believes they may occur) can reduce patient adherence when a generic is substituted for a brand-name medication. Patients may feel that the medication is less effective or experience more adverse effects, even if there is no actual pharmacologic difference induced.^43,44

The FDA continues to work on mitigating the adverse effects of NTIs. In 2015, they formed the NTI Drug Working Group to develop a consistent approach for NTI classification and transparently address and resolve current issues.³⁷ The Working Group also aims to standardize methodologies for assessing BE, including shrinking the conventional 80% to 125% limits or implementing a scaled average BE approach that adjusts limits based on the reference-listed drug's within-subject variability.⁴⁵ For example, the BE of levothyroxine has been tightened to 90% to 110% to account and critical dose-response. The FDA has implemented strict updates to cGMP, increasing oversight of excipient selection, formulation stability, and dissolution profiles. This proactive approach helps safeguard patient safety by ensuring that every stage of drug manufacturing—from sourcing raw materials to releasing the final product—adheres to the highest quality control and process validation standards.⁴⁶ Post-market surveillance and risk management programs designed explicitly for NTIs continuously monitor safety events. Adverse event reporting systems, combined with pharmacoepidemiologic studies and real-world data analysis, track emerging safety concerns or subtherapeutic performance.⁴⁷ The FDA also often requires a Risk Evaluation and Mitigation Strategies (REMS) program for NTIs, which includes clear and comprehensive product labeling, specialized medication guides, and proactive communication plans for medical emergencies.⁴⁸

The Orange Book

The "Orange Book" serves as a comprehensive guide for identifying drug products that the FDA considers therapeutically equivalent. It facilitates the substitution of brand-name medications with their generic counterparts.⁴⁹ The FDA’s division of Orange Book Publication and Regulatory Assessment within the Office of Generic Drugs updates the text monthly to ensure accurate and up-to-date information.⁵⁰ This equivalence is confirmed when generic drugs contain the same active ingredients, dosage form, strength, route of administration, and labeling as their brand-name equivalents, eliminating the need for repeated phase 1, 2, and 3 clinical trials. ⁵¹ The Orange Book thus supports state laws on generic substitution, allowing pharmacists to dispense therapeutically equivalent generic options, which greatly contributes to cost savings for both consumers and state healthcare systems.⁵² This approach aligns with public health goals by increasing access to affordable medications while ensuring safety and efficacy.^53,54

Despite its usefulness, relying solely on the Orange Book for interchangeability has limitations, especially in assessing BE for complex drug products and accounting for the diversity of state regulations that may influence substitution practices.⁵⁵ For example, some states permit therapeutic substitution, where a pharmacist can replace a prescribed drug with a chemically different but therapeutically similar alternative without prior approval. This differs from generic substitution, which requires that the drug be bioequivalent and pharmaceutically equivalent, ensuring the generic performs identically to the brand-name drug in the body.⁵⁰ The TE ratings listed in the book further illustrate the differences among approved products. The two-letter code associated with the drug product differentiates between TE and PE products. The coding system also indicates if a product has corrected previously identified BE issues. Table 6 provides an in-depth description of the coding system.⁵⁶

Table 6. TE Coding System⁵⁶

State regulations vary from mandatory substitution laws—where pharmacists must replace a drug with a less expensive generic unless the prescriber specifies otherwise—to permissive laws that allow but do not mandate substitution.⁵⁷ Some states also include therapeutic substitution policies, broadening the scope beyond bioequivalent generics to incorporate chemically different but clinically similar alternatives when approved by a physician. These diverse legal frameworks highlight the complex landscape of pharmaceutical dispensing, which is often shaped by state-specific views on safety, effectiveness, and cost control.⁵⁰

The Purple Book

The Purple Book, officially known as "Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations," operates similarly to the Orange Book but is specific to biologics. It provides guidance on substituting original biologics with their biosimilar and interchangeable biosimilar versions. This is crucial because biologic products, due to their complex manufacturing processes and natural variability, cannot be classified as standard generics like small-molecule drugs.⁵⁴ Unlike chemically-made small-molecule drugs, biologics come from living organisms, making exact replication impossible and necessitating a different regulatory approach for approval and interchangeability.⁵⁸ Consequently, the FDA has implemented strict criteria for biosimilarity, requiring comprehensive analytical, animal, and clinical data to demonstrate that a biosimilar is highly similar to the reference product, with no meaningful differences in safety, purity, and potency.⁵⁹ The Purple Book plays an essential role in promoting the development and accessibility of more affordable biologic products by identifying those that meet these high standards for biosimilarity and interchangeability.⁶⁰ This extensive resource supports healthcare providers and patients in making informed choices about biologic substitutions, intending to foster market competition and reduce healthcare costs for expensive biological therapies, which have historically lacked generic alternatives.

CONCLUSION

The journey of generic drugs, from initial regulatory challenges to their current indispensable role, underscores a continuous effort to balance medication accessibility, cost-effectiveness, and patient safety in healthcare.^1,4 We've seen how pivotal events, such as the Elixir Sulfanilamide tragedy and the subsequent FDCA of 1938, laid the foundation for robust drug regulation, which was further refined by amendments like the Durham-Humphrey and Kefauver-Harris Acts.^5,10,11

The landscape of generic drug approval was dramatically reshaped by the H-WA of 1984, which streamlined the ANDA process and significantly boosted generic competition.¹² While this led to an initial "generic drug boom," it also highlighted the need for stringent oversight, prompting reforms like the Generic Drug Enforcement Act following the Generic Drug Scandal.¹²

Crucially, the concept of TE, established through PE and BE, ensures that generic drugs perform identically to their brand-name counterparts, providing the same clinical benefits.^{2, 25} Resources like the Orange Book for small-molecule drugs and the Purple Book for biologics are essential guides for identifying therapeutically equivalent products, facilitating safe and effective substitutions.^{49, 60} However, the complexities associated with NTI drugs and the emergence of AGs demonstrate that vigilance and continuous regulatory adaptation are paramount to maintaining public trust and optimizing patient outcomes.^29,36

As approximately 90% of prescriptions are filled with generics and biosimilars, pharmacists, pharmacy technicians, and healthcare providers play a critical role in navigating these complexities.¹ The ongoing evolution of regulations, particularly around NTIs and biosimilars, reflects the commitment to ensuring that cost savings do not compromise the safety and efficacy of essential medications. Ultimately, the robust regulatory framework surrounding generic drugs aims to provide patients with access to affordable, high-quality treatments, reinforcing their status as a cornerstone of modern healthcare.

Finally, readers may be wondering about the Green Book, referenced in the title. The Green Book is the FDA’s List of Approved Animal Drug Products!

Download CE Activity

INTRODUCTION

"Imagine if you're [at a] truck stop, you take two bottles of that and you're driving down the road — now you're high on opioids.”¹ Researcher Todd Hillhouse.

The commentator above is not referring to a product purchased from a seedy individual at the rear of the parking area, but rather something purchased out in the open, off the shelf of the public retail outlet prominently located within the rest area. Can it possibly be true that the public can purchase a product that mimics opioids at a truck stop or convenience store or online, no questions asked? Not only does the drug allegedly produce a “high,” It’s been associated with increasing reports of serious adverse events and addiction.² Shouldn’t the FDA or DEA have regulations in place to prevent this from occurring?

The drug in question is tianeptine, colloquially referred to as “Gas Station Heroin,” and is only one of several examples of a commodity that poses a danger to the public but falls between the cracks of regulatory oversight.

Pharmacists are accustomed to dispensing prescription drugs that have undergone rigid clinical testing and been approved by the United States (U.S.) Food and Drug Administration (FDA). However, many products face less stringent requirements (e.g., over the counter [OTC] drugs, supplements) and some may receive no approval whatsoever. This activity will compare the regulatory standards for several categories of consumer products with an emphasis on substances that circumvent regulatory review.

DRUG APPROVAL

Generally, a drug will undergo some level of review before it makes it way to the public. However, the rigor of the scrutiny varies greatly depending on the nature of the drug.

As you are no doubt aware, prescription drugs on the market have been reviewed by the FDA which assesses evidence that the drug is safe and effective.³ The FDA's Center for Drug Evaluation and Research (CDER) evaluates evidence submitted by the manufacturer to ensure that drugs, both brand-name and generic, are effective for the target condition and that their health benefits outweigh their known risks.³ This is a structured process and generally requires at least two clinical trials. Approved drugs are also subject to post-market surveillance to ensure that they continue to be safe.³

The FDA also has several accelerated approval mechanisms that expedite the marketing of promising prescription therapies that treat serious or life-threatening conditions and provide therapeutic benefit over available therapies. Many drugs have been approved under these programs and have altered the course of treatment since these pathways were developed in 1992, including antiretroviral drugs used to treat HIV/AIDS and targeted anti-cancer agents.³

During the COVID pandemic, pharmacists became familiar with another modified drug approval mechanism, emergency use authorization (EUA).⁴ If the Secretary of Health and Human Services (HHS) declares a public health emergency, the FDA may authorize the emergency use of unapproved medical products or unapproved uses of approved medical products.

The FDA was granted authority to issue EUAs in 2004 when Congress passed the Project BioShield Act. That Act was intended to facilitate the development, procurement, and use of medical countermeasures against chemical, biological, radiologic, and nuclear terrorism agents.⁵ The Act was passed in response to the events following the terrorism episode on 9/11; although the intent was to protect against acts of terrorism, to date the only EUAs issued have been in response to pandemics. Medical products considered for an EUA undergo FDA review, but the standard used for approval is a lower level of evidence (“reasonable to believe that the product may be effective” rather than “effective”) than needed for full FDA approval.⁴ There also must be no adequate, approved, and available alternative to the candidate product for diagnosing, preventing, or treating the disease or condition.⁴ (“Unavailable” includes insufficient supplies of the existing product to meet the emergency while inadequate includes contraindications for special circumstances or populations, for example children.⁴)

Readers will be spared from a detailed review of the drug approval process, since pharmacists probably heard this numerous times while in school, but it is an important reminder that non-prescription compounds do not undergo the same rigorous pre-market evaluation by the FDA. OTC drugs are also approved by the FDA, but under different criteria. The primary difference is that the approval of prescription drugs requires approval of a specific drug product to treat a specific condition. Conversely, most OTC products must only conform with existing OTC monographs that describe the marketing standards including the active ingredients, labeling, and other general requirements.⁶

OTC monographs set the conditions under which OTC drug products are generally recognized as safe and effective for their intended use. A monograph covers active ingredients, dosages, formulations, and labeling claims; a new OTC product does not need FDA approval if its manufacturer complies with the relevant monograph. This is because the FDA had already evaluated the safety and effectiveness evidence as part of its monograph rulemaking process.⁶ However, the FDA assesses monograph compliance as part of its inspection process.⁷

If it is a new OTC product without an existing monograph, the manufacturer must submit a New Drug Application (NDA) with clinical trial data demonstrating safety and effectiveness.⁷

In addition, the sponsor must provide consumer behavior studies demonstrating that purchasers can use the nonprescription drug product safely and effectively without the supervision of a healthcare provider.⁷ Of course, a prescription drug may also become an OTC drug.⁸

In stark contrast, oversight of supplements is much less rigorous. Dietary supplements are not subject to the Food, Drug, and Cosmetic Act (FDCA Act), but rather are regulated by a different law, the Dietary Supplement Health and Education Act (DSHEA). DSHEA, enacted in 1994, states that “the Federal Government should not take any actions to impose unreasonable regulatory barriers limiting or slowing the flow of safe products and accurate information to consumers.”⁹ A dietary supplement is defined as a vitamin, mineral, amino acid, herb or other botanical, or a dietary substance for use by man to supplement the diet by increasing the total dietary intake.⁹

Unlike drugs, supplements are not subject to pre-market FDA approval.¹⁰ (Hence the disclaimer found on supplement labels [“This statement has not been evaluated by the Food and Drug Administration."]). The manufacturer does not have to provide the FDA with the evidence it relies on to substantiate safety before or after it markets its products. However, if a proposed dietary supplement contains a new dietary ingredient, the manufacturer must submit a notification to the FDA 75 days before introducing it to the market. The notice must include information on the basis of which the firm has concluded that the supplement will reasonably be expected to be safe.¹⁰ (Only a notice is required, the FDA does not evaluate the data.)

Manufacturers and distributors have the initial responsibility for ensuring that their dietary supplements meet the safety standards for dietary supplements. In general, the FDA’s ability to take action is limited to postmarket enforcement.¹¹ Manufacturers and distributors must record, investigate, and forward to FDA any reports they receive of serious adverse events associated with the use of their products.

The FDA cannot conduct post-market research on supplements to corroborate a manufacturer’s claims. It can only issue warning letters asking manufacturers to voluntarily recall adulterated or misbranded products. If a manufacturer refuses to voluntarily recall its product, the burden is on the FDA to prove that the supplement is harmful or adulterated.¹¹ The FDA must show that the dietary supplement has a significant or unreasonable risk of causing injury or illness, a very high bar. In addition to issues of safety, problems exist with respect to the purity and bioavailability of some products.¹¹

Supplement manufacturers do have restrictions on the types of claims they can make. They may not claim to diagnose, mitigate, treat, cure, or prevent a specific disease or class (which would make them a drug, hence the second part of the label disclaimer: “This product is not intended to diagnose, treat, cure, or prevent any disease”) but may claim to aid a structure or function of the human body, benefit a classical nutrient disease, or promote general well-being.¹⁰

PAUSE AND PONDER: Should supplements be subject to more stringent regulations and if so, in what ways?

IF I’M NOT A DRUG NOR A SUPPLEMENT, WHAT AM I?

Despite all these regulatory pathways providing some degree of control, products can wind up being available for retail sale without any oversight. As noted above, an example of this is tianeptine, which is not FDA-approved, is not generally recognized as safe for use in food, and does not meet the statutory definition of a dietary ingredient. It is, nevertheless, commonly available from retail outlets.¹²

“Gas Station” Drugs

A growing number of substances are available from gas stations, convenience stores, bodegas, vape shops, and even the Internet; they may even be purchased by minors.¹³ They have been given the label “gas station” drugs.

It is believed that the first instance of a “gas station” drug was the emergence of “Spice,” a synthetic cannabinoid (producing cannabis-like effects) in 2008.¹³ The drugs were sold under the guise of being herbal incense or potpourri to circumvent the approval process; the FDA eventually placed the drugs in Schedule I in 2011. A similar pattern was seen a few years later with synthetic cathinones being sold as “bath salts” with “warnings” that they were for external use only, even though testimonials clearly indicated that they were being taken internally. (Cathinone is a naturally occurring beta-ketone amphetamine analogue from the leaves of the Catha edulis plant. Synthetic cathinones derivatives may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects.) The Drug Enforcement Administration (DEA) eventually banned them after a series of fatalities occurred.¹³ Typically, substances like these continue to be sold until their dangerous consequences are recognized and there are calls to restrict them.¹³

Some examples of unregulated drugs available today include delta 8/10 tetrahydrocannabinol, Royal Honey, and Rhino which contain sildenafil, tianeptine, kratom, and phenibut.¹³ The latter three substances will be discussed more fully below.

PAUSE AND PONDER: What would you do if someone asked, “Does the pharmacy sell (one of the gas station drugs)”?

Tianeptine

One of the newer emerging gas station threats is the sale of products containing tianeptine.¹⁴ Tianeptine was synthesized in France in 1971 as an analog of the newly discovered tricyclic antidepressants. It was approved in France as an antidepressant in 1989 and is now available in more than 60 countries.^13,15

Tianeptine [(7-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino)heptanoic acid)] is an atypical tricyclic antidepressant approved in some European, Asian, and Latin American countries primarily for the treatment of major depression. It has also been used to treat anxiety and irritable bowel syndrome.¹³ Unlike traditional tricyclics which block serotonin reuptake in the CNS, tianeptine actually increases serotonin uptake.¹³ However, it is now believed that its antidepressant activity is related to modulating glutamate-mediated pathways involved in neuroplasticity (a process that involves adaptive structural and functional changes to the brain; in other words, the brain's ability to absorb information and evolve to manage new challenges).¹⁵ Unlike conventional tricyclic antidepressants, tianeptine is not primarily metabolized by cytochrome P450s, but is largely metabolized by β–oxidation (which would be a consideration with regard to potential drug interactions).¹⁵

More significantly for the purpose of this activity, tianeptine acts as a full agonist at the mu-opiate receptor and a weak agonist at the delta-opioid receptor.^13,14 It is moderately potent but highly efficacious as a mu agonist.¹⁵ As such, it causes opiate-like euphoria and carries a significant risk of overdose.¹³ Moreover, it has a short half-life that can lead to rapid withdrawal, increasing its potential for addiction and misuse.¹³ Some of the countries where tianeptine has been approved to treat depression and anxiety have restricted how tianeptine is prescribed or dispensed, or warned of possible risk of addiction.¹³

In the U.S., tianeptine is not an approved prescription drug, but has become more visible as an OTC product sold in retail stores under the names of ZaZa Red, Tianna Red, Neptune’s Fix, Pegasus, TD Red, and others.¹² The drug has earned the nickname “gas station heroin” due to its opioid-like effects and potential for similar abuse.¹²

U.S. law enforcement has encountered tianeptine in various forms, including bulk powder, counterfeit pills mimicking hydrocodone and oxycodone pharmaceutical products, and individual stamp bags (small wax packets commonly used to distribute heroin).¹⁴ Tianeptine has also been combined with antidepressants and antianxiety medications; patients often combine the drugs themselves, and some manufacturers make fixed-dose combinations.¹⁴

Tianeptine-containing products available to consumers include some with high doses and are making dangerous and unproven claims that tianeptine can improve brain function and treat anxiety, depression, pain, opioid use disorder, and other conditions.¹² Case reports in the medical literature describe U.S. consumers ingesting daily doses on the order of 1.3 to 250 times (50 mg to 10,000 mg) the daily tianeptine dose typically recommended in labeled foreign drug products.¹²

Risks

Reports of adverse reactions and adverse effects involving tianeptine have been increasing in the U.S.¹⁶ Poison control centers have reported that cases involving tianeptine exposure increased nationwide, from 4 cases in 2013 to nearly 350 cases in 2024. From 2020 to 2022, more than 600 calls were made to poison control centers after exposure, and five deaths occurred as a result.¹⁶

The FDA has identified cases in which consumers have experienced serious harmful effects from abusing or misusing tianeptine including agitation, drowsiness, confusion, sweating, rapid heartbeat, high blood pressure, nausea, vomiting, slowed or stopped breathing, coma and death.¹⁶ Naloxone is an appropriate countermeasure in cases of severe poisoning, since tianeptine has opioid effects.¹³ Users frequently consume tianeptine chronically and, if they stop tianeptine abruptly, they may experience withdrawal symptoms similar to those associated with opioid discontinuation (e.g., craving, sweating, “goose flesh,” diarrhea, myalgias).¹⁶ Tolerance and dependence appear to develop quickly.¹⁷ Severe withdrawal symptoms in humans that have led to hospitalization following the use of tianeptine have also been reported.^12,16

Like many drugs of this nature, tianeptine is frequently found combined with other illicit ingredients, often synthetic cannabinoids, which are not included on the product label.¹⁷ Poison control centers describe the signs of overdose to vary widely and include clamminess, nausea, low blood pressure, and unconsciousness as well as seizures and severe stomach cramps.¹⁷

It is difficult to get an accurate picture of the extent of tianeptine abuse. Reports to poison control centers are voluntary and hospitals do not test for it, so its prevalence is likely underreported.¹⁷ The drug also has a strong following on social media where its merits are hotly debated with one social media forum called “Quitting Tianeptine” attracting more than 5,000 followers.¹⁷

Regulation

Clearly, tianeptine is not an FDA-approved medication. Could its sale at convenience outlets be justified as being designated a dietary supplement and therefore an appropriate consumer product covered by DSHEA? The FDA says it does not meet the statutory criteria for a dietary supplement.¹⁸

Therefore, in the FDA’s view, “It is an unsafe food additive, and dietary supplements containing tianeptine are adulterated under the FD&C Act” (i.e., not “legal”). Nevertheless, many tianeptine products, frequently of non-U.S. origin, are openly marketed as supplements with many consumers mistakenly believing that it is a safe alternative to street opioids.¹⁷

FDA Action

In May 2025, the FDA issued warnings to consumers about the “dangerous and growing health trend facing our nation” about the increasing number of adverse events, including death, associated with tianeptine-containing products.¹² The agency warned consumers not to purchase or use any tianeptine product due to serious risks. The agency also issued warning letters to companies distributing and selling tianeptine products and issued an import alert to help block shipments to the U.S.¹⁹ However, its sale is not restricted.

Several states have taken steps to limit sales of these products. Some states have placed tianeptine on controlled drug schedules.²⁰ At least eight states (AL, FL, GA, IN, KY, MN, OH, VA) classify tianeptine as a C-I drug. Five others (AR, MI, NC, OK, TN) have placed it in C-II and Mississippi considers it a C-III substance. Other states have similar restrictions under consideration.²⁰

Increasing the control of tianeptine is also being discussed at the federal level. In 2024, members of Congress wrote to the FDA urging them to take steps beyond the issuing of warnings, stating that they believed that “more action on tianeptine use is needed to ensure the health and well-being of the American people.”²¹ There is a bill pending in Congress that would place the drug in C-III.²²

A more recent Congressional proposal would ban the sale of tianeptine entirely.²³ It remains to be seen if additional regulation becomes a reality.

KRATOM

Tianeptine is not the only product to exist in a regulatory gray area. Another example with a long history of regulatory wrangling is kratom.²⁴ Kratom (Mitragyna speciosa korth) is a tropical tree indigenous to regions of Southeast Asia (Thailand, Malaysia, Myanmar) and belongs to the same family as the coffee tree.²⁵ Traditionally, Thai and Malaysian laborers and farmers chewed the leaves to relieve fatigue. It has also been used as a substitute for opium when opium is unavailable and chronic opioid users have used it to manage opioid withdrawal symptoms.²⁵ Soldiers returning from the Vietnam war and immigrants from Southeast Asia introduced kratom to America.²⁶

The principal constituents of Kratom, mitragynine (MTG) and 7-hydroxymitragynine (7-HMG), have opioid receptor activity.²⁵ These compounds are indole alkaloids structurally related to yohimbine and have shown anti-inflammatory and analgesic activity in experimental animals.²⁷

MTG and 7-HMG both bind to the human opioid receptors with nanomolar affinity; they function as partial agonists at the mu-opioid receptor and weak antagonists at kappa-opioid and delta-opioid receptors.²⁷

7-HMG exhibits approximately 5-fold greater affinity at the mu-opioid receptor compared to MTG. In rats, MTG does not exhibit abuse liability and decreases the reinforcing effects of morphine. On the other hand, 7-HMG demonstrates abuse liability and increased morphine self-administration.²⁷ MTG can be converted to 7-HMG both in vitro and in a mouse model. It is likely that at least some of the activity attributed to kratom may be due to its metabolic conversion to 7-HMG.²⁷ It has been suggested that individuals who self-administer kratom tea to treat pain, addiction, or depression might achieve very different results depending on the alkaloid profile of the product that they use.²⁷ If so, it would be difficult for consumers to predict the magnitude of activity to expect from ingesting the product since the product labeling does not reflect the variability in alkaloid content .²⁷

Kratom produces both stimulant and sedative effects. At low doses, kratom produces stimulant effects, with users reporting increased alertness, physical energy, talkativeness, and sociable behavior, while high doses produce opioid effects including sedation and euphoria.²⁵ Effects occur within five to 10 minutes after ingestion and last for two to five hours.

The most significant issue with products labeled “kratom” is the introduction of high concentrations of a metabolite (7-HMG) as the most abundant alkaloid. The most abundant alkaloid in traditional kratom products is mitragynine, with concentrations ranging from 54% to 66% of the total alkaloid content. Many other alkaloids comprise the remaining 34% to 46% of total alkaloids, but 7-HMG only constitutes less than 1% of the total. In its natural, fresh state, kratom leaves do not contain 7-HMG. “Kratom” products, often enhanced with extra 7-HMG, are available from Internet sites where it is promoted as a legal psychoactive product.²⁵ Website entries include listings of vendors, methods of preparation, user experiences, and alleged medicinal uses.²⁵ Kratom products are commonly sold in powder form, which is bitter, and users typically consume it as a capsule or use the powder to make tea.²⁶ Common uses are as an alternative to prescription opioids for pain, self-management of opioid or other substance use disorder (including easing withdrawal symptoms), or treating anxiety and depression.^25,26 Reports of adverse effects have increased as the drug has become more popular, with more frequent admission to a healthcare facility and serious medical outcomes, such as seizure, respiratory distress, or slow heart rate.²⁶ According to data from the FDA's adverse event reporting system, mitragynine was involved in 1,255 cases from 2008 to September 2024 of which 1,171 cases were classified as serious and 637 cases resulted in death.²⁵

Regulatory Actions

The risks associated with kratom have prompted government officials to try to restrict its sales for almost a decade, but these efforts have been largely unsuccessful. In 2016, the DEA published its intent to temporarily place MTG and 7-HMG into Schedule I.²⁸ (The Controlled Substances Act empowers the Attorney General to temporarily place a substance into Schedule I for two years without regard to other administrative requirements if there is a finding that such action is “necessary to avoid an imminent hazard to the public safety.”) This decision was based, in part, on the DEA’s finding that the “severity of the reported outcomes, health effects, and increased use of kratom suggests an emerging public health threat.”²⁸ Organizations promoting kratom use did not receive this decision favorably.^24,26

Shortly after the DEA published its notice of intent, a “March for Kratom” was organized at the White House and the protests convinced 51 members of Congress on both sides of the aisle to sign a letter disagreeing with the DEA’s decision.²⁶ Kratom supporters also sent a petition containing more than 145,00 signatures opposing the DEA’s decision to President Obama.²⁶

Kratom advocates stressed several points. They disputed the DEA’s claim about the magnitude of the harm that the substance was producing and also cited reports of possible beneficial effects of kratom as a useful alternative to opioids in managing pain and treating opiate addiction. They maintained that kratom is safer than prescription opioids and that the deaths associated with kratom could be due largely to the simultaneous use of other substances.²⁶ Supporters also posted numerous online testimonials from users touting kratom’s beneficial effects.²⁶

As a result of the backlash, the DEA withdrew the proposed action less than two months after the initial publication, citing numerous comments from the public. The DEA initiated a period of public comment on the scheduling recommendation and received over 23,000 comments with 99% of them opposing the ban.²⁶

A year later, the FDA renewed its effort to schedule the kratom alkaloids and submitted an “eight factor” analysis to the DEA (see the SIDEBAR).²⁶ A month later, the FDA announced a public health advisory on kratom and supported stricter regulation by asserting that kratom was associated with 36 deaths and has similar effects and dangers to other opioids. This was followed by a recall based on contamination of samples with Salmonella or heavy metals.²⁶ However, its legal status has remained unchanged.

SIDEBAR: DEA 8 Factor Test

In determining into which schedule a drug or other substance should be placed, or whether a substance should be decontrolled or rescheduled, certain factors are required to be considered by the Controlled Substances Act [21 U.S.C §811(c) ].²⁹ These are

1. Its actual or relative potential for abuse.
2. Scientific evidence of its pharmacological effect, if known.
3. The state of current scientific knowledge regarding the drug or other substance.
4. Its history and current pattern of abuse.
5. The scope, duration, and significance of abuse.
6. What, if any, risk there is to the public health.
7. Its psychic or physiological dependence liability.
8. Whether the substance is an immediate precursor of a substance already controlled under CSA.

In 2021 the World Health Organization (WHO) announced that it would conduct a review of kratom as part of its role in making public health recommendations to the international community. The FDA participated in this process by submitting information, although two U.S. Senators urged the agency to oppose any effort to add kratom to the list of internationally controlled substances.²⁶ Ultimately, the Committee concluded that there is insufficient evidence to recommend a critical review of kratom.³⁰

The controversy over kratom has not abated, however. In 2023, bills were introduced in both houses of Congress to “protect access to kratom.”^26,31 The bills did not expressly address the legal status but would require the HHS Secretary to hold at least one public hearing to discuss the safety of kratom products. Significantly, if enacted, the law would prohibit HHS from imposing requirements on kratom that are more restrictive than those for foods or dietary supplements.^26,31 It would still permit states to impose more restrictive laws.

More recently, in July 2025, the FDA recommended that products with concentrated levels of 7-HMG be classified as C-I substances; the press release does not define concentrated and the warning only refers to "added" 7-HMG.³² This would apply to products containing high levels of 7-HMG in tablets, gummies, drinks, or parenteral, but not plant, products. FDA Commissioner Makary called the move an “effort to prevent another ‘wave of the opioid epidemic’” from blindsiding the country.”³²

Most states permit the sale, possession, and consumption of kratom, although some set limits.²⁶ There are age restrictions on the sale or possession of kratom products in 18 states; seven of the states restrict the distribution kratom to individuals 18 years of age or older while the other 11 states set an age restriction of 21.²⁶ Tennessee had banned kratom completely, but changed its law to permit natural forms of kratom to be used by individuals over the age of 21.³³ Other states have labelling requirements on kratom products.^26,34 For example, South Carolina passed a law in 2025 mandating that labels must provide details on alkaloid content, serving sizes, and include FDA disclaimers and age warnings. Violations incur civil penalties up to $2,000.³⁴

Some states have taken more aggressive steps to limit access to kratom. Michigan became the first state to ban sales of the drug, classifying it as a Schedule II controlled substance in 2018.¹ As of April 2025, 24 states and the District of Columbia regulate kratom products in some manner.²⁶ Seven states (AL, AK, IN, MI, RI, VT, and WI) and the District of Columbia, treat kratom’s psychoactive components as controlled substances.²⁶

Seven states (AL, AR, IN, LA, RI, VT, WI) effectively ban the sale of kratom by classifying both the plant material and the psychoactive alkaloids as a controlled substance.^33,34 Most have defined it as a C-I substance. Louisiana passed its law in August 2025 classifying the active ingredients, kratom products, and the Mitragyna tree as Schedule I controlled substances. Penalties are severe; producing or distributing kratom can lead to fines up to $50,000 and one to five years in prison, while possession incurs fines up to $1,000 or six months in jail for repeat offenses.³⁴

Other states have enacted more consumer-focused kinds of controls.³⁴ For example, Hawaii requires products to be registered with the Department of Health, have third-party lab testing, and comply with federal good manufacturing practices. Products may not exceed 2% 7-HMG, contain harmful substances like synthetic cannabinoids, or be designed to attract children (e.g., cartoon-shaped products).³⁴ Mississippi requires retailers to obtain permits and imposes an excise tax of $2.50 per ounce for kratom leaf and $5.00 per ounce for extracts.³⁴ Four states (AZ, GA, OK, UT) require that labels indicate the alkaloid content of the product.³⁴

PAUSE AND PONDER: Where should the line be drawn between protecting the public and patient autonomy?

PHENIBUT

Phenibut, known colloquially as Phenigamma and Phenygam among others, is another substance that has evaded regulatory control. Phenibut is a derivative of gamma-amino butyric acid (GABA) and acts as a GABA mimetic primarily at GABA-B receptors (like baclofen); it also affects GABA-A receptors but to a lesser extent. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic transmitter.³⁵ Both its desired and adverse effects appear similar to other GABA receptor modulators like benzodiazepines.³⁶

It was originally developed in the former Soviet Union in the 1960s to relieve anxiety and improve cognitive function in military personnel.³⁷ Later it was introduced into clinical medicine as a treatment for anxiety, insomnia, and various psychiatric conditions ranging from post-traumatic stress disorder to alcohol withdrawal. It has also been used to enhance cognition in young adults and to delay dementia in the elderly. Its presence has expanded to other parts of Europe and the U.S. where it is marketed as a putative OTC cognition enhancer.³⁷ The drug is available in different forms including as a powder, “fine crystals,” and capsules and is also found combined with other substances.^37,38

Phenibut produces a number of adverse effects including drowsiness, lethargy, agitation, tachycardia, and confusion.³⁷ In addition, it can lead to the development of tolerance and dependence and withdrawal may manifest as a severe abstinence syndrome that may require medical intervention.³⁷ The abstinence syndrome resembles benzodiazepine withdrawal and patients may experience insomnia, anger, irritability, tremulousness, decreased appetite, and heart palpations.³⁸ Phenibut also has the potential for interactions with related substances such as anxiolytics, antipsychotics, sedatives, opioids, and anticonvulsants.³⁷

During the period from 2009 to 2019, U.S. poison centers received 1,320 calls about phenibut exposures from all 50 states and the District of Columbia.³⁹ The most commonly reported adverse health effects included drowsiness or lethargy, agitation, tachycardia, and confusion. Coma was reported in 6% of cases. In half of the cases, the exposure resulted in moderate effects with no long-term impairment. About 12% of cases reported life-threatening effects or resulting in significant disability, with three deaths.³⁹ Physical dependence, withdrawal, and addiction have also been reported.³⁸

The FDA issued warning letters to companies whose products contained phenibut and were marketed as dietary supplements as far back as 2019. The FDA concluded that phenibut does not meet the statutory definition of a dietary supplement, and the products were therefore misbranded.⁴⁰ Yet, phenibut is still legally available for sale in the U.S., largely through online sources.

Phenibut has become increasingly available in the U.S. (and European) market, often labelled as a dietary supplement with claims such as promoting focus, relaxation, and positive mood; improving memory and concentration; counteracting irritability and restlessness; and increasing libido.³⁷ Studies of consumers have found that it is frequently purchased as a therapeutic substitute for benzodiazepines, and to manage withdrawal due to benzodiazepines, opioids, and alcohol.³⁷ Nevertheless, the FDA does not regard it as a dietary ingredient and considers phenibut-containing supplements declaring themselves as a dietary ingredient misbranded under the FDCA.

The agency sent warning letters to at least three companies that have marketed products containing phenibut labelled as dietary supplements in 2019. Despite the warnings, the quantity of phenibut increased in three of four brands of OTC phenibut supplements tested following the FDA’s action; in some cases, the amounts detected were 450% greater than a typical 250 mg pharmaceutical tablet manufactured in Russia.⁴¹

The warnings were obviously ineffective and phenibut remains readily available in the U.S., largely online.⁴² Several European countries have made phenibut a controlled substance. In the U.S., Alabama made phenibut a Schedule II drug in 2021and additional states are considering legislation to classify it as a controlled substance.⁴²

PEPTIDES

Another means used to circumvent FDA regulations is to sell drugs on-line advertised as “research compounds” or “lab use” although the promotional material and product reviews clearly show they are being used by individuals who are not enrolled in drug trails. These compounds are readily available online, including through Amazon.com.⁴³

There is a high demand for “research” compounds labelled as “peptides” especially among individuals seeking substances for athletic performance enhancement, improved libido, anti-aging effects, or weight loss (pseudo or real GLP-1 drugs).⁴⁴ This includes existing prescription drugs purchased online through clandestine overseas operations or true research compounds. One example is sermorelin, which modulates the release of growth hormone and allegedly increases muscle mass and possibly enhances libido.⁴⁴ The high demand has led to shortages of prescription products, further stimulating illicit sales.⁴⁴

FINAL COMMENTS

While most therapeutic substances are subject to some degree of control by the FDA, some products available in retail stores or on-line receive no regulatory approval. They present a risk to the public. Manufacturers of these substances may try to circumvent regulation by falsely depicting them as dietary supplements, research compounds, or for external use. Consumers may use these to self-manage their medical conditions or for recreational purposes with a risk of developing serious adverse effects or dependence. The FDA has tried to limit the use of these substances by issuing warnings to consumers and warning letters to manufacturers, but these tactics have had limited success. Pharmacists should be prepared to answer questions about these drugs which commonly gain momentum through social media and should point out that there is no oversight over their claims or safety.

Download CE Activity

“No one recognizes the level of stress they’re putting you under. You’re filling a prescription and the phone is ringing, saying, ‘One pharmacy call, two pharmacy calls, three pharmacy calls.’ I would stand there and feel the sweat come up the back of my neck.” - Pharmacist¹

INTRODUCTION

A recent survey found that more than half of United States (U.S.) consumers worry about potential problems with their prescriptions arising from inadequately staffed pharmacies.² Half of consumers worry about receiving the wrong drug, the wrong dose, or the wrong instructions.² Similarly, a 2024 study by the American data analytics, software, and consumer intelligence company J.D. Power found that overall patient satisfaction with pharmacies has declined, especially among chains, with only mail-order pharmacies showing an improvement in patient satisfaction.³ Only 51% of respondents said their pharmacist is trustworthy.³ The most significant problem areas emerging from the study are long wait times, lower levels of customer trust in pharmacists, and difficulty in ordering prescriptions.³ On a more positive note, 97% of American consumers agree that a pharmacist should have responsibility for informing them about the safety and/or effectiveness of their medications.²

It will probably come as no surprise to readers that pharmacists also report dissatisfaction with working conditions, particularly with issues of staffing, patient aggressiveness, and lack of meaningful communication between pharmacy personnel and management.⁴ The most commonly reported root causes for the disgruntlement were inadequate staffing, the use of performance metrics, and workflow design/policies.

Media reports have described pharmacists at chain pharmacies across the U.S. expressing concern that increased demand for prescriptions, vaccines, and other services are occurring without sufficient staff to fulfill those activities, making it nearly impossible for pharmacy staff to do their jobs properly or safely.⁵ A national survey released in 2022 showed that nearly 75% of pharmacist respondents felt they did not have enough time to safely perform clinical duties and patient care. Nearly two-thirds disagreed with the statement that “employer policies facilitate my ability to safely perform patient care/clinical duties.”⁶ The report also found that three-quarters of pharmacists rated their workload as high or extremely high and that job satisfaction was at the lowest point in 20 years.⁶

Has the modern community pharmacy become a danger to the public? This continuing education activity will examine the current sentiment about the pharmacy workplace, and the perceived risk associated with the current working conditions. It will also review legal and policy changes enacted or contemplated by pharmacists, regulatory bodies, and patients to improve the environment.

THE PHARMACY ENVIRONMENT

In 2022, 6.7 billion prescriptions were dispensed in the U.S., a more than 50% increase from the nearly 4 billion prescriptions dispensed in 2009.⁷ Some pharmacists may feel that they filled that many by themselves.

Currently, almost 70% of people in the U.S. between 40 and 79 years old take at least one prescription drug; 20% take five or more.⁸ In addition to prescriptions, between February 2020 and September 2022, pharmacy staffs administered more than 270 million vaccines, including more than half of all COVID-19 vaccines given in the U.S.⁹ Community pharmacy teams alone accounted for approximately 45% of the total, including more than 8 million COVID-19 vaccines for long term care residents. Pharmacy staffs also provide more than 50 million influenza vaccines per year, supply in excess of 42 million COVID tests, and prescribe and dispense many antiviral medications.⁹ Interventions by pharmacy staffs during this period is conservatively estimated to have averted more than 1 million deaths, 8 million hospitalizations, and saved $450 billion in healthcare costs.⁹

While these data, highlighting pharmacists’ value, should engender a deserved sense of pride, as the opening quote illustrates, pharmacists are also are feeling stress over their workload. Pharmacists interviewed by the Chicago Tribune and the New York Times reporting on pharmacy errors related that they felt flabbergasted by pressures at the workplace to work quickly and meet quotas.^10,11 As a result, a chief executive of a state pharmacy association noted that the number of complaints from members related to staffing cuts and worries about patient safety had become “overwhelming.”¹² Similarly, a survey conducted by the California State Board of Pharmacy found that 91% of chain pharmacists indicated that they lacked the staff needed to ensure adequate patient care.¹³ The Kansas Board of Pharmacy found similar results with more than half of pharmacists polled responding that they didn’t feel they could perform their jobs safely.¹³ The biggest reasons cited were a lack of adequate staffing and employer-imposed metrics, such as filling a specific number of prescriptions a day or providing service to patients within a set time.¹³

These added pressures are consistent with a reduction in the number of pharmacies. Chain pharmacies in particular have been reducing staffing levels and closing pharmacies while simultaneously burdening workers with additional duties.¹³ Staff who do not fill prescriptions or answer the phone fast enough or fail to solicit enough vaccinations reportedly may face discipline, reassignment, or termination.¹³ A former pharmacy school Dean likened the current working environment to the equivalent of a fast-food operation where workers feel pressured to race through every order.¹³

PAUSE AND PONDER: How has your job stress changed in the last few years? Have you seen errors in the workplace?

Consumers are also noticing problems or at least expressing a lack of confidence in pharmacists' attention to detail and public safety. Their concerns are not unfounded. A recent systematic review of 62 studies reported a pooled prevalence of dispensing errors across community, hospital, and other pharmacy settings of 1.6%.¹⁴ [It is difficult to accurately determine error rates due to differences in how studies are conducted, the definition of “error,” and other factors. Consequently, error rates vary widely among different studies. However, a generally accepted reasonable estimate of dispensing errors is approximately 1% to 2%.^15-17 This would represent approximately 67 to 134 million errors each year at the current prescription volume!]

Many factors may contribute to the occurrence of medication errors. An error may occur at any stage of therapy, including prescribing, transcribing, identifying the product, counseling, use by the patient, or monitoring. Errors can occur across all practice settings.¹⁷ Errors may result from an act of commission (e.g., dispensing the wrong drug or dose) or omission (e.g., failure to properly counsel a patient).^18,19 According to the Academy of Managed Care Pharmacy, the most common dispensing errors are dispensing an incorrect medication, dosage strength, or dosage form; miscalculating a dose; and failing to identify a drug interaction or contraindication.¹⁸ Medication errors can cause a range of undesirable outcomes including adverse drug events (dangerous and unintended events), hospitalization, and even death.¹⁷

What’s Workload Got to Do with It?

A few lines of evidence suggest that errors may be associated with workload. Numerous studies have described a relationship between prescription volume and errors.^20-22 A survey of pharmacists in Texas in 2001 found that the estimated risk of errors was positively related to the number of prescription orders filled per hour.²⁰

Other studies found that as prescription volume increased beyond 20 to 24 per hour, the number of errors increased significantly.^20-22 An earlier analysis by a prominent researcher also concluded that the rate of pharmacists’ errors increases after they fill more than 24 prescriptions an hour.²³

The potential for errors is no surprise to pharmacists.¹² One pharmacist reportedly wrote an anonymous letter to his State Board of Pharmacy saying, “I am a danger to the public working for (chain pharmacy).”¹²

Not only is the volume of prescriptions filled by a typical pharmacist a concern for its impact on the risk of errors, but the danger is aggravated by some pharmacy chains’ implementation of time guarantees, promising patients that prescriptions will be filled quickly.^1,12 While the guarantee should provide a benefit to the busy consumer, it is also a safety concern, since the haste to fulfill the guarantee may make it more likely that a medication error may occur. As one pharmacist interviewed by the New York Times wrote, “Metrics put unnecessary pressure on pharmacy staff to fill prescriptions as fast as possible, resulting in errors.”¹² One study of 49 community pharmacists, that had a robust response rate of 90.9%, found that the second most frequent source of error was “patient in a hurry.”²⁴

The former Dean quoted above also believes that “at … the huge pharmacies, errors are a cost of doing business.”¹³ One chain store pharmacist told a reporter that she was reprimanded for taking too long to verify prescriptions, even though her extra diligence had caught several serious mistakes.¹³

The major chains have made changes to address the pressures on pharmacists and promote a “better work-life balance” according to one chain spokesperson.¹³ Most now provide half-hour lunch breaks for staff and some have reduced pharmacy hours.¹³ However, pharmacists report that their workloads remain the same and that they are pressured to work through lunch or stay late to finish their tasks.¹³ Moreover, pharmacists report that when their hours were cut, they saw a corresponding decrease in their salary.¹³

PAUSE AND PONDER: What could be done to reduce workplace stress at your pharmacy?

PHARMACY DESERTS

Pharmacists are not the only ones strained when pharmacies close; it also increases the burden on patients who are left without easy access to pharmacies and their medications. This phenomenon, referred to as “pharmacy deserts,” creates disproportionate consequences for certain communities, notably in areas of patients with high levels of social vulnerability.²⁵ Poor access to pharmacies is often associated with lower medication adherence.²⁵

A pharmacy desert may be defined as a low-income urban area with no pharmacy within a mile radius for those with adequate vehicle access or half a mile for those with limited vehicle access. In rural areas, it refers to areas without an available pharmacy within a 10-mile radius for those with access to transportation.²⁶

The number of retail pharmacies in the U.S. declined by almost 4% (from 63,218 to 60,755) between 2018 and 2023.²⁷ The decrease was larger (5.9%) in rural communities. During the five-year period, 184 rural communities lost all of their retail pharmacies (although 195 rural communities gained retail pharmacies). The majority of the pharmacy losses in rural communities were among independent pharmacies.²⁷ Pharmacy closures were also more common in Black and Hispanic/Latino neighborhoods putting a further strain on health care accessibility in these communities.²⁵

EFFORTS TO CHANGE THE WORKPLACE

Recognition that the pharmacy workplace can contribute to staff burnout and risks to the public is growing. This has resulted in different types of reactions among various groups with the goal of improving the work environment.

Action By Pharmacists

Some pharmacists who have been adversely affected by the current working environment have responded. One action that pharmacists have taken is work stoppage with dozens and, at least in one case, hundreds of pharmacy personnel in chain stores calling out of work to protest working conditions.⁵ The pharmacists maintained that the increased focus on vaccinations added to their workload and made it more difficult for them to carry out their other duties and created a potentially unsafe condition. One pharmacist claimed that the chain has “turned into a vaccination clinic first and a pharmacy second” and added that “because immunizations are so profitable, filling prescriptions is almost an afterthought.”⁵ In at least one instance, pharmacist organizers planned to stage a multi-day nationwide walkout, termed “Pharmageddon,” to protest unsafe working conditions.²⁸

PAUSE AND PONDER: Under what conditions would you be supportive of pharmacists striking for better working conditions?

Action By Regulatory Agencies

Governmental and professional organizations that oversee the pharmacy profession have also become concerned with potentially unsafe conditions existing in the nation’s drugstores and have taken steps to change the workplace environment.

If a pharmacy staff member commits an error, a State Board of Pharmacy may take disciplinary action, but the application of the action differs among the states.²⁹ In the typical situation, the Board will learn of the incident when a patient or caregiver files a complaint, which the Board is obligated to investigate.^29,30 Most states do not have specific rules or regulations that specify that errors are actual regulatory violations, and most determinations are made on a case-by-case basis.³⁰

The most common types of punitive action include license suspension, probation, or revocation, and fines.³⁰ In a few states, incarceration is also a possible punitive action.³⁰ The most common bases for dispensing punitive action were to address public safety/health concerns and public complaints. At least two states (Maryland and Massachusetts) appear to take a nonpunitive approach, with a focus on system wide improvements rather than individual responsibility, and with punitive action reserved for pharmacists deemed incompetent.³⁰

A majority of state boards do not require pharmacies to report errors, and most investigations focus on pharmacists, not the conditions in their workplaces.¹² Some boards have instructed pharmacists in public meetings to quit or speak up if they believe conditions are unsafe. However, many pharmacists fear retaliation, knowing they could easily be replaced for doing so.¹²

Pharmacists have also reported that errors are not consistently disclosed, even internally.¹³ These pharmacists claim that small mistakes and those discovered early are routinely hidden or remain unreported especially by pharmacists who have previously made an error.¹³  One California chain pharmacist believes that "for every error that gets found out, there will be an error that never gets caught."¹³ Pharmacists also say that even when they do report potentially fatal errors, no one from their companies investigates how they occurred or makes changes to prevent them from repeating.¹³ Obviously these actions put the pubic at risk.

PAUSE AND PONDER: Should the reporting of pharmacy errors to a regulatory body be mandated?

Many pharmacy organizations have advocated for workplace changes to reduce the number of errors, including the elimination of prescription time guarantees.¹⁶ The American Pharmacists Association approved a resolution in 2018 which “encourages the adoption of patient-centered quality and performance measures that align with safe delivery of patient care services, and opposes the setting and use of operational quotas or time-oriented metrics that negatively impact patient care and safety.”⁴

Similarly, the trade group The National Pharmacists Association, advocated for pharmacist dispensing limits more than 30 years ago as a means to promote safety. They recommended that a pharmacist fill no more than 15 prescriptions an hour.²³

The former Dean says, “I don’t think the boards of pharmacy or the colleges of pharmacy or the professional associations are doing enough to address the issues.”¹³ However, in one recent event, the Nevada Board of Pharmacy fined and suspended the licenses of two pharmacists who mistakenly provided a pregnant woman with misoprostol instead of the fertility treatment she was prescribed.¹³ The Board also fined their chain pharmacy employer $10,000. However, the pharmacy’s lawyer objected to the fine saying they did nothing wrong, saying that “the only allegation” against the employer “is that they had these pharmacists.”¹³

Trends in State Intervention

Traditionally, state pharmacy boards and other regulatory bodies have considered sanctions after errors have occurred but have generally refused to intervene over workload complaints.¹³ They have seen their role as protecting consumer safety, not to intrude on what has been regarded as business decisions such as staffing metrics and workload.¹³ However, this stance has been changing.

As early as 2017, the Chicago City Council approved legislation that would limit pharmacists to filling a maximum of 10 prescriptions per hour and also required a 30-minute meal and two 15-minute bathroom breaks for pharmacists working at least a 7-hour shift.³¹ A pharmacy also would need to schedule at least 10 pharmacy technician hours per 100 prescriptions filled. The proposal came in response to an investigation by the Chicago Tribune which found that 52% of local pharmacies tested failed to warn a member of the investigative team of potentially serious or fatal drug interactions when presented with a pair of prescriptions.³¹

A few years later the state of Illinois went further, passing notable changes to their Pharmacy Practice Act in 2020 after the Tribune's undercover investigation.³¹ The Act prohibits a pharmacy from requiring staff to work more than 12 continuous hours, including breaks, per day. This applies to pharmacists, pharmacy technicians, and student pharmacists. It also requires at least one uninterrupted 30-minute meal break and another 15-minute break for a pharmacist working six or more continuous hours per day.³² The pharmacist may not work more than five continuous hours before being given the opportunity for a meal break and must be given access to a private break room if one is available.³²

The regulation permits the pharmacy to close during the break period but does not require closure. The pharmacist must be available for emergencies if the pharmacy remains open. Technicians and other authorized support staff may continue to perform normal duties while the pharmacist is on break, except for duties that require a pharmacist’s professional judgment. Prescriptions that have received final verification by a pharmacist and do not require counseling may be dispensed during the break period.³² If a mandated break period is not provided, the pharmacy must pay the pharmacist three times the pharmacist's regular hourly rate of pay for each workday with no break.

The Tribune’s investigation also prompted Illinois Senator Richard Durbin to call for nationwide policies to protect consumers, including asking the Centers for Disease Control and Prevention (CDC) to determine the prevalence of the problem and to provide guidance to pharmacy boards. He also asked the CDC to examine how workload, company performance metrics that track prescriptions, and the length of time consumers wait for prescriptions may impact patient safety and pharmacist errors.³³

Many years earlier (2007), North Carolina had passed a law restricting a pharmacist’s workday to no more than 12 continuous hours and required breaks for a shift of six hours or more.³¹

Other states have also considered regulations to reduce pharmacy stress, although many face opposition from employers. Minnesota is also considering a bill to require bathroom and meal breaks after pharmacists complained that they were afraid to drink liquids during a shift because they might not be able to get to the bathroom.³¹ New Hampshire also has enacted a rule permitting a 30-minute break for pharmacists who work more than eight hours. The new rule took more than four years to be implemented due to opposition from the pharmacy industry.³¹

The South Carolina board has discussed how to investigate conditions more thoroughly after a mistake. It also published a statement discouraging quotas and encouraging “employers to value patient safety over operational efficiency and financial targets.”³¹

PAUSE AND PONDER: Do you think that mandated breaks are beneficial in increasing safety in the pharmacy?

California recently instituted workplace regulations that go even further. The “Stop Dangerous Pharmacies Act” enacted in 2024 allows the pharmacist in charge (PIC) to make staffing decisions “to ensure sufficient personnel are present in the pharmacy to prevent fatigue, distraction, or other conditions that may interfere with a pharmacist’s ability to practice competently and safely.”³⁵ The California Board of Pharmacy estimates that pharmacists make 5 million errors in the state per year, prompting the need for workplace changes.³⁶ If the PIC is not available, a pharmacist on duty may adjust staffing according to workload if needed.³⁵ The pharmacist on duty may also close the pharmacy if, in their opinion, staffing at the pharmacy is inadequate to provide patient care in a safe manner.³⁷

In addition, a chain community pharmacy is required to be staffed at all times during normal business hours (defined as 8:00 am to 7:00 pm) with at least one clerk or pharmacy technician fully dedicated to performing pharmacy-related services.³⁵ This requirement is waived if the pharmacy’s average daily prescription volume is less than 75 prescriptions per day. However, the exemption does not apply if the pharmacist is also expected to provide additional pharmacy services such as immunizations or tests.³⁵ The new regulations also expanded duties that can be performed by a technician including accepting prescription transfers and clarifications of prescriptions.³⁵

California also prohibits chain pharmacies from establishing a quota related to the duties for which a pharmacist or pharmacy technician license is required.³⁸ (A quota is defined as “a fixed number or formula related to the duties for which a pharmacist or pharmacy technician license is required, against which the chain community pharmacy or its agent measures or evaluates the number of times either an individual pharmacist or pharmacy technician performs tasks or provides services while on duty” and includes prescriptions filled and “services rendered” to patients.³⁸)

However, California and other states have found that enforcing these rules is challenging.¹³ The California State Board of Pharmacy, for example, is coping with routine violations by retail pharmacies that then fail to provide records to inspectors seeking to verify complaints.¹³

Oklahoma also recently established rules to ensure adequate staffing levels.³⁹ Pharmacists are expected to complete a form whenever they are concerned about inadequate staffing due to inadequate number of support personnel or excessive workload. Each pharmacy must review completed staffing reports and address any issues listed and document any corrective action taken or justification for inaction. The reports must be made available to the Board during inspections. There is also a prohibition against disciplinary action or retaliation against the pharmacist filing the report.³⁹

Virginia also passed temporary emergency regulations banning production quotas and increasing staffing in late 2024.¹³ Other states, including West Virginia, New York, and Illinois have attempted to pass legislation similar to California’s prohibition of the use of quotas for duties performed by pharmacists or technicians, but the legislation failed to pass.³⁶

The Ohio Board of Pharmacy also took steps to address the pharmacy staffing shortage with new rules in 2024.⁴⁰ One new rule requires pharmacies to “ensure sufficient personnel are scheduled to work at all times in order to minimize fatigue, distraction, or other conditions which interfere with a pharmacist’s ability to practice with reasonable competence and safety.” It also calls for staffing levels to be based on “other requirements” related to the practice of pharmacy and not solely based on prescription volume and also bans the use of “quotas” for “ancillary services.” (Quotas are defined as “a fixed number or formula related to the duties of pharmacy personnel, against which the pharmacy or its agent measures or evaluates the number of times either an individual performs tasks or provides services while on duty.^”40)

To alleviate burnout that can lead to mistakes filling prescriptions, Ohio’s new rules will require that all pharmacies give all employees working six hours or more an uninterrupted 30-minute break.⁴⁰ The pharmacy does not need to close during the break if the pharmacist remains on the premises and prescriptions may still be sold but the recipient must be provided with an offer to counsel. A person who wishes to speak with a pharmacist must be told that the pharmacist is on break and that they may wait to speak with the pharmacist or provide a telephone number for contact after the break.

Significantly, the new rules require pharmacies to develop a formal system so pharmacists can request additional staff. They also require pharmacy owners to act promptly on those requests and prohibit owners from retaliating against pharmacists who request extra help. A written response to the request must occur within 14 business days and a copy of the response must be maintained in the pharmacy for three years for inspection by the Board.⁴⁰

Ohio’s Board also reacted to patients reporting delays in receiving their medication.⁴¹ The new rules require new prescriptions to be filled within three business days and those subject to auto refill to be done within five.⁴⁰ (The rule has exemptions for shortages, delays in insurance coverage, and where the prescription requires clarification or raises suspicion about its safety or validity.⁴⁰)

Pharmacy chains opposed the new rules.¹³ One chain wrote that the “Board should stay focused on the regulation of the practice of pharmacy rather than the business of pharmacy.”¹³ Chain representatives acknowledged the challenges their pharmacists have faced but denied allegations of unsafe working conditions. They claimed that metrics based on measurable objectives such as quick prescription turnarounds, short telephone hold times, and vaccination volumes are standard within the industry and meant to assess quality rather than penalize staff.¹³

Another effort to reduce errors being considered by some states is mandatory error reporting.³⁷ Pennsylvania requires healthcare facilities to report all incidents of harm and may be the only state currently doing so.³⁷ In Canada, Nova Scotia became the first jurisdiction to implement a requirement for community pharmacies to anonymously report medication incidents to a national repository in 2010 and several other Canadian provinces have followed.⁴² The stated purpose of the repository is to improve medication safety in the community through evidence-informed recommendations for reducing preventable harm related to medications.⁴²

Another approach to reduce errors in the pharmacy is to free up the pharmacist from certain traditional tasks by placing greater reliance on technicians. A formalized program is termed tech-check-tech (TCT) and enables a trained pharmacy technician to perform the final verification on a prescription for which the pharmacist has previously performed the prospective drug utilization review.⁴³ The TCT concept dates back to at least 1978 and has been well validated in institutional pharmacy settings.⁴⁴ Studies have found that technicians perform at least as well as pharmacists in final verification activities in institutional settings and have demonstrated that utilization of technicians in this way allows pharmacists to devote one to five more hours per day to direct patient services.^43,44 While this expanded role for technicians is becoming common in institutional settings, few states have adopted it for use in the community pharmacy.⁴³

PAUSE AND PONDER: In your workplace, what additional tasks could certified technicians perform?

SUMMARY

To err is human, and pharmacy staff will make errors despite their best efforts. Errors can occur at any step during prescription processing. The error rate is not well validated due to many methodological variables, and estimates vary widely although 1% to 2% is a commonly accepted value. However, even at these low rates, the number of patients affected is large and the consequences, although usually minor, can be catastrophic. Pharmacy staffs, of course, do not want to commit errors and removing the triggers for errors is a worthy goal. Evidence supports the concept that workplace pressures and insufficient staffing, high prescription volume, and interruptions and distractions exacerbate the risk of errors. The trend towards reducing the number of pharmacies while expanding pharmacy services has added additional strains to the health care system. Patients have become more aware of the risks associated with the pharmacy environment and burnout. This has also lessened the public’s perception of pharmacists.

Concerns over errors have spurred a growing number of states to revise their Pharmacy Practice Acts to relieve some of the workload pressure on pharmacists. Typical changes include limits on the length of the workday, mandated breaks, limits on the number of prescriptions a pharmacist can dispense over time, and reconsideration of tracking metrics. However, these changes have encountered resistance by employers and implementation and enforcement are spotty. Other changes include expanding the use of technicians and allowing more time for pharmacists to provide services related to patient care. It remains to be seen whether more regulatory oversight of the workplace will impact the number of errors committed. In the meantime, pharmacists and technicians should be extra vigilant to avoid being the object of the next media investigation that casts the profession in a bad light and hope they do not become “a danger to the public.”

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INTRODUCTION

Kratom. What a funny little word. It's six letters and preponderance of consonants give it an explosive, almost exotic sound. When Pete, a 31-year-old construction worker who has been on workers compensation for six months for a back injury asks about it, the pharmacist, Cindy, is baffled. Educated to never respond with “I don’t know,” Cindy replies, “I don’t know but I will gather some information. Can you give me a couple of days to do some research?” Pete agrees and Cindy gathers information using open-ended questions to determine his goals. Pete says he heard that kratom relieves pain much like opioids do, and it’s a “natural product.” He says that his physician is weaning him from opioids, but he still has pain unrelieved by nonopioid pain killers. His bowling league teammate said “7” would be “better than that regular kratom stuff.” He sees both products at the gas station, and he would like to know if they have the same side effects as opioids do. He says, “I would really like to be done with the constipation.”

PAUSE AND PONDER: What things should Cindy think about as she assesses Pete’s situation?

People native to Southeast Asia (Cambodia, Indonesia, Malaysia, Myanmar, Papua New Guinea, and Thailand) have a deep-rooted history of using kratom, derived from the whole fresh or dried leaves of tropical Mitragyna speciosa trees, dating back centuries.^{1, 2} Once harvested, the leaves can be chewed or brewed into a tea for multiple purposes. Western medical literatures’ earliest mention of kratom dates to the 19^th Century. Traditional uses of kratom in Southeast Asia include improving productivity and combatting physical fatigue in manual laborers, treating morphine dependence, and enhancing religious ceremonies.³

In recent years, kratom-containing products have garnered popularity within the recreational drug market. Approximately five million Americans (aged 12 years old or older) have used kratom.⁴ The predominant demographic of users has recently shifted from middle-aged males to younger people and females.⁵ Consumers can purchase these products in smoke shops, convenience stores, gas stations, and over the Internet without a prescription.⁴ In the United States (U.S.), kratom is available in several dosage forms (capsules, concentrated extracts, powder, raw leaves, and tablets) and doses (depends on the dosage form). Around the world, traditional kratom products have been used as a replacement for traditional opioids or other substances of abuse, or for treatment of anxiety or depression. However, no clinical trials substantiate these benefits.^6,7,8

Cindy focuses on the allegation that kratom and similar products are “natural,” recalling that “natural” is not equivalent to “harmless.” Natural products are often contaminated with elemental impurities (also known as heavy metals).⁹ Kratom specifically can be tainted with heavy metals like arsenic, lead, manganese, and nickel. The Food and Drug Administration (FDA) specifies the permissible daily exposure (maximum acceptable intake) for arsenic, lead, and nickel in dietary supplement products and the tolerable upper intake level of manganese would also be exceeded by some products. However, some kratom products have been found to exceed these regulatory thresholds; non-extract products (capsules, powders, and tablets) often have higher concentrations compared to extracts.⁵

A potential cause of lead and nickel contamination is the country of origin of the kratom trees (Indonesia and Thailand, for example, naturally have greater lead concentrations in their soil and water).^10,11 Local water is used to wash the picked leaves which may leave an elemental impurity residue and the trees themselves can pick up the heavy metal from the soil. Machinery use (harvesting, grinding, storing, and shipping), pesticide and herbicide use, and volcanic rock leeching are the ultimate sources of the heavy metals.^10,11 Regardless of the source, elemental impurities may be retained on harvested, dried leaves which can then be sold to consumers leading to excessive heavy metal exposure. Some products sold as kratom in the U.S. have been adulterated with synthetic compounds such as 7-hydroxymitragynine ((7-OH-MG), an alkaloid of kratom and a growing concern nationally) or even with fentanyl or hydrocodone.¹²

Readers should take a moment to review the various chemical names and pronunciations used in this continuing education (CE) activity in the SIDEBAR.

SIDEBAR: Chemical Components of Kratom

• Alkaloids: natural organic compounds that provide varying physiological effects on animals
• Corynantheidine*: a minor alkaloid of kratom with antinociceptive activity
• Corynoxine/corynoxine B: a minor alkaloid of kratom and derivative of corynantheidine; full agonist of the μ-opioid receptor
• Mitragynine*: a major (most abundant) alkaloid of kratom; provides pain-relieving and stimulating effects
• Mitragynine pseudoindoxyl: a 7-OH-MG metabolite; a more potent μ-opioid receptor agonist compared to mitragynine
• Paynantheine: a major, secondary alkaloid of kratom with high binding affinity to serotonin receptors (5-HT_1A and 5-HT_2B)
• Speciofoline: a minor alkaloid of kratom with no measurable binding affinity at the µ-, δ- or ƙ-opioid receptors
• Speciogynine: a minor alkaloid of kratom with high binding affinity to serotonin receptors (5-HT_1A and 5-HT_2B)
• Specioliatine*: a minor, rare alkaloid of kratom; modulates the pain-relieving and stimulating effects of mitragynine
• 7-hydroxymitragynine (7-OH-MG): an active metabolite of mitragynine; a potent partial μ-opioid receptor agonist exhibiting pain-relief, sedation, and opioid-induced addiction potential (as indicated in animal studies; see below)

*partial agonist of the μ-opioid receptor

Kratom remains a Drug Enforcement Administration (DEA) substance of concern but is not currently scheduled.⁶ Kratom products’ overall risk profile is much lower than some substances of abuse (traditional opioids, amphetamines, cocaine) and similar or slightly lower than cannabis and alcohol.⁷ However, when traditional kratom products are used to treat substance use disorders (SUDs), two observational studies (N = 160, N = 32, respectively) found fewer subsequent episodes of illicit substance abuse and fewer risky lifestyle behaviors such as injecting drugs and needle sharing.^9,13

Another observational study (N = 163) found a lower likelihood of constipation, cravings, fatigue, insomnia, and sexual performance issues than those associated with traditional opioid use.¹⁴ One small clinical trial (N = 26) demonstrated that traditional kratom products can increase pain tolerance. Following a cold pressor task (a procedure where participants immerse their dominant hand into an ice bath and verbally report pain onset), kratom reduced pain sensitivity. The study also suggests that chronic use may cause hyperalgesia (an increased sensitivity to pain) when kratom alkaloid concentrations are low compared to drug-naïve states.^6,15 Whole leaf kratom has modest stimulant effects, so the risk of respiratory depression is low but it does produce adverse events, especially in higher doses, and it has the potential to cause a kratom use disorder (kratom-specific substance use disorder, K-SUD).^6,16  The main adverse events include nausea and vomiting, constipation, tachycardia, hypertension, agitation, confusion, elevated liver function tests, and seizures.

Notable changes have occurred in the kratom product marketplace. In January 2024, an exposition (trade show) in Las Vegas for buyers and sellers of legal recreational substances hosted just two companies selling products with high concentrations of a metabolite (7-OH-MG) as the most abundant alkaloid.¹⁷ By the time the next exposition was held in Chicago in June 2024, 37 companies in the marketplace with 7-OH-MG as a prominent ingredient in a product or products attended; it’s likely that there are many more that did not attend.¹⁷ According to the National Drug Early Warning System (surveillance system that detects early signals of potential drug epidemics), chatter about 7-OH-MG had increased steeply. It rose from roughly 10 posts weekly between September 2023 to November 2024 and spiked to about 20 posts for several weeks from November 2023 to March 2024. From March to June 2024, posts spiked considerably to 30 to 45 posts weekly for several weeks.¹⁸ This CE activity will attempt to tackle several key questions regarding this trend towards higher 7-OH-MG products including

1. How does the alkaloid composition in traditional kratom products compare with high 7-OH-MG concentration products?
2. What do preclinical studies (studies conducted in animal models) suggest about the pharmacologic effects of traditional kratom products compared to high 7-OH-MG concentration products?
3. What insight can be gleaned from consumers about the comparative effects of taking traditional kratom products rather than high 7-OH-MG products?

TRADITIONAL KRATOM VS. 7-HYDROXYMITRAGYNINE

As displayed in Figure 1, the most abundant alkaloid in traditional kratom products is mitragynine, with concentrations ranging from 54% to 66% of the total alkaloid content.¹ Many other alkaloids comprise the remaining 34% to 46% of total alkaloids, but 7-OH-MG only constitutes less than 1% of the total.

Figure 1. Histogram of the Relative Percentage of Alkaloids in Traditional Kratom Products Versus 7-Hydroxymitragynine Products

READING THIS HISTOGRAM: Whole leaf kratom (either fresh or leaf) has 54% mitragynine, 16% specioliatine, 12% cornoxine/cornoxine B, 10% paynantheine, and <1% 7-hydroxymitragynine. 7-OH-MG products contain 93% 7-hydroxymitragynine, 7% mitragynine, and none of these other natural alkaloids.

In its natural, fresh state, kratom leaves do not contain 7-OH-MG; however, 7-OH-MG is a degradation product found minutely in older leaves.¹ In one laboratory evaluation of 53 commercial kratom products, mitragynine, and 7-OH-MG concentrations were related to the speciofoline concentration, a major alkaloid found in the kratom plant that has unspecified activity at the mu and kappa opioid receptors.¹⁹ “High speciofoline” varieties comprised 4.13 mg/G of kratom powder with mitragynine and 7-OH-MG content of 8.13 mg/G and 0.03 mg/G, respectively. “Low speciofoline” varieties had undetectable speciofoline content but mitragynine and 7-OH-MG content of 11.45 mg/G and 0.06 mg/G, respectively. While not found in kratom leaves, the active metabolite of 7-OH-MG is an alkaloid called mitragynine pseudoindoxyl.¹⁹

Although several brands of kratom are available, a popular product is called 7-OHMZ. In this product’s certificate of analysis (CoA; see SIDEBAR), the manufacturer reports 14.9 mg of 7-OH-MG and 1.3 mg of mitragynine per tablet (92% 7-OH-MG).²⁰ A different product, Hydroxie, is an ultra-pure 7-hydroxy kratom. Its CoA shows it contains 16.5 mg of 7-OH-MG and 1.3 mg of mitragynine (93% 7-OH-MG).²¹ A third product, Press’d, has an available CoA that indicates it contains 18.5 mg of 7-OH-MG and 1.5 mg of mitragynine (93% 7-OH-MG).²² The 7-OHMZ and Hydroxie companies state they extract the 7-OH-MG naturally for their products. However, high speciofoline dried kratom leaves contain only 0.03 mg/G of 7-OH-MG. To make a single 7-OH-MG dose with traditional kratom powder, 7-OHMZ and Hydroxie requires between 466 g to 550 g of dried kratom leaves and Press’d requires 616 g of dried leaves which is an entire tree’s harvest of leaves.¹⁹

SIDEBAR: TECH TALK: Understanding Product Verification Absent FDA Approval²³

As kratom and 7-OH-MG products become more available, consumers need to be aware that they are not FDA-approved. Without FDA approval, the FDA takes no responsibility for ensuring that the kratom or 7-OH-MG concentration on the label matches the product content. Monitoring these products is especially important.

Plants can absorb heavy metals, pesticides, and other potentially harmful chemicals that may be in the soil or water easily, and analysts find these contaminants in the leaves, flowers, and stems. Therefore, consumers—and the pharmacists and technicians who advise them—need to investigate the kratom products available on the market if they make recommendations or find a product is widely used in their localities.

Consumers can request products’ Certificate of Analysis (CoA), which provides information about testing for contaminants and active ingredient levels. If the retailer cannot provide it, consumers should avoid that product. States and retailers are starting to take the initiative to ensure consumers have needed information.

When looking at the CoA, consumers can be more confident of the quality if the CoA states that the lab meets “ISO 17025” standards. Consumers can also look to see if the CoA states that the lab complied with the standards set by one of three organizations:

• the Association of Official Agricultural Chemists (AOAC),
• the American Herbal Pharmacopoeia (AHP), or
• the U.S. Pharmacopeia (USP).

Consumers should beware of products that list the total concentration in the product (i.e., 250 mg in the bottle) and not the active ingredient concentration (i.e., 2.5 mg/mL). Of course, products should clearly define a “dose,” and list the amount of active ingredient in a dose and not in the entire product. These products may contain other related compounds besides mitragynine and 7-OH-MG. Consumers should also beware of “proprietary blends” where the alkaloids in the product are given with a total dosage but the amount of each alkaloid is not provided.

PHARMACOLOGIC COMPARISON OF ALKALOID PHARMACOLOGY

Results of In Vitro Studies

Stimulating the μ-opioid receptor with traditional opioids (like morphine) has been associated with feelings of wellbeing, euphoria, pain relief/antinociception (reduced sensitivity to pain), and constipation. It can also lead to central nervous system depression that impairs the normal respiratory response to rising carbon dioxide levels in the blood. Mitragynine and 7-OH-MG are partial μ-opioid agonists while morphine is a full agonist.¹ In an in vitro study, the μ-opioid receptor Ki receptor binding affinity (lower Ki means tighter binding) and EC50 for cAMP accumulation (lower cAMP accumulation means greater suppression of adenylate cyclase production) were determined for mitragynine and 7-OH-MG. The μ-opioid receptor Ki for mitragynine was 15-fold higher than 7-OH-MG (238 nM vs. 16 nM) and 159 times higher than morphine (238 nM vs. 1.5 nM). The μ-opioid receptor cAMP EC50 was 29-fold (398 nM vs. 13.6) higher for mitragynine versus 7-OH-MG and 83-fold (398 nM vs. 4.8 nM) higher than morphine.¹⁹ In other words, 7-OH-MG and morphine bind tighter to the μ-opioid receptor and suppress adenylate cyclase production at magnitudes far greater than mitragynine. For reasons that are poorly understood, mitragynine and 7-OH-MG are less likely to cause respiratory depression than traditional opioids in preclinical studies.^6,19 Other kratom alkaloids (specioliatine, paynantheine, and speciogynine) bind weakly to μ-opioid receptors with Ki values ranging from 410 to 728 nM.¹⁹

Understanding how these products work and their effects on various systems is emerging. The composition of kratom is highly variable; although mitragynine is the predominant alkaloid, around one-third of kratom is composed of other, minor alkaloids. Whether minor or major, kratom’s alkaloids have specific binding affinities and therapeutic outcomes. Physiologic effects of kratom therefore depend on all the alkaloids present. For example,

• Stimulating alpha-1 and alpha-2 adrenoceptors with mitragynine provides modest antinociception (pain reduction). These effects can be attenuated by alpha-1 and alpha-2 antagonists (prazosin—an antihypertensive—and yohimbine—a supplement allegedly used for benign prostatic hyperplasia and sexual function, respectively).¹⁹
• Stimulating alpha-2 adrenoceptors, like with clonidine, can prevent sympathetic outflow (signaling leading to activation of the sympathetic nervous system) in people with withdrawal symptoms from traditional opioids. Research indicates this effect may attenuate opioid withdrawal symptoms that patents experience.
• Mitragynine has moderate nonselective agonist effects across alpha-1 and alpha-2 adrenoceptors with Ki values ranging from 1.3 to 9.3 mcM.
• Speciogynine provides strong alpha-2 agonist effects for many alpha-2 adrenoceptors (Ki for alpha-2A, alpha-2B, and alpha-2C from 0.4 to 2.6 mcM) but has no effect on alpha-1 adrenoceptors.
• Corynantheidine is a potent agonist for alpha-1D adrenoceptors with a Ki value of 0.042 mcM. Stimulation of serotonin receptors can enhance mood and alertness.
• Mitragynine has modest agonist effects at serotonin receptors with Ki values at 5-HT-1A, -2A, and -2B ranging from 1.3 to 5.9 mcM.
• Paynantheine and speciogynine are potent agonists at serotonin receptors with Ki values for 5-HT-1A and -2B ranging from 0.02 to 0.04 mcM and 5-HT-2B Ki values ranging from 0.8 to 1.3 mcM.¹⁹

Traditional kratom products’ pharmacology is complex. Consider this: the human enzyme CYP3A4 converts a portion of mitragynine to 7-OH-MG in the brush border of the gastrointestinal tract and the liver. Next, CYP3A4 circulating in the plasma converts a portion of this active metabolite to mitragynine pseudoindoxyl, a molecule with the ability to interact with central opioid receptors.²⁴ Mitragynine pseudoindoxyl is at least as potent an opioid agonist as 7-OH-MG and lacks alpha adrenoceptor or serotonin receptor effects.²⁵

Human studies are needed to explore kratom's utility in analgesia, euphoria, and addiction more thoroughly. As of January 10, 2025, only nine ongoing studies were listed in clinicaltrials.gov. Most were small, although a few larger studies are underway.^26,27 In one now complete study, human plasma converted 7-OH-MG into mitragynine pseudoindoxyl much more effectively than plasma from other species.²⁵ The percentages of mitragynine pseudoindoxyl formed at the end of 120 minutes of incubation with 7-OH-MG in dog, monkey, mouse, and rat plasma were below 4.3% but 53.8% in human plasma. This suggests that mitragynine pseudoindoxyl’s contribution to the overall opioid receptor’s impact could differ between species. The impact is that pharmacologic effects might also differ between animals and humans with more dangerous effects in people.²⁵ Taken together, the receptor pharmacology of traditional kratom products is a constellation of μ-opioid, alpha-1 and alpha-2 adrenergic, and serotonin receptor effects from multiple alkaloids while 7-OH-MG products focus almost exclusively on μ-opioid receptor effects, which is similar to traditional opioids.^1,6,19,24,25

PAUSE AND PONDER: What takeaways can you list for the heavy science presented in the last few paragraphs?

As Cindy assembles all of the information, she is somewhat confused. She calls a professor at her alma mater and asks if he can discuss these findings with her. After an hour of discussion, she says, “Let me summarize what I have learned so I can explain this to my patient:

• Kratom alkaloids in the highest abundance in whole leaf products primarily interact with alpha-1 and alpha-2 adrenergic and serotonin receptors with indirect and weak opioid effects
• Metabolism of mitragynine via CYP3A4 results in metabolites (7-OH-MG and then mitragynine pseudoindoxyl) that more potently exhibit opioid agonist properties
• 7-OH-MG binds the μ-opioid receptor far greater than mitragynine and 7-OH-MG products have far more 7-OH-MG than whole leaf products could ever provide
• Differences in metabolite amounts and μ-opioid receptor quantities and locations may be species-specific but the effects seen with 7-OH-MG in animals would likely be greater in humans.”

Cindy’s professor says that she got it! He suggests that now that she knows the basic pharmacology, she should move on to some animal studies.

Results of Animal Studies

A step up from in vitro study is the use of animal models. Researchers select animal models carefully based on the purpose of their study. In the case of kratom and 7-OH-MG products, researchers’ intent is to determine how the products compare to opioids in terms of pain relief, euphoria, and addiction potential. For that purpose, the ideal models are small rodents (rats and mice). Many rodent models of pain and addiction exist. Many of the experimental animals can and will self-medicate in response to pain or craving.

A mouse model (tail-flick test) study sought to establish the equipotent antinociception doses of mitragynine and 7-OH-MG.¹ Overall, mitragynine 140 mg/kg subcutaneously provided a similar tail-flick response to 0.7 mg/kg of 7-OH-MG. (See how much more potent 7-OH-MG is compared to mitragynine?) The brain concentrations of 7-OH-MG were almost identical in the mitragynine group (with 7-OH-MG created via metabolism) and the group given 7-OH-MG, suggesting that 7-OH-MG is a driver of mitragynine’s opioid mediated pain-relieving effects.¹ In another mouse study, 7-OH-MG produced a potent antinociceptive effect, similar to morphine and mainly through activation of μ-opioid receptors.²⁸ Tolerance to 7-OH-MG’s antinociceptive effect developed, similar to the tolerance that develops with morphine. Importantly, cross-tolerance to morphine was evident in mice rendered tolerant to 7-OH-MG or morphine when the drugs were switched. Finally, naloxone-induced withdrawal signs occurred equally in mice chronically treated with 7-OH-MG or morphine.²⁸

Overall, 7-OH-MG appears to have greater abuse potential than mitragynine.²⁹ In a rat model, investigators took morphine-addicted rats and allowed them to self-administer 7-OH-MG or mitragynine in a substitution phase. Rats preferred 7-OH-MG over mitragynine and did so in a manner that was dose-dependent and similar to their previous morphine use. After the substitution phase, the researchers allowed morphine self-administration again. Rats using 7-OH-MG ingested higher morphine doses than they had previously while those who used mitragynine ingested lower morphine doses. Nalxonaxine, an experimental μ-opioid receptor antagonist, reduced 7-OH-MG and morphine self-administration doses.²⁹

Less is known about mitragynine pseudoindoxyl’s antinociceptive and withdrawal effects.³⁰ In one model, researchers tested mice to see how long they could retain their tails in a hot water bath at baseline. Then they administered repeated saline or escalating doses of morphine, kratom alkaloid extract, mitragynine, or mitragynine pseudoindoxyl for four days. Immediately before day 5 dosing, the mice previously treated with morphine (~11 + 2 to 2 + 1 s), kratom extract (~10 + 1 to 4 + 1 s) or mitragynine (10 + 1 to 4 + 1 s) demonstrated significantly more drug-induced hyperalgesia, but the normal saline group did not (~10 + 1 to 8 + 1 s). The mitragynine pseudoindoxyl group had reductions from baseline (~11 + 2 to ~6 + 1 s) but this did not achieve statistical significance. Mice were then administered naloxone on day 5 after their assigned drug was administered. When exposed to naloxone, all active groups had less severe withdrawal symptoms than the morphine group for some measures, although for some measures the withdrawal symptoms were greater with the kratom extract, mitragynine, and mitragynine pseudoindoxyl groups than the normal saline group.³⁰

These studies suggest that 7-OH-MG has more potent antinociceptive effects, opioid users would be more likely to seek it, and would promote the subsequent use of higher doses of traditional opioids (called a reinforcing effect) than mitragynine.^28,29,30

In a recent editorial, prominent kratom basic scientists expressed grave concern about 7-OH-MG products.³¹ They believe that manufacturers are taking mitragynine extract and chemically converting it into 7-OH-MG producing unknown alkaloids in the process. Creating alkaloids that do not exist in nature or as a known metabolite in the human body poses unknown risks to patients. They also believe that the pharmacology of 7-OH-MG is inherently riskier than that of mitragynine.³¹

PAUSE AND PONDER: What is the pharmacist’s role in preventing kratom misuse? How would you advise your patients to approach using this product safely?

Kratom this. Kratom that. Cindy is learning all about kratom extracts! After reviewing the animal studies, she calls her professor back. Concerned with the opioid-like properties of kratom’s alkaloids and metabolites, Cindy is unclear if kratom would be a good alternative for Pete’s pain. Cindy’s professor, understanding her concern, sends her to search the World Wide Web for personal, raw experiences from users.

ANECDOTAL EFFECTS OF 7-HYDROXYMITRAGYNINE PRODUCTS

Anecdotal experiences with kratom include discussions of pain relief, energizing or relaxing effects, or its use to prevent opioid withdrawal in between opioid doses, or as a chronic replacement for opioids.^6,8,9,13,14 The euphoric effects caused by traditional opioids reportedly do not occur for many consumers who take traditional kratom products; this makes traditional kratom products an unsuitable substitute for people who use them recreationally.⁸ There is said to be a ceiling effect for the mood elevation with traditional kratom products and that nausea experienced when escalating doses tempers the desire to binge dose.^6,32

The reported consumer experiences with 7-OH-MG products to date are characteristically different than experiences users describe with traditional kratom products.³² Table 1 provides some direct quotes from Reddit chat rooms concerning 7-OH-MG. They are categorized into initial experiences, addiction and withdrawal, and the use of kratom to manage 7-OH-MG withdrawal.³² To summarize these comments, users described 7-OH-MG products’ euphoric effects as more intense. Although the users didn’t report if the pain was due to injury or to hyperalgesia. They reported pain relief but indicated that effects were short lived. 7-OH-MG products can lead to rapid dose increases, with tolerance and withdrawal developing more quickly than with traditional kratom products. A 7-OH-MG addiction can result in financial distress as consumers lose the ability to control their use. A three-tablet pack of Press’d 7-OH-MG 18 mg costs $17 and the suggested dose is ½ tablet. If patients take ½ tablet twice a day, that is $5.70 per day or $2,081 per year. Extrapolating to recreational use and tolerance, patients who take 12 tablets a day expend $68 a day or $24,820 a year. Confusing 7-OH-MG products with traditional kratom products can lead to relapse for consumers using kratom as a chronic opioid substitute.

Table 1. Anecdotal customer experiences with 7-hydroxymitragynine products.³²

Experiencing the euphoric high with 7-OH-MG products (that whole leaf kratom or mitragynine extract products lack) can undo addiction control. Finally, while some consumers try to stop using 7-OH-MG cold turkey, many consumers describe needing to move from 7-OH-MG to whole leaf kratom products or mitragynine extracts to deal with withdrawal symptoms and cravings. Importantly, the posts do not describe people moving from 7-OH-MG to traditional opioids or other illicit opioid-like products such as tianeptine (atypical tricyclic antidepressant with opioid receptor agonist properties; also called “gas station heroin”)(see SIDEBAR). These products were virtually unheard of only a few months ago. It is still too early to know the full measure of adverse events that they could cause.³²

SIDEBAR: TIANEPTINE^33,34

Globally, several health regulatory agencies have approved tianeptine for the treatment of major depressive disorder since its discovery in the 1980s, but the FDA has not. This molecule, originally called an atypical tricyclic antidepressant, appears to have potential benefits for patients experiencing anxiety and irritable bowel disease, but it does not work like other tricyclics. Later research found it targets the opioid mu receptor. Despite its status as an unapproved drug in the U.S., individuals are able to procure it online and at some retail locations (e.g., bodegas, corner stores, gas stations, mini marts, smoke shops). The origins of these substances is sketchy; it’s possible that they are commercially produced by drug manufacturers but just as likely synthesized in underground laboratories. Tianeptine, labeled as "Zaza" and "Tianna Red," has joined the various gas station drugs and has earned the name “gas station heroin.” It is often packaged in shot-sized bottles, and frequently contains synthetic cannabinoids. Recreational users seek tianeptine for its ability to produce a euphoric, opioid-like high. Sadly, chronic use can lead to dependence, tolerance, addiction, and overdose. Some users have attempted suicide. Calls to poison control centers have skyrocketed since 2014.

WHERE SHOULD WE GO FROM HERE?

Why are these products available for sale legally in the U.S.? As noted, several members of Congress asked the DEA not to list kratom products in Schedule I. Traditional whole leaf kratom products contain a natural ingredient with a blend of alkaloids from dried leaves that have effects on opioid receptors (without reinforcing effects), alpha adrenoceptors, and serotonin receptors.⁸ Traditional kratom products have been used around the globe for medical purposes for decades and evidence about its relative safety compared to other substances of abuse is increasing.^6-9,13,14

Congress's concerns included the fact that a bipartisan majority felt that that ban would be made with no opportunity for public comment from researchers, consumers, and other stakeholders. They indicated that such a precipitous decision could be deleterious to consumer access and choice of an internationally recognized herbal supplement; it could also stop progress on studies targeting the treatment of individuals suffering from opioid and other addictions.³⁵

As Cindy did more research, she found that kratom and related products are illegal in some states even though the federal government has not restricted its use. Restrictions may simply impose age limits, employ a more comprehensive kratom consumer protection restrictions, or may ban these products entirely. The Global Kratom Coalition maintains a map (https://globalkratomcoalition.org/regulation-map)³⁶ with updated information of the restrictions in the U.S. (see reference), but it is always wise to determine the laws in your state from original sources. As of January 1, 2025, many states, including California, Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, and Pennsylvania have no statewide restrictions. Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin have outlawed kratom products. Many other states, including Florida, Georgia, and Texas have enacted kratom consumer protection regulations. Healthcare providers need to know if their state has passed bans or regulations, and what the regulations specify. A few localities in states where kratom is legal have established their own restrictions. Some examples include San Diego, California (sale or possession are illegal), Denver, Colorado (no sale for human consumption), Jerseyville, Illinois (banned entirely), Sarasota County, Florida (banned entirely), and Union County, Mississippi (banned entirely).³⁷

The Kratom Consumer Advisory Board is comprised of a scientist and pharmacist (C. Michael White, PharmD) and consumers who have been helped or harmed by kratom products.³⁸ They develop position statements and advise researchers, legislators, and advocacy groups about best practices regarding kratom use. The position statements can be accessed in the references and describe potential regulatory language and rationale behind preventing children from accessing kratom, the risks of 7-OH-MG products, proper labeling, and the need to register products that are being sold to consumers in the state to enforce safety regulations and good manufacturing practices.³⁸

This regulatory environment surrounding kratom should not extend to products with doses of 7-OH-MG that could never exist in nature. Emboldened by the DEA and the FDA’s inaction to date, newer products such as the “Press’d: The Hulk Blend” are combining 15 mg of 7-OH-MG with 15 mg of mitragynine pseudoindoxyl.³⁹ There is one product that contains only mitragynine pseudoindoxyl.⁴⁰ It is indefensible that these products could possibly be considered natural since mitragynine pseudoindoxyl does not exist in kratom leaves at all. Now, other semi-synthetic alkaloids of mitragynine are being created and placed in products such at 8- and 11-hydroxymitragynine and “Red-OH” with no published animal or human data.⁴¹ The HOPES research group at the University of Connecticut is actively cataloging a comprehensive list of 7-OH-MG, mitragynine pseudoindoxyl, 8-hydroxymitragynine, and “Red-OH” products on the market so states that register products sold in their state can assure that these drugs are excluded from sale. If the tianeptine debacle has taught us anything, it is that we need to identify products being sold as natural products and determine if they are truly reflective of nature.⁴²

Finally, new clouds are on the horizon with mitragynine and 7-OH-MG extracts that are being placed into candy formulations (popping crystals, noobs, chocolate bars, gummies, taffy, and ice cream cones), flavorings like strawberry, raspberry, mango, and grape, and sold with cute cartoon mascots.⁴³ The more kratom products resemble sweet treats, the greater the risk of children consuming them. The HOPES research group is also cataloging a comprehensive list of these products that could entice children so states that register products sold in their state can restrict their sales.⁴³

PAUSE AND PONDER: Does your practice state or municipality have regulations towards 7-OH-MG? Mitragynine? Kratom? Should it?

In this CE activity, we have shown that 7-OH-MG and mitragynine pseudoindoxyl relies entirely on opioid receptor effects, rather than impacting a balanced series of receptors like traditional kratom products do.^1,8,19,28,29 Preclinical studies suggest that 7-OH-MG has reinforcing effects that mitragynine (the most abundant alkaloid in traditional kratom products) does not have; this is a warning sign for its addiction potential.^28,29 Customer experiences with 7-OH-MG products suggest euphoric effects that mimic traditional opioids, faster tolerance and shorter duration of action, and faster onset with more severe withdrawal compared to traditional kratom.³² Until more is known about 7-OH-MG’s effects, shouldn’t customers be protected from accessing products that can potentially result in a lifetime of addiction? If nothing else, can we at least ensure that 7-OH-MG products are not classified as kratom products? If a consumer substitutes kratom for traditional opioids and accidentally experiences the euphoric effects from 7-OH-MG, it might be analogous to giving alcoholics a drink and restarting their cravings. If a wave of bad press about 7-OH-MG products falls under the umbrella of “kratom products,” both products could become Schedule I; a risk to consumers who rely on kratom to manage their opioid use disorder (OUD).

California is working on legislation that would protect their citizens from 7-OH-MG products.⁴³ In its legislation, kratom products would have a dose of 7-OH-MG that is a small fraction of total alkaloids in the product. This proposed California legislation can be a national model or can be emulated state by state.⁴⁴

What are health professionals’ responsibilities regarding 7-OH-MG products? The first is to be aware of changes in the kratom marketplace. Providers who have patients using traditional kratom products or who inquire about its use need to tell them that 7-OH-MG products—which they may call “7” or “7-OH”—are not kratom and could reinforce opioid addiction rather than provide relief. They should also educate patient’s that the U.S. FDA has approved therapies for OUD where the positive balance of benefits to risks are well known, augmenting that counseling providers can tell patients how to access services.⁴⁵ If people are addicted to 7-OH-MG products, they need treatment to overcome their K-SUD, just like they would for other opioid receptor agonists. Finally, health professionals should alert regulators and our legislators about emerging threats to our patients’ health and well-being so they can take action.

Cindy finished her research and scheduled an appointment to meet with Pete. She has reviewed all of the science, reconnected with her professor to clarify a few things, and also examined her state and local laws. She looked for articles, podcasts, and radio transcripts to find facts about local, state, and national trends. When Pete arrives, she is prepared to discuss the risks associated with 7-OH-MG. She tells him that “7” is not a natural product, explains why that is the case, and that it could be downright dangerous. Next, she discusses cost (which can be steep) and the fact that it isn’t covered by insurance. She expresses concern that we know little about its safety and gas station products are often labeled poorly or misleadingly. Finally, she tells Pete that it will not “fix” his problem with constipation. Kratom may be a potential option for some patients, but other FDA-approved options are available to support Pete that have proven clinical trial effects and would be better initial options to explore.

Cindy realizes that this is an opportunity to help Pete. She explains that he is having breakthrough pain, and it may be time for the multidisciplinary team to become more involved. Pete admits he has not been going to physical therapy as scheduled, and he blushes when she asks if he’s been taking a stimulant laxative (he hasn’t). Cindy takes some time to contact the primary prescriber, and they work with the physical therapist to develop a better treatment plan for Pete. That new plan does not include 7-OH-MG.

CONCLUSIONS

Products with 7-OH-MG and/or mitragynine pseudoindoxyl act solely through opioid receptors. Preclinical studies and human anecdotal experiences show 7-OH-MG provides euphoric effects that traditional kratom products (whole leaf or mitragynine extracts) do not. Given the known risks of OUD, 7-OH-MG and/or mitragynine pseudoindoxyl products should not be thought of, or listed as kratom and regulators should not transfer the hands-off attitude towards kratom to 7-OH-MG. It is inappropriate to have opioid receptor stimulators like 7-OH-MG or mitragynine pseudoindoxyl sold in gas stations, smoke shops, and over the internet without a prescription, limitations in dosage, and medical oversight.

Download CE Activity

If you’ve heard it once, you've probably heard it a dozen or more times: pharmacists are the most accessible healthcare resource. Most people live close to a pharmacy. A 2022 study reported 89% of persons in the United States (U.S.) live within five miles of a pharmacy and all but 3% are within 10 miles.¹ Despite being this accessible, pharmacies are closing in record numbers.^2,3 These closures are creating pharmacy deserts—communities in which residents must travel farther to access the nearest pharmacy to fill prescriptions—in communities in urban centers or with Black and Latine (see SIDEBAR) populations most at risk.^2,3

SIDEBAR: Latine or Latinx?

Americans have used many terms to describe individuals or groups who live in the United States and have Latin American roots. Traditionally, the word “Latino” has been used to describe males or males and females, and sometimes “Latina” has been used for females. The most widely used term, however, was “Hispanic” and included people of Spanish origin (i.e., from Spain). Several years ago, the term Latinx emerged as a gender-neutral, more inclusive term. Language, however, evolves, and some people with Latin American origins objected to the inclusion of the letter X. Older languages in Latin America did not include the letter X. Colonists forced indigenous people to add X into languages during the conquest. Its pronunciation is odd or unnatural in many dialects.

While Latinx is currently used more frequently in the academic literature, the term Latine is becoming more commonly accepted in the community. For the purposes of this continuing education activity, they are interchangeable.

Vaccines are one of the most successful interventions in public health in our generation. Worldwide, vaccines have prevented 154 million deaths since 1974.⁴ In the U.S., routine childhood vaccinations provided to children born between 1994 and 2023 have had an impressive impact. Within this population, they have saved $540 billion in direct costs and prevented more than 500 million illnesses, 32 million hospitalizations, and 1.1 million deaths.⁵

Immunizing for Influenza and COVID-19

Influenza and COVID-19 vaccines are examples of vaccines whose primary goal is to prevent severe disease and death. Influenza vaccine specifically has shown to decrease risk of intensive care admission (odds ratio [OR] = 0.74 (95% confidence interval [CI]: 0.58-0.93)) and death (OR = 0.69 (95% CI 0.52-0.92)) among adults hospitalized with influenza disease.⁶ An odds ratio less than 1.0 indicates a protective effect; therefore an OR of 0.74 indicates the influenza vaccine reduces the risk of an intensive care admission by 26%, and an OR of 0.69 indicates 31% less risk of death when hospitalized with influenza disease. The CI reflects there is 95% confidence the true risk of an intensive care admission is reduced by 7% to 42%, and the risk of death is reduced by 8% to 48%.  In the first year of use, primary COVID-19 vaccination prevented 14.4 million deaths.⁷ The 2023-2024 booster vaccines provided 51% and 36% effectiveness against hospitalization for the seven to 79 days post-vaccination in healthy non-immunocompromised and immunocompromised patients. Unfortunately, vaccine efficacy wanes significantly by four to six months in all people, but especially those who are immunocompromised, explaining the recommendations for boosters.⁸

Pharmacists, pharmacy technicians and interns, and pharmacies have become the most relied-upon resources for obtaining recommended vaccines, especially the COVID-19 and influenza vaccines. Sixty-eight percent of COVID-19 vaccines from September 2022 to September 2023 were administered in a pharmacy.⁹ More recently, these numbers have risen, with data showing that pharmacists provided 90% (23.5 million doses) of the 26.1 million doses of COVID-19 vaccines from August 31 through November 30, 2024.¹⁰ Data shows similar trends for adult influenza vaccinations at pharmacies, with growth from 49% in 2019 through 2020 steadily increasing each year; initial estimates (through November 2024) indicate that for the 2024-2025 season report, pharmacies have administered 64% of influenza vaccines.¹¹

Pharmacy’s response to the COVID-19 pandemic has amplified the pharmacist’s and pharmacy technician’s value and accessibility to providers, policymakers, and the public. Expanding the pharmacist’s clinical functions will only become more critical as the physician workforce continues to shrink through the coming decades. According to the Association of American Medical Colleges (AAMC), the U.S. is projected to face a physician shortage of up to 86,000 physicians by 2036, with the most significant shortage expected in primary care specialties.¹²

More than Immunizations

Beyond immunizing, the pandemic revealed the pharmacist’s valuable contributions involving point-of-care testing and follow-up care through treatments not only for COVID-19, but also for influenza, urinary tract infections, HIV, and contraceptives. The Centers for Disease Control and Prevention (CDC) recognized pharmacy’s contributions during the COVID-19 pandemic by stating, “The COVID-19 pandemic has demonstrated needed roles for the community pharmacist in an emergency, including continuity of provision of medications, providing preventive services, and ensuring health equity. Along with medication management, pharmacists provide infectious disease mitigation, point-of-care testing, and vaccinations.”¹³

The COVID-19 pandemic resulted in an excess burden of mortality in at-risk populations, precipitated by racial and ethnic disparities in health care access and use. While, as stated, 89% of Americans live within five miles of a pharmacy, heightened awareness of newly emerging pharmacy deserts in Black and Latine communities resulting in higher risk of morbidity and mortality disparities is needed.^1,3 Health Affairs published a pharmacy closure study in December 2024. It revealed that independent pharmacies were at greater risk for closure than chain pharmacies across all neighborhood and market characteristics. The authors hypothesized that independent pharmacies in predominantly Black and Latine neighborhoods would be at greatest risk for closure because they are more likely than chain pharmacies to serve populations insured through Medicaid or Medicare. The reason is that Medicaid and Medicare incentivize patients to use preferred pharmacy networks managed by pharmacy benefit managers. Because preferred networks often exclude independent pharmacies, this policy limits patient volumes and profits of independent (nonpreferred) pharmacies, thus potentially increasing their risk for closure. This may have created previous health disparities and may potentially exacerbate future disparities by worsening access and lowering adherence rates to medications and other therapies.^2,3

PUBLIC READINESS AND EMERGENCY PREPAREDNESS (PREP) ACT

The Public Readiness and Emergency Preparedness (PREP) Act is not new. Initially approved by Congress in 2005 and signed by then-President George W. Bush in 2005. The PREP Act authorizes the Secretary of Health and Human Services (HHS) to limit legal liability for losses relating to the administration of medical countermeasures such as diagnostics, treatments, and vaccines. In a declaration effective February 4, 2020, the Secretary of HHS invoked the PREP Act and declared Coronavirus Disease 2019 (COVID-19) to be a public health emergency warranting liability protections for covered countermeasures. The PREP Act is currently on its 12th amendment.¹⁴ The PREP Act defines a “covered person” to include licensed health professionals and other individuals authorized to prescribe, administer, or dispense covered countermeasures under state law, and other categories of persons identified by the Secretary in a PREP Act declaration.^14-16

The April 2020 amendment to the Act provided pharmacists federal authority to order and administer FDA-authorized COVID-19 tests. The August 2020 Amendment to the PREP Act expanded the definitions of covered diseases and covered persons. It expanded the categories of disease representing a public health emergency to include diseases resulting from “the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.” This allowed pharmacists to prescribe and administer, and interns to administer vaccines in accordance with the Advisory Committee for Immunization Practices (ACIP) to children 3 through 18 years old.^14-16

In the fall of 2020, the Secretary of HHS modified the Act twice more. In August, it added COVID-19 vaccines to the vaccines pharmacists and interns were permitted to administer. In September, notably, for the first time it included pharmacy technicians in the authority provisions, allowing them to administer childhood and COVID-19 vaccines to those aged 3 years and older. A year later, in August and September of 2021, the Act extended authorization covering pharmacy interns and technicians to administer seasonal influenza vaccination for those 19 years and older as recommended by ACIP. It also authorized pharmacists to prescribe and administer specific COVID-19 therapeutics, such as monoclonal antibodies, and interns and technicians to administer these products.^14-16 In July 2022, another amendment added the authority for pharmacists to prescribe nirmatrelvir/ritonavir tablets (Paxlovid).^14,16

As a public health crisis resolves, the PREP Act is amended to eliminate provisions no longer deemed necessary. HHS declared the Public Health Emergency was no longer in effect as of May 11, 2023, however COVID-19 was deemed to still present a “credible risk of a future public health emergency.” As the COVID-19 emergency was no longer at its peak, the 11th Amendment in May 2023 began to decrease the authority of pharmacists, interns, and technicians. Specifically, the 11th Amendment of the PREP Act extended authority through December 31, 2024, but the authorization would only allow pharmacists to order and administer, and pharmacy interns and technicians to administer COVID-19 and seasonal influenza vaccines to age 3 and over and COVID-19 tests. The authorization no longer covers all childhood vaccines but continues to allow pharmacists to prescribe nirmatrelvir/ritonavir tablets.¹⁵

Is the PREP Act Still Needed?

COVID-19 continues to cause significant illness and death and considered to present a credible risk of a future public health emergency. In 2024, the CDC’s COVID Data Tracker reported between 300 and 2500 deaths from COVID-19 each week.¹⁷ Congress delegated the ability to amend the PREP Act to the HHS Secretary. This motivated Xavier Becerra, the then HHS Secretary, to issue the 12th amendment to the PREP Act in December 2024.¹⁴ Effective January 1, 2025, it was amended to continue PREP Act coverage through December 31, 2029, barring any change from the HHS Secretary. This extension granted by the 12th amendment to the PREP act allows pharmacists, pharmacy interns, and technicians to continue providing essential services for seasonal influenza and COVID-19.¹⁴ These services include allowing pharmacists to prescribe and administer seasonal influenza and COVID-19 vaccines for those as young as 3 years of age (see SIDEBAR) in line with the ACIP recommendations (see Table 1). They still have the authority to prescribe nirmatrelvir/ritonavir tablets. Pharmacy interns and pharmacy technicians are also authorized under the Act to provide these two immunizations to these patients under the pharmacist’s supervision.

SIDEBAR: What’s Magic about Age 3?²¹

The PREP Act authorized administration of inactivated vaccines in children as young as 3 years of age. The minimum age of 3 years old was chosen because that is the age at which the vaccine administration process is the same as that employed for adults. Before age 3, the thigh is the preferred site because of the greater muscle mass.

Specifically, as these shots are all inactivated vaccines, the preferred site of administration, beginning at age 3 years, is the deltoid muscle. When administering inactivated vaccines, immunizers should inject them at a 90-degree angle into the deltoid muscle, avoiding the top 1/3 of the muscle and staying above the armpit. It is important to landmark the deltoid and use the recommended vaccine needle size to ensure efficacy and prevent shoulder injury related to vaccine administration (SIRVA).

Table 1.  PREP Act Requirements for Pharmacists, Pharmacy Interns, and Pharmacy Technicians^14,18

*FDA authorized COVID-19 vaccines: Novavax for those 12 years and older, Moderna and Pfizer BioNTech for those 6 months through 11 years. FDA approved COVID-19 vaccines: Moderna and Pfizer BioNTech for those 12 years of age and older.

The HHS Secretary decides to amend or declare the PREP Act based on a variety of factors. HHS gathers expert advice and public health data and assesses legal considerations by consulting with relevant stakeholders before issuing a declaration or amendment. The HHS Secretary must consider the many variables involved encouraging the use of countermeasures (interventions that help prevent or slow the spread of disease). These include the design, clinical testing, manufacturing, labeling, marketing, purchase, donation, dispensing, licensing, prescribing, and administering of the countermeasure. A determination of a public health emergency is different than a PREP Act declaration. If HHS determines a public health emergency exists, HHS can waive certain Medicaid, Medicare, State Children’s Health Insurance Program (CHIP), and Health Insurance Portability and Accountability Act (HIPPA) requirements. A PREP Act declaration may be made in advance of a public health emergency and may provide liability immunity for activities both before and after a declared public health emergency.

Public Health Emergencies vs PREP Act Declarations

A public health emergency determination or other emergency declaration is only required for immunity under the PREP Act if this is explicitly stated in the declaration.¹⁸ Therefore, when it is determined that there is no longer concern for significant COVID-19 related illnesses, it is likely that the Secretary of HHS will sunset this provision as well. Thus, it is very important that pharmacists, pharmacy interns, and pharmacy technicians continue to advocate for expansion of their immunization authority. This advocacy, specifically in states where full immunization authority is absent, will enhance immunization care to patients in need.

PAUSE AND PONDER: What does your state authorize pharmacists, pharmacy interns, and pharmacy technicians to provide and are there vaccine or age restrictions?

In addition to the vaccination authority, the Act continues to allow pharmacists to prescribe and administer, and for interns and technicians to administer under the pharmacist supervision, COVID-19 tests.¹⁴ Multiple types of COVID-19 tests are able to be used in the pharmacy. It is important for all immunizers and support staff to review the instructions on the specific tests carried in the pharmacy. Many tests (e.g., antigen, nucleic acid amplification tests [NAATs]) require nasal or nasopharyngeal sampling, but some NAAT tests may require oropharyngeal, sputum, or saliva sampling.¹⁹ Importantly, the Act continues to provide liability protection for those who provide these services (i.e. vaccines, tests) per the recommendations.¹⁴

ADULT VACCINATION UPTAKE POOR, PEDIATRIC RATES DECREASING

Although the 11th amendment of the PREP Act in May 2023 removed federal authority for pharmacists to provide routine childhood vaccines (other than seasonal influenza or COVID-19), many states have worked to expand their state laws to provide these authorities. As of January 2025, only one state, Delaware, does not authorize pharmacists to provide any vaccines to children under its state laws.^15,22-24 Currently, 42 states provide pharmacists authority to administer routine vaccines beyond influenza and COVID-19 to children younger than 12 years old. At this time, 36 states allow vaccines other than COVID-19 and influenza to be administered by a pharmacist to children 7 years of age or younger.^22-30 Many states currently have no minimum age for pharmacists to provide childhood vaccines. Further, pharmacists in most states can provide many routine vaccines to adults. It is important that pharmacists continue to educate and advocate for timely vaccination of children and adults and provide an accessible way for patients to easily obtain these vaccines, when authorized.

PAUSE AND PONDER: How do you routinely advocate and provide immunizations to patients? How could you improve?

Many adults do not know that they should receive any vaccines. Data from 2022 demonstrates that only 22.8% of adults received appropriate immunizations for age including influenza. Further concerning is that Black and Latine populations reported lower rates at 12.1% and 17%, respectively.³¹ When rates associated with individual vaccines were analyzed, tetanus vaccination in the past 10 years (59.2% of all adults) and pneumococcal vaccination in those 65 years and older (64%) were the highlights, having the best coverage. Some significant deficits included pneumococcal vaccination for high-risk adults (23%) and a single dose of recombinant zoster vaccination of individuals 50 years and older (25.6%).³¹ These data provide yet another reason to continue efforts to educate adult patients within your practice that they may need vaccines.

PAUSE AND PONDER: What can you do in your pharmacy to provide education to adult individuals about their needs for vaccinations?

Unfortunately, vaccine misinformation is rampant and has led to many children not receiving the vaccines they need. Survey data from those entering kindergarten suggests that overall immunization rates have dropped from 95% just a few years ago to overall 93%.³² Some parents are either avoiding some or all vaccinations or spacing them beyond what is recommended. This has been noted by a large increase in vaccine exemptions for children.^32-34 States and localities generally establish vaccination requirements for school attendance. They also develop conditions and procedures for exemptions from vaccine requirements, timeframes for submitting documentation, and conditional registration for students who need more time to be vaccinated. In the 2023-2024 academic year, 3.3% of children who prepared to enroll in kindergarten had at least one vaccine exemption overall. Thirty states had exemption rates higher than this with Idaho reporting 14.3% of children with at least one vaccine exemption. Of note, 93% of these exemptions were nonmedical in nature.³² Readers can find the exemption rates for their own states here in Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC11486350/

It is a problem when many individuals decide not to be vaccinated or to not have their children vaccinated, because when a community no longer maintains a high percent of a population protected (generally considered at least 90%), the population loses herd immunity.³⁵ Without herd immunity protecting a community population, the community will be susceptible to outbreaks of these vaccine preventable diseases.

Measles is a prime example of this phenomenon. Measles is a very contagious infection that requires about 95% of a population to be vaccinated to prevent spread in a community.³⁶ Recent data suggests that the percent of children entering kindergarten receiving two doses of MMR vaccination dropped below 95% (at 93.9%) in 2021-2022 and further decreased to 92.7% in 2023-2024.^{32, 34} We have begun seeing increases in measles cases again, with 284 cases (40% requiring hospitalization) reported in 2024.^35,37

The percentage of the population that needs to be vaccinated to achieve herd immunity depends on the disease. While herd immunity for measles requires about 95% of the population to be vaccinated, for polio the threshold is about 80%. It may take several years to determine herd immunity for a specific disease, and it will likely vary according to the community, the vaccine, the populations prioritized for vaccination, and other factors.

CONCLUSION

The December 2024 12th amendment of the PREP Act provided liability immunity for pharmacists, pharmacy interns, and pharmacy technicians to continue to provide COVID-19 and influenza vaccination and testing and treatment for COVID-19. The age at which these two immunizations have been expanded by the Act is for those 3 years and older. This age was chosen for these inactivated vaccines as the administration route is the same as it is for adults (i.e., intramuscular in the deltoid). Effective January 1, 2025, the 12th Amendment of the PREP Act Declaration was extended to continue coverage through December 31, 2029.

It is essential to have pharmacy personnel continue to advocate and provide easily accessible vaccines as pharmacists are the most accessible healthcare providers, as a pharmacy is within five miles of nearly 90% of the population. However, a potentially significant health disparity is developing as decreasing access is occurring due to pharmacy closures, especially independent pharmacies and those in Black and Latine communities. Policy makers should consider strategies to increase the participation of independent pharmacies in Medicare and Medicaid preferred networks managed by pharmacy benefit managers and to increase public insurance reimbursement rates for pharmacies that are at the highest risk for closure.

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