Download CE Activity

INTRODUCTION

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

 

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

 

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

 

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

THYROID GLAND AND FUNCTION

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

 

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

 

Hypothalamic-Pituitary-Thyroid Axis

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

 

THYROID DISEASE AND ETIOLOGY

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

 

Hypothyroid Disease

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

Hashimoto’s Thyroiditis

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

 

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

 

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

 

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

 

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

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

 

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

 

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

 

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

 

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

 

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

 

Iodine Deficiency Hypothyroidism

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

 

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

 

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

 

Thyroidectomy and Cancer Treatment Resulting in Hypothyroidism

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

 

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

 

Medication-Induced Hypothyroidism

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

 

Table 1. Medications that May Lead to Thyroid Dysfunction
Drug class/medications	Hypothyroidism	Hyperthyroidism
Antidysrhythmic:
Amiodarone	X	X
Bipolar Disorder Medication:
Lithium	X	X
Thyroid Medications:
PTU	X
Methimazole	X
Radioactive Iodine	X
Cancer Medications:
Biological response modifiers:
Interferon	X
Interleukin-2	X
Tyrosine kinase inhibitors:
Sunitinib	X
Sorafenib	X
Checkpoint inhibitors:
Nivolumab	X	X
Pembrolizumab	X	X
Ipilimumab	X	X
Multiple Sclerosis Medication:
Alemtuzumab		X

 

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

 

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

 

Hyperthyroid Disease

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

 

Graves’ Disease

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

 

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

 

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

 

Thyroid Eye Disease

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

 

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

 

Medication Induced Hyperthyroidism

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

 

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

 

PAUSE and PONDER

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

 

PREVALENCE

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

 

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

 

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

 

SYMPTOMS

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

 

Table 2. Thyroid Disease’s Common Symptoms
	Hypothyroidism	Hyperthyroidism
Whole body	Fatigue, lethargy, cold sensitivity	Hunger, fatigue, weakness, sweating, increased appetite, heat intolerance, insomnia
Mood/Behavioral	Depression, irritability, sluggish, brain fog	Nervousness, restlessness, hyperactivity, panic attacks
Cardiac	Bradycardia, elevated cholesterol	Tachycardia, palpitations
Weight	Weight gain	Weight loss
Hair, skin, nails	Hair loss, dry skin/hair, brittle nails	Hair loss, warm skin
Eyes/face	Periorbital edema, puffy face	Proptosis (abnormal protrusion of eyes)
Gastrointestinal	Constipation	Frequent bowel movements
Menstruation/fertility	Heavy or irregular menstrual periods, fertility problems	Amenorrhea, lighter or irregular menstrual periods, fertility problems
Musculoskeletal	Joint/muscle pain	Osteoporosis
Thyroid presentation	May be enlarged	May be enlarged

 

 

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

 

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

 

 

LABS TO ASSESS THYROID FUNCTION

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

 

Table 3. Thyroid Function Tests in Hypothyroidism and Hyperthyroidism ³²

 

	TSH (Thyrotropin)	FT4 (Thyroxine)	T3
Lab Reference range*	0.5-4.8 mIU/L	0.7-1.8 ng/dL	80-220 ng/dL
Hypothyroidism
Primary, untreated	High	Low	Low or normal
Secondary to pituitary disease	Low or Normal	Low	Low or normal
Hyperthyroidism
Untreated	Low	High	High
T3 toxicosis	Low	Normal	High

*Reference ranges may vary among laboratories.

 

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

 

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

 

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

 

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

 

TREATMENT APPROACHES

 

Levothyroxine

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

 

Table 4. Various Strengths and Colors of Levothyroxine Tablets

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

 

 

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

 

Sidebar: Tech Tasks for Thyroid Medications

 

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

 

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

 

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

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

 

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

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

 

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

 

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

 

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

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

 

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

 

PAUSE and PONDER

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

 

Liothyronine

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

 

Iodine

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

 

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

 

Selenium

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

 

Subclinical Hypothyroid Disease

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

 

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

 

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

 

Antithyroid Drugs

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

 

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

 

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

 

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

 

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

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

 

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

 

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

 

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

 

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

 

Teprotumumab

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

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

 

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

 

PAUSE and PONDER

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

 

Surgery

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

 

Radioactive Iodine

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

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

 

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

 

Pregnancy

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

 

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

 

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

 

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

 

Pharmacy Team’s Role

 

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

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

 

Conclusion

 

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

 

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

 

 

 

Download CE Activity

Introduction

 

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

FIGURE 1

 

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

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

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

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

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

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

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

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

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

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

Pathogenesis

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

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

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

DISEASE MODIFYING THERAPIES

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

 

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

 

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

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

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

SIDEBAR: Financial Burden of MS Therapies⁵¹ 

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

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

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

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

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

 

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

Table 1. Currently Approved Agents for MS¹⁰

 

Drug Name (Brand)	Recommended Dose
Fumarates
Dimethyl fumarate (Tecfidera)	120 mg PO BID for 1 week, then 240 mg PO BID
Diroximel fumarate (Vumerity)	231 mg PO BID for 7 days, then 462 mg PO BID
Monomethyl fumarate (Bafiertam)	95 mg PO BID for 7 days, then 190 mg PO BID
Monoclonal Antibodies
Alemtuzumab (Lemtrada)	Year 1: 12 mg/day IV infusion on 5 consecutive days Year 2: 12 mg/day IV infusion for 3 consecutive days. Year 3&4- no treatment
Natalizumab (Tysabri)	300 mg IV infusion every 4 weeks
Ocrelizumab (Ocrevus)	Start dose: 300 mg IV infusion, followed by 300 mg IV infusion 2 weeks later Subsequent dose: 600 mg IV every 6 months
Ofatumumab (Kesimpta)	Week 0,1 &2: 20 mg SC Week 4: 20 mg per month starting at week 4
Platform therapies
Glatiramer acetate (Copaxone, Glatopa)	20 mg SC QD 40 mg SC TIW
Interferon beta-1b (Avonex)	30 mcg IM once weekly
Interferon beta-1b (Betaseron, Extavia)	250 mcg SC every other day
Interferon beta-1b (Rebif)	22-44 mcg SC TIW
PegINF beta-1b (Plegridy)	125 mcg SC or IM every 14 days
Purine analogue
Teriflunomide (Aubagio)	7 mg or 14 mg PO QD
Pyrimidine synthesis inhibitor
Cladribine (Mavenclad)	3.5 mg/kg of body weight divided into two yearly treatment courses. Each treatment course divided is divided into two treatment cycles of 4-5 days separated by 4 weeks
Sphingosine-1 phosphate receptor modulators
Fingolimod (Gilenya)	0.5 mg PO QD
Ozanimod (Zeposia)	0.23 mg PO QD on days 1-4, 0.46 mg PO QD on days 5-7, 0.92 mg PO QD on day 8 and thereafter
Ponesimod (Ponvory)	2 mg PO QD, titrated over 15 days to maintenance dose of 20 mg PO QD
Siponimod (Mayzent)	0.25 mg PO QD, titrated to 2 mg PO QD over a six-day period

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

 

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

 

 

Platform Therapies

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

Monoclonal Antibodies

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

Anti-CD20 Therapies

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

 

Ocrelizumab  

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

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

Ofatumumab

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

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

 

Anti-Integrin Therapy

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

 

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

SIDEBAR: What is Progressive Multifocal Leukoencephalopathy?⁵⁰ 

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

 

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

Anti-CD52

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

 

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

 

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

 

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

Oral Therapies

Fumarates

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

 

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

 

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

Teriflunomide

 

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

 

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

 

Sphingosine-1 Phosphate Receptor Modulators 

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

 

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

 

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

 

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

 

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

 

Cladribine

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

 

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

DMTs in Special Populations

 

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

Preconception Counseling

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

Figure 2. Safety and Efficacy of DMTs in Pregnancy²⁸

Figure 3. Recommended DMT wash out period for pregnancy²⁸

 

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

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

 

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

 

Pregnancy and Post-Partum

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

Monoclonal Antibodies

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

 

Natalizumab

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

 

Anti-CD20 Therapies

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

 

Alemtuzumab

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

Treatment of Relapses during Pregnancy and Postpartum

 

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

Pediatric Multiple Sclerosis

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

 

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

 

Treatment 

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

 

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

 

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

Vaccine Recommendations

 

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

Table 2. Live Vaccine Considerations for Patients with MS on DMTs^27,39-47

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

 

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

 

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

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

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

Pharmacist Responsibilities in MS Patient Management

 

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

Table 4. Monitoring Strategies for Adverse Effect Management⁴⁹

Drug Name	Potential adverse effect	Adverse effect management
Fumarates	·       Gastrointestinal symptoms ·       Flushing	·       Slow dose titration, from 120 mg twice daily to 240 mg twice daily over 4 weeks (instead of 7-day uptitration schedule) ·       Administration with high-fat, high-protein, and low-starch food ·       If symptoms persist, temporary dose reduction and symptomatic treatment with antacids, promethazine may be required ·       Non-enteric coated aspirin up to 325 mg administered 30 minutes prior to dosing reduces the incidence or severity of flushing
Infusion therapies	·       Infusion associated reactions (chills, flushing, fever, nausea, hives, dyspnea, and itching) and allergic reactions	·       For alemtuzumab and ocrelizumab, appropriate premedication with corticosteroids, antihistamines, and antipyretics. ·       Blood pressure monitoring is important, especially for alemtuzumab.
Interferon-beta and glatiramer acetate	·       Injection site reactions	·       Cold compress, premedication with NSAIDs
S1PR modulators (spingolimod)	·       Bradycardia, atrioventricular block	·       Monitor patients for six hours after initial dose, with pulse and blood pressure assessment hourly

 

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

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

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

CONCLUSION

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

 

Introduction

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

 

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

 

SIDEBAR: Common Misperceptions

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

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

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

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

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

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

• Myth: All CBD products are the same.

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

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

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

 

Legal Status of CBD-Rx and Unapproved CBD Products

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

 

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

 

Comparing Products: Quality and Purity Differences, Dosage Fluctuations

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

 

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

 

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

 

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

 

Adulteration and Contamination

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

 

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

 

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

 

CBD Alone or CBD + Other Cannabis Constituents

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

 

Pharmacokinetic Profile Comparison of CBD-Rx and Unapproved CBD Products

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

CBD-Rx’s Efficacy in Refractory Rare Seizure Disorders

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

 

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

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

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

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Properly Using CBD-Rx in Seizure Disorders

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

 

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

 

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

 

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

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

 

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

 

Counseling for CBD-Rx

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

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

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

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

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

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

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

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

 

CBD-Rx or Unapproved CBD in Other Diseases and Disorders

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

Table 1. Relative Strength of Evidence Base for CBD

Condition	Evidence Base
Anxiety THC Induced or Opioid Withdrawal Public Speaking Stressor Prophylaxis Chronic Anxiety	++ ++ + 0
Psychosis/Schizophrenia THC Induced Other	++ +
Pain and/or Spasticity	+
Parkinson’s Disease Movement disorders Sleep	+ +
Acne Sebum production Fewer Breakouts	+ 0
Rosacea, Eczema, Psoriasis	0
Crohn’s Disease	0
Cancer	0

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

 

SIDEBAR: What do these statistical terms mean?

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

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

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

 

Anxiety

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

 

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

 

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

 

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

 

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

 

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

 

Psychosis and Schizophrenia

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

 

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

 

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

 

Pain and Spasticity

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

 

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

 

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

 

Parkinson’s Disease

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

 

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

 

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

 

Topical CBD for Skin Related Disorders

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

 

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

 

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

 

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

 

Crohn’s Disease

 

Cancer

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

 

Counseling for Unapproved CBD Products

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

 

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

 

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

 

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

 

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

 

Conclusion

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

Download CE Activity

Introduction

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

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

 

Exposure to Monkeypox

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

 

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

 

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

 

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

 

Symptom Presentation

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

The monkeypox rash progresses through sequential stages⁶:

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

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

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

 

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

 

Avoiding Monkeypox                                        

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

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

 

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

 

Researchers recommend the following measures to prevent infection with monkeypox²:

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

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

Potential Health Impact

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

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

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

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

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

 

APPROACH TO TREATMENT

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

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

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

PEP is not recommended for people with low or uncertain risk (e.g., health care providers entering a patient’s room without eye protection). Eligible intermediate- and high-risk contacts are offered PEP with^2,12,13

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

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

 

Table 1. Approved and Investigational Therapeutics for Monkeypox^12-17

Generic Name (Brand Name; Manufacturer)	Current FDA approved indication
Smallpox (Vaccinia) Vaccine, Live (ACAM2000)	Vaccine indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection
Smallpox and Monkeypox Vaccine, Live, Non-replicating (Jynneos)	Vaccine indicated for prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection
Tecovirimat (TPOXX)	Capsules and injection indicated for the treatment of human smallpox disease in adults and pediatric patients weighing ≥ 3 kg
Cidofovir (Vistide)	Infusion indicated for CMV retinitis in patients with acquired immunodeficiency syndrome
Brincidofovir (Tembexa)	Tablets and oral solution indicated for the treatment of human smallpox disease in adult and pediatric patients, including neonates
Vaccinia immune globulin (human) (Vigiv)	Intravenous immune globulin indicated for the treatment of complications due to vaccinia vaccination, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, vaccinia infections in individuals who have skin conditions, aberrant infections induced by vaccinia virus

 

Smallpox Vaccine

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

Smallpox and Monkeypox Vaccine

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

 

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

 

Tecovirimat

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

Cidofovir and Brincidofovir

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

Vaccinia Immune Globulin

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

 

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

Ancillary Treatment Options, Supportive Care

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

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

CONCLUSION

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

Download CE Activity