Director, International Drug Information Center

Joseph P. Nathan, MS, PharmD

Obesity is a worldwide major public health concern. In the US, approximately 74% of adults are either overweight (BMI 25-29.9 kg/m2) or obese (BMI > 30 kg/m2).

Obesity is associated with serious health complications including type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease.

 As such, obesity is considered a multi-faceted chronic disease that requires appropriate management. According to the American Association of Clinical Endocrinologists and the American College of Endocrinology, lifestyle modification, consisting of a reduced-calorie diet and physical activity, is the first-line management strategy for overweight and obesity.

 Pharmacotherapy is recommended as an adjunct to lifestyle modifications in patients with a BMI > 30 kg/m2 or in patients with a BMI > 27 kg/m2 in the presence of weight-related comorbidities, such as diabetes, hypertension, and dyslipidemia.

 The recent FDA approval of semaglutide for weight management presents an important advancement in the pharmacotherapy options available to the practitioner as well as to the patient. The aim of this article is to provide a brief overview of the agents that are FDA-approved for chronic weight management.

Pharmacological Agents Approved for Chronic Weight Management

Five medications are currently approved by the FDA for chronic weight management (see 

); these include semaglutide (Wegovy; Novo Nordisk), liraglutide (Saxenda; Novo Nordisk), naltrexone extended-release (ER)/bupropion ER (Contrave; Orexigen Therapeutics Inc), phentermine/topiramate ER (Qsymia; Vivus, Inc), and orlistat (Xenical and Alli).

 Notably, semaglutide, naltrexone ER/bupropion ER, and phentermine/topiramate ER are approved for adult use only, whereas liraglutide and orlistat are also approved for children aged 12 and older.

 None of the approved agents are recommended in pregnancy or in patients planning a pregnancy.

 An additional medication, setmelanotide (Imcivree; Rhythm Pharmaceuticals), is approved for the treatment of obesity caused by 3 rare genetic conditions and is not indicated for weight management in the general patient population.

 The choice of which medication to use in a given patient is influenced by patient comorbidities and patient preferences including the route of administration and dosing frequency, as well as cost.

FDA Approved Medication for Chronic Weight Management

In addition to the aforementioned medications indicated for chronic weight management, several agents are approved for short-term (<12 weeks) use. Clinical guidelines, though, recommend weight loss medications to be used chronically for a sustained effect.

 When comparing the efficacy of weight-loss agents, it is important to note that even a sustained 5% weight loss has been shown to produce a clinically meaningful reduction in triglycerides, blood glucose, blood pressure, and the risk of developing type 2 diabetes.

The most recently approved medication, semaglutide, is a glucagon-like peptide-1 (GLP-1) agonist that is also approved for use in type 2 diabetes. Compared with the other approved agents, semaglutide resulted in the greatest weight loss among patients who used it. Animal studies showed that semaglutide activates neurons in brain regions involved in the regulation of appetite, thus decreasing food intake.

The recommended initial dose is 0.25 mg injected subcutaneously once weekly for 4 weeks with dose increments every 4 weeks to a maintenance dose of 2.4 mg once weekly. The rationale behind this titration is to decrease gastrointestinal adverse effects (AEs) that are associated with the GLP-1 agonist drug class. AEs reported with the use of semaglutide in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (44%), diarrhea (30%), vomiting (24%), constipation (24%), abdominal pain (20%), headache (14%), fatigue (11%), dyspepsia (9%), dizziness (8%), abdominal distension (7%), eructation (7%), hypoglycemia in patients with type 2 diabetes (6%), flatulence (6%), gastroenteritis (6%), and gastroesophageal reflux disease (5%). Semaglutide carries a black box warning for thyroid C-cell tumors; a warning that is based on data from animal studies. Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Additional warnings include acute kidney

injury, mostly due to volume depletion, as well as acute pancreatitis, acute gallbladder disease, increase in heart rate, and suicidal ideation. Patients with type 2 diabetes, who use semaglutide for weight loss, are at an increased risk for hypoglycemia, especially if they are using insulin or an insulin secretagogue (eg, sulfonylurea), and for diabetic retinopathy complications.

Pharmacists should advise the patient to stay hydrated, rotate injection sites with each injection, and use semaglutide on the same day each week. Patients should not use semaglutide with other GLP-1 agonists.

Like semaglutide, liraglutide is a GLP-1 agonist with similar pharmacology and AE profile. Liraglutide is administered as a subcutaneous injection. The dose is initiated at 0.6 mg daily which is titrated in weekly intervals to a maintenance dose of 3 mg daily. AEs reported with the use of liraglutide in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (39.3%), diarrhea (20.9%), constipation (19.4%), vomiting (15.7%), injection site reactions (13.9%), headache (13.6%), hypoglycemia in patients with type 2 diabetes (12.6%), dyspepsia (9.6%), fatigue (7.5%), dizziness (6.9%), abdominal pain (5.4%), increased lipase (5.3%), and upper abdominal pain (5.1%). Liraglutide carries a black box warning for thyroid C-cell tumors; a warning that is based on data from animal studies. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, as well as in pregnancy. Additional warnings include acute pancreatitis, acute gallbladder disease, hypoglycemia, especially if used with insulin or an insulin secretagogue, increase in heart rate, renal impairment, mostly due to volume depletion, and suicidal ideation. Caution should be used when initiating liraglutide in patients with renal dysfunction or hepatic impairment. In addition to counseling on injection techniques and AEs, pharmacists should counsel patients to discontinue liraglutide if they have not achieved 4% weight loss from baseline by 16 weeks, as it is not likely that continued treatment would result in clinically meaningful weight loss. Patients should not use liraglutide with other GLP-1 agonists.

Naltrexone is an opioid antagonist which is also indicated for opioid use disorder, and bupropion is a dopamine and norepinephrine reuptake inhibitor which is also indicated for depression and smoking cessation. The 2 medications work synergistically by stimulating 2 areas of the brain involved with the regulation of food intake: the hypothalamus and the mesolimbic dopamine circuit. This medication is available as ER tablets containing 8 mg of naltrexone and 90 mg of bupropion. The recommended initial dose is 1 tablet once daily orally with weekly increments to a maintenance dose of 2 tablets in the morning and 2 tablets in the evening.

AEs reported with the use of naltrexone ER/bupropion ER in clinical trials at the rate of > 5% and with frequencies greater than placebo included nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%). Because bupropion is an antidepressant, naltrexone ER/bupropion ER carries a black box warning for an increased risk of suicidal thoughts and behaviors. Naltrexone ER/bupropion ER is contraindicated in patients with uncontrolled hypertension, chronic opioid use, seizure disorders, anorexia nervosa or bulimia, patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, patients using other bupropion products, and patients who have taken monoamine oxidase inhibitors (MAOIs) within the last 14 days. Other precautions include neuropsychiatric events, which were reported in patients who used bupropion for smoking cessation, hepatotoxicity associated with naltrexone, activation of mania, increase in blood pressure and heart rate, angle-closure glaucoma, and hypoglycemia in patients with type 2 diabetes who are on insulin or an insulin secretagogue.

This medication should also not be used in patients with end-stage renal disease or severe hepatic impairment. Pharmacists should counsel patients to avoid taking this medication with a high-fat meal, since doing so increases systemic exposure to the medication, and to avoid drinking alcohol. If after 12 weeks at the maintenance dose, the patient does not achieve at least 5% weight loss from baseline, naltrexone ER/ bupropion ER should be discontinued.

Phentermine’s mechanism in weight loss is believed to involve the release of catecholamines in the hypothalamus, leading to decreased appetite and food intake. It is also available as monotherapy for short-term weight management.

 Topiramate produces weight loss by suppressing appetite and enhancing satiety, which is achieved by several possible pharmacological mechanisms.

Phentermine/topiramate ER is taken orally once daily in the morning to avoid insomnia. The initial dose is 3.75 mg/23 mg daily and titrated up to 7.5 mg/46 mg daily after 14 days. After 12 weeks on the latter dose, the patient’s weight loss is evaluated and if the patient does not achieve at least 3% weight loss from baseline, the medication may be discontinued as continued use on this dose is not likely to produce clinically meaningful weight loss. Alternatively, at that point, the dose may be increased to 11.25 mg/69 mg daily for 14 days followed by 15 mg/92 mg daily, which is the maximum recommended dose. If the patient does not achieve at least 5% weight loss from baseline after 12 weeks on the maximum dose, the medication should be discontinued. AEs reported with the use of phentermine/topiramate ER in clinical trials at the rate of > 5% and with frequencies greater than placebo included paresthesia (19.9%), dry mouth (19.1%), constipation (16.1%), upper respiratory tract infection (13.5%), headache (10.6%), dysgeusia (9.4%), insomnia (9.4%), nasopharyngitis (9.4%), dizziness (8.6%), sinusitis (7.8%), nausea (7.2%), back pain (6.6%), fatigue (5.9%), diarrhea (5.6%), blurred vision (5.4%), bronchitis (5.4%), and urinary tract infection (5.2%).

Because it contains phentermine, an amphetamine-like stimulant, this medication is classified as a schedule IV controlled substance. Phentermine/topiramate ER is contraindicated in pregnancy, glaucoma, hyperthyroidism, and within 14 days of MAOI use. Due to teratogenic risk, this medication is available through a Risk Mitigation and Evaluation Strategy (REMS) program. Warnings associated with the use of the medication include an increase in heart rate, suicidal ideation, acute myopia and secondary angle closure glaucoma, cognitive impairment, mood and sleep disorders, metabolic acidosis, elevation in creatinine, kidney stones, oligohidrosis and hyperthermia, and hypokalemia. Patients should have their laboratory chemistry profiles analyzed periodically throughout the treatment. 

Additionally, patients should discontinue the medication gradually, since abrupt discontinuation of topiramate can precipitate a seizure. The medication has been shown to increase the risk for hypoglycemia in patients who take antidiabetic medications, the risk for hypotension in patients who use antihypertensive medications, and it may potentiate central nervous system (CNS) depression in patients who drink alcohol or use any other CNS depressants. This agent should not be used in patients with end-stage renal disease or severe hepatic impairment. Pharmacists should advise patients to avoid driving or operating heavy machinery while using this medication, since it may cause dizziness or confusion. Patients should also avoid drinking alcohol and be aware of the medication’s teratogenic risk and potential for drug-drug interactions.

Orlistat is the only chronic weight management medication available both over the counter (60 mg capsules) and by prescription (120 mg capsules). This agent acts by inhibiting gastrointestinal lipases, resulting in decreased fat absorption.

The recommended dose of the OTC product is 60 mg 3 times daily while the prescription product is dosed at 120 mg 3 times daily. Orlistat must be taken within 1 hour of a meal containing fat. The patient should be on a reduced-calorie diet that contains approximately 30% of calories from fat. If the patient’s meal is skipped or does not contain fat, the dose of the medication can be omitted. AEs reported within the first year of using prescription orlistat in clinical trials at the rate of > 5% and with incidence which was at least twice seen with placebo were oily spotting (26.6%), flatus with discharge (23.9%), fecal urgency (22.1%), fatty/oily stool (20%), oily evacuation (11.9%), increased defecation (10.8%), and fecal incontinence (7.7%). Orlistat is contraindicated in pregnancy, chronic malabsorption syndrome, and cholestasis. Warnings include decreased absorption of fat-soluble vitamins, rare cases of severe liver injury, increased levels of urinary oxalate, increased risk of cholestasis in patients who achieve substantial weight loss, and increased gastrointestinal AEs in patients who have a diet high in fat (>30% total daily calories from fat).

The OTC orlistat also contains a warning for organ transplant recipients noting that orlistat can interact with immunosuppressants (eg, cyclosporine).

Pharmacists should advise patients to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after taking orlistat.

 Furthermore, pharmacists should monitor for drug-drug interactions with this medication.

Medications for chronic weight management differ in their mechanisms, efficacy, safety, and dosing profiles, as well as in their cost of therapy. Patient-specific factors should be considered when choosing a weight loss agent and, once therapy is initiated, it is necessary to monitor the patient’s response and tolerability. Pharmacists should discuss the expected benefits and risks of weight loss agents with their patients, emphasizing that these medications need to be taken long-term for a sustained effect and should be used in conjunction with a healthy lifestyle.

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3. Prescription medications to treat overweight and obesity. National Institute of Diabetes and Digestive and Kidney Health. Updated June 2021. Accessed June 18, 2021. https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity#available

4. FDA approves first treatment for weight management for people with certain rare genetic conditions. US Food and Drug Administration. Published November 27, 2020. Accessed June 18, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-first-treatment-weight-management-people-certain-rare-genetic-conditions#:~:text=%5B11%2F27%2F2020%5D,POMC

5. Wegovy. Prescribing information. Novo Nordisk; 2021. Accessed June 11, 2021. https://www.novo-pi.com/wegovy.pdf

6. Saxenda. Prescribing information. Novo Nordisk; 2020. Accessed June 14, 2021. https://www.novo-pi.com/saxenda.pdf

7. Contrave. Prescribing information. Nalpropion Pharmaceuticals LLC; 2021. Accessed June 17, 2021. https://contrave.com/contrave-pi/

8. Qsymia. Prescribing information. Vivus, Inc.; 2020. Accessed June 17, 2021. https://qsymia.com/patient/include/media/pdf/prescribing-information.pdf

9. Xenical. Prescribing information. H2-Pharma LLC; 2020. Accessed June 17, 2021. https://xenical.com/pdf/PI_Xenical-brand_FINAL.PDF

10. Alli. Drug label information. GlaxoSmithKline Consumer Healthcare Holdings (US) LLC; 2020. Accessed June 17. 2021. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a2d3bd73-f3af-4ea5-a57c-66b0004cfe4f

Articles

Five medications are currently approved by the FDA for chronic weight management.

A Review of FDA-Approved Medications for Chronic Weight Management

Since the onset of the COVID-19 pandemic, emphasis has been placed on monitoring health status, screening for disease states, and ensuring that the general public is not exposed to the virus and/or exhibiting signs and symptoms of COVID-19. One of the methods used to detect illness and prevent the spread of the disease is monitoring for fever with the use of thermometers. According to IRI, a Chicago-based market research firm, the sale of personal thermometers increased by 297% during the 4-week period ending March 22, 2020, compared to the same time period 1 year earlier.

 Since COVID-19 remains a public concern, it is important for pharmacists to be familiar with the various types of thermometers available on the market and to provide proper guidance on their use.

The body maintains a state of homeostasis regulated by the hypothalamic thermoregulatory center. The center balances excess heat production from metabolic activity in the muscle and liver by allowing heat to be released from the skin and lungs to maintain a mean oral temperature of 36.8

 0.7o F). Fluctuations in body temperature occur throughout the day, with temperature being lower in the morning and higher in the evening.

 Furthermore, the temperature considered to be fever differs based on the measurement site (

Body Temperature per Site of Measurement

Considerations When Selecting a Thermometer

Various thermometers are available on the US market. When selecting a thermometer, identifying one that will provide an accurate reading is most important. Since the FDA regulates thermometers as medical devices, all approved thermometers are considered accurate and reliable, when used appropriately.

 To do so, considerations must be given to the ease of use, which may be a function of the site of temperature measurement. Thus, consideration should be given to the versatility afforded by certain thermometers, allowing for measurements to be obtained in more than one body site. The following is a discussion of various types of thermometers. 

Rectal thermometers have been generally accepted as the “gold standard” for measuring temperature in very young children; however, some caregivers refrain from using them due to their intrusive nature and associated risks. These risks may include the development of peritonitis, rectal or intestinal perforation, and retaining of the thermometer inside the rectum.

 Rectal temperature measurements should not be taken in patients with obstructive hemorrhoids or diarrhea, as well as in patients with neutropenia due to their increased susceptibility to infection. Other considerations when measuring rectal temperature are that it is cumbersome and time consuming and that rapid changes in body temperature may not be detected due to the large muscle mass and poor blood flow to the rectal area.

 Notably, rectal temperatures tend to run higher than oral temperatures.

Oral thermometers are commonly used in medical offices and within households. However, to obtain accurate readings, certain factors must be kept in mind. For instance, oral temperature readings should be obtained at least 20 to 30 minutes after drinking and/or eating and should not be taken in patients who have a difficult time keeping the thermometer under their tongue and/or difficulty creating a tight seal around the thermometer.

 For younger patients who may struggle with these issues, pacifier thermometers are an alternative option to measure temperature. To obtain a proper reading with a pacifier thermometer, patients should wait 30 minutes after eating or drinking and should hold the pacifier in their mouth without moving it for 2 to 6 minutes.

 Lastly, oral temperatures should not be obtained in patients who are hyperventilating, uncooperative, lethargic, confused, and/or those who have had recent oral surgery.

Tympanic thermometers are usually used in pediatric offices to take the temperature via the ear. These provide a relatively quick and accurate measurement because the ear is close to the hypothalamus which allows for an accurate reading of core body temperature.

 However, proper positioning of the thermometer is extremely important to ensure an accurate reading. Other factors such as inflammation of the ear canal, age (children younger than 6 months do not have fully developed ear canals), and earwax buildup may also affect temperature readings.

 Additionally, cold or hot weather can affect temperature readings so it is recommended to wait at least 15 minutes after being exposed to extreme temperatures before using the thermometer.

Proper technique requires the user to pull the ear backward to help straighten the ear canal and to aim the tip of the probe towards the patient's eye on the opposite side of his or her head.

Temporal touch thermometers use an infrared scanner to scan the temporal artery in the forehead. This task is completed by placing the thermometer on 1 side of the forehead and then moving it across the forehead; the process usually takes a few seconds. This method of measuring temperature can be very sensitive in detecting fever but the scanner needs to be in contact with the skin at all times. Overall, this method provides an easy and accurate temperature reading in most patients.

 Yet, one must keep in mind that direct sunlight, cold temperature, sweaty forehead, and poor technique can impact the accuracy of the reading.

Noncontact temporal thermometers also use infrared technology but these do not require direct contact with the skin. Thermometers are generally held between 1.2 and 6 inches from the skin.

 Using a forehead noncontact infrared thermometer is quick, convenient, noninvasive, and carries a low risk of disease transmission. Studies suggest that taking temperature immediately after coming in from the cold underestimates body temperatures and as such, infrared temporal thermometers are not ideal for screening for diseases during cold weather.

 To ensure accuracy, measurements should be taken at least 10 minutes after coming in from the cold.

 These thermometers should also be used in environments free from secondary infrared sources, such as direct sunlight and incandescent lamps.

Axillary temperatures usually run lower than oral temperatures. Compared with the rectal and oral methods of measuring temperature, axillary thermometers are less reliable at detecting fevers.

 Although they may be favored because of their ease of use and noninvasive nature, their use should be discouraged because of concerns with accuracy.

 When used, temperatures should not be taken directly after vigorous activity or bathing since these can alter body temperature.

Basal thermometers are used to monitor basal body temperature for the purpose of tracking ovulation in women who are trying to conceive or prevent pregnancy.

 The digital basal thermometers have smaller gradations than regular thermometers (0.1 degree vs 0.2 degree), enabling them to detect small changes in body temperatures. This is important since the temperature increase that follows ovulation is small (approximately 0.4 to 1.0

Temperature can be taken orally, rectally, or vaginally; however, the same site must be used each day. Temperature must also be taken at approximately the same time each morning before rising, after at least 3 hours of sleep.

Color change thermometers usually involve placing a strip on the forehead, which changes color according to the heat radiating from the body. These thermometers are easy to use, provide a quick reading, and are sometimes reusable. However, they can be inaccurate as they do not reliably detect changes in the core temperature but only changes in skin temperature.

Glass Thermometers vs Digital Thermometers

Two types of glass thermometers are available, one with mercury and the other without it. Mercury-containing thermometers are no longer recommended due to toxic effects and may be banned in some states.

 Notably, though, individuals may still have access to these thermometers at home. Before taking measurements, it is important to ensure that the thermometer’s mercury is at the bottom of the measurement column. If this is not the case, the thermometer should be flicked to bring down the mercury in the column. Mercury-free glass thermometers use a gallium-indium-tin alloy, as a substitute for mercury.

 Glass thermometers differ in their tips. Those that utilize a long, thin tip are indicated for oral and axillary use whereas those with a short, round tip are for rectal use.

Digital thermometers are commonly used as an alternative to glass thermometers since they are faster, easier to read, and remove the environmental concern of mercury.

 Furthermore, there are no clinically significant differences between the accuracy of glass thermometers and digital thermometers.

 Digital thermometers are portable and can be used to measure oral, axillary, and rectal temperatures.

Several factors should be considered when selecting a thermometer. Thermometers vary in their mechanisms of measuring temperatures and in their intended uses. Pharmacists must be familiar with the different thermometers so they can ensure proper use by the consumer.

1. COVID-19 and the Economy: Tacking the Dramatic Pivot of U.S. Consumer and Shopper Behavior. IRI Worldwide. Published April 3, 2020. Accessed May 12, 2021. https://www.iriworldwide.com/iri/media/library/covid-19-thought-leadership-4-3-2020.pdf

2. Dinarello CA, Porat R. Fever. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. 

Harrison’s Principles of Internal Medicine

, 20th ed. McGraw Hill: 2020. Accessed March 16, 2021.

3. Lemay V, Feret BM. Fever. In: Krinsky DL, ed. 

Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care.

 19th ed. APhA Publications; 2018:97-110. 

4. Temperature: Digital and Glass Thermometers. Nationwide Children’s. Updated February 2017. Accessed March 24, 2021. https://www.nationwidechildrens.org/family-resources-education/health-wellness-and-safety-resources/helping-hands/temperature-digital-and-glass-thermometers

5. Thermometers: Understanding the Options. Mayo Clinic. Updated November 17, 2020. Accessed March 25, 2021. https://www.mayoclinic.org/diseases-conditions/fever/in-depth/thermometers/art-20046737

6. Non-Contact Temperature Measurement Devices: Considerations for use in Port of Entry Screening Activities. Centers for Disease Control and Prevention. Published August 22, 2014. Accessed March 19, 2021. https://stacks.cdc.gov/view/cdc/24857/cdc_24857_DS1.pdf

7. Dzien C, Halder W, Winner H, Lechleitner M. COVID-19 screening: are forehead temperature measurements during cold outdoor temperatures really helpful? 

. 2021;133(7-8):331-335. doi: 10.1007/s00508-020-01754-2.

8. Erenberk U, Torun E, Ozkaya E, Uzuner S, Demir AD, Dundaroz R. Skin temperature measurement using an infrared thermometer on patients who have been exposed to cold. 

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9. Briggs GC. Home Testing and Monitoring Devices. In: Krinsky DL, ed. 

 19th ed. APhA Publications; 2018:899-922. 

10. Basal Body Temperature for Natural Family Planning. Mayo Clinic. Updated March 3, 2021 Accessed May 26, 2021. https://www.mayoclinic.org/tests-procedures/basal-body-temperature/about/pac-20393026

11. Mercury Thermometers. US Environmental Protection Agency. Updated March 30, 2021. Accessed June 9, 2021. 

https://www.epa.gov/mercury/mercury-thermometers

12. Baura G. Thermometers. In: Baura G, ed. 

Medical Device Technologies: A System Based Overview Using Engineering Standards.

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13. Hardu G, Murugan R. Is there a significant difference between digital and glass mercury thermometers? 

Pharmacists must be familiar with the different thermometers so they can ensure proper use by the consumer. 

Thermometers: A Review

Back in December 2020, the FDA issued an emergency use authorization for Pfizer-BioNTech’s COVID-19 vaccine, followed by authorization for the Moderna and Janssen (Johnson & Johnson) vaccines. Many Americans have yet to be vac- cinated, with the most common reasons for refusing being fear of potential adverse effects (AEs) and concerns about the rapid vaccine development process.

Pharmacists must be familiar with the safety profiles of the vaccines to assure the public of their safety.

COVID-19 Vaccines Available in the United States

Three vaccines are currently available on the US market. The Pfizer and Moderna vaccines are both messenger RNA (mRNA) vaccines, whereas the Janssen is a viral-vector vaccine.

 All 3 result in the production of SARS-CoV-2 spike proteins, which trigger the development of antibodies. The development of immunity and memory cells typically takes a few weeks and, when complete, these protect the body against COVID-19 infections.

 Although the vaccines stimulate an immune response, they do not cause a full COVID-19 infection.

Before a vaccine receives FDA approval, it undergoes a series of trials during which its efficacy and safety profiles are established. Trials begin in animal models and continue with 3 phases of clinical trials. A vaccine gains FDA approval only if the efficacy and safety data prove that its benefits outweigh the risks. Once a vaccine has been approved and launched, postmarketing surveillance begins. Such surveillance allows for the collection of safety data in a larger and more diverse population.

Postmarketing safety information for COVID-19 vaccines has been gathered in several ways. For all vaccines, the FDA’s Center for Biologics Evaluation and Research monitors vaccine safety through passive and active surveillance.

 Passive surveillance consists of adverse event reports received from the public and health care professionals, which are entered into the Vaccine Adverse Event Reporting System. Active surveillance involves proactively obtaining and analyzing information from large health care data systems to verify safety signals identified through passive surveillance or to detect additional safety signals. If a possible link between a vaccine and an AE is identified, public health officials assess the benefits and risks and determine whether the vaccine can continue to be administered and whether administration guidelines require adjustment.

Reported Adverse Effects Associated With COVID-19 Vaccines

The AEs reported with the COVID-19 vaccines are generally mild and resolve within a few days.

 These effects tend to be more intense after the second dose of the mRNA vaccines and are more likely to occur in younger individuals. Ongoing surveillance has identified additional AEs, but it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure (see 

 This point can be illustrated by the reporting in mid-April 2021 of a few cases of thrombocytopenia with cerebral venous sinus thrombosis in individuals who had received the Janssen COVID-19 vaccine. Although these cases appear to be very rare, as of the time of this writing, the FDA and CDC have recommended a pause in the use of this vaccine until this matter is thoroughly investigated.

The more commonly reported AEs associated with the use of COVID-19 vaccines are usually related to the vaccine’s pharmacology and not considered immune-mediated or allergic reactions.

 Despite that, news reports concerning severe postmarketing reactions including anaphylaxis instilled fear among the public.

Anaphylaxis is a severe acute-onset immunologic reaction, generally immunoglobulin E (IgE) mediated, which typically occurs in response to preformed IgE antibodies.

 Acute-onset immunologically mediated reactions commonly manifest as urticaria, swelling, gastrointestinal upset, respiratory distress, or cardiovascular collapse associated with severe cases of anaphylaxis. The onset of acute allergic reactions generally occurs within 30 minutes of exposure, although a reaction may also develop hours to days later, in which case it usually presents as a cutaneous reaction. Generally, the mRNA, DNA, or other antigen components in vaccines are not the culprits for allergic reactions. Allergic reactions are usually attributed to other product components such as stabilizing agents and adjuvants, and, rarely, to latex in the vial’s rubber stopper. The Pfizer and Moderna COVID-19 vaccines contain mRNA, lipids, polyethylene glycol (PEG) 2000, electrolytes, sucrose, and a saline diluent. Although the etiology of anaphylaxis to the COVID-19 vaccines is not known, PEG and related polysorbates have been associated with cases of anaphylaxis to other agents. Individuals who exhibit signs of allergic reaction after COVID-19 vaccination are advised to avoid new PEG exposure and to undergo further evaluation with a board-certified allergist or immunologist.

Although cases of anaphylaxis were not reported in clinical trials with the mRNA vaccines, 21 incidents of possible anaphylaxis were subsequently reported with the Pfizer vaccine (11.1 cases per million doses), with 70% occurring within 15 minutes of administration.

 Ten cases of possible anaphylaxis were reported after vaccination with the Moderna vaccine (2.5 cases per million doses) and 1 case of anaphylaxis was reported with the Janssen vaccine.

 The less extensive use of the Janssen vaccine to date prohibits a comparative assessment of the overall safety of this vaccine relative to the mRNA vaccines.

The CDC recommends that the COVID-19 vaccines not be administered to individuals who have a history of severe or immediate allergic reaction to any vaccine component (eg, PEG in the case of the mRNA vaccines, polysorbate in the case of the Janssen vaccine).

 Patients who experienced a severe or immediate allergic reaction to a COVID-19 vaccine should not receive subsequent doses.

The CDC recommends a postvaccination observation period of 30 minutes for those at high risk for anaphylactic reactions and 15 minutes for all other individuals.

When providing counseling, it is important to emphasize the vaccine’s efficacy. Individuals receiving the mRNA vaccines also should be counseled on the importance of completing the vaccination series with the same product. They should be counseled on the expected postvaccination symptoms: Of those receiving the mRNA vaccines, local symptoms are experienced by 80% to 89%, and systemic symptoms by 55% to 83%; of those receiving the viral-vector vaccine, local symptoms are experienced by 50%, and systemic symptoms by 55%. Reassure recipients that systemic postvaccination symptoms are generally mild to moderate in severity, occur within the first 3 days of vaccination, and resolve within 3 days of onset. Advise recipients that antipyretic or analgesic medications can be taken for postvaccination local or systemic symptoms.

The available COVID-19 vaccines are effective in reducing the spread of the disease. Serious reactions are rare, and the public should be educated on the overall safety of these vaccines.

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https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html

4. COVID-19 vaccine safety surveillance. Food & Drug Administration. Updated February 9, 2021. Accessed April 1, 2021. 

https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/covid-19-vaccine-safety-surveillance

5. Ensuring the safety of vaccines in the United States. CDC. Updated January 2018. Accessed April 1, 2021

https://www.cdc.gov/vaccines/hcp/conversations/downloads/vacsafe-ensuring-color-office.pdf

6. Possible side effects after getting a COVID-19 vaccine. CDC. Updated March 16, 2021. Accessed April 2, 2021. 

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/expect/after.html

7. Pfizer-BioNTech COVID-19 Vaccine- bnt162b2 injection, suspension. DailyMed. Updated February 26, 2021. Accessed April 1, 2021. 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=908ecbe7-2f1b-42dd-94bf-f917ec3c5af8

8. Moderna COVID-19 Vaccine- cx-024414 injection, suspension. DailyMed. Updated March 29, 2021. Accessed April 1, 2021. 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0651c7a-2fe2-459d-a766-0d59e919f058

9. Janssen COVID-19 Vaccine- ad26.cov2.s injection, suspension. DailyMed. Updated April 2, 2021. Accessed April 6, 2021. 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14a822ff-f353-49f9-a7f2-21424b201e3b

10. Recommendation to pause use of Johnson & Johnson’s Janssen COVID-19 vaccine. Centers for Disease Control and Prevention website. Accessed April 15, 2021. 

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/JJUpdate.html

11. Kuder MM, Lang DM, Patadia DD. Anaphylaxis to vaccinations: a review of the literature and evaluation of the COVID-19 mRNA vaccinations. 

. Published online March 1, 2021. doi:10.3949/ccjm.88a.ccc075

12. Rolla G, Brussino L, Badiu I. Maintaining safety with SARS-CoV-2 vaccines. 

. 2021;384(10):e37. doi:10.1056/NEJMc2100766

13. Information about COVID-19 vaccines for people with allergies. CDC. Updated March 25, 2021. Accessed April 5, 2021. 

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14. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. CDC. Last reviewed March 5, 2021. Accessed April 5, 2021. 

https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html

Ease patients’ concerns by being well versed in the safety profiles of each vaccine.

COVID-19 Vaccines: A Focus on Safety

In March 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was declared a global pandemic. Since then, the scientific community has been searching for methods of prevention, diagnosis, and treatment of the newfound virus. In the absence of proven treatments for coronavirus disease 2019 (COVID-19), a variety of pharmaceutical agents have been explored for their potential benefit. Alongside these pharmaceutical agents, a number of dietary supplements, such as vitamin C, zinc, and magnesium have been used as well. One particular vitamin that has caught the attention of both health care professionals and consumers is vitamin D. In this article, we will review the evidence describing a possible link between vitamin D and COVID-19.

Vitamin D is a fat-soluble secosteroid hormone that is primarily responsible for the maintenance of calcium and phosphorus homeostasis, which is important for bone health.

 Vitamin D3, or cholecalciferol, is produced in the skin through exposure to sunlight. Cholecalciferol is then converted to calcidiol (25-hydroxyvitamin D3) in the liver and then further converted in the kidneys to calcitriol (1,25-dihydroxyvitamin D3), the physiologically active form of vitamin D. 

In addition to the natural production of vitamin D3 in the body, exogenous vitamin D3 can also be obtained from dietary sources, such as eggs and fish, or from OTC supplements. Vitamin D2 (ergocalciferol) is another form of vitamin D that is available as prescription-only supplements. The serum concentration of vitamin D generally considered adequate for bone and overall health in healthy individuals is > 50 nmol/L (>20 ng/mL).

 It is estimated that 24% of the US population has vitamin D levels that are lower than 50 nmol/mL.

Groups at risk for having low vitamin D levels include older adults, those with limited sun exposure, individuals with dark skin, individuals with conditions that limit fat absorption, and those who are obese or have undergone gastric bypass surgery.

The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine established recommended dietary allowances (RDAs) that are necessary to maintain proper bone health and calcium metabolism in healthy individuals.

 The daily RDA for vitamin D for adults 18 through 70 years of age is 15 mcg (600 IU). The RDA for adults 71 years and older is 20 mcg (800 IU) per day.

In addition to its impact on bone health, vitamin D’s actions on genes expressed by immune cells, coupled with circumstantial but considerable evidence linking vitamin D deficiency with COVID-19 severity, have led to speculations that vitamin D status may play a role in the management of COVID-19.

 To identify literature that examined the relationship between vitamin D and COVID-19, we conducted a search of PubMed using combinations of the following search terms: 

COVID, COVID-19, coronavirus, vitamin D, deficiency, SARS-CoV-2, cholecalciferol,

 In order to obtain the highest level of evidence, we limited our search to meta-analyses.

In a systematic review and meta-analysis of 6 retrospective studies

 Munshi et al. examined the relationship between vitamin D serum levels and COVID-19 severity and prognosis.

 The investigators reported that based on data from 376 patients who were included in the studies, a low vitamin D level was significantly associated with poorer patient outcomes and prognosis. The investigators thus concluded that diagnosis of vitamin D deficiency could be a helpful adjunct in assessing patients' potential for developing severe COVID-19.

In a systematic review and meta-analysis by Pereira et al, the investigators explored the association between vitamin D deficiency and the prevalence of COVID-19 as well as its association with disease severity.

 A total of 25 observational studies involving 8176 patients with COVID-19 were included in the meta-analysis. The investigators reported that vitamin D deficiency was not associated with the development of COVID-19 infection. In contrast, the investigators did observe a positive association between vitamin D deficiency and disease severity. The investigators also noted that there was no support for vitamin D supplementation in individuals with normal blood vitamin D values with the aim of prevention, prophylaxis, or reducing the severity of the disease.

Liu et al. performed a systematic review and identified 10 case-controlled studies that were included in a meta-analysis aimed at examining the association between COVID-19 and vitamin D deficiency; a total of 376,596 subjects were included in this analysis.

The investigators reported that vitamin D deficiency or insufficiency was associated with an increased risk for COVID-19 infection. Furthermore, they noted that COVID-19 infected individuals had lower vitamin D levels than those who were not infected. The investigators thus concluded that low serum vitamin D status might be related to an increased risk for COVID-19.

A systematic review and meta-analysis by Shah et al. examined the relationship between vitamin D supplementation and the severity of COVID-19 illness, as measured by intensive care unit (ICU) stay and mortality outcomes.

 The meta-analysis included 2 randomized controlled trials and 1 case-control study, yielding a total of 532 hospitalized COVID-19 positive patients. The investigators identified a statistically significant lower ICU admission rate in those who were receiving supplements compared to those who were not supplemented with vitamin D. The investigators, however, reported that vitamin D supplements had no effect on mortality as compared with placebo treatment/usual care. The investigators concluded that the meta-analysis suggests a potential role for vitamin D in reducing COVID-19 severity.

Numerous studies assessing a relationship between vitamin D and COVID-19 infection and severity have been published over the past several months. These studies, which suffered from significant limitations, yielded mixed results. As such, we evaluated meta-analyses published on this topic, as they typically provide the highest level of evidence, especially when individual studies result in conflicting findings.

However, the meta-analyses that we identified did not provide conclusive evidence, especially as it relates to an association between low vitamin D levels and the incidence of COVID-19 infection. Collectively, the meta-analyses did seem to suggest an association between vitamin D supplementation or adequate vitamin D levels and better COVID-19 outcomes. It is important to note, however, that similar to the individual studies, the meta-analyses suffered from major limitations, and as such, drawing conclusions from the data is difficult.

Considering the limited and conflicting evidence, guidelines addressing this topic have not advocated for routine supplementation with vitamin D to prevent or treat COVID-19. The National Institutes of Health’s COVID-19 Treatment Guidelines state that there is insufficient evidence either for or against vitamin D supplementation in the prevention or treatment of COVID-19.

Likewise, the United Kingdom’s National Institute for Health and Care Excellence (NICE) COVID-19 Guidelines state that vitamin D supplementation should not be recommended for the sole purpose of prevention or treatment of COVID-19, except as a part of a clinical trial.

 NICE does encourage the public to follow general advice on vitamin D supplementation to maintain adequate bone health. As of the end of January 2021, more than 70 observational and interventional studies to investigate the relationship between vitamin D and COVID-19 were registered on the ClinicalTrials.gov registry. Additional and more robust data should facilitate a better understanding of this topic.

Dr Nathan is the director at the International Drug Information Center and associate professor at Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University.

Dr Grossman is a drug information specialist at the International Drug Information Center and adjunct assistant professor at Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University.

1. National Institutes of Health. Office of Dietary Supplements. Updated October 2, 2020. 

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

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3. Amrein K, Scherkl M, Hoffmann M, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. 

In this article, we will review the evidence describing a possible link between vitamin D and COVID-19. 