Director, International Drug Information Center

Joseph P. Nathan, MS, PharmD

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.

1. WHO coronavirus (COVID-19) dashboard. World Health Organization. Updated April 6, 2021. Accessed April 6, 2021. 

2. Nguyen KH, Srivastav A, Razzaghi H. COVID-19 vaccination intent, perceptions, and reasons for not vaccinating among groups prioritized for early vaccination–United States, September and December 2020. 

. 2021;70(6):217-222. doi:10.15585/mmwr.mm7006e3

3. Understanding how COVID-19 vaccines work. CDC. Updated March 9, 2021. Accessed April 1, 2021. 

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. 

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/specific-groups/allergies.html

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

Articles

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/

2. Hossein-nezhad A, Holick MF. Vitamin D for health: a global perspective. 

. 2013;88(7):720-755. doi:10.1016/j.mayocp.2013.05.011

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

https://doi.org/10.1038/s41430-020-0558-y

4. Griffin G, Hewison M, Hopkin J, et al. Vitamin D and COVID-19: evidence and recommendations for supplementation. 

. 2020;7(12):201912. Published 2020 Dec 1. doi:10.1098/rsos.201912

5. Munshi R, Hussein MH, Toraih EA, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. 

. 2021;93(2):733-740. doi:10.1002/jmv.26360

6. Pereira M, Dantas Damascena A, Galvão Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. 

. 2020;1-9. doi:10.1080/10408398.2020.1841090

7. Liu N, Sun J, Wang X, et al. Low vitamin D status is associated with coronavirus disease 2019 outcomes: A systematic review and meta-analysis. 

. 2021;S1201-9712(20)32600-X. doi:10.1016/j.ijid.2020.12.077

8. Shah K, Saxena D, Mavalankar D. Vitamin D supplementation, COVID-19 & disease severity: a meta-analysis. 

. 2021;hcab009. doi:10.1093/qjmed/hcab009

9. National Institutes of Health. COVID-19 Treatment Guidelines: vitamin D. Updated July 17, 2020. Accessed February 1, 2021. 

https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/vitamin-d/

10. National Institute for Health and Care Excellence (UK). COVID-19 Rapid Guideline: vitamin D. Updated December 17, 2020. Accessed February 1, 2021. 

https://www.ncbi.nlm.nih.gov/books/NBK566063/

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

Vitamin D and COVID-19: An Evidence-Based Review

According to the American Burn Association, about 450,000 serious burn injuries occur in the United States every year that require medical attention.

 Overall, the goals of treatment are to control pain, remove dead tissue, prevent infection, reduce scarring, and regain function.

Depending on the burn severity, appropriate management may involve initial resuscitation and stabilization, pain management, and wound care, which often involves the use of antimicrobial agents.

 One antimicrobial agent commonly used in the management of burns is silver sulfadiazine (SSD). Formulated as a 1% topical cream, SSD is FDA-approved as an adjunct for the prevention and treatment of wound sepsis in patients with second- and third-degree burns.

Anecdotally, though, SSD may have become the agent of choice for all types of burns, including minor burns.

 Despite SSD’s popularity, compelling evidence to support its use in the management of burns is lacking. The aim of this article is to provide the reader with an assessment of SSD’s utility for managing burns.

Silver sulfadiazine, which combines silver ions with a sulfonamide moiety, has broad antimicrobial activity. It is bactericidal for many gram-negative and gram-positive bacteria and also has activity against yeast.

 Silver sulfadiazine is considered to be safe, however, dermatologic, gastrointestinal, hematologic, hepatic, neurologic, and renal effects have been reported with its use. The product is contraindicated in patients with severe hypersensitivity reactions following application, pregnant women at or close to term, premature infants, and in infants during the first 2 months of life.

 Although SSD is available as a prescription medication marketed under the brand names Silvadene and Thermazene, it is available generically, as well. The average wholesale price for a 50 g jar of SSD cream is approximately $15.00 and the wholesale acquisition cost is approximately $12.00.

To assess whether clinical evidence supports the use of SSD in the management of burns, we performed a search of PubMed using the terms “silver sulfadiazine” and “burns”. In order to obtain the highest level of evidence, our search was limited to meta-analyses and systematic reviews. Although our search yielded a total of 24 articles, this review focuses on the 5 meta-analyses and systematic reviews wherein the emphasis was on the comparison of SSD with other interventions in the management of burns. The comparative interventions included aloe vera, bacitracin, collagenase, honey, petrolatum, as well as various other preparations/dressings.

A 2019 systematic review and meta-analysis by Maciel et al. evaluated the efficacy of SSD versus numerous other treatments when used for wound healing in burn patients.

 The authors analyzed 11 randomized controlled trials (RCTs) and identified wound-healing time as the primary outcome. The authors concluded that the comparator treatments were statistically superior to SSD with respect to the mean time for complete wound healing.

In a 2018 systematic review and meta-analysis, Nímia et al. examined the efficacy of SSD versus silver-containing and non-silver-containing dressings.

 The outcomes that were assessed included time to wound healing and rate of infection. After analyzing 24 RCTs, the authors concluded that dressings with and without silver showed better outcomes than SSD with respect to time to wound healing. Additionally, burns treated with non-silver-containing dressings were less likely to become infected than burns treated with SSD; there were no differences between silver-containing dressings and SSD with respect to this outcome.

A 2017 systematic review and meta-analysis by Aziz et al. examined the effects of honey as compared with SSD in the management of burns.

 The primary outcomes included time to complete wound healing and proportion of infected wounds rendered sterile (free from bacteria). The meta-analysis of 9 RCTs found that honey was more effective than SSD in the aforementioned parameters. The authors concluded that although this analysis favored honey over SSD, high quality evidence to support the use of honey in clinical practice is scarce.

A 2016 systematic review by Heyneman et al. analyzed 52 RCTs to evaluate the role of SSD as compared with a variety of burn dressings in the treatment of partial-thickness burns.

 The outcome parameters included wound healing, infection, pain, and patient satisfaction. The authors concluded that most viscous, solid, and biological dressings had better healing properties, resulted in less pain, and increased patient satisfaction compared to SSD. With respect to the infection parameter, the efficacy of SSD was comparable to the other dressings. The authors also concluded that since rapid wound closure is essential to obtain optimal functional and aesthetic outcomes, the standard use of SSD in the noninvasive treatment of burn wounds can no longer be supported. 

A 2014 systematic review and meta-analysis by Rashaan et al. assessed 7 RCTs to evaluate the efficacy of SSD as compared to non-silver treatments in the management of partial-thickness burns in children.

The outcome measures included wound healing time, number of dressing changes, pain, length of hospital stay, infection, and grafting rates. The authors concluded that non-silver treatment may be preferred over SSD with respect to wound healing time, dressing changes, pain, and length of hospital stay.

Although SSD is commonly prescribed for the management of burns, numerous systematic reviews and meta-analyses found that overall, SSD was inferior to the various agents that it was compared with. Moreover, SSD seemed to have had a negative impact on some of the outcomes related to wound healing. In view of the above, and as expressly noted in some of the aforementioned reports, the use of SSD as an agent of choice in the management of burns should be discouraged.

American Burn Association. Advanced burn life support course: Provider manual 2018 update. Published 2018. Accessed December 1, 2020. http://ameriburn.org/wp-content/uploads/2019/08/2018-abls-providermanual.pdf

Burns: Diagnosis and treatment. Mayo Clinic. July 28, 2020. Accessed December 1, 2020. https://www.mayoclinic.org/diseases-conditions/burns/diagnosis-treatment/drc-20370545

Silvadene. Package insert. Pfizer Inc; 2020. Accessed December 1, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c437213a-1cd4-445e-a39f-bbcacb9f746f

Chung JY, Herbert ME. Myth: silver sulfadiazine is the best treatment for minor burns. 

. 2001;175(3):205-206. doi:10.1136/ewjm.175.3.205

RED BOOK: IBM Micromedex. Truven Health Analytics/IBM Watson Health; 2020. Accessed December 1, 2020. https://www.ibm.com/products/micromedex-red-book

Maciel ABDS, Ortiz JF, Siqueira BS, Zanette GF. Tissue healing efficacy in burn patients treated with 1% silver sulfadiazine versus other treatments: a systematic review and meta-analysis of randomized controlled trials. 

. 2019;94(2):204-210. doi:10.1590/abd1806-4841.20198321

Nímia HH, Carvalho VF, Isaac C, Souza FÁ, Gemperli R, Paggiaro AO. Comparative study of silver sulfadiazine with other materials for healing and infection prevention in burns: A systematic review and meta-analysis. 

. 2019;45(2):282-292. doi:10.1016/j.burns.2018.05.014

Aziz Z, Abdul Rasool Hassan B. The effects of honey compared to silver sulfadiazine for the treatment of burns: A systematic review of randomized controlled trials. 

. 2017;43(1):50-57. doi:10.1016/j.burns.2016.07.004

Heyneman A, Hoeksema H, Vandekerckhove D, Pirayesh A, Monstrey S. The role of silver sulphadiazine in the conservative treatment of partial thickness burn wounds: A systematic review. 

. 2016;42(7):1377-1386. doi:10.1016/j.burns.2016.03.029

Rashaan ZM, Krijnen P, Klamer RR, Schipper IB, Dekkers OM, Breederveld RS. Nonsilver treatment vs. silver sulfadiazine in treatment of partial-thickness burn wounds in children: a systematic review and meta-analysis. 

. 2014 Jul-Aug;22(4):473-82. doi: 10.1111/wrr.12196

One antimicrobial agent commonly used in the management of burns is silver sulfadiazine.

Reevaluating the Use of Silver Sulfadiazine Cream in the Management of Burns

During the past several years, the US market has seen an explosion in the popularity of cannabidiol (CBD)-containing products. These products are readily available to consumers through various retailers. Additionally, Epidiolex, a natural form of CBD, is available as a prescription drug for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients aged 1 year and older.

 Under US federal law, cannabis-derived products with very low levels of Δ-9-tetrahydrocannabinol (THC; 

 0.3%) are considered “industrial hemp”.

 Per the Agriculture Improvement Act of 2018 (the 2018 Farm Act), cannabis plants and derivatives that contain no more than 0.3 % THC are not considered controlled substances.

 It is important to note that CBD-containing products currently are not classified by the FDA as dietary supplements.

"As the use of CBD-containing products continues to rise, it is imperative pharmacists be familiar with the clinical implications of CBD’s use, especially in patients who use other pharmacologically active substances."

As the use of CBD-containing products continues to rise, it is imperative pharmacists be familiar with the clinical implications of CBD’s use, especially in patients who use other pharmacologically active substances.

The cannabis plant possesses many compounds, including cannabinoids, terpenoids, flavonoids, nitrogenous compounds, and other molecules.

 Three major cannabinoids are Δ-9-THC (the psychoactive component associated with the intoxicating effects of cannabis and primarily involved in its recreational use), cannabinol (CBN), and CBD. The pharmacology of CBD is not fully understood. Studies suggest that its effects are related to its interaction with the endocannabinoid system.

 Some of its effects, however, are attributed to other mechanisms; for example, its anticonvulsant activities may involve a number of mechanisms, including blockade of G protein-coupled receptor 55 (GPR55) and T-type voltage-gated calcium channels, as well as stimulation of 5-HT1a and 5-HT2a receptors.

CBD-containing products are marketed as remedies for various conditions, such as joint pain, back pain, insomnia, stress, depression, inflammation, mood elevation, immunity enhancement, improved brain activity, maintenance of hormonal balance, and indigestion.

 Many, if not most, of these claims have not been substantiated. In contrast, there are conditions for which limited evidence does exist that CBD may be of benefit. Examples include psychosis and schizophrenia, substance use disorders, seizure disorders, Parkinson disease and spasticity, and anxiety disorders.

 It is important to recognize that much of the clinical evidence for the use of CBD stems from case reports and/or from a small number of studies that often carry significant limitations. Moreover, the clinical implications of effects identified in case reports and studies cannot always be ascertained. Likewise, the source of CBD (eg, synthetic or plant extract) used in these case reports and studies is not always specified. All these limitations preclude drawing firm conclusions on the benefits of CBD in the clinical management of these conditions in the general population.

Based on clinical trials data described in Epidiolex’s prescribing information, the most common adverse effects (occurring in at least 10% of patients treated with Epidiolex and to a greater extent than with placebo) in patients with Lennox-Gastaut syndrome or Dravet syndrome are somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, asthenia, rash, insomnia, sleep disorder, and infections.

 The most common adverse effects in patients with tuberous sclerosis complex are diarrhea, transaminase elevations, decreased appetite, somnolence, pyrexia, and vomiting.

CBD has an estimated oral bioavailability of 6% and is highly lipophilic, readily crossing the blood-brain barrier.

 High-fat/high-calorie meals significantly increase the maximum concentration and the area under the curve.4 CBD has a large volume of distribution and is greater than 94% protein bound.

 At steady state, the time to peak plasma concentration occurs between 2.5 and 5 hours.

 CBD is primarily metabolized in the liver (and to some extent in the gut) through cytochromes P450 (CYP2C19 and CYP3A) and uridine 5′-diphospho-glucuronosyltransferase (UGT1A7, UGT1A9, and UGT2B7 isoforms).

 CBD has 1 active metabolite, 7-OH-CBD, which is metabolized to the inactive metabolite, 7-COOH-CBD.4 CBD is almost exclusively excreted in the feces and has an elimination half-life of 56 to 61 hours.

CBD’s pharmacokinetic and pharmacologic properties have implications on its potential to interact with other pharmacologically active substances. Much of what is known about these potential interactions comes from data available for the prescription drug Epidiolex.

Based on in vitro data, pharmacokinetic interactions are predicted with:

CYP1A2 substrates (eg, theophylline, caffeine),

CYP2B6 substrates (eg, bupropion, efavirenz),

CYP2C8 and CYP2C9 (eg, phenytoin) substrates,

Uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates (eg, diflunisal, propofol, fenofibrate), and

UGT2B7 substrates (eg, gemfibrozil, lamotrigine, morphine, lorazepam).

Additionally, in vivo data show that coadministration of CBD increases plasma concentrations of CYP2C19 substrates (eg, clobazam, diazepam) or their metabolites, and thus may increase the risk of adverse effects from these agents. Conversely, concurrent use with a strong CYP3A4 and CYP2C19 inducer (eg, rifampin) will result in a substantial decrease in CBD’s plasma concentration. As such, an increase in CBD’s dose should be considered when a strong inducer of CYP3A4 and/or CYP2C19 is coadministered.

Concomitant use of CBD and valproate has resulted in liver enzyme elevations. Reports in the literature also suggest that cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus; the mechanism of this interaction is not clear. Likewise, concomitant use of CBD with other CNS depressants may increase the risk of sedation and somnolence

Much of the data concerning the potential interactions between CBD and other pharmacologically active agents is derived from studies and observations involving Epidiolex, a standardized form of CBD subject to strict FDA regulations and requirements. It is important to note, though, that CBD-containing products that are readily available to the consumer may not be subjected to the same rigorous quality assurance measures (eg, standards for growth, production, testing/analysis). Such issues have been identified in the past and found to result in variable amounts of CBD among marketed CBD-containing products.

 There are limited data on the bioavailability of CBD following oral administration of various CBD-containing dosage forms. This limits the ability to predict CBD’s pharmacokinetic parameters (ie, absorption, distribution, metabolism, excretion) as well as its pharmacologic and clinical effects, including its potential to interact with other agents.

Pharmacists and other health care professionals must be aware that these issues may affect exposure to CBD and affect concurrent pharmacologically active therapies. Pharmacists must carefully monitor drug therapy in patients using any form of CBD. While the clinical significance of the potential interactions between CBD and other agents is not certain, it is important for pharmacists to be mindful of them and recommend appropriate courses of action.

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Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. 

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As the use of CBD-containing products continues to rise, pharmacists need to be familiar with the clinical implications of CBD use, especially in patients who use other pharmacologically active substances.