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Do You Know How to Assess Risks Posed by Over-the-Counter Vitamin A Supplements?

Learning Objectives
1. Explain a new or unfamiliar viewpoint on a topic of ethical or professional conduct
2. Evaluate the usefulness of this information for his or her practice, teaching, or conduct
3. Decide whether and when to apply the new information to his or her practice, teaching, or conduct
1 Credit CME
Abstract

Dietary supplements are regulated as foods by the US Food and Drug Administration (FDA) and, despite their potentially harmful effects, are not subject to labeling rules that apply to prescription medications. This commentary responds to a case about vitamin A supplement safety. The commentary compares regulation of vitamin A-derivative prescription medications, such as isotretinoin, to regulation of high-dose vitamin A supplements, illuminating both products' potential for causing birth defects. Label analysis is key to educating patients about risks of vitamin A-containing supplements. The commentary also suggests the need for more FDA oversight of the dietary supplement industry.

Case

A 24-year-old woman asks a dermatologist about an acne supplement she purchased online. An advertisement for this product suggests that other products only cleanse the skin's surface, while this one is designed to prevent repeated breakouts of acne by making the immune system stronger. The product's label recommends 2 servings daily and specifies vitamin A content per serving as 1150% of the recommended dietary allowance of vitamin A in micrograms (mcg) of retinyl palmitate and beta-carotene. The dermatologist is concerned that this dose of vitamin A could be teratogenic, since isotretinoin is a vitamin A derivative requiring rigorous monitoring, especially to prevent birth defects. The patient asks, “Is this product safe?”

Commentary

The US Food and Drug Administration (FDA) defines a dietary supplement as a product taken by mouth that contains vitamins, minerals, herbs, botanicals, amino acids, and other ingredients intended to supplement a diet.1 Acne is common among young adults, and several dietary supplements available online—including some containing high doses of vitamin A—claim to help treat it.2 While vitamin A is an essential nutrient, high-dose vitamin A dietary supplements can harm patients, given their teratogenic potential.2,3 These supplements are widely available, have confusing labels, and lack the equivalent of a category X warning label,2,4 so physicians should help patients understand these products' risks.

Regulatory Differences

Quiz Ref IDPotentially teratogenic prescription medications must include a package insert with pregnancy warning categories D or X, which indicate evidence of fetal risk. The FDA requires patients taking prescription isotretinoin (a category X derivative of vitamin A) who could become pregnant to comply with requirements of the iPLEDGE Program, which involves monthly pregnancy tests and multiple forms of birth control.57 To emphasize this warning, isotretinoin packaging must prominently display multiple warnings against use during pregnancy.5

Dietary supplements are not subject to the same labeling and compliance standards that the FDA requires for prescription medications like isotretinoin,8,9 which is a source of serious clinical and ethical concern for clinicians caring for patients consuming vitamin A dietary supplements available without a prescription. Unlike prescription drugs that must be proven safe and effective to receive FDA approval for sale in the US market, dietary supplements do not require FDA approval and are easy to buy and widely consumed.4 The FDA may remove products from the market, but only if they are determined to be unsafe, adulterated, or mislabeled (ie, as treatment, prevention, or cure).10

Vitamin A Safety

Quiz Ref IDConsumers taking large doses of vitamin A are subject to the same risks of harm as patients taking prescription isotretinoin,3,5,7 yet over-the-counter (OTC) vitamin A supplement labels are not required by the FDA to indicate risk of birth defects.2,4

Assessing risk from amount. One study found that, among acne products available online with potentially teratogenic doses of vitamin A, 2 products lacked a warning about these potential harms and 2 products recommended only to consult a physician prior to use if pregnant.2 Supplement labels are required by the FDA to convey how much vitamin A a product contains. Quiz Ref IDThis is important, since one large study found that the ratio of the prevalence of cranial neural crest defects in babies born to women who took more than 10 000 international units (IUs) of preformed vitamin A daily during pregnancy to that of babies whose mothers took 5000 IUs or less was 4.8, indicating higher odds of such birth defects in babies born to women taking high doses of vitamin A during pregnancy, 1 in 57 of whom had a baby with a cranial neural crest defect.3 These results are based on the numbers of IUs, while supplement labels typically display other units of measurement and thus require conversion to assess risk of harm.

Assessing risk from form. In addition to the number of IUs, the source, or form, of vitamin A is needed on a supplement's label. Quiz Ref IDDietary or supplemental sources of vitamin A provide either preformed vitamin A (ie, retinol and retinyl esters) or vitamin A precursors (ie, provitamin A carotenoids, including beta-carotene).11 Labeling the percentage of preformed vitamin A and vitamin A precursors in a supplement is important because excess preformed vitamin A can be stored in the body and cause harm.3 The risk of excess vitamin A precursors—including risk of teratogenicity in humans—is not known.3 Despite the importance of the form of vitamin A, providing the percentage of vitamin A supplied as preformed and precursor forms in nutrition labels is voluntary, according to FDA regulations.9

Another challenge in interpreting vitamin A dosage is that the units of measure need not be listed on the label. The recommended dietary allowance of vitamin A is currently reported not in IUs but in a measure called retinol activity equivalents (RAEs) by the Food and Nutrition Board,8,9,11 and manufacturers are expected to use RAEs to calculate the percent daily value (% DV) on product labels. However, manufacturers are not required by the FDA to list the word RAE on supplement labels. Clinicians and consumers tend to assume that manufacturers comply with this labeling regulation but would have to perform calculations to confirm this supposition. If these sources of confusion are neither recognized nor resolved, it's impossible to accurately ascertain how much vitamin A is actually in a consumer's body and therefore impossible to accurately assess that consumer's risk of harm from vitamin A.

Using amount and form to assess safety. In the case, the vitamin A supplement label lists 10 500 mcg per serving from retinol palmitate (preformed vitamin A) and beta-carotene (a precursor) but does not specify whether 10 500 mcg means mcg RAE or mcg of retinol palmitate and beta-carotene. The only hint available on the label is the % DV, which is listed as 1167%. An extremely well-informed and health-literate consumer or a good clinician would try to confirm that the 10 500 mcg indicated on the label means 10 500 mcg RAE. To do this, one would need to know to look for—and find—in the Code of Federal Regulations the reference daily intake (RDI) for vitamin A: for adults and children aged 4 and older, it's 900 mcg RAE.9 Multiplying 900 mcg by the DV (11.67) calculated from the % DV on the label, one could indeed confirm that 10 503 mcg RAE is close enough to the 10 500 mcg value indicated on the supplement's label.8,9 The Table gives IU equivalents in mcg RAE and the teratogenic dose for different sources of vitamin A.Quiz Ref ID

Table. IU Equivalents in mcg RAE and Teratogenic Dose for 3 Sources of Vitamin Aa

RetinolbSource of vitamin A
Supplemental beta-carotenecDietary beta-carotenec
IU equivalent0.3 mcg RAE0.3 mcg RAE0.05 mcg RAE
Risk of toxicity>3000 mcg RAEUnknownNot applicable

If one knows that a teratogenic dose of vitamin A is greater than 10 000 IU (3000 mcg RAE) of preformed vitamin A,3 then one could question whether and to what extent the product poses risk of harm. A vitamin A supplement that contained 10 500 mcg RAE from preformed vitamin A would contain 35 000 IUs of vitamin A per serving.11 Although this amount is a potentially dangerous dose for people who might be pregnant, especially during early gestation (eg, 7 weeks or earlier),3 responsibility for considering the safety of OTC high-dose vitamin A supplements currently devolves upon consumers and clinicians, not the FDA or manufacturers.

Need for Expanded Oversight

Consumers and clinicians can't know the risks posed by vitamin A supplements if they don't know or can't learn the amount of vitamin A active in a consumer's body when that supplement is used. Is it reasonable to expect that consumers and clinicians know how to assess risk of a vitamin A dietary supplement? Even assuming it is reasonable, one study found that for 5 of 26 vitamin A-containing acne supplements sold online, the IUs of vitamin A could not be calculated from information listed on the label or there was no specification of the form of vitamin A or the relative proportions of vitamin forms in the supplement.2

Due to vitamin A's teratogenic potential, the FDA should require manufacturers to label amounts of vitamin A in mcg RAE and percentages of vitamin A forms so that consumers and clinicians can quantify vitamin A amounts and assess risk.3,4 We recommend that packaging of dietary supplements containing high doses of vitamin A provide pregnancy warning labels, that phrases such as “dermatologist formulated, tested, and approved” be clarified as insufficient evidence of a product's safety, and that adverse events from dietary supplemental vitamin A be reported by clinicians or consumers to the FDA's MedWatch program.12

In the case, the dermatologist should learn or calculate relevant clinical information about the amount of vitamin A in a dose of the supplement and educate the patient about those amounts' risks. At the policy level, the FDA should expand oversight of dietary supplements with teratogenic risk.

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The AMA Journal of Ethics exists to help medical students, physicians and all health care professionals navigate ethical decisions in service to patients and society. The journal publishes cases and expert commentary, medical education articles, policy discussions, peer-reviewed articles for journal-based, video CME, audio CME, visuals, and more. Learn more

Article Information

AMA Journal of Ethics

AMA J Ethics. 2022;24(5):E376-381.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships.

If applicable, all relevant financial relationships have been mitigated.

Editor's Note

The case to which this commentary is a response was developed by the editorial staff.

Conflict of Interest Disclosure: Dr Katta is a member of the advisory board of Vichy Laboratories. The other authors had no conflicts of interest to disclose.

The people and events in this case are fictional. Resemblance to real events or to names of people, living or dead, is entirely coincidental. The viewpoints expressed in this article are those of the author(s) and do not necessarily reflect the views and policies of the AMA.

Author Information:

  • Dina H. Zamil is a second-year medical student at Baylor College of Medicine in Houston, Texas. She graduated from the University of Houston in 2020 with a degree in honors biomedical sciences and minors in medicine and society, chemistry, and Arab studies. Dina is interested in medical humanities, global health, and refugee service, in addition to clinical medicine; Emily K. Burns is a fourth-year medical student at Baylor College of Medicine in Houston, Texas. She graduated from the University of Texas at Austin in 2018 with a degree in Plan II honors and is interested in pediatric dermatology and medical ethics; Ariadna Perez-Sanchez, MD is an internal medicine resident physician at the University of Texas Health Science Center at San Antonio. Interested in clinical dermatology and infectious diseases, she volunteers with several nonprofit organizations; Rajani Katta, MD is clinical professor of dermatology at the McGovern Medical School at the University of Texas Health Science Center at Houston and clinical assistant professor of medicine at the Baylor College of Medicine. She has written and lectured extensively on medical education, allergic contact dermatitis, and diet and dermatology. She also serves on the Media Expert Team of the American Academy of Dermatology.

References:
1.
 Questions and answers on dietary supplements.  US Food and Drug Administration. July 22 , 2019. Accessed July 28, 2021. https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements
2.
Zamil  DH, Burns  EK, Perez-Sanchez  A, Parke  MA, Katta  R.  Risk of birth defects from vitamin A “acne supplements” sold online.  Dermatol Pract Concept. 2021;11(3):e2021075.Google Scholar
3.
Rothman  KJ, Moore  LL, Singer  MR, Nguyen  USDT, Mannino  S, Milunsky  A.  Teratogenicity of high vitamin A intake.  N Engl J Med. 1995;333(21):1369–1373.Google ScholarCrossref
4.
Institute of Medicine; National Research Council.  Dietary Supplements: A Framework for Evaluating Safety. National Academies Press; 2005.
5.
 Roche medication guide: Acutane® (ACK-u-tane) (isotretinoin capsules).  Roche Laboratories, Inc. Revised January 2010. Accessed June 7, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018662s061medguide.pdf
6.
 What Is the iPLEDGE® REMS (risk evaluation and mitigation strategy)?  iPledge®. Accessed June 2, 2021. https://www.ipledgeprogram.com/iPledgeUI/aboutProgram.uGoogle Scholar
7.
iPledge Program.  The iPLEDGE program patient introductory brochure.  December 2 , 2007. Accessed March 9, 2022. https://www.vegasdermatology.net/wp-content/uploads/2011/09/Patient-Intro-Broch.pdf
8.
 Dietary supplement labeling guide: Chapter IV. Nutrition labeling.  US Food and Drug Administration. April 1 , 2005. Accessed March 27, 2021. http://www.fda.gov/food/dietary-supplements-guidance-documents-regulatory-information/dietary-supplement-labeling-guide-chapter-iv-nutrition-labeling
9.
Nutrition Labeling of Food. 21 CFR §101.9 (2022).
10.
 What you need to know about dietary supplements.  US Food and Drug Administration. February 2020. Accessed July 28, 2021. https://www.fda.gov/food/buy-store-serve-safe-food/what-you-need-know-about-dietary-supplements
11.
 Vitamin A fact sheet for health professionals.  Office of Dietary Supplements, National Institutes of Health. Updated March 26, 2021. Accessed June 1, 2021. https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/
12.
 MedWatch: The FDA safety information and adverse event reporting program.  US Food and Drug Administration. Updated April 2021. Accessed July 28, 2021. https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program
AMA CME Accreditation Information

CME Expiration Date: 05/01/2025

Credit Designation Statement:  The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to: 

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program; and
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program;

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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