Evidence-Based Reviews

Black-box warnings: How they can improve your clinical practice

Current Psychiatry. 2019 December;18(12):18-26J

References

1. Spravato [package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019.
2. U.S. Food and Drug Administration. FDA drug safety announcement: FDA adds boxed warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. Published April 30, 2019. Accessed October 28, 2019.
3. Zulresso [package insert]. Cambridge, Mass.: Sage Therapeutics Inc.; 2019.
4. Gassman AL, Nguyen CP, Joffe HV. FDA regulation of prescription drugs. N Engl J Med. 2017;376(7):674-682.
5. Solotke MT, Dhruva SS, Downing NS, et al. New and incremental FDA black box warnings from 2008 to 2015. Expert Opin Drug Saf. 2018;17(2):117-123.
6. Murphy S, Roberts R. “Black box” 101: how the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. J Allergy Clin Immunol. 2006;117(1):34-39.
7. U.S. Food and Drug Administration. Guidance document: Warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products – content and format. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/warnings-and-precautions-contraindications-and-boxed-warning-sections-labeling-human-prescription. Published October 2011. Accessed October 28, 2019.
8. Beach JE, Faich GA, Bormel FG, et al. Black box warnings in prescription drug labeling: results of a survey of 206 drugs. Food Drug Law J. 1998;53(3):403-411.
9. Matlock A, Allan N, Wills B, et al. A continuing black hole? The FDA boxed warning: an appeal to improve its clinical utility. Clinical Toxicol (Phila). 2011;49(6):443-447.
10. Elraiyah T, Gionfriddo MR, Montori VM, et al. Content, consistency, and quality of black box warnings: time for a change. Ann Intern Med. 2015;163(11):875-876.
11. Yeh JS, Sarpatwari A, Kesselheim AS. Ethical and practical considerations in removing black box warnings from drug labels. Drug Saf. 2016;39(8):709-714.
12. Boudes PF. Risk Evaluation and Mitigation Strategies (REMSs): are they improving drug safety? A critical review of REMSs requiring Elements to Assure Safe Use (ETASU). Drugs R D. 2017;17(2):245-254.
13. U.S. Food and Drug Administration. Approved risk evaluation mitigation strategies (REMS): Spravato (esketamine) REMS program. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=386. Updated June 25, 2019. Accessed October 28, 2018.
14. Stevens JR, Jarrahzadeh T, Brendel RW, et al. Strategies for the prescription of psychotropic drugs with black box warnings. Psychosomatics. 2014;55(2):123-133.
15. Friedman RA. Antidepressants’ black-box warning--10 years later. N Engl J Med. 2014;371(18):1666-1668.
16. Stone MB. The FDA warning on antidepressants and suicidality--why the controversy? N Engl J Med. 2014;371(18):1668-1671.
17. Mathis MV, Muoio BM, Andreason P, et al. The US Food and Drug Administration’s perspective on the new antipsychotic pimavanserin. J Clin Psychiatry. 2017;78(6):e668-e673. doi: 10.4088/JCP.16r11119.
18. Nuplazid [package insert]. San Diego, CA: Acadia Pharmaceuticals Inc.; May 2019.
19. Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213-222.
20. Maust DT, Kim HM, Chiang C, et al. Association of the Centers for Medicare & Medicaid Services’ National Partnership to Improve Dementia Care with the use of antipsychotics and other psychotropics in long-term care in the United States from 2009 to 2014. JAMA Intern Med. 2018;178(5):640-647.
21. Dorsey ER, Rabbani A, Gallagher SA, et al. Impact of FDA black box advisory on antipsychotic medication use. Arch Intern Med. 2010;170(1):96-103.
22. U.S. Food and Drug Administration. FDA drug safety communication: FDA revises description of mental health side effects of the stop-smoking medicines Chantix (varenicline) and Zyban (bupropion) to reflect clinical trial findings. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-description-mental-health-side-effects-stop-smoking. Published December 16, 2016. Accessed October 28, 2019.

This class warning has had widespread effects. For example, it has prompted less use of antipsychotics in nursing home facilities, as a result of stricter Centers for Medicare and Medicaid Services regulations²⁰; overall, there is some evidence that there has been reduced prescribing of antipsychotics in general.²¹ Additionally, this black-box warning is unusual in that it warns about a specific off-label indication, which is itself poorly supported by evidence.²¹ Concomitantly, few other treatment options are available for this clinical situation. These medications are often seen as the only option for patients with dementia complicated by severe behavioral disturbance, and thus this black-box warning reflects real-world practices.¹⁴

Varenicline and neuropsychiatric complications. The withdrawal of the black-box warning on potential neuropsychiatric complications of using varenicline for smoking cessation shows that black-box warnings are not static and can, though infrequently, be removed as more safety data accumulates.¹¹ As additional post-marketing information emerged on this risk, this black-box warning was reconsidered and withdrawn in 2016.²² Its withdrawal could potentially make clinicians more comfortable prescribing varenicline and in turn, help to reduce smoking rates.

How to use black-box warnings

To enhance their clinical practice, prescribers can use black-box warnings to inform safe prescribing practices, to guide shared decision-making, and to improve documentation of their treatment decisions.

Informing safe prescribing practices. A prescriber should be aware of the main safety concerns contained in a medication’s black-box warning; at the same time, these warnings are not meant to unduly limit use when crucial treatment is needed.¹⁴ In issuing a black-box warning, the FDA has clearly stated the priority and seriousness of its concern. These safety issues must be balanced against the medication’s utility for a given patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Clinicians are not required to disclose black-box warnings to patients, and there are no criteria that clearly define the role of these warnings in patient care. As is often noted, the FDA does not regulate the practice of medicine.⁶ However, given the seriousness of the potential adverse effects delineated by black-box warnings, it is reasonable for clinicians to have a solid grasp of black-box warnings for all medications they prescribe, and to be able to relate these warnings to patients, in appropriate language. This patient-centered discussion should include weighing the risks and benefits with the patient and educating the patient about the risks and strategies to mitigate those risks. This discussion can be augmented by patient handouts, which are often offered by pharmaceutical manufacturers, and by shared decision-making tools. A proactive discussion with patients and families about black-box warnings and other risks discussed in product labels can help reduce fears associated with taking medications and may improve adherence.

Continue to: Improving documentation of treatment decisions

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Black-box warnings: How they can improve your clinical practice

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How to use black-box warnings

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