Evidence-Based Reviews

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

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

Author(s):

A better understanding of these warnings leads to safer, more effective prescribing.

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.
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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.
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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.
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Recently, the FDA issued “black-box” warnings, its most prominent drug safety statements, for esketamine,¹ which is indicated for treatment-resistant depression, and the Z-drugs, which are indicated for insomnia² (Table 1). A black-box warning also comes with brexanolone, which was recently approved for postpartum depression.³ While these newly issued warnings serve as a timely reminder of the importance of black-box warnings, older black-box warnings also cover large areas of psychiatric prescribing, including all medications indicated for treating psychosis or schizophrenia (increased mortality in patients with dementia), and all psychotropic medications with a depression indication (suicidality in younger people).

In this article, we help busy prescribers navigate the landscape of black-box warnings by providing a concise review of how to use them in clinical practice, and where to find information to keep up-to-date.

What are black-box warnings?

A black-box warning is a summary of the potential serious or life-threatening risks of a specific prescription medication. The black-box warning is formatted within a black border found at the top of the manufacturer’s prescribing information document (also known as the package insert or product label). Below the black-box warning, potential risks appear in descending order in sections titled “Contraindications,” “Warnings and Precautions,” and “Adverse Reactions.”⁴ The FDA issues black-box warnings either during drug development, to take effect upon approval of a new agent, or (more commonly) based on post-marketing safety information,⁵ which the FDA continuously gathers from reports by patients, clinicians, and industry.⁶ Federal law mandates the existence of black-box warnings, stating in part that, “special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box” (21 CFR 201.57(e)).

When is a black-box warning necessary?

The FDA issues a black-box warning based upon its judgment of the seriousness of the adverse effect. However, by definition, these risks do not inherently outweigh the benefits a medication may offer to certain patients. According to the FDA,⁷ black-box warnings are placed when:

an adverse reaction so significant exists that this potential negative effect must be considered in risks and benefits when prescribing the medication
a serious adverse reaction exists that can be prevented, or the risk reduced, by appropriate use of the medication
the FDA has approved the medication with restrictions to ensure safe use.

Table 2 shows examples of scenarios where black-box warnings have been issued.⁸ Black-box warnings may be placed on an individual agent or on an entire class of medications. For example, both antipsychotics and antidepressants have class-wide warnings. Finally, black-box warnings are not static, and their content may change; in a study of black-box warnings issued from 2007 to 2015, 29% were entirely new, 32% were considered major updates to existing black-box warnings, and 40% were minor updates.⁵

Critiques of black-box warnings focus on the absence of published, formal criteria for instituting such warnings, the lack of a consistent approach in their content, and the infrequent inclusion of any information on the relative size of the risk.⁹ Suggestions for improvement include offering guidance on how to implement the black-box warnings in a patient-centered, shared decision-making model by adding evidence profiles and implementation guides.¹⁰ Less frequently considered, black-box warnings may be discontinued if new evidence demonstrates that the risk is lower than previously appreciated; however, similarly to their placement, no explicit criteria for the removal of black-box warnings have been made public.¹¹

When a medication poses an especially high safety risk, the FDA may require the manufacturer to implement a Risk Evaluation and Mitigation Strategy (REMS) program. These programs can describe specific steps to improve medication safety, known as elements to assure safe use (ETASU).⁴ A familiar example is the clozapine REMS. In order to reduce the risk of severe neutropenia, the clozapine REMS requires prescribers (and pharmacists) to complete specialized training (making up the ETASU). Surprisingly, not every medication with a REMS has a corresponding black-box warning¹²; more understandably, many medications with black-box warnings do not have an associated REMS, because their risks are evaluated to be manageable by an individual prescriber’s clinical judgment. Most recently, esketamine carries both a black-box warning and a REMS. The black-box warning focuses on adverse effects (Table 1), while the REMS focuses on specific steps used to lessen these risks, including requiring use of a patient enrollment and monitoring form, a fact sheet for patients, and health care setting and pharmacy enrollment forms.¹³

Continue to: Psychotropic medications and black-box warnings

References

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

References

What are black-box warnings?

When is a black-box warning necessary?

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