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.

Micromedex (www.micromedex.com), which is widely available through medical libraries, is a subscription-based web service that provides black-box warning information from a separate tab that is easily accessed in each drug’s information front page. There is also an alphabetical list of black-box warnings under a separate tab on the Micromedex landing page.

ePocrates (www.epocrates.com) is a subscription-based service that provides extensive drug information, including black-box warnings, in a convenient mobile app.

Bottom Line

Black-box warnings are the most prominent drug safety warnings issued by the FDA. Many psychotropic medications carry black-box warnings that are crucial to everyday psychiatric prescribing. A better understanding of blackbox warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of your treatment decisions.

Related Resources

US Food and Drug Administration. DRUGS@FDA: FDAapproved drug products. www.accessdata.fda.gov/scripts/cder/daf/.
US Food and Drug Administration. Drug safety and availability. www.fda.gov/drugs/drug-safety-and-availability. Updated October 10, 2019.
BlackBoxRx. www.blackboxrx.com. (Subscription required.)
Mircromedex. www.micromedex.com. (Subscription required.)
ePocrates. www.epocrates.com. (Subscription required.)

Drug Brand Names

Amitriptyline • Elavil, Vanatrip
Amoxatine • Strattera
Amoxapine • Asendin
Aripiprazole • Abilify
Asenapine • Saphris
Brexanolone • Zulresso
Brexpiprazole • Rexulti
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Cariprazine • Vraylar
Chlorpromazine • Thorazine
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Disulfiram • Antabuse
Doxepin • Prudoxin, Silenor
Droperidol • Inapsine
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Eszopiclone • Lunesta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Haloperidol • Haldol
Iloperidone • Fanapt
Imipramine • Tofranil
Isocarboxazid • Marplan
Lamotrigine • Lamictal
Levomilnacipran • Fetzima
Levothyroxine • Synthroid
Linezolid • Zyvox
Lisdexamfetamine • Vyvanse
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Lurasidone • Latuda
Maprotiline • Ludiomil
Methadone • Dolophine, Methadose
Methylphenidate • Ritalin, Concerta
Midazolam • Versed
Milnacipran • Savella
Mirtazapine • Remeron
Naltrexone • Revia, Vivitrol
Nefazodone • Serzone
Nortriptyline • Aventyl, Pamelor
Olanzapine • Zyprexa
Paliperidone • Invega
Paroxetine • Paxil
Perphenazine • Trilafon
Phenelzine • Nardil
Pimavanserin • Nuplazid
Prochlorperazine • Compro
Protriptyline • Vivactil
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline • Emsam
Sertraline • Zoloft
Thioridazine • Mellaril
Thiothixene • Navane
Tranylcypromine • Parnate
Trazodone • Desyrel, Oleptro
Trifluoperazine • Stelazine
Trimipramine • Surmontil
Valproate • Depakote
Varenicline • Chantix, Wellbutrin
Vilazodone • Viibryd
Venlafaxine • Effexor
Vortioxetine • Trintellix
Zaleplon • Sonata
Ziprasidone • Geodon
Zolpidem • Ambien

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

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