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BLACK-BOX WARNINGS: How they can improve your clinical practice A better understanding of these warnings leads to safer, more effective prescribing

Matthew A. Schreiber, MD, PhD ecently, the FDA issued “black-box” warnings, its most promi- Staff Psychiatrist 1 Puget Sound VA Health Care System nent drug safety statements, for esketamine, which is indicated Seattle, Washington for treatment-resistant depression, and the Z-drugs, which are Assistant Professor R 2 indicated for insomnia (Table 1, page 20). A black-box warning also Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine comes with brexanolone, which was recently approved for postpar- Seattle, Washington tum depression.3 While these newly issued warnings serve as a timely Michelle Wiese, MD, MPH reminder of the importance of black-box warnings, older black-box PGY-3 Psychiatry Resident warnings also cover large areas of psychiatric prescribing, including all University of Washington School of Medicine Seattle, Washington indicated for treating or (increased mortality in patients with dementia), and all psychotropic medications Disclosures The authors report no financial relationships with any with a depression indication (suicidality in younger people). company whose products are mentioned in this article, or with In this article, we help busy prescribers navigate the landscape manufacturers of competing products. The views expressed are of black-box warnings by providing a concise review of how to use those of the authors and do not reflect the official policy of the Department of Veterans Affairs or the US Government. 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- WEB EXCLUSIVES threatening risks of a specific prescription . The black-box warning is formatted within a black border found at the top of the More on black-box warnings manufacturer’s prescribing information document (also known as the Supplemental tables summarizing package insert or product label). Below the black-box warning, potential the indications, off-label uses, and risks appear in descending order in sections titled “Contraindications,” common adverse effects of: “Warnings and Precautions,” and “Adverse Reactions.”4 The FDA • first-generation issues black-box warnings either during drug development, to take effect • second-generation antipsychotics • • mood stabilizers

• other psychotropic medications Current Psychiatry

ADAM NIKLEWICZ Vol. 18, No. 12 19 Table 1 Recent black-box warnings for psychotropic medications Year Medication(s) issued Black-box warning Comments Brexanolone 2019 Excess sedation REMS with ETASU associated with warning, Risk of sudden loss includes administration in specific care settings of consciousness only (for monitoring) Black-box 2019 Sleep behaviors, possibly Single, specific for a class of warnings Eszopiclone resulting in death drugs (Z-drugs for insomnia) Zaleplon Esketamine 2019 Sedation and Multiple adverse effects and misuse potential dissociation for a single drug; REMS with ETASU Abuse and misuse associated with warning Increased risk of suicide in younger patients Pimavanserin 2016 Increased risk of death Single, specific adverse effect for an entire Clinical Point in geriatric patients with class of drugs (all antipsychotics), but with an dementia exception for Parkinson’s disease psychosis The FDA issues a specific to pimavanserin black-box warning ETASU: elements to assure safe use; REMS: Risk Evaluation and Mitigation Strategy based upon its judgment of the seriousness of the upon approval of a new agent, or (more Table 2 (page 21) shows examples of commonly) based on post-marketing safety scenarios where black-box warnings have adverse effect information,5 which the FDA continuously been issued.8 Black-box warnings may be gathers from reports by patients, clinicians, placed on an individual agent or on an and industry.6 Federal law mandates the entire class of medications. For example, existence of black-box warnings, stating in both antipsychotics and antidepressants part that, “special problems, particularly have class-wide warnings. Finally, black- those that may lead to death or serious box warnings are not static, and their con- injury, may be required by the [FDA] to be tent may change; in a study of black-box placed in a prominently displayed box” (21 warnings issued from 2007 to 2015, 29% CFR 201.57(e)). were entirely new, 32% were considered major updates to existing black-box warn- ings, and 40% were minor updates.5 When is a black-box warning Critiques of black-box warnings focus necessary? on the absence of published, formal criteria The FDA issues a black-box warning based for instituting such warnings, the lack of a upon its judgment of the seriousness of consistent approach in their content, and the adverse effect. However, by definition, the infrequent inclusion of any information these risks do not inherently outweigh the on the relative size of the risk.9 Suggestions benefits a medication may offer to certain for improvement include offering guidance patients. According to the FDA,7 black-box on how to implement the black-box warn- warnings are placed when: ings in a patient-centered, shared decision- • an adverse reaction so significant exists making model by adding evidence profiles Discuss this article at that this potential negative effect must be and implementation guides.10 Less fre- www.facebook.com/ considered in risks and benefits when pre- quently considered, black-box warnings MDedgePsychiatry scribing the medication may be discontinued if new evidence dem- • a serious adverse reaction exists that onstrates that the risk is lower than previ- can be prevented, or the risk reduced, by ously appreciated; however, similarly to appropriate use of the medication their placement, no explicit criteria for the • the FDA has approved the medication removal of black-box warnings have been Current Psychiatry 20 December 2019 with restrictions to ensure safe use. made public.11 Table 2 Examples of categories addressed by psychotropic black-box warnings

Category Examples of black-box warnings MDedge.com/psychiatry A subset of patients is at Teratogenesis for pregnant patients with elevated risk for severe Serious dermatologic reactions for patients with the HLA-B*1502 allele adverse effects (highest risk with Asian ancestry) with carbamazepine A drug or food interaction Food interaction: dietary tyramine with MAOI (tranylcypromine) resulting can result in critical safety in hypertensive crisis issues Drug interaction: SSRI, SNRI, linezolid, methylene blue, phenylephrine and other medications, with MAOI (tranylcypromine) Monitoring can provide Toxicity with lithium early detection of a severe Severe neutropenia with adverse effect Hepatotoxicity with valproate Behavioral risk for all Risk of misuse and dependence with stimulants patients

MAOI: monoamine oxidase inhibitor; SNRI: -norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor Clinical Point Black-box warnings may be placed on an When a medication poses an especially difficult to find black-box warnings for mul- individual agent or high safety risk, the FDA may require the tiple medications in one place, we have pro- on an entire class of manufacturer to implement a Risk Evaluation vided 2 convenient resources to address this medications and Mitigation Strategy (REMS) program. gap: a concise summary guide (Table 3, page These programs can describe specific steps 22) and a more detailed database (Table 4, to improve medication safety, known as ele- Table 5, Table 6, Table 7, and Table 8, available ments to assure safe use (ETASU).4 A famil- at MDedge.com/psychiatry). In these Tables, iar example is the clozapine REMS. In order the possible risk mitigations, off-label uses, to reduce the risk of severe neutropenia, the and monitoring are not meant to be formal clozapine REMS requires prescribers (and recommendations or endorsements but are pharmacists) to complete specialized train- for independent clinician consideration ing (making up the ETASU). Surprisingly, only. not every medication with a REMS has a The information in these Tables was corresponding black-box warning12; more drawn from publicly available data, pri- understandably, many medications with marily the Micromedex and FDA web sites black-box warnings do not have an associ- (see Related Resources, page 25). Because ated REMS, because their risks are evalu- this information changes over time, at the ated to be manageable by an individual end of this article we suggest ways for clini- prescriber’s clinical judgment. Most recently, cians to stay updated with black-box warn- esketamine carries both a black-box warning ings and build on the information provided and a REMS. The black-box warning focuses in this article. These tools can be useful for on adverse effects (Table 1, page 20), while day-to-day clinical practice in addition to the REMS focuses on specific steps used to studying for professional examinations. lessen these risks, including requiring use of The following are selected high-profile a patient enrollment and monitoring form, a black-box warnings. fact sheet for patients, and health care setting and pharmacy enrollment forms.13 Antidepressants and suicide risk. As a class, antidepressants carry a black-box warning on suicide risk in patients age ≤24. Psychotropic medications and Initially issued in 2005, this warning was black-box warnings extended in 2007 to indicate that depression Psychotropic medications have a large num- itself is associated with an increased risk Current Psychiatry ber of black-box warnings.14 Because it is of suicide. This black-box warning is used Vol. 18, No. 12 21 Table 3 Quick guide to black-box warnings for psychotropic medications Black-box warning Medication(s) Possible risk mitigation Increased risk of death All antipsychotics, except Shared decision-making with patient/ in elderly patients with when pimavanserin is used family/caregivers dementia-related psychosis for Parkinson’s disease- related psychosis Black-box Severe sedation (including Extended-release Risk and benefit discussion with patient; coma) after injection; must REMS warnings observe for 3 hours Aplastic anemia and Carbamazepine Baseline CBC; CBC after drug initiation agranulocytosis and at intervals as clinically indicated; monitor WBC and platelet count in particular Severe neutropenia Clozapine Absolute neutrophil count monitoring; REMS QTc prolongation leading Baseline ECG; if inpatient, telemetry to possible Torsades de if available; assess for other QT Clinical Point Pointes prolongation risks Myocarditis Clozapine Symptom discussion with patient, There are no frequent check-ins, consider baseline published, formal ECG Orthostatic hypotension Clozapine Symptom discussion with patient; criteria for instituting baseline orthostatics black-box warnings Seizures Clozapine Consider seizure disorder history; use lowest effective dose (dose-dependent) Serious and sometimes Carbamazepine Symptom discussion with patient to stop fatal dermatologic reactions medication if rash; discussion about (including Stevens-Johnson medication adherence and risk; patients syndrome and toxic with HLA-B*1502 alleles should not be epidermal necrolysis) treated with carbamazepine; check for allele in patients with Asian ancestry Hepatotoxicity Valproate Risk and symptom discussion with Naltrexone patient; baseline LFTs; LFTs after medication initiation and at intervals as clinically indicated Pancreatitis Valproate Symptom discussion with patient, lab monitoring as clinically indicated Teratogenicity Valproate Discussion of teratogenic risk vs clinical benefit in pregnancy; review of pregnancy prevention; pregnancy screen prior to medication initiation; pregnancy screens as clinically indicated Suicidality in adolescents All antidepressants Shared decision-making with patient/ and young adults parents; frequent follow-up upon initiation of medication Brexipiprazole Suicidal thoughts and Esketamine REMS; shared decision-making with behaviors patient; frequent clinical contact Sedation and dissociation Esketamine Shared decision-making with patient; information sheet, monitoring, REMS Hypertensive crisis in Tranylcypromine (although Nutrition review with patient; discussion combination with foods potentially relevant to all of dietary restrictions; possible containing tyramine MAOIs) consultation with nutritionist Thyroid toxicity (not to Levothyroxine Symptom discussion with patient; be used for weight loss/ baseline TSH level; repeat TSH levels as obesity) clinically indicated Subject to abuse, misuse, Methylphenidates Shared decision-making with patient/ addiction, diversion parents; frequent follow-ups; monitor for Current Psychiatry misuse or diversion; UDS as indicated 22 December 2019 Esketamine Table 3 continued Black-box warning Medication(s) Possible risk mitigation Misuse may cause serious Amphetamines Shared decision-making with cardiovascular adverse patient/parents; review and discuss MDedge.com/psychiatry events and sudden death cardiovascular risk Contraindicated during Disulfiram Risk discussion with patient focused on intoxication; concomitant alcohol use; involve family/ requires patient’s full relatives in shared decision-making if knowledge possible Respiratory depression; Methadone Shared decision-making with patient; added risk with available for prescribing through certified /CNS programs only depressants Complex sleep behaviors, Zaleplon Risk discussion with patient focused some resulting in injury or Eszopiclone on dangers of sleep behaviors; advise death patient to disclose to prescriber urgently Zolpidem if these occur Excess sedation, sudden Brexanolone Shared decision-making, monitoring, loss of consciousness REMS program; administered in monitored setting only Clinical Point CBC: complete blood count; ECG: electrocardiogram; LFTs: function tests; MAOIs: monoamine oxidase inhibitors; REMS: Risk Evaluation and Mitigation Strategy; TSH: thyroid-stimulating hormone; UDS: urine drug screen; WBC: white REMS programs blood cell describe specific Source: Micromedex (www.micromedex.com) and the FDA (www.fda.gov/drugs). Possible risk mitigations are not meant to be formal recommendations or endorsements but are for independent clinician consideration only steps to improve medication safety, known as elements to assure safe use for an entire class of medications as well as pimavanserin, even though this agent’s for a specific patient population (age ≤24). proposed dif- Moreover, it indicates that suicide rates in fers from that of other antipsychotics.17 patients age >65 were lower among patients However, it specifically allows for use in using antidepressants. Parkinson’s disease psychosis, which is Among psychotropic medication black- pimavanserin’s indication.18 In light of box warnings, this warning has perhaps recent research suggesting pimavanserin been the most controversial. For example, is effective in dementia-related psycho- it has been suggested that this black-box sis,19 it bears watching whether this agent warning may have inadvertently increased becomes the first to have this suicide rates by discouraging clinicians from warning removed. prescribing antidepressants,15 although this This class warning has had widespread also has been called into question.16 This effects. For example, it has prompted less black-box warning illustrates that the con- use of antipsychotics in nursing home sequences of issuing black-box warnings facilities, as a result of stricter Centers for can be very difficult to assess, which makes Medicare and Medicaid Services regula- their clinical effects highly complex and tions20; overall, there is some evidence challenging to evaluate.14 that there has been reduced prescribing of antipsychotics in general.21 Additionally, Antipsychotics and dementia-related this black-box warning is unusual in that psychosis. This warning was initially it warns about a specific off-label indica- issued in 2005 for second-generation tion, which is itself poorly supported by antipsychotics and extended to first- evidence.21 Concomitantly, few other treat- generation antipsychotics in 2008. Anti­ ment options are available for this clini- psychotics as a class carry a black-box cal situation. These medications are often warning for increased risk of death in seen as the only option for patients with patients with dementia (major neuro­ dementia complicated by severe behav- cognitive disorder). This warning extends ioral disturbance, and thus this black-box Current Psychiatry to the recently approved antipsychotic warning reflects real-world practices.14 Vol. 18, No. 12 23 continued and neuropsychiatric compli- patient handouts, which are often offered cations. The withdrawal of the black-box by pharmaceutical manufacturers, and by warning on potential neuropsychiatric com- shared decision-making tools. A proac- plications of using varenicline for smoking tive discussion with patients and families cessation shows that black-box warnings about black-box warnings and other risks are not static and can, though infrequently, discussed in product labels can help reduce be removed as more safety data accumu- fears associated with taking medications Black-box lates.11 As additional post-marketing infor- and may improve adherence. warnings mation emerged on this risk, this black-box warning was reconsidered and withdrawn Improving documentation of treatment in 2016.22 Its withdrawal could potentially decisions. Fluent knowledge of black-box make clinicians more comfortable prescrib- warnings may help clinicians improve ing varenicline and in turn, help to reduce documentation of their treatment deci- smoking rates. sions, particularly the risks and benefits of their medication choices. Fluency with black-box warnings will help clinicians Clinical Point How to use black-box warnings accurately document both their aware- As a class, To enhance their clinical practice, prescrib- ness of these risks, and how these risks ers can use black-box warnings to inform informed their risk-benefit analysis in spe- antidepressants safe prescribing practices, to guide shared cific clinical situations. carry a black-box decision-making, and to improve docu- Despite the clear importance the FDA warning for suicide mentation of their treatment decisions. places on black-box warnings, they are risk in patients not often a topic of study in training or in Informing safe prescribing practices. A postgraduate continuing education, and as age ≤24 prescriber should be aware of the main a result, not all clinicians may be equally safety concerns contained in a medication’s conversant with black-box warnings. While black-box warning; at the same time, these black-box warnings do change over time, warnings are not meant to unduly limit use many psychotropic medication black-box when crucial treatment is needed.14 In issu- warnings are long-standing and well- ing a black-box warning, the FDA has clearly established, and they evolve slowly enough stated the priority and seriousness of its con- to make mastering these warnings worth- cern. These safety issues must be balanced while in order to make the most informed against the medication’s utility for a given clinical decisions for patient care. patient, at the prescriber’s clinical judgment.

Guiding shared decision-making. Keeping up-to-date Clinicians are not required to disclose black- There are practical and useful ways for busy box warnings to patients, and there are no clinicians to stay up-to-date with black-box criteria that clearly define the role of these warnings. Although these resources exist in warnings in patient care. As is often noted, multiple locations, together they provide the FDA does not regulate the practice of convenient ways to keep current. medicine.6 However, given the seriousness of the potential adverse effects delineated The FDA provides access to black-box by black-box warnings, it is reasonable for warnings via its comprehensive database, clinicians to have a solid grasp of black-box DRUGS@FDA (https://www.accessdata. warnings for all medications they prescribe, fda.gov/scripts/cder/daf/). Detailed infor- and to be able to relate these warnings to mation about REMS (and corresponding patients, in appropriate language. This ETASU and other information related to patient-centered discussion should include REMS programs) is available at REMS@FDA weighing the risks and benefits with the (https://www.accessdata.fda.gov/scripts/ patient and educating the patient about cder/rems/index.cfm). Clinicians can make the risks and strategies to mitigate those safety reports that may contribute to FDA Current Psychiatry 24 December 2019 risks. This discussion can be augmented by decision-making on black-box warnings by contacting MedWatch (https://www. fda.gov/safety/medwatch-fda-safety- Related Resources information-and-adverse-event-reporting- • US Food and Drug Administration. DRUGS@FDA: FDA- approved drug products. www.accessdata.fda.gov/scripts/ MDedge.com/psychiatry program), the FDA’s adverse events report- cder/daf/. ing system. MedWatch releases safety infor- • US Food and Drug Administration. Drug safety and availability. mation reports, which can be followed on www.fda.gov/drugs/drug-safety-and-availability. Updated Twitter @FDAMedWatch. Note that FDA October 10, 2019. information generally is organized by spe- • BlackBoxRx. www.blackboxrx.com. (Subscription required.) cific drug, and not into categories, such as • Mircromedex. www.micromedex.com. (Subscription required.) psychotropic medications. • ePocrates. www.epocrates.com. (Subscription required.) Drug Brand Names BlackBoxRx (www.blackboxrx.com) is a • Elavil, • Loxitane Vanatrip • Latuda subscription-based web service that some Amoxatine • Strattera • Ludiomil clinicians may have access to via facility • Asendin Methadone • Dolophine, or academic resources as part of a larger Aripiprazole • Abilify Methadose • Saphris • FormWeb software package. Individuals Brexanolone • Zulresso Ritalin, Concerta also can subscribe (currently, $89/year). • Rexulti Midazolam • Versed Clinical Point • Wellbutrin Milnacipran • Savella Carbamazepine • Tegretol • Remeron As a class, Micromedex (www.micromedex.com), • Vraylar Naltrexone • Revia, Vivitrol which is widely available through medical • Thorazine • Serzone antipsychotics carry • Celexa • libraries, is a subscription-based web ser- • Anafranil Aventyl, Pamelor a black-box warning vice that provides black-box warning infor- Clozapine • Clozaril Olanzapine • Zyprexa for increased risk of • Norpramin • Invega mation from a separate tab that is easily Desvenlafaxine • Pristiq Paroxetine • Paxil death in patients accessed in each drug’s information front Dexmethylphenidate • • Trilafon Phenelzine • Nardil with dementia page. There is also an alphabetical list of Focalin Dextroamphetamine/ Pimavanserin • Nuplazid black-box warnings under a separate tab on • Adderall • Compro the Micromedex landing page. Disulfiram • Antabuse • Vivactil • Prudoxin, Silenor Quetiapine • Seroquel Droperidol • Inapsine • Risperdal ePocrates (www.epocrates.com) is a • Cymbalta • Emsam Escitalopram • Lexapro • Zoloft subscription-based service that provides Esketamine • Spravato Thioridazine • Mellaril extensive drug information, including Eszopiclone • Lunesta Thiothixene • Navane black-box warnings, in a convenient • Prozac Tranylcypromine • Parnate • Prolixin • Desyrel, Oleptro mobile app. Fluvoxamine • Luvox • Stelazine • Haldol • Surmontil References • Fanapt Valproate • Depakote 1. Spravato [package insert]. Titusville, NJ: Janssen • Tofranil Varenicline • Chantix, Pharmaceutical Companies; 2019. Isocarboxazid • Marplan Wellbutrin 2. U.S. Food and Drug Administration. FDA drug Lamotrigine • Lamictal • Viibryd safety announcement: FDA adds boxed warning for Levomilnacipran • Fetzima • Effexor risk of serious injuries caused by sleepwalking with Levothyroxine • Synthroid • Trintellix certain prescription insomnia medicines. https:// Linezolid • Zyvox Zaleplon • Sonata www.fda.gov/drugs/drug-safety-and-availability/ Lisdexamfetamine • Vyvanse • Geodon fda-adds-boxed-warning-risk-serious-injuries-caused- sleepwalking-certain-prescription-insomnia. Published Lithium • Eskalith, Lithobid Zolpidem • Ambien April 30, 2019. Accessed October 28, 2019. continued

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 black- box warnings can enhance your clinical practice by informing safe prescribing practices, guiding shared decision-making, and improving documentation of Current Psychiatry your treatment decisions. Vol. 18, No. 12 25 3. Zulresso [package insert]. Cambridge, Mass.: Sage fda.gov/scripts/cder/rems/index.cfm?event=IndvRems Therapeutics Inc.; 2019. Details.page&REMS=386. Updated June 25, 2019. Accessed 4. Gassman AL, Nguyen CP, Joffe HV. FDA regulation October 28, 2018. of prescription drugs. N Engl J Med. 2017;376(7):674-682. 14. Stevens JR, Jarrahzadeh T, Brendel RW, et al. Strategies 5. Solotke MT, Dhruva SS, Downing NS, et al. New and for the prescription of psychotropic drugs with black box incremental FDA black box warnings from 2008 to 2015. warnings. Psychosomatics. 2014;55(2):123-133. Expert Opin Drug Saf. 2018;17(2):117-123. 15. Friedman RA. Antidepressants’ black-box warning--10 6. Murphy S, Roberts R. “Black box” 101: how the Food years later. N Engl J Med. 2014;371(18):1666-1668. and Drug Administration evaluates, communicates, and 16. Stone MB. The FDA warning on antidepressants manages drug benefit/risk. J Allergy Clin Immunol. 2006; and suicidality--why the controversy? N Engl J Med. 117(1):34-39. 2014;371(18):1668-1671. Black-box 7. U.S. Food and Drug Administration. Guidance document: 17. Mathis MV, Muoio BM, Andreason P, et al. The US Food and warnings Warnings and precautions, contraindications, and boxed Drug Administration’s perspective on the new antipsychotic warning sections of labeling for human prescription pimavanserin. J Clin Psychiatry. 2017;78(6):e668-e673. doi: drug and biological products – content and format. 10.4088/JCP.16r11119. https://www.fda.gov/regulatory-information/search- 18. Nuplazid [package insert]. San Diego, CA: Acadia fda-guidance-documents/warnings-and-precautions- Pharmaceuticals Inc.; May 2019. contraindications-and-boxed-warning-sections-labeling- human-prescription. Published October 2011. Accessed 19. Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, October 28, 2019. tolerability, and of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, 8. Beach JE, Faich GA, Bormel FG, et al. Black box warnings in randomised, placebo-controlled, double-blind study. Lancet labeling: results of a survey of 206 drugs. Neurol. 2018;17(3):213-222. Food Drug Law J. 1998;53(3):403-411. 20. Maust DT, Kim HM, Chiang C, et al. Association of the 9. Matlock A, Allan N, Wills B, et al. A continuing black hole? Centers for Medicare & Medicaid Services’ National The FDA boxed warning: an appeal to improve its clinical Partnership to Improve Dementia Care with the use of Clinical Point utility. Clinical Toxicol (Phila). 2011;49(6):443-447. antipsychotics and other psychotropics in long-term care 10. Elraiyah T, Gionfriddo MR, Montori VM, et al. Content, in the United States from 2009 to 2014. JAMA Intern Med. Black-box warnings consistency, and quality of black box warnings: time for a 2018;178(5):640-647. change. Ann Intern Med. 2015;163(11):875-876. are not static and 21. Dorsey ER, Rabbani A, Gallagher SA, et al. Impact of FDA 11. Yeh JS, Sarpatwari A, Kesselheim AS. Ethical and practical black box advisory on antipsychotic medication use. Arch considerations in removing black box warnings from drug Intern Med. 2010;170(1):96-103. can, although labels. Drug Saf. 2016;39(8):709-714. 22. U.S. Food and Drug Administration. FDA drug safety infrequently, 12. Boudes PF. Risk Evaluation and Mitigation Strategies communication: FDA revises description of mental (REMSs): are they improving drug safety? A critical review health side effects of the stop-smoking medicines Chantix be removed as of REMSs requiring Elements to Assure Safe Use (ETASU). (varenicline) and Zyban (bupropion) to reflect Drugs R D. 2017;17(2):245-254. findings. https://www.fda.gov/drugs/drug-safety-and- more safety data 13. U.S. Food and Drug Administration. Approved risk availability/fda-drug-safety-communication-fda-revises- evaluation mitigation strategies (REMS): Spravato description-mental-health-side-effects-stop-smoking. accumulates (esketamine) REMS program. https://www.accessdata. Published December 16, 2016. Accessed October 28, 2019.

Current Psychiatry 26 December 2019 Table 4 Black-box warnings for first-generation antipsychotics Black-box warning: Elderly patients with dementia-related psychosis treated with antipsychotic MDedge.com/psychiatry medications are at an increased risk of death Common Medication Labeled indication(s) Off-label use(s) adverse effects Chlorpromazine Behavioral problems Nausea/vomiting of EPS Bipolar disorder pregnancy Sedation Hiccups Psychosis/agitation QTc prolongation associated with dementia Hyperactivity in children Nausea/vomiting Acute intermittent porphyria Psychotic disorders Restlessness and apprehension prior to surgery Tetanus (adjunctive) Droperidola Postoperative nausea/ Acute undifferentiated QTc prolongation vomiting agitation Hypotension Sedation EPS Fluphenazine Psychotic disorders Chorea of Huntington’s EPS disease Chronic tic disorders Psychosis/agitation associated with dementia Haloperidol Schizophrenia Hyperactive delirium QTc prolongation Tourette’s disorder Chemotherapy-induced (especially IV formulation) Behavioral disorders nausea/vomiting EPS Hyperactivity Postoperative nausea/ vomiting Chorea of Huntington’s disease OCD Psychosis/agitation associated with dementia Rapid tranquilization Loxapine Schizophrenia Psychosis/agitation EPS Agitation associated with associated with dementia Hypotension schizophrenia or bipolar I Sedation disorder Dysgeusia Perphenazine Severe nausea and vomiting Psychosis/agitation EPS in adults associated with dementia QTc prolongation Schizophrenia Prochlorperazine Schizophrenia Nausea/vomiting of EPS Severe nausea/vomiting pregnancy QTc prolongation Thiothixene Schizophrenia Psychosis/agitation EPS associated with dementia ECG changes Trifluoperazine Nonpsychotic anxiety Psychosis/agitation Orthostatic Schizophrenia associated with dementia hypotension EPS aDroperidol has a second black-box warning for QTc prolongation leading to fatal cardiac arrhythmias. Similarly, thioridazine has this warning and is only available in the United States as a generic; also had this warning and was removed from the US market ECG: electrocardiogram; EPS: ; OCD: obsessive-compulsive disorder Sources: Micromedex (www.micromedex.com) and Up-to-Date (www.uptodate.com). Off-label uses and monitoring are not meant to be formal recommendations or endorsements, but are for independent clinician consideration only. This list is not intended to be exhaustive Current Psychiatry Vol. 18, No. 12 26A Table 5 Black-box warnings for second-generation antipsychotics Black-box warning: Elderly patients with dementia-related psychosis treated with antipsychotic medications are at an increased risk of death

Labeled Medication indication(s) Off-label use(s) Common adverse effects Aripiprazolea Bipolar disorder Psychosis/agitation Headache (12%) Black-box Irritability associated associated with dementia Akathisia (2% to 12%) warnings with ASD Weight gain (17% to 22%) MDD (adjunctive) Metabolic syndrome (4% to 22%) Schizophrenia Tourette disorder Asenapine Bipolar disorder Psychosis/agitation Drowsiness (13% to 26%) Schizophrenia associated with dementia Insomnia (10% to 16%) Akathisia (4% to 15%) EPS (4% to 12%) Weight gain (1% to 22%) Metabolic syndrome (5% to 16%) Brexpiprazole MDD (adjunctive) Psychosis/agitation Akathisia (4% to 14%) Schizophrenia associated with dementia Increased triglycerides (8% to 13%) Increased weight gain (3% to 11%) Cariprazine Bipolar disorder MDD (adjunctive) EPS (15% to 41%) Schizophrenia Akathisia (9% to 20%) Headache (14%) Insomnia (9% to 13%) Nausea (7% to 13%) Clozapineb Schizophrenia Bipolar disorder Neutropenia (<3%) (treatment- (treatment-resistant) Agranulocytosis (<1%) resistant) Psychosis/agitation Myocarditis (<1%) Suicidal behavior associated with dementia Tachycardia (17% to 25%) in schizophrenia (treatment-resistant) Hypotension (9% to 13%) or schizoaffective Psychosis in Parkinson’s disorder disease Hypertension (4% to 12%) Drowsiness (39% to 46%) Dizziness (14% to 27%) Vertigo (<19%) Sialorrhea (13% to 48%) Weight gain (4% to 31%) Constipation (14% to 25%) Nausea (5% to 17%) Iloperidone Schizophrenia Psychosis/agitation Tachycardia (3% to 12%) associated with dementia Dizziness (10% to 20%) Drowsiness (9% to 15%) Weight gain (9% to 18%) Hyperprolactinemia (26%) Lurasidone Bipolar depression MDD Drowsiness (8% to 26%) Schizophrenia Psychosis/agitation EPS (4% to 39%) associated with dementia Akathisia (7% to 22%) Increased fasting glucose (6% to 13%) Increased triglycerides Current Psychiatry (10% to 11%) 26B December 2019 Table 5 continued

Labeled Medication indication(s) Off-label use(s) Common adverse effects MDedge.com/psychiatry Olanzapinec Schizophrenia Chemotherapy- Metabolic syndrome (20% to 26%) Acute mania associated acute and Weight gain (22% to 64%) delayed nausea or associated with Increased appetite (3% to 24%) bipolar disorder vomiting prevention Orthostatic hypotension (5%) Maintenance Chemotherapy- treatment of bipolar associated breakthrough Dizziness (2% to 18%) disorder nausea or vomiting Akathisia (5% to 27%) Treatment-resistant Delirium bipolar I disorder Delusional infestation MDD Psychosis/agitation (in combination associated with dementia with fluoxetine) PTSD Tourette syndrome Paliperidone Schizophrenia Delusional infestation Tachycardia (3% to 14%) Schizoaffective EPS (2% to 15%) disorder Drowsiness (5% to 12%) Hyperprolactinemia (geriatric, 44% to 56%) Weight gain (3% to 9%) Metabolic syndrome (6% to 13%) Pimavanserin Parkinson’s disease None described Peripheral edema (7%) psychosis Confusion (6%) Abnormal gait (2%) Nausea (7%) QTc prolongation Quetiapine Bipolar disorder Agitation Drowsiness (16% to 57%) Schizophrenia Delirium Weight gain (3% to 28%) MDD (adjunctive) Delusional disorder Metabolic syndrome (4% to 20%) GAD Xerostomia (9% to 44%) MDD (monotherapy) Increased appetite (2% to 12%) OCD (adjunctive) Headache (17% to 21%) PTSD Psychosis/agitation associated with dementia Psychosis in Parkinson’s disease Risperidone Bipolar disorder Delusional infestation Sedation (5% to 11%) (IM only) MDD EPS (2% to 35%) Bipolar mania PTSD Headache (12% to 21%) Irritability Psychosis/agitation Hyperprolactinemia (adults <4%, associated associated with dementia children 49% to 87%) with ASD Tourette syndrome Weight gain Schizophrenia Metabolic syndrome Ziprasidone Acute agitation Agitation Drowsiness (8% to 31%) (IM only) Delirium EPS (1% to 31%) Bipolar disorder Delusional infestation Headache (5% to 18%) Schizophrenia MDD Dizziness (3% to 16%) Psychosis/agitation Nausea (8% to 12%) associated with dementia

aAripiprazole also has a black-box warning for suicidality in adolescents and young adults bClozapine has other black-box warnings for agranulocytosis, myocarditis, orthostatic hypotension, and seizures cA black-box warning also exists for extended-release olanzapine for severe sedation (including coma) after injection. Patients must be observed at the health care facility by a clinician for at least 3 hours ASD: autism spectrum disorder; EPS: extrapyramidal symptoms; GAD: generalized anxiety disorder; MDD: major depressive disorder; OCD: obsessive-compulsive disorder; PTSD: posttraumatic stress disorder Current Psychiatry Vol. 18, No. 12 26C Table 6 Black-box warnings for antidepressants Black-box warning: Increased risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with MDD and other psychiatric disorders compared with placebo Medication Labeled indication(s) Off-label use(s) Common adverse effectsa Selective serotonin reuptake inhibitors Black-box Citalopram MDD OCD QTc prolongation (<2%) warnings Panic disorder Diaphoresis (5% to 18%) PMMD Dizziness (14%) Hot flashes Headache (18%) Hip fracture (46%, geriatric) Escitalopram MDD OCD Diarrhea (6% to 14%) GAD Panic disorder Nausea (15% to 18%) PMDD Reduced libido (3% to 7%) Social phobia QTc prolongation Fluoxetine MDD Body dysmorphic Diarrhea (8% to 18%) OCD disorder Indigestion (6% to 10%) Panic disorder Hot flashes Hyponatremia (<1%) PMDD Dysthymia Bulimia nervosa PTSD Bipolar depressionb Raynaud phenomenon Fluvoxamine OCD MDD Nausea (34% to 40%) Eating disorder Xerostomia (10% to 14%) Panic disorder Diarrhea (11% to 18%) Social phobia Paroxetine GAD Hot flashes Palpitations (3%) MDD Premature ejaculation Diaphoresis (5% to 14%) OCD Constipation (16%) Panic disorder Diarrhea (18%) PTSD Nausea (26%) PMDD Social phobia Sertraline MDD Binge eating disorder Diarrhea (13% to 24%) OCD Bipolar depression Constipation (3% to 8%) Panic disorder (adjunctive) Nausea (13% to 30%) PTSD Dysthymia Dizziness (6% to 17%) PMDD GAD Headache (25%) Social phobia Reduced libido (up to 11%) Hyponatremia (<1%) Serotonin-norepinephrine reuptake inhibitors Desvenlafaxine MDD Anxiety disorders Diaphoresis (10% to 21%) Bipolar depression Increased cholesterol (3% PTSD to 10%) Vasomotor symptoms Nausea (22% to 41%) Constipation (9% to 14%) Dizziness (10% to 16%) Reduced libido (3% to 6%) Duloxetine Diabetic peripheral Chemotherapy- Hypertension (2%) neuropathy induced peripheral Diaphoresis (6%) neuropathy Fibromyalgia Constipation (10%) Urinary incontinence GAD Diarrhea (9%) MDD Nausea (18% to 23%) Chronic Current Psychiatry musculoskeletal pain 26D December 2019 Table 6 continued Medication Labeled indication(s) Off-label use(s) Common adverse effectsa Levomilnacipran MDD Fibromyalgia Palpitations (6%) MDedge.com/psychiatry Diaphoresis (9%) Nausea (17%) Orthostatic hypotension (12%) Milnacipran Fibromyalgia Depression Hypertension (5% to 18%) Palpitations (7%) Constipation (16%) Nausea (37%) Venlafaxine GAD Hot flashes Hypertension (3% to 13%) MDD ADHD Diaphoresis (7% to 25%) Panic disorder Binge eating disorder Constipation (15%) Social phobia Peripheral neuropathy Nausea (21% to 58%) OCD Weight loss (3% to 47%) PTSD Headache (25% to 38%) PMDD Blurred vision (4% to 6%) Dysthymia Hyponatremia Tension headache (prophylaxis) Atypical/other antidepressants Bupropion MDD ADHD Tachycardia (11%) Depression associated Weight gain (9%) with seasonal affective Weight loss (14% to 19%) disorder Nausea (13% to 18%) Headache (25% to 34%) Agitation (2% to 9%) Mirtazapine MDD Anxiety Increased appetite (17%) Dysthymia Increased liver enzymes OCD (2%) Panic disorder Somnolence (54%) Nefazodone MDD None described Orthostatic hypotension (4%) Nausea (14% to 23%) Constipation (10% to 17%) Headache (26% to 52%) Dizziness (11% to 22%) Abnormal ECG Trazodone MDD Insomnia Nausea (21%) Xerostomia (14% to 34%) Dizziness (25%) Somnolence (45%) Hypotension (4% to 7%) Priapism Prolonged QTc Vilazodone MDD None described Diarrhea (29%) Nausea (24%) Premature ventricular beats (<1%) Vortioxetine MDD None described Nausea (21% to 32%) Hyponatremia Current Psychiatry Vol. 18, No. 12 26E Table 6 continued Medication Labeled indication(s) Off-label use(s) Common adverse effectsa antidepressants Amitriptyline MDD Fibromyalgia Weight gain Headache Constipation Irritable bowel Xerostomia syndrome Blurred vision Black-box Pain Somnolence warnings Postherpetic neuralgia Dizziness Tinnitus Hypotension Amoxapine MDD Anxiety Prolonged QTc Insomnia Tachycardia Clomipramine OCD MDD Cardiac dysrhythmia ASD Agranulocytosis Panic disorder Hyponatremia Desipramine MDD ADHD Diabetic neuropathy Postherpetic neuralgia Doxepin Anxiety Urticaria Depression Insomnia (other than Insomnia (Silenor only) Silenor) Pruritus (limited settings) Imipramine MDD Diabetic neuropathy Nocturnal enuresis Binge eating disorder Panic disorder Urinary incontinence Maprotiline Bipolar depression Pain MDD Dysthymia Nortriptyline MDD ADHD Diabetic neuropathy Neurogenic bladder Nocturnal enuresis Postherpetic neuralgia Smoking cessation Protriptyline MDD None described Trimipramine MDD None described Monoamine oxidase inhibitors Isocarboxazid MDD None described Constipation Phenelzine MDD Agoraphobia Weight gain Bulimia nervosa Increased LFTs Social phobia Nausea Selegiline patch MDD None described Xerostomia Tranylcyprominec MDD None described Orthostatic hypotension Cardia dysrhythmia Hypertensive crisis with foods containing tyramine aSelective serotonin reuptake inhibitors: increased risk of bone fracture in geriatric population, increased bleeding risk, and hyponatremia bIn combination with olanzapine cTranylcypromine has another black-box warning for hypertensive crisis in combination with foods containing tyramine ADHD: attention-deficit/hyperactivity disorder; ASD: autism spectrum disorder; ECG: electrocardiogram; EPS: Current Psychiatry extrapyramidal symptoms; GAD: generalized anxiety disorder; LFTs: liver function tests; MDD: major depressive disorder; OCD: obsessive-compulsive disorder; PMDD: premenstrual dysphoric disorder; PTSD: posttraumatic stress disorder 26F December 2019 Table 7 Black-box warnings for mood stabilizers Medication Black-box warning Labeled indication(s) Off-label use(s) Common adverse effects Carbamazepine Serious, sometimes fatal dermatologic reactions Bipolar disorder Agitation Nausea (including Stevens-Johnson syndrome and Seizure disorder Behavioral syndrome Anemia toxic epidermal necrolysis) have been reported, Trigeminal neuralgia Thrombocytopenia especially in patients with the inherited allelic variant Black-box HLA-B*1502 Dizziness warnings Aplastic anemia and agranulocytosis Hyponatremia Lamotrigine Cases of life-threatening serious rashes, including Bipolar I disorder OCD Rash (7% to 14%) Stevens-Johnson syndrome and toxic epidermal Lennox-Gastaut syndrome Trigeminal neuralgia Abdominal pain (5% to 10%) necrolysis, or rash-related death have been caused Partial seizure Refractory epilepsy Blurred vision (24% to 49%) by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults Generalized tonic-clonic seizure Migraine Nausea (7% to 25%) Valproate Hepatotoxicity (some cases fatal), usually Bipolar disorder Juvenile myoclonic Alopecia (6% to 24%) occurring during the first 6 months of treatment, Migraine prophylaxis epilepsy Rash (6%) has been reported in patients receiving valproate Absence seizure Myoclonic seizure Weight gain (4% to 47%) and its derivatives. Children age <2 and patients Generalized tonic clonic with hereditary mitochondrial disease are at a Complex partial seizure Diarrhea (12% to 23%) seizure considerably increased risk of developing fatal Nausea (22% to 48%) hepatotoxicity Agitation associated Headache (5% to 31%) with TBI Pancreatitis Hyperammonemia Teratogenicity Lithium Lithium toxicity is closely related to serum lithium Bipolar disorder (acute None described levels and can occur at doses close to therapeutic and maintenance) Hypothyroidism levels. Facilities for prompt and accurate serum Hyperparathyroidism lithium determinations should be available before initiating therapy Weight gain Nephrotoxicity Leukocytosis Xerostomia Increased thirst (28%) Bradyarrhythmia OCD: obsessive-compulsive disorder; TBI: traumatic brain injury

Current Psychiatry 26G December 2019 Table 7 Black-box warnings for mood stabilizers

Medication Black-box warning Labeled indication(s) Off-label use(s) Common adverse effects MDedge.com/psychiatry Carbamazepine Serious, sometimes fatal dermatologic reactions Bipolar disorder Agitation Nausea (including Stevens-Johnson syndrome and Seizure disorder Behavioral syndrome Anemia toxic epidermal necrolysis) have been reported, Trigeminal neuralgia Thrombocytopenia especially in patients with the inherited allelic variant HLA-B*1502 Dizziness Aplastic anemia and agranulocytosis Hyponatremia Lamotrigine Cases of life-threatening serious rashes, including Bipolar I disorder OCD Rash (7% to 14%) Stevens-Johnson syndrome and toxic epidermal Lennox-Gastaut syndrome Trigeminal neuralgia Abdominal pain (5% to 10%) necrolysis, or rash-related death have been caused Partial seizure Refractory epilepsy Blurred vision (24% to 49%) by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults Generalized tonic-clonic seizure Migraine Nausea (7% to 25%) Valproate Hepatotoxicity (some cases fatal), usually Bipolar disorder Juvenile myoclonic Alopecia (6% to 24%) occurring during the first 6 months of treatment, Migraine prophylaxis epilepsy Rash (6%) has been reported in patients receiving valproate Absence seizure Myoclonic seizure Weight gain (4% to 47%) and its derivatives. Children age <2 and patients Generalized tonic clonic with hereditary mitochondrial disease are at a Complex partial seizure Diarrhea (12% to 23%) seizure considerably increased risk of developing fatal Nausea (22% to 48%) hepatotoxicity Agitation associated Headache (5% to 31%) with TBI Pancreatitis Hyperammonemia Teratogenicity Lithium Lithium toxicity is closely related to serum lithium Bipolar disorder (acute None described Acne levels and can occur at doses close to therapeutic and maintenance) Hypothyroidism levels. Facilities for prompt and accurate serum Hyperparathyroidism lithium determinations should be available before initiating therapy Weight gain Nephrotoxicity Leukocytosis Xerostomia Increased thirst (28%) Bradyarrhythmia OCD: obsessive-compulsive disorder; TBI: traumatic brain injury

Current Psychiatry Vol. 18, No. 12 26H Table 8 Black-box warnings for other medications Medication(s) Black-box warning(s) Labeled indication(s) Off-label use(s) Common adverse effects Methylphenidate Subject to misuse, abuse, addiction, or ADHD Geriatric depression Increased systolic blood Dexmethylphenidate diversion Narcolepsy (methylphenidate) Post-TBI fatigue pressure Dextroamphetamine/ Subject to misuse, abuse, addiction, ADHD narcolepsy (dextroamphetamine/ Geriatric depression Increased heart rate amphetamine or diversion; misuse may cause serious amphetamine) Post-TBI fatigue Weight loss Black-box Lisdexamfetamine cardiovascular adverse events and Binge eating disorder (lisdexamfetamine) Increased appetite sudden death warnings Headache Anxiety Naltrexone Hepatotoxicity Alcohol use disorder Drug withdrawal Nausea Opioid use disorder Morphine adverse Myalgia reaction Headache Premenstrual syndrome Anxiety Self-injurious behavior Hepatotoxicity Disulfiram Contraindicated during alcohol intoxication; Alcohol use disorder None described Hepatitis requires patient’s full knowledge Liver failure Optic neuritis Midazolam Respiratory depression Procedural sedation Postoperative nausea/ Somnolence Induction of general anesthesia vomiting Hiccups Status epilepticus Seizure Headache Methadone Death due to rapid titration; QT Opioid use disorder (detoxification Neuropathic pain Hypotension prolongation; abuse and misuse; neonatal and maintenance) Nausea syndrome; use in certified programs only Pain Sedation Prolonged QTc Zolpidem Complex sleep behaviors Insomnia (short-term) Insomnia (long-term) Dizziness Zaleplon Catatonia (zolpidem) Visual disturbance Eszopiclone Abnormal sleep behaviors Anaphylaxis (rare) Levothyroxine Life-threatening thyroid toxicity; ineffective Hypothyroidism Augmentation of Palpitations for weight reduction Sweating Weight loss Insomnia Anxiety Esketamine Suicidal behavior; sedation and MDD (treatment-resistant, adjunctive) None described Nausea (28%) dissociation; abuse and misuse; available Emesis (9%) only with REMS Dizziness (29%) Vertigo (23%) Anxiety (11%) ADHD: attention-deficit/hyperactivity disorder; MDD: major depressive disorder; REMS: Risk Evaluation and Mitigation Strategy; TBI: traumatic brain injury

Current Psychiatry 26I December 2019 Table 8 Black-box warnings for other medications

Medication(s) Black-box warning(s) Labeled indication(s) Off-label use(s) Common adverse effects MDedge.com/psychiatry Methylphenidate Subject to misuse, abuse, addiction, or ADHD Geriatric depression Increased systolic blood Dexmethylphenidate diversion Narcolepsy (methylphenidate) Post-TBI fatigue pressure Dextroamphetamine/ Subject to misuse, abuse, addiction, ADHD narcolepsy (dextroamphetamine/ Geriatric depression Increased heart rate amphetamine or diversion; misuse may cause serious amphetamine) Post-TBI fatigue Weight loss Lisdexamfetamine cardiovascular adverse events and Binge eating disorder (lisdexamfetamine) Increased appetite sudden death Headache Anxiety Naltrexone Hepatotoxicity Alcohol use disorder Drug withdrawal Nausea Opioid use disorder Morphine adverse Myalgia reaction Headache Premenstrual syndrome Anxiety Self-injurious behavior Hepatotoxicity Disulfiram Contraindicated during alcohol intoxication; Alcohol use disorder None described Hepatitis requires patient’s full knowledge Liver failure Optic neuritis Midazolam Respiratory depression Procedural sedation Postoperative nausea/ Somnolence Induction of general anesthesia vomiting Hiccups Status epilepticus Seizure Headache Methadone Death due to rapid titration; QT Opioid use disorder (detoxification Neuropathic pain Hypotension prolongation; abuse and misuse; neonatal and maintenance) Nausea syndrome; use in certified programs only Pain Sedation Prolonged QTc Zolpidem Complex sleep behaviors Insomnia (short-term) Insomnia (long-term) Dizziness Zaleplon Catatonia (zolpidem) Visual disturbance Eszopiclone Abnormal sleep behaviors Anaphylaxis (rare) Levothyroxine Life-threatening thyroid toxicity; ineffective Hypothyroidism Augmentation of Palpitations for weight reduction antidepressant Sweating Weight loss Insomnia Anxiety Esketamine Suicidal behavior; sedation and MDD (treatment-resistant, adjunctive) None described Nausea (28%) dissociation; abuse and misuse; available Emesis (9%) only with REMS Dizziness (29%) Vertigo (23%) Anxiety (11%) ADHD: attention-deficit/hyperactivity disorder; MDD: major depressive disorder; REMS: Risk Evaluation and Mitigation Strategy; TBI: traumatic brain injury

Current Psychiatry Vol. 18, No. 12 26J