Box Warning Research Articles

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug-drug interactions and hepatotoxicity.

Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life-threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug-induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time-dependent inhibition of the enzyme-also called mechanism-based inhibition (MBI) or inactivation-can occur and lead to pharmacokinetic drug-drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM-positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.

High-risk opioid prescribing trends in the outpatient setting prior to issuance of federal guidance.

Co-prescription of opioid and benzodiazepine products increases the risk of overdose-related mortality four-fold due to respiratory depression. Accordingly, prevention of high-risk opioid prescribing (HROP) has become a focus over the past two decades and was the subject of a black-box warning (BBW) issued by the U.S. Food and Drug Administration (FDA) on August 31, 2016. Because older patients are at increased risk for these outcomes, we compared rates of HROP for older (aged ≥65 years) and younger (aged 18–64 years) adults using a repeated cross-sectional cohort design. Data from the National Ambulatory Medical Care Survey of U.S. office-based physician visits were accessed for 2006–2016 August. From 2006 to 2016, the opioid-prescribing rate increased by 40% among those aged 18–64 years and by 54% among those aged ≥65 years. From 2012–2013 to 2014–2016, the HROP rate, expressed as a proportion of all opioid-prescribing visits, increased to 26.6% among those aged 18–64 years but declined to 21.0% among those aged ≥65 years, primarily because of changes for patients aged ≥75 years. Prior to the FDA-issued BBW, the HROP prescribing rate trended upward for all adults, except in 2014–2016 when it began to decline among older adults.

Novel pharmacological therapy in type 2 diabetes mellitus with established cardiovascular disease: Current evidence.

Cardiovascular diseases (CVDs) remain the leading cause of death in the world and in most developed countries. Patients with type 2 diabetes mellitus (T2DM) suffer from both microvascular and macrovascular diseases and therefore have higher rates of morbidity and mortality compared to those without T2DM. If current trends continue, the Center for Disease Control and Prevention estimates that 1 in 3 Americans will have T2DM by year 2050. As a consequence of the controversy surrounding rosiglitazone and the increasing prevalence of diabetes and CVDs, in 2008 the Food and Drug Administration (FDA) established new expectations for the evaluation of new antidiabetic agents, advising for pre and, in some cases, post-marketing data on major cardiovascular events. As a direct consequence, there has been a paradigm shift in new antidiabetic agents that has given birth to the recently published American Diabetes Association/European Association for the Study of Diabetes consensus statement recommending sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon like peptide-1 receptor agonists (GLP-1RA) in patients with T2DM and established CVD. As a result of over a decade of randomized placebo controlled cardiovascular outcome trials, the aforementioned drugs have received FDA approval for risk reduction of cardiovascular (CV) events in patients with T2DM and established CV disease. SGLT2i have been shown to have a stronger benefit in patients with congestive heart failure and diabetic kidney disease when compared to their GLP-1RA counterparts. These benefits are not withstanding additional considerations such as cost and the multiple FDA Black Box warnings. This topic is currently an emerging research area and this mini-review paper examines the role of these two novel classes of drugs in patients with T2DM with both confirmed, and at risk for, CVD.

When and How to Treat Agitation in Alzheimer's Disease Dementia With Citalopram and Escitalopram

Agitation is a common neuropsychiatric symptom (NPS) in the early and middle stages of Alzheimer's disease (AD) dementia, which is difficult to treat and causes much distress. The U.S. Food and Drug Administration (U.S. FDA) issued black box warnings against the use of antipsychotics in dementia in 2005 and 2008 due to the increased risk of morbidity and mortality, resulting in the reduction in antipsychotic use for treating dementia-related NPS and spurring the quest for safer and more effective pharmacological options. The data favoring the use of citalopram for treating agitation in AD dementia is particularly compelling, and this may be a class effect for all selective serotonin reuptake inhibitors. However, concerns about the cardiac side-effects of citalopram have limited its widespread use for this indication. In this article, available efficacy and safety data for the use of citalopram and escitalopram in treating agitation in AD dementia is reviewed, using a composite case to illustrate key points. Practical recommendations are made to facilitate the use of these medications in routine clinical practice, risk mitigation strategies are discussed and salient issues for future clinical research are emphasized.

The FDA “Black Box” Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?

The decision made in the year 2004 by the U.S. Food and Drug Administration (FDA) to require a boxed warning on antidepressants regarding the risk of suicidality in young adults still represents a matter of controversy. The FDA warning was grounded on industry-sponsored trials carried one decade ago or earlier. However, within the past decade, an increasing number of reports have questioned the actual validity of the FDA warning, especially considering a decline in the prescription of the antidepressant drugs associated with an increase in the rate of suicidal events among people with severe depression. The present report provides an overview of the FDA black box warning, also documenting two Major Depressive Disorder patients whose refusal to undergo a pharmacological antidepressant treatment possibly led to an increased risk for suicidal behaviors. The concerns raised by the FDA black box warning need to be considered in real-world clinical practice, stating the associated clinical and public health implications.

PIH9 UNMET NEED ASSOCIATED WITH AVAILABLE THERAPEUTIC OPTIONS FOR MANAGEMENT OF DYSPAREUNIA RELATED TO GENITOURINARY SYNDROME OF MENOPAUSE: A SYSTEMATIC LITERATURE REVIEW

Genitourinary syndrome of menopause (GSM) is a chronic, progressive condition affecting up to 60% of post-menopausal women in the United States. Dyspareunia, or pain with sexual intercourse, has been recognized as one of GSM’s most bothersome symptoms. Despite high prevalence and availability of treatments, many women are not adequately managed, and unmet need remains. The objective of this systematic literature review was to characterize the unmet need. A systematic PubMed search for studies focusing on unmet need, efficacy, and safety of GSM treatments published from 2013-2018 was conducted using the PRISMA guidelines. Identified abstracts were scored by two independent reviewers to assess eligibility for inclusion. This yielded 116 full-text articles meeting the final inclusion criteria. Clinical guidelines recommend a step-wise approach to GSM management, utilizing over the counter (OTC) products as first-line therapies followed by prescription therapies as indicated for persistent symptoms. These products consist of systemic and vaginal estrogens, prasterone or synthetic dehydroepiandrosterone (DHEA), and an oral selective estrogen receptor modulator (SERM), with systemic estrogen therapy generally reserved for women with concomitant vasomotor symptoms. Studies have shown that OTC treatments provide only temporary symptomatic relief. Further, all estrogen products and SERMs have class-effect boxed warnings for endometrial cancer and adverse cardiovascular outcomes, causing reluctance among women and healthcare professionals (HCPs) to use these products. Given that GSM is a chronic condition requiring long-term treatment, many women and HCPs have safety concerns even with vaginal estrogens. Prasterone, a non-estrogen vaginal insert, does not carry a boxed warning and has demonstrated efficacy in moderate to severe dyspareunia due to menopause. Despite availability of multiple treatments for GSM, unmet need remains. Non-estrogen prasterone addresses both medical needs and safety concerns of HCPs and women suffering from moderate to severe dyspareunia associated with GSM.

(292) Lumbar Radiculopathy in the Pregnant Patient

Lumbar radiculopathy is a common cause of low back and leg pain in many patients. While there are multiple interventions both medical and surgical for the treatment of lumbar radiculopathy, the options become limited in the pregnant patient. We present the case of a 35-year-old female at 25-week gestational age with new onset severe low back and right leg pain. The patient had a history of prior lumbar laminectomy and discectomy for similar symptoms. She presented after failed conservative management with gabapentin and acetaminophen and the pain began to interfere with her daily activities. On presentation to the clinic the patient had severe lumbosacral radiculopathy consistent with Magnetic Resonance Imaging (MRI) findings of a new large disc extrusion on the right. After a discussion of the possible interventions the decision was made to treat the lumbar radiculopathy with caudal epidural steroid injection (ESI) performed under ultrasound guidance. Though there is no set maximum radiation dose deemed safe for the fetus by the American College of Obstetricians and Gynecologists (ACOG), the consensus is to limit the radiation dose to 50mGy before 15-week gestational age and 250mGy thereafter. Ultrasound guided caudal ESI was decided to be the safest course of action to decrease the amount of radiation to the fetus and minimize the risk of dural puncture given her previous laminectomy. Success was confirmed with easy passing of an epidural catheter and a decreased pain score after the procedure. Additionally, during the management of this patient we noted the new classification system from the Food and Drug Administration (FDA) regarding medications in pregnancy. Despite most medication black box warnings maintaining the old category system of A, B, C, D and X; the new FDA system emphasizes the Pregnancy and Lactations Labeling Rule (PLLR) to guide patient discussions and medical management.

Associated Toxicities: Assessment and Management Related to CAR T-Cell Therapy.

The impressive disease response observed with chimeric antigen receptor (CAR) T-cell therapy is accompanied by the potential for unique and severe toxicities. Cytokine release syndrome (CRS) and neurologic toxicities have emerged as prominent toxicities associated with this treatment modality. This article presents an overview of pathophysiology, assessment, and evidence-based management of CAR T-cell therapy-associated toxicities, with particular attention paid to CRS and neurologic toxicity management. Implications for nursing practice are included for prominent toxicities to guide clinical practice. An overview of recent guidelines and evidence for CAR T-cell therapy toxicity assessment and management is provided. Evidence-based approaches to CAR T-cell therapy toxicities continue to evolve. As organizational and institutional guidelines emerge, nurses must be aware of anticipated toxicities and interventions used in clinical practice to provide timely and effective care.

Outcome, costs and dollar value of anticancer drugs in non-small cell lung cancer with emphasis on pembrolizumab.

104 Background: Drug outcomes were analyzed in 9 clinical studies of advanced/metastatic non-small-cell lung cancer (NSCLC). Overall survivals were not reached in some studies. Objective: Weigh hazard ratios (HR), costs and dollar value of each drug vs. its control with emphasis on pembrolizumab (pembro). Methods: Protocols were followed, and parent company costs quoted. yearly-costs of pembro, bevacizumab (bev), pemetrexed (peme) and docetaxel (doc) were calculated. Probability of survival (PoS) was defined as (1.0-HR) and dollar value as cost/PoS. Results: Doc and bev carried black box warnings with estimated grade 3/4 adverse events > 20% compared with pembro <10% and peme < 15%. Doc costs were $63,648. In second-line, estimated HR of doc versus supportive care was 0.70 and value $212,169. Pembro costs at 2mg/Kg x 80 Kg q3 weeks were $125,770. Compared with doc, pembro HR in PD-L1 > 1.0% tumor proportion score (TPS) was 0.71 and value $433,690. Using the 200mg total dose, costs were $157,213 and value $542,114. In first-line, pembro versus chemo in > 1.0% chemo demonstrated HR 0.81, and value $827,439, improving in > 50% to 0.69 and $507,139 respectively. Pembro + chemo versus chemo in < 1.0% were 0.59 and $383,446 improving in > 50% to 0.42 and $271,057. Bev costs were $132,314, HR 0.79 and value $630,067. Peme were $97,947, 0.63-0.78 and $264,722-$445,213. Conclusions: Pembro at 160 mg total dose in 80 Kg patients reduced the 200 mg costs by 20% with proportionate savings at lower weights. Pembro dollar value were enhanced by dose adjustment, PD-L1 enrichment and chemotherapy.

Brodalumab for the treatment of plaque psoriasis: up-to-date

ABSTRACTIntroduction: Brodalumab is one of the most efficacious biologic agents available for psoriasis. It also has a unique mechanism; it is the only agent that blocks the entire interleukin 17 receptors instead of blocking individual cytokines. However, the main drawback is that brodalumab has an FDA mandated black box warning regarding suicide. This is an up-to-date article reviews the scientific validity of this issue with brodalumab and suicide.Areas covered: A worldwide literature search was conducted on the above issue regarding suicide risk and brodalumab. All relevant articles on this topic searchable in public domain were utilized.Expert opinion: The FDA black box warning is based on three completed suicides that happened in one research location out of 390 research sites worldwide. All three completed suicides have alternative explanations unrelated to brodalumab. The overall data from phase III clinical trials shows that psoriasis patients recorded significant improvement in depression after treatment with brodalumab. The overall impression is that the suicide issue is far from being scientifically validated and this is why the FDA itself stated in the package insert that “the cause and effect relationship these suicides and brodalumab has not been established.”

Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA

BackgroundAdverse Drug Reactions (ADRs) are of great public health concern. FDA-approved drug labeling summarizes ADRs of a drug product mainly in three sections, i.e., Boxed Warning (BW), Warnings and Precautions (WP), and Adverse Reactions (AR), where the severity of ADRs are intended to decrease in the order of BW > WP > AR. Several reported studies have extracted ADRs from labeling documents, but most, if not all, did not discriminate the severity of the ADRs by the different labeling sections. Such a practice could overstate or underestimate the impact of certain ADRs to the public health. In this study, we applied the Medical Dictionary for Regulatory Activities (MedDRA) to drug labeling and systematically analyzed and compared the ADRs from the three labeling sections with a specific emphasis on analyzing serious ADRs presented in BW, which is of most drug safety concern.ResultsThis study investigated New Drug Application (NDA) labeling documents for 1164 single-ingredient drugs using Oracle Text search to extract MedDRA terms. We found that only a small portion of MedDRA Preferred Terms (PTs), 3819 out of 21,920 or 17.42%, were observed in a whole set of documents. In detail, 466/3819 (12.0%) PTs were in BW, 2023/3819 (53.0%) were in WP, and 2961/3819 (77.5%) were in AR sections. We also found a higher overlap of top 20 occurring BW PTs with WP sections compared to AR sections. Within the MedDRA System Organ Class levels, serious ADRs (sADRs) from BW were prevalent in Nervous System disorders and Vascular disorders. A Hierarchical Cluster Analysis (HCA) revealed that drugs within the same therapeutic category shared the same ADR patterns in BW (e.g., nervous system drug class is highly associated with drug abuse terms such as dependence, substance abuse, and respiratory depression).ConclusionsThis study demonstrated that combining MedDRA standard terminologies with data mining techniques facilitated computer-aided ADR analysis of drug labeling. We also highlighted the importance of labeling sections that differ in seriousness and application in drug safety. Using sADRs primarily related to BW sections, we illustrated a prototype approach for computer-aided ADR monitoring and studies which can be applied to other public health documents.

Professional or Patsy?

Professional or Patsy?

Reader response: Evaluating depression and suicidality in tetrabenazine users with Huntington disease.

I read with interest the article by Schultz et al.,1 which addressed a key issue faced by many clinicians treating patients with Huntington disease (HD)—the conundrum of whether or not to start tetrabenazine (TBZ) for treating chorea in those with a history of depression, given its black box warning of increased depression and suicidality risk. Nevertheless, I was puzzled by the study's finding that among the total group of patients with HD, especially the subgroup with a history of depression, TBZ use was associated with lower odds of both depression and suicidality.1 The most likely explanation for this finding is the phenomenon known as confounding by indication—a form of selection bias introduced by the fact that clinicians are simply less likely to prescribe TBZ to those with severe depressive symptoms due to the perceived detrimental effects of this drug on mood.2–4 Although the multiple logistic regression analysis was adjusted for a range of potential confounders,1 conditional regression estimates generally do not provide an unbiased estimate of true marginal effect in contexts where treatment selection is partially based on the outcome of interest (i.e., depression and suicidality).3 This issue can, at least partly, be addressed by applying inverse probability of treatment weighing using propensity scores.2,4 Therefore, it is important to know whether application of this method would result in similar findings or, conversely, support the notion of confounding by indication.4

Prescription Patterns of Antidepressants: The Effect of the Black Box Warning among Pediatric Patients

<p><strong><em>Introduction</em></strong><em>:<strong> </strong></em><em>Our aim was to investigate the prescription patterns of antidepressant in the southern Israel during the years 2000 to 2005, before and after the FDA black box warning issued regarding the prescription of antidepressants in children. </em><em></em></p><p><strong><em>Patients and methods</em></strong><em>:</em><em> </em><em>A cross sectional study. Data regarding prescription of anti-depressant drugs was examined retrospectively. All information was obtained from the computerized databases of the Clalit Health care services, southern county. Data was analyzed by using descriptive statistics, and analytical statistics. Multi-variate analysis was performed when applicable.</em></p><p><strong><em>Results</em></strong><em>: When comparing the prescription rate of fluoxetine and fluvoxamine versus other SSRI’s included in the health agencies warnings during the years mentioned, there was a gradual increase in the percentage of the other SSRI’s until 2003 from 12.2% in 2000 to 64.2% in 2003 and then a reversal of this trend from 51.9% in 2004 to 47.8% in 2005.</em><em></em></p><strong><em>Discussion and conclusions</em></strong><em>: This study shows that the CSM advice has not had a significant effect in reversing the rising prevalence of antidepressant prescribed to children and adolescents in primary care. It has however changed the choice of antidepressant medication chosen within the group of SSRI’s.</em>

Assessing provider and racial/ethnic variation in response to the FDA antidepressant box warning

IntroductionAfter the 2004 FDA box warning raised concerns about increased suicidal ideation among youth taking antidepressants, antidepressant use decreased for White youth but slightly increased for Black and Latino youth. Better understanding of patient and provider factors contributing to these differences is needed to improve future risk warning dissemination.MethodsWe analyzed antidepressant prescriptions for youth aged 5‐17 in 2002‐2006 Medicaid claims data from four states (CA, FL, NC, and NY). In multilevel models, we assessed provider‐ and patient‐level contributions to changes in antidepressant use by race/ethnicity and compared responses to the box warning between providers with large (>2/3) and small (<1/3) proportions of minority patients.ResultsA significant amount of variance in overall prescribing patterns (calculated by the ICC) was explained at the provider level. Significant provider‐level variation was also identified in the differential effect of the box warning by racial/ethnic group. In a test of the influence of provider panel mix, we found that providers with large proportions of minority patients reduced antidepressant prescribing more slowly after the box warning than other providers.DiscussionThis study is the first to assess provider‐ and patient‐level variation in the impact of a health care policy change on treatment disparities. Black and Latino youth Medicaid beneficiaries were seen by largely different providers than their White counterparts, and these distinct providers were influential in driving antidepressant prescription patterns following the box warning. Concerted outreach to providers of minority beneficiaries is needed to ensure that risk warnings and clinical innovations diffuse swiftly across racial/ethnic minority groups.

What Is the Risk for Unexpected Death Among Children and Youths Taking Antipsychotics

Although the antipsychotic thioridazine was initially considered “virtually free of side effects,” it later accumulated black-box warnings, including

Implications of Removing Rosiglitazone's Black Box Warning and Restricted Access Program on the Uptake of Thiazolidinediones and Dipeptidyl Peptidase-4 Inhibitors Among Patients with Type 2 Diabetes.

Medications are increasingly being approved with limited, short-term evidence regarding safety. Regulatory safety concerns may emerge for these drugs but later may be reversed if additional evidence suggests no warning is indicated. To describe trends over time in the initiation of rosiglitazone and pioglitazone-both in the thiazolidinedione (TZD) class-and medications from the dipeptidyl peptidase-4 (DPP-4) inhibitor class before and after the FDA removed a black box warning and restricted access program for rosiglitazone regarding an increased risk of myocardial infarction. This retrospective study evaluated initiation of TZDs and DPP-4 inhibitors using 2001-2015 administrative claims data from a U.S. commercially insured population. Patients were aged 18-64 years and were new users of either a TZD or DPP-4 inhibitor. Among all patients who were new users of either a TZD or a DPP-4 inhibitor during each quarter-year (Q), the percentage of patients who initiated rosiglitazone, pioglitazone, and DPP-4 inhibitors were calculated. There were 630,977 patients eligible for the study. During 2007, rosiglitazone initiators decreased from 39.1% to 8.0% in 2007 Q4 when the black box warning was implemented. During 2010, rosiglitazone initiators decreased from 7.6% to 1.0%, as safety evidence accumulated and the restricted access program requirement was announced. Rosiglitazone initiation remained below 1.0%, even after regulatory restrictions were removed in November 2013. Pioglitazone initiation decreased from 46.4% in 2010 Q1 to 14.8% in 2011 Q4 and remained relatively constant between 14.5% and 17.8% after regulatory restrictions for rosiglitazone were removed. After DPP-4 inhibitors first became available in 2006 Q3, initiation of this medication class increased rapidly, stayed relatively constant between 42.8% and 45.5% in 2009, and then quickly rose and remained above 80% from 2012 through 2015. This case study provides some evidence that adding and later reversing drug safety warnings-particularly those with restricted access requirements-may affect the uptake of the targeted product into the population when multiple clinically relevant treatment alternatives are available (such as type 2 diabetes). Once a treatment falls out of favor, removal of safety warnings and/or restricted access programs may not lead to increased use. This project was not directly supported by any funding. Hickson was supported by the National Heart, Lung, and Blood Institute through a National Research Service Award (NRSA) training grant (4T32HL007055-41) as a postdoctoral research fellow with the Cardiovascular Disease Epidemiology Program at The University of North Carolina at Chapel Hill (UNC-CH). Cole was supported by a NRSA Predoctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by The Cecil G. Sheps Center for Health Services Research, UNC-CH (grant no. T32-HS000032) and a predoctoral fellowship from the American Foundation for Pharmaceutical Education. Unrelated to this project, Cole was a part-time employee of Truven Health Analytics/IBM Watson Health. Dusetzina has nothing to disclose.

Postmarketing Safety-Related Modifications of Drugs Approved by the US Food and Drug Administration Between 1999 and 2014 Without Randomized Controlled Trials

ObjectiveTo investigate whether US Food and Drug Administration approval of new drugs without randomization or an active drug comparator is associated with more postmarketing safety-related label modifications. MethodsWe searched Drugs@FDA for new drugs approved from January 1, 1999, through December 31, 2014. Drugs approved without supporting randomized controlled trials (RCTs) were matched to between 1 and 2 controls from similar therapeutic categories approved with supporting RCTs within 3 years of the reference drug. Study characteristics, regulatory pathways, and label modifications up to December 2017 were collected from drug labels. Differences in postmarketing safety modifications between cases and controls were assessed using conditional logistic regression. ResultsThe study cohort included 52 drugs approved without supporting RCTs and 91 matched controls. Drug approvals not supported by RCTs were associated with lower sample size (odds ratio [OR] per 100 patients, 0.77; 95% CI, 0.68-0.87) and were more likely to receive orphan drug designation (OR, 5.10; 95% CI, 2.23-11.69), fast-track designation (OR, 4.80; 95% CI, 2.25-10.23), and accelerated approval (OR, 7.00; 95% CI, 3.14-15.60). Drugs approved without supporting RCTs were associated with more modifications in black box warnings (28.8% vs 13.2%; OR, 2.67; 95% CI, 1.13-6.27), warnings and precautions (73.1% vs 52.7%; OR, 2.43; 95% CI, 1.16-5.09), and common adverse reactions (48.1% vs 23.1%; OR, 3.09; 95% CI, 1.49-6.41). ConclusionFood and Drug Administration approval of new drugs without supporting RCTs is associated with more postmarketing safety-related label modifications than drugs approved with supporting RCTs. Robust postmarketing studies are required for drugs approved without supporting RCTs. Health care professionals should be vigilant for unrecognized adverse effects when prescribing these drugs.

Employment Effects of Healthcare Policy: Evidence from the 2007 FDA Black Box Warning on Antidepressants

Public policies aimed at improving health may have indirect effects on outcomes such as education and employment. We study the labor market effects of a 2007 regulatory action by the US Food and Drug Administration, in which they expanded the black box warning on antidepressants. Using nationally representative data from the National Survey on Drug Use and Health and a difference-in-differences strategy, we find that employment among women aged 35-49 with a history of depression decreased by 6.1 percent (4.4 percentage points) in response to the warning. We explore potential mechanisms generating these employment effects and find that both antidepressant and psychotherapy use among women aged 35-49 decreased after the warning. Our estimates suggest these same women did not substitute towards non-medical alternatives such as marijuana or alcohol. We find no employment or mental health treatment response among men or among women younger than 35. Overall, our analysis suggests that the 2007 expanded black box warning reduced US labor force participation by 0.23 percentage points and led to roughly $13 billion in lost wages.

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018.

As part of FDA’s MedWatch program, important changes to the safety labeling of drugs and therapeutic biologics, including boxed warnings, are posted on the agency’s website. Boxed warnings are ordinarily used to highlight (1) an adverse reaction so serious in proportion to the potential benefit