Food And Drug Administration Black Box Warning Research Articles

Plastic Surgeons' Perspective on the FDA Breast Implant Regulatory Mandates.

In 2021, the US FDA issued a new checklist, labeling, and rupture-screening recommendations for breast implants to improve the decision-making process. The aim of this study was to understand plastic surgeons' perspective on these changes and their perceived impact on clinical practice. In September 2023, a 27-question multiple-choice cross-sectional survey was distributed to 4352 active members of the American Society of Plastic Surgeons to evaluate attitudes on the FDA's black-box warning, informed decision checklist, and updated rupture-screening recommendations. A total of 591 responses were collected (13.6%). The majority of respondents were between the ages of 45 and 64 years (58%) and had been in practice for more than 20 years (52%). Surgeons felt that some additions were appropriate; however, the majority (57%) stated that the informed decision checklist did not have a positive impact on workflow; 66% were also neutral or disagreed with the reported incidence rates related to complications and cancer. Nearly half of respondents (47%) did not feel the black-box warning improved their patients' understanding of the risks and benefits. Additionally, 47% of respondents also believed these requirements, in combination, did not improve the overall patient experience with implants. Respondents had an overall positive response towards the addition of risk information provided by the FDA-issued guidance and updates to rupture-screening recommendations. However, they remained divided as to whether the black-box warning and patient decision checklist had an overall positive impact on clinical practice patterns.

Opioid and Benzodiazepine Co-Prescribing Trends from the Emergency Department from 2012 to 2019: A National Analysis

BackgroundIn 2016, the U.S. Food and Drug Administration (FDA) issued its strongest safety warning (“Black Box Warning”) for concomitant use of prescription opioids and benzodiazepines due to overdose deaths. ObjectiveOur objective was to look at trends of opioid and benzodiazepine co-prescribing in the emergency department (ED) using national data, because recent data are sparse. MethodsThis is a retrospective review of data collected by the National Hospital Ambulatory Medical Care Survey between 2012 and 2019. Our primary outcome was to determine whether there was a trend in ED visits when opioids and benzodiazepines were co-prescribed at discharge. We also compared the rate of visits when co-prescribing occurred before (2012–2015) and after (2017–2019) the 2016 FDA warning. We identified commonly co-prescribed benzodiazepines and opioids, and the rate of naloxone co-prescribing. We used descriptive statistics and bivariate tests to describe data. ResultsBetween 2012 and 2019, there were 4,489,613 ED visits (0.41% of ED visits) when benzodiazepines and opioids were co-prescribed. There was no trend in the rate of co-prescribing overall, but a decrease in visits after the 2016 FDA Black Box Warning (2012–2015: mean 0.49%; 2017–2019: mean 0.29%; p < 0.0001). There were 7980 ED visits (0.18%) when naloxone was co-prescribed for these visits within this time frame and an increase over time (p < 0.001). ConclusionsOur study found that between 2012 and 2019, there was no overall reduction in co-prescribing of opioids and benzodiazepines across EDs nationwide, but a decrease after the 2016 Black Box Warning.

Safety and Efficacy of Oral Benzodiazepines for Periprocedural Anxiolysis: A Systematic Review.

Oral benzodiazepines (BZDs) are useful tools for periprocedural anxiolysis. The United States Food and Drug Administration (FDA) recently issued a black-box warning of their risks of abuse and dependence. We performed a systematic review evaluating the safety and efficacy of oral BZDs for periprocedural anxiolysis in outpatient dermatologic, plastic surgery, dental, and ophthalmologic procedures performed under local anesthesia. A systematic review of 5 databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Oral benzodiazepine safety and efficacy data were extracted from eligible articles. A total of 43 articles and 4,060 subjects were included. Oral BZDs consistently imparted a positive anxiolytic effect and demonstrated superior or equivalent scores in patient satisfaction, surgeon satisfaction, pain, and anxiety to comparator groups in most studies. Thirty-five subjects experienced transient hypoxia, and 2 experienced transient hypertension. A total of 195 mild, self-limited adverse effects were reported. None of the studies addressed the risks of abuse and dependence in this clinical setting. Short-term use of oral BZDs for periprocedural anxiolysis seems to be safe and effective. The 2020 FDA black-box warning should not deter their appropriate use in dermatologic surgery and other low-risk outpatient procedures.

Enhancing Regulatory Decision Making for Postmarket Drug Safety

The U.S. Food and Drug Administration (FDA) regulates the approval and safe public use of pharmaceutical products in the United States. The FDA uses postmarket surveillance systems to monitor drugs already on the market; a drug found to be associated with an increased risk of adverse events (ADEs) is subject to a recall or a warning. A flawed postmarket decision-making process can have unintended consequences for patients, create uncertainty among providers and affect their prescribing practices, and subject the FDA to unfavorable public scrutiny. The FDA’s current pharmacovigilance process suffers from several shortcomings (e.g., a high underreporting rate), often resulting in incorrect or untimely decisions. Thus, there is a need for robust, data-driven approaches to support and enhance regulatory decision making in the context of postmarket pharmacovigilance. We propose such an approach that has several appealing features—it employs large, reliable, and relevant longitudinal databases; it uses methods firmly established in literature; and it addresses selection bias and endogeneity concerns. Our approach can be used to both (i) independently validate existing safety concerns relating to a drug, such as those emanating from existing surveillance systems, and (ii) perform a holistic safety assessment by evaluating a drug’s association with other ADEs to which the users may be susceptible. We illustrate the utility of our approach by applying it retrospectively to a highly publicized FDA black box warning (BBW) for rosiglitazone, a diabetes drug. Using comprehensive data from the Veterans Health Administration on more than 320,000 diabetes patients over an eight-year period, we find that the drug was not associated with the two ADEs that led to the BBW, a conclusion that the FDA evidently reached, as it retracted the warning six years after issuing it. We demonstrate the generalizability of our approach by retroactively evaluating two additional warnings, those related to statins and atenolol, which we found to be valid. This paper was accepted by Vishal Gaur, operations management.

Bleeding After Musculoskeletal Surgery in Hospitals That Switched From Hydroxyethyl Starch to Albumin Following a Food and Drug Administration Warning.

While US Food and Drug Administration (FDA) black box warnings are common, their impact on perioperative outcomes is unclear. Hydroxyethyl starch (HES) is associated with increased bleeding and kidney injury in patients with sepsis, leading to an FDA black box warning in 2013. Among patients undergoing musculoskeletal surgery in a subset of hospitals where colloid use changed from HES to albumin following the FDA warning, we examined the rate of major perioperative bleeding post- versus pre-FDA warning. The authors of this article used a retrospective, quasi-experimental, repeated cross-sectional, interrupted time series study of patients undergoing musculoskeletal surgery in hospitals within the Premier Healthcare Database, in the year before and year after the 2013 FDA black box warning. We examined patients in 23 "switcher" hospitals (where the percentage of colloid recipients receiving HES exceeded 50% before the FDA warning and decreased by at least 25% in absolute terms after the FDA warning) and patients in 279 "nonswitcher" hospitals. Among patients having surgery in "switcher" and "nonswitcher" hospitals, we determined monthly rates of major perioperative bleeding during the 12 months after the FDA warning, compared to 12 months before the FDA warning. Among patients who received surgery in "switcher" hospitals, we conducted a propensity-weighted segmented regression analysis assessing differences-in-differences (DID), using patients in "nonswitcher" hospitals as a control group. Among 3078 patients treated at "switcher" hospitals (1892 patients treated pre-FDA warning versus 1186 patients treated post-FDA warning), demographic and clinical characteristics were well-balanced. Two hundred fifty-one (13.3%) received albumin pre-FDA warning, and 900 (75.9%) received albumin post-FDA warning. Among patients undergoing surgery in "switcher" hospitals during the pre-FDA warning period, 282 of 1892 (14.9%) experienced major bleeding during the hospitalization, compared to 149 of 1186 (12.6%) following the warning. In segmented regression, the adjusted ratio of slopes for major perioperative bleeding post- versus pre-FDA warning was 0.98 (95% confidence interval [CI], 0.93-1.04). In the DID estimate using "nonswitcher" hospitals as a control group, the ratio of ratios was 0.93 (95% CI, 0.46-1.86), indicating no significant difference. We identified a subset of hospitals where colloid use for musculoskeletal surgery changed following a 2013 FDA black box warning regarding HES use in sepsis. Among patients undergoing musculoskeletal surgery at these "switcher" hospitals, there was no significant decrease in the rate of major perioperative bleeding following the warning, possibly due to incomplete practice change. Evaluation of the impact of systemic changes in health care may contribute to the understanding of patient outcomes in perioperative medicine.

Too Many Avoidable Suicides Occur Worldwide in Young Patients.

United States (US) and European Union (EU) laws attempt to counterbalance the presumed discrimination of children in drug treatment and drug development. The US Food and Drug Administration (FDA)-rewarded pediatric studies with antidepressants triggered in 2004 an FDA black-box warning of suicidality in young patients. Fewer antidepressants were prescribed, and the number of completed suicides of young persons increased. The dilemma between this warning and the need to adequately treat young depressed patients remains unsolved. We analyzed the history of drug development, the evolving view of diseases in young patients, US/EU pediatric laws, and pediatric studies triggered by FDA/European Medicines Agency (EMA) in depression and other diseases on the background of developmental pharmacology; financial, institutional, and other interests; and the literature. The FDA/EMA define children administratively, not physiologically, as <17 (FDA)/<18 years old (EMA). But young persons mature physiologically well before their 17th/18th birthday. Depression occurs in young persons, has special characteristics, but is not fundamentally different from adult depression. Young persons are not another species. Regulatory requirements for “pediatric” studies focus on “pediatric” labels. Many “pediatric” studies, including those in depression, lacked and lack medical sense and harm patients by placebo treatment although effective drugs exist. The FDA has partially abandoned separate “pediatric” efficacy studies, but not in psychiatry. Clinicians, parents, institutional review boards, and ethics committees should become aware of questionable “pediatric” studies, should re-evaluate ongoing ones, consider to suspend them, and to reject new ones. The concept of separate “pediatric” drug approval needs to be abandoned.

Impact of Chronic Risperidone Use on Behavior and Survival of 3xTg-AD Mice Model of Alzheimer's Disease and Mice With Normal Aging.

Psychosis and/or aggression are common problems in dementia, and when severe or persistent, cause considerable patient distress and disability, caregiver stress, and early institutionalization. In 2005, the Food and Drug Administration (FDA) determined that atypical antipsychotics were associated with a significantly greater mortality risk compared to placebo, which prompted the addition of an FDA black-box warning. The American College of Neuropsychopharmacology (ACNP) White Paper, 2008, reviewed this issue and made clinical and research recommendations regarding the use of antipsychotics in dementia patients with psychosis and/or agitation. Increased mortality risk has also been described in cerebrovascular adverse events in elderly users of antipsychotics. In the present work, at the translational level, we used male 3xTg-AD mice (PS1M146V, APPSwe, tauP301L) at advanced stages of the disease reported to have worse survival than females, to study the behavioral effects of a low chronic dose of risperidone (0.1 mg/kg, s.c., 90 days, from 13 to 16 months of age) and its impact on long-term survival, as compared to mice with normal aging. Animals were behaviorally assessed for cognitive and BPSD (behavioral and psychological symptoms of dementia)-like symptoms in naturalistic and experimental conditions (open-field test, T-maze, social interaction, Morris water maze, and marble test) before and after treatment. Weight, basal glucose levels, and IPGTT (i.p. glucose tolerance test) were also recorded. Neophobia in the corner test was used for behavioral monitoring. Survival curves were recorded throughout the experiment until natural death. The benefits of risperidone were limited, both at cognitive and BPSD-like level, and mostly restricted to burying, agitation/vibrating tail, and other social behaviors. However, the work warns about a clear early mortality risk window during the treatment and long-lasting impact on survival. Reduced life expectancy and life span were observed in the 3xTg-AD mice, but total lifespan (36 months) recorded in C57BL/6 × 129Sv counterparts with normal aging was also truncated to 28 months in those with treatment. Sarcopenia at time of death was found in all groups, but was more severe in wild-type animals treated with risperidone. Therefore, the 3xTg-AD mice and their non-transgenic counterparts can be useful to delimitate critical time windows and for studying the physio-pathogenic factors and underlying causal events involved in this topic of considerable public health significance.

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.

Rise in Antidepressant Prescriptions for Youth Raises Questions About Why

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessRise in Antidepressant Prescriptions for Youth Raises Questions About WhyNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:31 Jan 2018https://doi.org/10.1176/appi.pn.2018.2a10AbstractAfter an initial decline in the use of antidepressants by youth following actions taken by the Food and Drug Administration in 2004, one study finds antidepressant use among youth has rebounded.In October 2004, the Food and Drug Administration (FDA) directed pharmaceutical companies to issue a black-box warning about the potential link between the use of antidepressants and increased suicidal ideation among youth. Following this directive, the number of depression diagnoses and antidepressant prescriptions for children and adolescents—which had been on the rise—fell over the next few years.Though there is an extensive body of research exploring this initial decline in prescriptions, fewer studies have looked at long-term prescribing trends. A study published last December in Psychiatric Services in Advance found that following that initial decline, the rate of antidepressant prescribing to children eventually returned to pre-2004 levels. Nilay Kafali, Ph.D., of RTI International and colleagues found that 2.26 percent of children aged 5 to 17 were prescribed antidepressants in 2009, similar to the 2003 level of 2.29 percent. Between 2004 and 2008, that rate had dropped to below 2 percent.The authors calculated these rates using data from the Medical Expenditure Panel Survey (a set of nationally representative surveys of individuals, medical providers, and employers that detail the use and costs of health care services and health insurance coverage). They included available data on children aged 5 to 17 between 2000 and 2011. To estimate how the impact of the black-box warning on antidepressant use among children changed over time, the authors divided the entire sample period into four periods: early prewarning (2000–2001), prewarning (2002–2003), early postwarning (2004–2007), and late postwarning (2008–2011). They found that there was a 0.5 percent statistically significant decline in antidepressant use during the early postwarning years compared with prewarning years, with a particularly strong decrease among children rated as having non-severe psychological impairment. (The authors defined non-severe psychological impairment as a Columbia impairment Scale score of <16). Antidepressant use was 1.1 percent for this group in 2003, dropped to around 0.7 percent between 2004-2007, and rose to 1.09 percent in 2008. Rates of antidepressant use for children with severe psychological impairment showed a gradual decline from 2003 to 2007, but then also rose to pre-2004 levels. “These findings suggest that providers and families of youth may have reacted to the black-box warning in an appropriate manner, weighing the warning with the risks and benefits of the treatment,” Kafali and colleagues wrote. “A return to the rates of antidepressant use before the black-box warning raises concern that this thoughtful accounting of the risks and benefits may have dissipated over time.”A central question for future research is what factors drove this rise in use after 2008. “It is possible that over time physicians have become somewhat inured to the safety warnings,” said Mark Olfson, M.D., M.P.H., a professor of psychiatry and epidemiology at Columbia University Medical Center. “However, it is also possible that increasing prevalence of depression or anxiety among young people during the great recession played a role,” he added.Olfson, who was not involved with this study, noted that other community surveys including the Youth Risk Behavior Survey, the National Survey on Drug Use and Health, and the Monitoring the Future surveys have revealed a recent increase in depressed mood and major depressive episodes among children and adolescents. “An important policy implication of our findings could be that more frequent updates of FDA risk warnings might be necessary to prevent patients and the providers from ‘forgetting’ the potential risks outlined in the original warning,” Kafali and colleagues wrote. ■An abstract of “Long-Run Trends in Antidepressant Use Among Youths After the FDA Black Box Warning” can be accessed here. ISSUES NewArchived

Ten years after the FDA black box warning for antidepressant drugs: a critical narrative review

Background The United States Food and Drug Administration (FDA) has warned about the increased suicidality risk associated with the use of selective serotonin reuptake inhibitors (SSRI) and venlafaxine in children and adolescents. Objectives To critically appraise the available evidence supporting the FDA Black box warning concerning to the use of antidepressants in child and adolescents. Methods A critical review of articles in Medline/PubMed and SciELO databases regarding the FDA Black box warning for antidepressants, and the impact of FDA warnings on antidepressant prescriptions and suicide rates. Results The warning was based on surveys that did not report either cases of suicide nor a significant difference supporting an increased suicidality rate. The concept was defined in an ambiguous way and there is currently more available evidence to support such definition. The use of SSRI and venlafaxine has been associated to lower suicidality rates, but the prescription fall due to the warning increased suicide rates. Discussion Suicidality is an inherent feature of depressive disorders so it would be desirable to consider how much of the phenomenon may be attributed to antidepressants per se. It would be appropriate to consider that suicide rates might increase also as a consequence of the warning.

Should Physicians Prescribe Antipsychotics in Dementia?

Neuropsychiatric symptoms are nearly universal in patients with major neurocognitive disorder and cause significant distress in patients and caregivers. Nonpharmacologic behavioral management is effective; however, in patients with persistent and severe neuropsychiatric symptoms, those who are unresponsive to nonpharmacologic approaches, and those who pose a danger of harm to themselves or others, pharmacologic agents are required. There are currently no US Food and Drug Administration (FDA)-approved agents. Antipsychotics have modest efficacy with the best evidence for risperidone and olanzapine at low doses. The increased risk of mortality with the use of both typical and atypical antipsychotics in dementia has consistently been reproduced in studies, and reflected in the FDA black box warning. Among the agents studied, haloperidol has the highest relative mortality risk and quetiapine the lowest compared to risperidone. The mortality risk shows a dose-response relationship. Antipsychotics have also been implicated with an increased risk of cerebrovascular events. Antipsychotics should be used cautiously in dementia with a thorough consideration of risks and benefits in discussion with patients and families. The lowest effective dose should be used and discontinuation should be attempted periodically. [ Psychiatr Ann . 2016;46(2):97–102.]

First-generation Antipsychotics Are Often Prescribed in the Emergency Department but Are Often Not Administered with Adjunctive Medications

BackgroundAlthough first-generation antipsychotics (FGAs) have long been used in the emergency department (ED) to treat acute agitation, little is known about how these medications are used in modern clinical practice. In particular, little work has been published about whether ED clinicians administer FGAs with adjunctive medications in accordance with expert guidelines or the prescribing practices of FGAs over time. Objectives1) To provide a comparison of the frequency with which FGAs are administered with adjunctive benzodiazepines or anticholinergic medications. 2) To analyze the prescribing trends for FGAs over time, particularly in the years after the U.S. Food and Drug Administration (FDA) black-box warning for droperidol. MethodsThis is a structured review of a retrospective cohort of patients receiving haloperidol or droperidol in two EDs over a 7-year period. ResultsHaloperidol or droperidol was administered on 2833 patient visits during the study period, with haloperidol being administered most often. Adjunctive medications are administered less than half of the time. The use of droperidol has remained relatively static, whereas the use of haloperidol has increased. ConclusionsFirst-generation antipsychotics are still widely utilized in the ED. When administered, these medications are used with adjunctive medications that may decrease side effects less than half of the time. Droperidol use has remained unchanged in the years after the FDA black-box warning, whereas use of haloperidol has continued to rise.

Replacement of Promethazine With Ondansetron for Treatment of Opioid- and Trauma-Related Nausea and Vomiting in Tactical Combat Casualty Care.

The current Tactical Combat Casualty Care (TCCC) Guidelines recommend parenteral promethazine as the single agent for the treatment of opioid-induced nausea and/or vomiting and give a secondary indication of "synergistic analgesic effect." Promethazine, however, has a well-documented history of undesired side effects relating to impairment and dysregulation of the central and autonomic nervous systems, such as sedation, extrapyramidal symptoms, dystonia, impairment of psychomotor function, neuroleptic malignant syndrome, and hypotension. These may be particularly worrisome in the combat casualty. Additionally, since 16 September 2009, there has been a US Food and Drug Administration (FDA) black box warning for the injectable form of promethazine, due to "the risk of serious tissue injury when this drug is administered incorrectly." Conversely, ondansetron, which is now available in generic form, has a well-established favorable safety profile and demonstrated efficacy in undifferentiated nausea and vomiting in the emergency department and prehospital settings. It has none of the central and autonomic nervous system side effects noted with promethazine and carries no FDA black box warning. Ondansetron is available in parenteral form and an orally disintegrating tablet, providing multiple safe and effective routes of administration. Despite the fact that it is an off-label use, ondansetron is being increasingly given for acute, undifferentiated nausea and vomiting and is presently being used in the field on combat casualties by some US and Allied Forces. Considering the risks involved with promethazine use, and the efficacy and safety of ondansetron and ondansetron?s availability in a generic form, we recommend removing promethazine from the TCCC Guidelines and replacing it with ondansetron.

A Survey of Lawsuits for Metoclopramide and Tardive Dyskinesia

Introduction: Metoclopramide, (Reglan), is used to treat gastroparesis and other gastrointestinal disorders. In 2009, the Food and Drug Administration (FDA) issued a black box warning about the association of metoclopramide and tardive dyskinesia (TD). TD is a permanent neurological disorder characterized by involuntary muscle movements. This study examined lawsuits involving metoclopramide-induced tardive dyskinesia in an effort to inform physicians of the legal risks of prescribing metoclopramide. Methods: The Westlaw database, one of the primary online legal research services for legal professionals, was used for the study. A first search was conducted for all cases containing “metoclopramide” or “reglan” and “tardive dyskinesia” (search: “adv: metoclopramide reglan and tardive dyskinesia”). This search yielded 96 cases where patients filed a claim. All appeals were excluded from the total number of cases. Of these, 10 (11%) were filed against prescribing physicians, 1 (1%) against a pharmacist, and the remaining 85 (88%) were filed against manufacturers. Cases were commonly filed based off the following premises: fail to warn, medical malpractice. Failure to warn is defined as when a manufacturer or distributor does not provide adequate information regarding the dangers associated with the product. Medical malpractice is when a health care provider does not provide a quality level of care that usually results in harm to a patient. Results: Of the 10 cases filed against physicians, 5 were compliant for malpractice and 5 were for failure to warn. The remaining 85 cases were brought against the generic and brand manufacturers of the drug for negligence or failure to warn physicians and patients about the potential side effects of metoclopramide, including tardive dyskinesia. The number of lawsuits has increased dramatically since the black box warning (Figure 1).Figure 1Conclusion: At present, there appears to be only a small legal risk to physicians prescribing metoclopramide. However, the trends related to lawsuits against physicians need careful monitoring, as the number of suits for metoclopramide and tardive dyskinesia has increased since the FDA black box warning.

Impact of FDA Actions, DTCA, and Public Information on the Market for Pain Medication.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most important classes of prescription drugs used by primary care physicians to manage pain. The NSAID class of products has a somewhat controversial history, around which a complex regulatory and informational environment has developed. This history includes a boxed warning mandated by the Food and Drug Administration (FDA) for all NSAIDs in 2005. We investigate the impact that various information shocks have had on the use of prescription medications for pain in primary care in the USA. We accomplish this by extracting data on nearly 600,000 patients from a unique nationwide electronic medical record database and estimate the probability of any active prescription for the four types of pain medications as a function of FDA actions, advertising, media coverage, and patient characteristics. We find that even after accounting for multiple sources of information, the FDA label changes and boxed warnings had a significant effect on pain medication prescribing. The boxed warning did not have the same impact on the use of all NSAID inhibitors. We find that the boxed warning reduced the use of NSAID COX-2 inhibitor use, which was the focus of much of the press attention. In contrast, however, the warning actually increased the use of non-COX-2 NSAID inhibitors. Thus, the efficacy of the FDA's black box warning is clearly mixed.

Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time series

BackgroundIn March, 2007, a black box warning was issued by the Food and Drug Administration (FDA) to use the lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with renal disease. The goal is to determine if a change in ESA use was observed following the warning among US dialysis patients.MethodsESA therapy was examined from September 2004 through August 2009 (thirty months before and after the FDA black box warning) among adult Medicare hemodialysis patients. An interrupted time series model assessed the impact of the warnings.ResultsThe FDA black box warning did not appear to influence ESA prescribing among the overall dialysis population. However, significant declines in ESA therapy after the FDA warnings were observed for selected populations. Patients with a hematocrit ≥36% had a declining month-to-month trend before (−164 units/week, p = <0.0001) and after the warnings (−80 units/week, p = .001), and a large drop in ESA level immediately after the black box (−4,744 units/week, p = <.0001). Not-for-profit facilities had a declining month-to-month trend before the warnings (−90 units/week, p = .009) and a large drop in ESA dose immediately afterwards (−2,487 units/week, p = 0.015). In contrast, for-profit facilities did not have a significant change in ESA prescribing.ConclusionsESA therapy had been both profitable for providers and controversial regarding benefits for nearly two decades. The extent to which a FDA black box warning highlighting important safety concerns influenced use of ESA therapy among nephrologists and dialysis providers was unknown. Our study found no evidence of changes in ESA prescribing for the overall dialysis population resulting from a FDA black box warning.

Anti-D immunoglobulin therapy for pediatric ITP: Before and after the FDA's black box warning

In March 2010, the Food and Drug Administration (FDA) issued a black box warning for anti-D immunoglobulin (anti-D), an approved treatment for immune thrombocytopenia (ITP). It is unknown if and how clinical practice at U.S children's hospitals has since changed. We sought to describe inpatient anti-D usage, laboratory monitoring, and anti-D complications before and after the FDA warning. Using the Pediatric Health Information System, we collected data from 41 children's hospitals. There was a modest but statistically significant decrease in anti-D usage from pre-warning to post-warning. Severe complication rates were very low and did not change appreciably.

Challenging the FDA Black Box Warning for High Aspirin Dose With Ticagrelor in Patients With Diabetes

Ticagrelor, a novel reversible antiplatelet agent, has a Food and Drug Administration (FDA) black box warning to avoid maintenance doses of aspirin (ASA) >100 mg/daily. This restriction is based on the hypothesis that ASA doses >100 mg somehow decreased ticagrelor’s benefit in the Platelet Inhibition and Patient Outcomes (PLATO) U.S. cohort. However, these data are highly postrandomized, come from a very small subgroup in PLATO (57% of patients in the U.S. site), and make no biological sense. Moreover, the ticagrelor-ASA interaction was not significant by any multivariate Cox regression analyses. The Complete Response Review for ticagrelor indicates that for U.S. PLATO patients, an ASA dose >300 mg was not a significant interaction for vascular outcomes. In the ticagrelor-ASA >300 mg cohort, all-cause and vascular mortality were not significantly increased (hazard ratio [HR] 1.27 [95% CI 0.84–1.93], P = 0.262 and 1.39 [0.87–2.2], P = 0.170), respectively. Furthermore, for major adverse cardiovascular events (MACEs), 30-day all-cause mortality, and 30-day vascular mortality, the strongest interaction is the diabetes-ASA interaction. That is, patients who had diabetes had significantly fewer MACEs through study end (0.49 [0.34–0.63], P < 0.0001), significantly less 30-day all-cause mortality (0.33 [0.20–0.56], P < 0.0001), and significantly less 30-day vascular mortality (0.35 [0.22–0.55], P < 0.0001), respectively, when given high-dose (300–325 mg) ASA, regardless of treatment (clopidogrel or ticagrelor) assignment. The black box warning for the use of maintenance ASA doses >100 mg with ticagrelor is inappropriate for patients with diabetes and not evidence based.

Trends in anti‐D immune globulin for childhood immune thrombocytopenia: Usage, response rates, and adverse effects

In 2010, the Food and Drug Administration (FDA) added a black box warning to anti-D immune globulin (Rho(D) immune globulin, anti-D) for immune thrombocytopenia (ITP) to warn of the complications related to severe hemolysis. The objective of this retrospective medical record review was to examine recent trends in anti-D use to treat ITP and rates of adverse events in a single large pediatric hematology program. Over a 7-year period, 176 (35%) of 502 ITP patients at our center received anti-D. Anti-D was the second most commonly prescribed drug for ITP from 2003 to 2010 overall and was given first most frequently (41%). Sixty-four percent of patients responded to anti-D, but 36% had adverse effects, including five patients requiring hospitalization. From 2003 to 2010, the use of anti-D as an initial therapy for ITP significantly decreased (P < 0.001). This trend preceded the 2010 FDA black box warning. In our experience, anti-D was associated with a significant number of adverse effects when used as a treatment for ITP, although none were life-threatening. Despite recent guidelines suggesting anti-D therapy for initial treatment for ITP, anti-D therapy for ITP has significantly decreased over the past 7 years.

Droperidol Analgesia for Opioid-Tolerant Patients

Background Patients with acute and chronic pain syndromes such as migraine headache, fibromyalgia, and sickle cell disease represent a significant portion of emergency department (ED) visits. Certain patients may have tolerance to opioid analgesics and often require large doses and prolonged time in the ED to achieve satisfactory pain mitigation. Droperidol is a unique drug that has been successfully used not only as an analgesic adjuvant for the past 30 years, but also for treatment of nausea/vomiting, psychosis, agitation, sedation, and vertigo. Objectives In this review, we examine the evidence supporting the use of droperidol for analgesia, adverse side effects, and controversial United States (US) Food and Drug Administration (FDA) black box warning. Discussion Droperidol has myriad pharmacologic properties that may explain its efficacy as an analgesic, including: dopamine D2 antagonist, dose-dependent GABA agonist/antagonist, α2 adrenoreceptor agonist, serotonin antagonist, histamine antagonist, muscarinic and nicotinic cholinergic antagonist, anticholinesterase activity, sodium channel blockade similar to lidocaine, and μ opiate receptor potentiation. Conclusion Droperidol is an important adjuvant for patients who are tolerant to opioid analgesics. The FDA black box warning does not apply to doses below 2.5 mg.