Drug Administration Black Box Warning Research Articles

Assessing the risks of treatment in Parkinson disease psychosis: An in-depth analysis.

Parkinson disease (PD) psychosis (PDP) is a disabling non-motor symptom. Pharmacologic treatment is limited to pimavanserin, quetiapine, and clozapine, which do not worsen parkinsonism. A Food and Drug Administration black box warning exists for antipsychotics, suggesting increased mortality in elderly patients with dementia. However, the reasons for higher mortality are unknown. Expanding on prior work exploring mortality in treated PDP patients, we conducted a retrospective comparison to understand the links between treatment regimen, clinical characteristics, and negative outcomes. Electronic medical record data extraction included clinically diagnosed PD patients between 4/29/16-4/29/19 and excluded patients with primary psychiatric diagnoses or atypical parkinsonism. Mortality and clinical characteristics during the study period were compared between untreated patients and those receiving pimavanserin, quetiapine, or both agents (combination). Mortality analyses were adjusted for age, sex, levodopa equivalent daily dose (LEDD), and dementia. The pimavanserin group (n = 34) had lower mortality than the untreated group (n = 66) (odds ratio = 0.171, 95% confidence interval: 0.025-0.676, p = 0.026). The untreated group had similar mortality compared to the quetiapine (n = 147) and combination (n = 68) groups. All treated groups had a higher LEDD compared to the untreated group, but no other differences in demographics, hospitalizations, medical comorbidities, medications, or laboratory values were found between the untreated and treated groups. PDP patients receiving pimavanserin had lower mortality than untreated patients. We found no other clear differences in clinical characteristics to explain the mortality risk. Prospective randomized trials are needed to definitively identify the optimal PDP treatment regimen and associated risks.

Tramadol Use in Pediatric Surgery: Trends After the Food and Drug Administration Black-Box Warning

IntroductionThe U.S. Food and Drug Administration (FDA) issued a black-box warning in 2017 contraindicating tramadol in children <12 y. Longitudinal trends and factors associated with perioperative tramadol use in children remain unclear. MethodsA retrospective, multi-institutional cohort study utilizing the Pediatric Health Information System database was performed for children 2-18 y who underwent one of ten common surgeries from 1/2009-2/2020. Temporal trends correlated with the FDA tramadol contraindication were evaluated. Hierarchical multivariable logistic regression analysis identified factors associated with tramadol use. ResultsOf 477,153 children undergoing surgery, 5857(1.2%) received tramadol during hospitalization. Tramadol use occurred in 942 (16.1%) children after the black-box warning, 390 of whom were <12 y. For children <12 y, annual tramadol use peaked at 1.87% (2016) and decreased to 0.66% (2019). Female sex (odds ratio OR 1.32; 95% confidence interval CI:1.24,1.40), age ≥12 y (OR 2.79; 95%CI: 2.62,2.97), and Midwest location (OR 4.07; 95% CI:1.64,10.11) increased likelihood of receiving tramadol. Tramadol use was more likely after cholecystectomy (OR 1.17; 95% CI:1.04,1.32) and in children with gastrointestinal (OR 2.39; 95% CI: 2.19,2.60), metabolic (OR 1.39; 95% CI:1.26,1.53) or transplant-related (OR 1.82; 95% CI: 1.57,2.10) comorbidities. Children of Hispanic/Latino ethnicity and those with public insurance had decreased likelihood of receiving tramadol. Adjusting for patient and hospital characteristics, children <12 y were less likely to receive tramadol following the black-box warning (OR 0.65; 95% CI: 0.59,0.70). ConclusionsDespite the FDA contraindication, tramadol prescribing continues among children <12 y undergoing surgery, with use varying by patient and institutional factors. Interventions are required to reduce perioperative tramadol use in children.

Physician Network Connections Associated With Faster De-Adoption of Dronedarone for Permanent Atrial Fibrillation.

Physicians' professional networks are an important source of new medical information and have been shown to influence the adoption of new treatments, but it is unknown how physician networks impact the de-adoption of harmful practices. We analyzed changes in physicians' use of dronedarone after the PALLAS trial (Palbociclib Collaborative Adjuvant Study; November 2011) showed that dronedarone increased the risk of death from cardiovascular events among patients with permanent atrial fibrillation. Deidentified administrative claims from the OptumLabs Data Warehouse were combined with physicians' demographic information from the Doximity database and publicly available data on physicians' patient-sharing relationships compiled by the Centers for Medicare and Medicaid Services. We used a linear probability model with an interrupted linear time trend specification to model the impact of the PALLAS trial on physicians' dronedarone usage between 2009 and 2014. Before the PALLAS trial, the use of dronedarone was increasing by 0.22 percentage points per quarter (95% CI, 0.19-0.25) in our Medicare Advantage sample (N=343 429 patient-quarter observations) and 0.63 percentage points per quarter (95% CI, 0.52-0.75) in our commercially insured sample (N=44 402 patient-quarter observations). After the PALLAS trial and subsequent United States Food and Drug Administration black box warning, physicians in the Medicare Advantage sample with an above-median number of network connections to other physicians decreased their quarterly usage of dronedarone by 0.12 percentage points more per quarter (95% CI, -0.20 to -0.04; P=0.031) than physicians with equal to or below the median number of network connections. Similar patterns existed in the commercially insured sample (P=0.0318). After controlling for a wide range of patient, physician, and geographic characteristics, physicians with a greater number of network connections were faster de-adopters of dronedarone for patients with permanent atrial fibrillation after the PALLAS trial and subsequent United States Food and Drug Administration black box warning detailed the harmfulness of dronedarone for these patients. Policies for improving physicians' responsiveness to new medical information should consider utilizing the influence of these important professional network relationships.

Perioperative safety of tofacitinib in surgical ulcerative colitis patients.

The literature regarding monoclonal antibodies and increased postoperative complications in inflammatory bowel disease remains controversial. There have been no studies investigating tofacitinib. The aim of this work was to determine preoperative exposure to the small-molecule inhibitor tofacitinib and postoperative outcomes. We conducted a retrospective review of all adult patients exposed to tofacitinib within 4weeks of total abdominal colectomy for medically refractory ulcerative colitis between 1 January 2018 and 1 September 2020 at four inflammatory bowel disease referral centres. Data collected included patient demographics and 90-day postoperative morbidity, readmission and reoperation rates. Fifty-three patients (32 men, 60%) with ulcerative colitis underwent a total abdominal colectomy (n=50 laparoscopic, 94%) for medically refractory disease. Previous exposure to monoclonal antibodies included infliximab (n=34), adalimumab (n=35), certolizumab pegol (n=5), vedolizumab (n=33) and ustekinumab (n=10). Twenty-seven (51%) patients were on concurrent prednisone at a median daily dose of 30mg by mouth (range 5-60mg). There were no postoperative deaths. Ninety-day postoperative complications included ileus (n=7, 13.2%), superficial surgical site infection (n=4, 7.5%), intra-abdominal abscess (n=2, 3.8%) and venous thromboembolism (VTE) (n=7, 13.2%). Locations of VTE included portomesenteric venous thrombus (n=4), internal iliac vein (n=2) and pulmonary embolism (n=1). Nine (17%) patients were readmitted to hospital and five (9%) patients had a reoperation. Mirroring the recently issued US Food and Drug Administration black box warning of an increased risk of VTE in medically treated ulcerative colitis patients taking tofacitinib, preoperative tofacitinib exposure may present an increased risk of postoperative VTE events. Consideration should be given for prolonged VTE prophylaxis on hospital discharge.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk of Amputation: What Is Currently Known?

Diabetes mellitus is a major cause of morbidity and mortality in the United States. Twelve medication classes on the market reduce serum glucose including sodium-glucose cotransporter-2 (SGLT2) inhibitors. Potential benefits of these agents include improved glycemic control, weight loss, reduction in blood pressure, and possible reduction in cardiovascular events in patients with elevated cardiovascular risk. Recently, several adverse events have been identified including increased possible risk of amputation associated with SGLT2 inhibitor therapy. We conducted a review of published literature and identified 32 trials reviewing incidence of SGLT2 inhibitor-related amputation. The potential increased risk for amputation is mostly of the lower extremities. Of the SGLT2 inhibitors currently available, canagliflozin has the highest association with an increased risk of lower extremity amputation and is the only agent with a Food and drug Administration Black Box Warning. Most canagliflozin amputation occurred in a single study. Risk factors for amputation with SGLT2 inhibitors may include those who have a history of amputations, susceptible to foot ulcers and those with baseline cardiovascular disease. For at-risk patients who desire an agent from this drug class, empagliflozin or dapagliflozin should be considered, as studies have not found a significant increase in amputations when compared with placebo or in retrospective reviews. Despite the increased risk of amputation found with canagliflozin, providers can use SGLT2 inhibitors with frequent monitoring to safely manage diabetes in low-risk patients. Patient education on associated risks is warranted. Diabetes educators can inform patients of risk factors to assist with monitoring.

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice.

Although montelukast is generally well tolerated, postmarketing studies have reported serious neuropsychiatric adverse drug reactions (ADRs) leading to a United States Food and Drug Administration black box warning. The objective of this study was to determine the incidence of neuropsychiatric ADRs leading to discontinuation of montelukast in asthmatic children.We conducted a retrospective cohort study in children aged 1-17 years initiated on montelukast. In a nested cohort study, children initiated on montelukast as monotherapy or adjunct therapy to inhaled corticosteroids (ICS) were matched to those initiated on ICS monotherapy. A non-leading parental interview served to ascertain the occurrence of any ADRs with any asthma medication, and circumstances related to, and evolution of, the event.Out of the 106 participants who initiated montelukast, most were male (58%), Caucasian (62%) with a median (interquartile range) age of 5 (3-8) years. The incidence (95% CI) of drug cessation due to neuropsychiatric ADRs was 16 (10-26)%, mostly occurring within 2 weeks. Most frequent ADRs were irritability, aggressiveness and sleep disturbances. The relative risk of neuropsychiatric ADRs associated with montelukast versus ICS was 12 (2-90).In the real-life setting, asthmatic children initiated on montelukast experienced a notable risk ofneuropsychiatric ADRs leading to drug cessation, that is significantly higher than that associated withICS.

Antidepressants and suicidality: History, the black-box warning, consequences, and current evidence

Abstract Introduction The first published literature on the topic of antidepressants and suicidality dates back to the mid-1950s. Today, 10 years after the black-box warning was issued, this controversial topic is still debated. This article will review the data behind the black-box warning and its revision; address the subsequent impact the warning had on depression diagnoses, prescribing patterns, follow-up visits, and suicide rates in the United States; and summarize meta-analyses on this topic published since the revised warning was issued in 2007. Methods A PubMed database search using the MeSH terms Antidepressive Agents and Suicide was conducted from January 2012 through October 2014 to identify articles published on the impact the Food and Drug Administration's black-box warning had on health care at a national level and from January 2007 through October 2014 using the same MeSH terms to identify meta-analyses on the current research regarding the link between antidepressants and suicidality. Search results for both topics were further limited to those articles published in English on human participants with the age criteria Child: Birth – 18 years, Adolescent: 13-18 years, or Young Adult: 19-24 years. Results Due to the black-box warning, depression diagnoses and antidepressant prescription issuance rates declined in young patients. It is still debated whether the black-box warning had an untoward effect on suicide rates. Most of the meta-analyses identified a small risk of suicidality in the populations studied. Because of the varying nature of the meta-analyses and the major limitation of the limited availability of prospectively collected suicidality data, an absolute risk is still yet to be determined. Discussion/Conclusion More studies on antidepressants conducted to prospectively identify suicidality in patients with Major Depressive Disorder and other varying diagnoses need to be completed to truly identify the incidence of suicidal behavior and ideation when initiating antidepressants. Albeit seemingly low, there is a risk of suicidality when initiating antidepressants; there is also risk in not treating depressed patients with antidepressants in whom they are indicated. Clinicians must be cognizant of this risk and monitor high-risk patients per the Food and Drug Administration–recommended guidelines.

Antidepressant Use in Children, Adolescents, and Young Adults: 10 Years After the Food and Drug Administration Black Box Warning

Depression in children, adolescents, and young adults can jeopardize health status, well-being, and development. Almost a decade ago, risks and benefits of antidepressant use in this group prompted the Food and Drug Administration (FDA) to ask manufacturers to include black box warnings on antidepressant prescriptions. This article reviews initial FDA decisions related to black box warnings for antidepressants in youth, reviews effects of the warnings, and considers clinical implications of prescribing antidepressants for treatment of youth depression. Health care providers must consider the risks and benefits of initiating antidepressant medication treatment, closely monitoring adherence, patient outcomes, and suicidal ideation.

A Good Doctor Can Give Bad Advice on Antipsychotics

A Good Doctor Can Give Bad Advice on Antipsychotics

The use of droperidol before and after the Food and Drug Administration black box warning: a survey of the members of the Society of Ambulatory Anesthesia

Study Objective To determine the practice of members of the Society of Ambulatory Anesthesia (SAMBA) in the management of postoperative nausea and vomiting (PONV) before and after the Food and Drug Administration (FDA) black box warning on droperidol. Design Survey questionnaire. Setting The Society of Ambulatory Anesthesia. Measurements After institutional review board approval, a survey was posted on the SAMBA Web site from June 1, 2005, until October 30, 2005. Visitors of the Web site were invited to participate in the survey. The survey was designed to elicit information about the management of PONV, particularly the use of droperidol, before and after the FDA black box warning. Participants were also asked about reasons for not using droperidol in their current practice and whether they believed that the black box warning was justified. Main Results Two hundred ninety-five physicians of 1,179 eligible SAMBA members completed the survey for a 25% response rate. For PONV prophylaxis, the choice of droperidol as a first-line agent decreased from 47% to 5% after the black box warning appeared ( P < 0.0001). Similarly, for treatment of established PONV, the choice of droperidol decreased from 38% to 8% during this same period ( P < 0.0001). A total of 261 (92%) of responders did not believe that the black box warning was justified. Conclusions Although most surveyed practitioners believed that the FDA black box warning on droperidol is not justified, the use of this cost-effective agent has significantly declined.

Does Low-dose Droperidol Administration Increase the Risk of Drug-induced QT Prolongation and Torsade de Pointes in the General Surgical Population?

The US Food and Drug Administration issued a black box warning regarding the use of droperidol and the potential for torsade de pointes (TdP). The primary objective of this retrospective study was to determine whether low-dose droperidol administration increased the incidence of TdP in the general surgical population during a 3-yr time period before and after the Food and Drug Administration black box warning. A random sample of 150 surgical patients during each time interval was selected to estimate the droperidol use for each time period. During the time period before the black box warning (July 1, 1998 to June 30, 2001), 2,321/139,932 patients (1.66%) had QT prolongation, TdP, or death within 48 h after surgery. We could identify no patients who clearly developed TdP before the black box warning. There was one patient for whom the cause of death could not positively be ruled out as due to TdP. In the time period after the black box warning (July 1, 2002 to June 30, 2005), 2,207 patients (1.46%) had documented QT prolongation, TdP, or death within 48 h after surgery, including only two cases (<0.1%) of TdP. The incidence of droperidol exposure was approximately 12% (exact 95% confidence interval, 7.3-18.3%) before the black box warning and 0% after placement of the black box warning on droperidol. Therefore, we estimate that approximately 16,791 patients (95% confidence interval, 10,173-25,607) were exposed to droperidol, none of whom experienced documented TdP. This indicates that the Food and Drug Administration black box warning for low dose droperidol is excessive and unnecessary.