Box Warning Research Articles

Brodalumab: 4-Year US Pharmacovigilance Report.

Brodalumab is an interleukin-17 receptor A antagonist approved for the treatment of moderate-to-severe psoriasis in adults without response or with loss of response to other systemic therapies. Brodalumab carries a boxed warning in the United States regarding suicidal ideation and behavior, though no causal relationship has been established. Here, we summarize 4 years of pharmacovigilance data, from August 15, 2017, through August 14, 2021, reported to Ortho Dermatologics by US patients and healthcare providers. The most common AEs listed in the brodalumab package insert (incidence ≥1%) and AEs of special interest are described. Brodalumab exposure estimates were calculated using the time between the first prescription-dispensing authorization date and last prescription-dispensing authorization date. Data were collected from 4019 patients with an estimated brodalumab exposure of 4563 patient-years. The most common AE was arthralgia (115 events; 2.52 events per 100 patient-years). No completed suicides and no new suicidal attempts were reported. There were 102 cases with serious infections; however, no serious fungal infections (including no new cases of oral candidiasis) were reported. There were 26 COVID-19 cases, and 3 of the cases with comorbid conditions were fatal. There were no new cases of Crohn’s disease. Of 37 reported malignancies among 32 cases, none were deemed related to brodalumab. Four-year pharmacovigilance data are consistent with the established safety profile reported in long-term clinical trials and 3-year pharmacovigilance data. J Drugs Dermatol. 2023;22(4) doi:10.36849/JDD.7344 Citation: Lebwohl M, Koo J, Leonardi C, et al. Brodalumab: 4-Year US pharmacovigilance report. J Drugs Dermatol. 2023;22(4):419-422. doi:10.36849/JDD.7344.

Deprescribing Strategies for Opioids and Benzodiazepines with Emphasis on Concurrent Use: A Scoping Review.

While the Food and Drug Administration's black-box warnings caution against concurrent opioid and benzodiazepine (OPI-BZD) use, there is little guidance on how to deprescribe these medications. This scoping review analyzes the available opioid and/or benzodiazepine deprescribing strategies from the PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases (01/1995-08/2020) and the gray literature. We identified 39 original research studies (opioids: n = 5, benzodiazepines: n = 31, concurrent use: n = 3) and 26 guidelines (opioids: n = 16, benzodiazepines: n = 11, concurrent use: n = 0). Among the three studies deprescribing concurrent use (success rates of 21-100%), two evaluated a 3-week rehabilitation program, and one assessed a 24-week primary care intervention for veterans. Initial opioid dose deprescribing rates ranged from (1) 10-20%/weekday followed by 2.5-10%/weekday over three weeks to (2) 10-25%/1-4 weeks. Initial benzodiazepine dose deprescribing rates ranged from (1) patient-specific reductions over three weeks to (2) 50% dose reduction for 2-4 weeks, followed by 2-8 weeks of dose maintenance and then a 25% reduction biweekly. Among the 26 guidelines identified, 22 highlighted the risks of co-prescribing OPI-BZD, and 4 provided conflicting recommendations on the OPI-BZD deprescribing sequence. Thirty-five states' websites provided resources for opioid deprescription and three states' websites had benzodiazepine deprescribing recommendations. Further studies are needed to better guide OPI-BZD deprescription.

Montelukast and Mental Health In Children Before and After Black Box Warning

In March 2020, the U.S. Food and Drug Administration (FDA) required a Black Box Warning for montelukast due to serious mental health side effects. We hypothesized that the warning would lead to an overall decrease in reports of mental health symptoms and disorders related to montelukast use among pediatric patients.

524 - Montelukast and mental health in pre-adolescent and adolescent patients before and after black box warning

524 - Montelukast and mental health in pre-adolescent and adolescent patients before and after black box warning

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.

Brincidofovir: A Novel Agent for the Treatment of Smallpox.

This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox. A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms Tembexa, brincidofovir, CMX001, smallpox treatment, and variola treatment. Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir. Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo. Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.

Time to Change: A Systems Pharmacology Approach to Disentangle Mechanisms of Drug-Induced Mitochondrial Toxicity.

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, which is associated with almost half of all Food and Drug Administration black box warnings, a variety of drug withdrawals, and attrition of drug candidates. This can mainly be attributed to a historic lack of sensitive and specific assays to identify the mechanisms underlying mitochondrial toxicity during drug development. In the last decade, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based systems pharmacological approaches. Here, we propose the implementation of a tiered systems pharmacology approach to detect adverse mitochondrial drug effects during preclinical drug development, which is based on a toolset developed to study inherited mitochondrial disease. This includes phenotypic characterization, profiling of key metabolic alterations, mechanistic studies, and functional in vitro and in vivo studies. Combined with binding pocket similarity comparisons and bottom-up as well as top-down metabolic network modeling, this tiered approach enables identification of mechanisms underlying drug-induced mitochondrial dysfunction. After validation of these off-target mechanisms, drug candidates can be adjusted to minimize mitochondrial activity. Implementing such a tiered systems pharmacology approach could lead to a more efficient drug development trajectory due to lower drug attrition rates and ultimately contribute to the development of safer drugs. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs adversely affect mitochondrial function, which can be detected using phenotypic assays. However, these methods provide only limited insight into the underlying mechanisms. In recent years, a better understanding of drug-induced mitochondrial dysfunction has been achieved by network-based and structure-based system pharmacological approaches. Their implementation in preclinical drug development could reduce the number of drug failures, contributing to safer drug design.

Emerging Role of Baricitinib in Dermatology Practice: All We Need to Know!

Baricitinib is a competitive inhibitor of the Janus Kinase family of non-receptor protein kinases, predominantly acting against JAK-1 and JAK-2 subtypes. By downregulating transcription of various pro-inflammatory cytokines, this drug has shown efficacy across various dermatoses. Approved for severe cases of alopecia areata and moderate-severe atopic dermatitis in adults, baricitinib is being increasingly tried across many other indications with promising results. It is prudent that dermatologists remain aware of boxed warnings and precautions with the use of this much-discussed molecule, including its infectious, thrombotic, cardiovascular, and malignant ramifications. Long-term data on the use of baricitinib in dermatological conditions are lacking and further research is warranted since most data on safety profile is extrapolated from its use in rheumatology. The present review aims to highlight the immunopathogenic mechanisms of JAK-1/2 blockade, approved and off-label uses in dermatology, along with a concise review of laboratory monitoring and the side-effect profile of baricitinib.

1754. Implementation of a targeted antimicrobial stewardship clinical decision support system on outpatient fluoroquinolone prescribing

Abstract Background Fluoroquinolones are broad spectrum antibiotics with several Food and Drug Administration (FDA)-issued black box warnings. Due to these risks, the FDA recommends reserving fluoroquinolones for situations with no alternatives. Beginning in 2020, the Joint Commission required outpatient antimicrobial stewardship activities due to overprescribing and growing resistance to antimicrobials. The role of this study was to implement a clinical decision support system (CDSS) targeting inappropriate outpatient fluoroquinolone prescribing. Methods This was a single center, quasi-experimental study evaluating patients prescribed oral fluoroquinolones in an outpatient ambulatory care setting between December 1, 2020-February 28, 2021 and December 1, 2021-February 28, 2022. Patients included in this study were divided into Pre-CDSS and Post-CDSS groups if they received oral antibiotics for pre-determined indications (see table 2 for the list of indications). The primary outcome was overall reduction in outpatient fluoroquinolone prescribing. Secondary objectives were reduction in outpatient fluoroquinolone prescribing by indication, orders by provider type, appropriate fluoroquinolone dosing per renal function and incidence of an emergency department (ED) visit or hospitalization within 90 days consistent with a fluoroquinolone adverse drug reaction. Results A total of 2,447 (1,105 in Pre-CDSS vs. 1,342 in Post-CDSS) were included for analysis. Fluoroquinolone prescribing significantly decreased in Post-CDSS group compared to Pre-CDSS group (4.9% vs. 3.4%; p = 0.03). There was a significant reduction in fluoroquinolone prescribing in abscess (8.5% vs. 4.9%; p = 0.003), dental abscess (4.4% vs. 0%; p < 0.00001), sinusitis (2.4% vs. 0.2%; p < 0.00001) and soft skin tissue infections (5.3% vs. 0.8%; p < 0.00001). In the fluoroquinolone subgroups, prescribing per provider type and appropriate dosing per renal function were similar, and there were no adverse events leading to an ED visit or hospitalization within 90 days. Conclusion Implementation of a CDSS resulted in a reduction of overall and targeted indication inappropriate fluoroquinolone prescribing. Disclosures Teri Fanizza, Pharm.D., BCPS, BCIDP, Merck & co inc: Stocks/Bonds|Pfizer Inc: Stocks/Bonds.

Codeine prescribing practices before and after the 2017 FDA warning at an academic health system

BackgroundIn April of 2017, the U.S. Food and Drug Administration (FDA) issued a boxed warning contraindicating codeine use in all patients younger than 12 years of age. ObjectivesThe purpose of this study was to describe changes in codeine prescribing practices across a broad range of professions and specialties before and after the boxed warning and identify opportunities for optimization of a health system-wide response to changes in evidence-based practice recommendations. MethodsPatients younger than 12 years of age with codeine-containing products prescribed between February 2017 and April 2018 at a single health system were included. Patient demographics, provider specialty, and prescription indication were collected by retrospective chart review. For categorical variables, frequency and percentage were calculated; for continuous variables, means with standard deviations or medians with interquartile ranges were calculated. ResultsCodeine prescriptions for patients younger than 12 years of age declined after the boxed warning issued by the FDA. Some provider specialties reacted promptly whereas others took longer to change their practice. Temporally, the largest decreases in prescribing centered around the month after the FDA communication release in April 2017 and the later implementation of electronic health record (EHR) alerts in June 2017. ConclusionGiven the persistence of codeine prescribing even after EHR soft-stop alerts were implemented, future pharmacy informatic responses to changes in evidence-based practice recommendations could be optimized using hard-stop alerts for high-impact recommendations. Studies comparing combination codeine products and other opioid medications for chronic pain in pediatric patients would be helpful to characterize the true level of risk in this population.

CYP2D6 Substrate Dispensing Among Patients Dispensed Mirabegron: An Administrative Claims Analysis.

Overactive bladder (OAB) is characterized by the presence of bothersome urinary symptoms. Pharmacologic treatment options for OAB include anticholinergics and β3-adrenergic agonists. Use of β3-adrenergic agonists may result in similar treatment efficacy with a decreased side effect profile compared with anticholinergics because high anticholinergic burden is associated with cardiovascular and neurologic side effects. However, the β3-adrenergic agonist mirabegron, one of two approved drugs within this class, is a moderate cytochrome P450 (CYP) 2D6 inhibitor, and coadministration of drugs that are CYP2D6 substrates with mirabegron may lead to adverse drug effects. The aim of this study was to quantify how often CYP2D6 substrates were dispensed in patients receiving mirabegron among adults of any age and among those ≥ 65 years of age. In this retrospective descriptive analysis, a deidentified administrative claims database in the United States, IQVIA PharMetrics® Plus, was used to identify dispensing claims for CYP2D6 substrates and mirabegron from November 2012 to September 2019. Prevalence of CYP2D6 substrate dispensing was assessed in patients dispensed mirabegron among all adults ≥ 18 years old and additionally among a cohort of those ≥ 65 years old. Patient baseline profiles at the time of mirabegron and CYP2D6 substrate codispensing and at the time of mirabegron dispensing were compared. CYP2D6 substrates were categorized as those with the potential for increased risk of QT prolongation, with anticholinergic properties, with narrow therapeutic index (NTI), contraindicated or having a black box warning when used with CYP2D6 inhibitors, or used for depression or other psychiatric disease. Dispensing data and patient profiles were summarized descriptively. Overall, 68.5% of adults ≥ 18 years old dispensed mirabegron had overlapping dispensings for one or more CYP2D6 substrate; 60.6% and 53.6% had overlapping dispensings for CYP2D6 substrates with anticholinergic properties or risk of QT prolongation, respectively. CYP2D6 substrates with NTI, contraindicated with CYP2D6 inhibitors, or for psychiatric use were codispensed in 17.7%, 16.6%, and 38.0% of adult mirabegron users, respectively. Mirabegron users receiving one or more concurrent CYP2D6 substrate were more likely to be older, have more comorbidities and baseline polypharmacy, and have increased healthcare resource utilization compared with those without concurrent CYP2D6 substrates. Commonly codispensed CYP2D6 substrates included hydrocodone, oxycodone, tramadol, metoprolol, and tamsulosin. Findings were similar for patients in the older cohort (≥ 65 years old), with 72.1% receiving overlapping CYP2D6 substrates. Codispensing of CYP2D6 substrates, especially those with anticholinergic properties or risk of QT prolongation, was common among adults and older adults receiving mirabegron. Results highlight the need for improved awareness of CYP2D6 substrate prescribing among patients receiving pharmacologic treatment for OAB that inhibits the CYP2D6 pathway.

Investigation of the boxed warnings in package inserts of prescription medicines for medical professionals in Japan.

In the Japanese Pharmacists Act, article 25-2, revised in 2013, it states that pharmacists shall provide the necessary information and guidance to the patient based on pharmaceutical knowledge and experience for ensuring the proper use of the medicine dispensed. The package insert is one of the documents to be referred to when providing the information and guidance. The boxed warnings in package inserts that include the precautions and responses are the most significant parts, however, the suitability of boxed warnings for pharmaceutical practice has not been evaluated. The aim of this study was to investigate the boxed warning descriptions in package inserts of prescription medicines for medical professionals in Japan. Package inserts of prescription medicines listed in the Japanese National Health Insurance drug price list on March 1st 2015 were collected one by one by hand from the website of the Japanese Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/english/). Package inserts with boxed warnings were classified according to the Standard Commodity Classification Number of Japan based on the pharmacological activity of each medicine. They were also compiled according to their formulations. The boxed warnings were divided into the precautions and responses parts, and their characteristics were compared among medicines. The number of package inserts found on the website of the Pharmaceuticals and Medical Devices Agency was 15,828. Boxed warnings were present in 8.1% of the package inserts. A description of adverse drug reactions accounted for 74% of all precautions. Most of the precautions were observed in the warning boxes of antineoplastic agents. Blood and lymphatic system disorders were the most common precaution. Responses in the boxed warnings directed toward medical doctors, pharmacists, and other healthcare professionals accounted for 100, 77, and 8% of all package inserts with a boxed warning, respectively. Explanations for patients were the second most frequent response. The majority of boxed warnings request therapeutic contribution by pharmacists, and the descriptions of these explanations and guidance by pharmacists to patients were found to be consistent with the Pharmacists Act.

Clinical Utility of Romosozumab in the Management of Osteoporosis: Focus on Patient Selection and Perspectives.

As one of the most potent osteoanabolic agents with a unique mechanism of action, romosozumab has high efficacy for osteoporosis treatment. It is a monoclonal antibody against sclerostin, a natural inhibitor of the Wnt signaling pathway, and by inhibiting sclerostin, activation of Wnt signaling occurs with a cascade of changes ultimately leading to bone mineral density (BMD) gains. Romosozumab stimulates bone modeling and has a dual effect of activating bone formation while inhibiting bone resorption. With this unique mechanism of action, treatment with romosozumab leads to a rapid and significant gain in BMD; these gains are higher than seen with bisphosphonates, denosumab, or parathyroid hormone (PTH) analogs. The FRAME and ARCH studies represent two pivotal trials demonstrating the efficacy of romosozumab in treating osteoporosis. Treatment with romosozumab should be followed by an antiresorptive agent, as this approach has demonstrated maintenance of or greater increases in BMD and reduced fracture risk even after finishing romosozumab treatment. As an osteoanabolic agent, romosozumab has shown superiority to alendronate in reducing fracture risk, increasing bone density, and potentially more rapid fracture risk reduction. Recent data have suggested that romosozumab prior to antiresorptive therapy may be the ideal treatment sequence, especially in high-risk patients and patients at imminent risk of fracture. Carrying a black box warning, romosozumab should be avoided in patients who have had myocardial infarction or stroke in the past year. Further studies are needed to clarify the increased cardiovascular risk attributed to this drug. Romosozumab has expanded our osteoporosis armamentarium and has enabled novel approaches, including "treat to target." Future studies are needed to evaluate the optimal use sequence and to assess its safety, especially in patients with cardiovascular risk factors.

Increased Readmission Rates in Younger Male Patients Due to Suicidal Risk in Newly Diagnosed Depressive Disorders After Initiation of Serotonin Reuptake Inhibitors.

Background Depressive disorders have a prevalence of 322 million people worldwide and are a leading cause of morbidity. These disorders can affect individuals of all ages and can present over time. Due to the diversity in the presentation of depressive disorders, vigilance towards depressive disorders can lead to more timely and effective treatment. Serotonin Selective Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are the first lines of treatment for these disorders. Moreover, the United States Food and Drug Administration (FDA) issued a black-box warning for several antidepressants, stating an increased risk of suicidality in individuals under 25 years old. However, the placement of this black-box warning has been controversial. In this study, the authors aim to investigate if there is a relationship between the use of SSRI or SNRI on patients with newly diagnosed depressive disorder and hospital readmission due to suicide-related events. Methods For this retrospective cohort study, de-identified data were obtained from the HCA Healthcare database by searching for patients newly diagnosed with depressive disorders and started on SSRIs or SNRIs. Patient data were evaluated for readmissions due to suicide-related events within 90 days of discharge from the hospital and establishing their initial SSRI/SNRI prescription. Results After data was obtained and evaluated via statistical analysis, the variables with statistical significance were: age (p-value = 0.0164) and sex (p-value = 0.0150). These two were significantly associated with the rate of readmission: younger and male patients had an increased risk of readmission due to suicide-related events within 90 days of discharge after starting SSRI, or SNRI, to treat depressive disorders. Conclusion These results support the importance of monitoring patients started on SSRI or SNRI, with particularly careful consideration in depressed young male patients.

Safety and Tolerability of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd), a recombinant fusion protein composed of diphtheria toxin fragments and human interleukin-2 was approved and marketed (as ONTAK) in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. Manufacturing improvements (to decrease the presence of misfolded and aggregated proteins) resulted in a new, more bioactive formulation, E7777. It is considered a new drug by the FDA and required a new registrational clinical trial. Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial in which the primary efficacy and safety of E7777 were assessed. Here, we report the safety results of E7777. Methods: E7777 was given at 9 mcg/kg/day for 5 days every 21 days up to 8 cycles in patients with relapsed/refractory CTCL. Key inclusion/exclusion criteria: histopathologic diagnosis of CTCL; ECOG PS 0 or 1; no prior exposure to ONTAK. Evaluation of safety included incidence and severity of treatment-emergent AEs (TEAEs), and adverse events of special interest (AESIs). Key AESIs include capillary leak syndrome (CLS), infusion reaction, visual impairment (these three AEs were listed as Box warnings in the ONTAK label); and hepatotoxicity. Results: The Primary Efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR; detailed efficacy data will be presented in a separate abstract. In the subset of patients with Stage I-III disease (n=69), the median age was 64 years and the median number of E7777 cycles received was 6 (range 1 to 42); 66 patients had mycosis fungoides and 3 had Sezary syndrome, and 39 (57%) had disease of stage IIb or worse. The most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Thirty patients (43.5%) had a Grade ≥3 TEAE (90% Grade 3; 10% Grade 4)). The most common serious adverse events (≥ 5%) were capillary leak syndrome (10%) and infusion reactions (9%). Overall, the mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles. Most patients [92.8%] had at least 1 AESI (mostly Grade 1/2). Overall, 22 patients (31.9%) experienced AESIs that were Grade ≥3; (7.2%) had drug discontinuation; (4.3%) had drug dose reduction, and (26.1%) had drug dose interruption. Fourteen patients (20.3%) had CLS. CLS was defined as the occurrence of at least 2 of the following: hypotension, edema, or serum albumin < 3.0 g/dL. CLS was Grade 1 in 2.9%, Grade 2 in 11.6%, Grade 3 in 4.3%, and Grade 4 in 1.4%. Nine patients (13.0%) underwent drug modification: (4.3%) discontinued E7777; and (10.1%) had either dose reduction or temporary dose interruption. CLS typically occurred in the first 1/2 cycles. Risk/severity of CLS was mitigated by fluid management; confirmation of serum albumin levels (≥ 3.0 g/dl); close monitoring of weight, edema, and BP; early drug interruption; and rapid initiation of diuretic therapy on recovery. Fifty-one patients (73.9%) had an AESI related to infusion reaction. Grade 1 in 43.5%, Grade 2 in 26.1%, and Grade 3 in 4.3%. One patient (1.4%) had study drug discontinuation, and (11.6%) had either study drug dose reduction or interruption. In the event of infusion-related reactions, systemic corticosteroids may be added to premedication for subsequent E7777 infusions. Nine patients (13.0%) had an event related to visual impairment; all were AEs of blurred vision, which was Grade 1 in 11.6% and Grade 2 in 1.4%; no Grades 3, 4, or 5. One patient (1.0%) had drug interruption; no events led to study drug dose reduction. Twenty-five patients (36.2%) had AESI related to hepatoxicity. The TEAEs were Grade 1 in 17.4%, Grade 2 in 7.2%, Grade 3 in 11.6%, and no Grade 4/5. The majority of hepatic adverse events were elevations in transaminases that occurred within the first or second cycle, resolved without medical intervention, and did not require treatment discontinuation. Conclusion: No new safety signals were observed with E7777 when compared to the safety profile of ONTAK. There is no evidence of cumulative toxicity. Most patients had at least 1 TEAE which were mostly Grade 1/2. Specific AESIs: CLS, infusion reactions, and visual impairment (prior ONTAK Box warnings) were mostly Grade 1/2 and effectively managed. Overall, E7777 was well-tolerated with the use of pre-medications, close patient monitoring, and prompt initiation of supportive measures and drug management. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Public Perceptions of Breast Implant Complications and the FDA Boxed Warning on Implants.

A cross-sectional survey was administered to adult women in the United States in December 2021 using Amazon Mechanical Turk to assess perceptions of breast implant risks communicated in the FDA-issued guidance. Sociodemographic predictors of responses were identified using multivariable models. There were 494 complete responses. Respondents had a mean age of 36.9 years, and 80% had an associate's degree or higher. At baseline, most would consider receiving implants for reconstructive or cosmetic purposes (65%). Some were unsure or indicated that it is not possible to undergo mammograms after receiving implants (42%). After provided information in the FDA guidance, the majority strongly agreed or agreed that they were less likely to receive implants knowing the risk of anaplastic large cell lymphoma (75%), because implants contain chemicals/heavy metals (74%), and because implants are not lifetime devices (68%), with greater odds among Hispanic respondents (OR, 2.35; P < 0.01) and lower odds among higher-income respondents (OR, 0.64; P = 0.03). There are misconceptions with regard to breast implant-associated risks. Despite most laywomen indicating that they would consider receiving implants at baseline, the risks communicated in the 2021 FDA boxed warning may make patients less likely to receive implants, with variability among different sociodemographic populations.

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2022.

As part of FDA’s MedWatch program, important changes to the safety labeling of drugs and therapeutic biologicals, 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 from the drug that it is essential that the reaction be considered in assessing the risks and benefits of using the drug, (2) serious adverse reactions that can be prevented or reduced in frequency or severity by appropriate use of the drug, and (3) situations in which FDA approved a drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.1 The following revisions to warnings were implemented in the 3 months ending September 2022. The revised boxed warning emphasizes that diclofenac sodium/misoprostol is contraindicated during pregnancy and is not recommended for use by women of childbearing potential. Prescribers should verify the pregnancy status of females of reproductive potential before initiating therapy and advise them to use effective contraception during treatment.

Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease.

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD.

Anxiety Disorders in Children.

Anxiety disorders are the most common mental health disorders in children with clearly defined and empirically based treatment. However, assessment and treatment pose several obstacles for pediatric providers. A child who may have age-appropriate communication skills will still struggle to accurately report the presence, timing, and severity of symptoms. Reports from parents, caregivers, and teachers are often subjective and can focus on 1 aspect of the child's behavior. Untreated, anxiety disorders have an adverse effect on a child's functioning, and impairments in physical health, academic performance, and social competence can lead to lifelong consequences. Well-validated and rapidly administered screening tools can be used to gather data from schools and other resources to inform the diagnosis, guide treatment recommendations, and track improvements. Limited training on behavioral health diagnosis and fear of "black box warnings" have left many pediatric clinicians reluctant to prescribe medications. There are readily available practice guidelines for these medications, and data documenting the efficacy of these medications for children should encourage their use.

JAK Inhibitor Safety Compared to Traditional Systemic Immunosuppressive Therapies.

Dermatologists treating atopic dermatitis are interested in the safety profile of the recently available JAK inhibitors, upadacitinib and abrocitinib, especially after they received boxed safety warnings. Long-term clinical trial data using these JAK inhibitors for the treatment of atopic dermatitis suggest that they are associated with very low incidence rates of malignancy, major adverse cardiac events, and thromboembolic events. However, a knowledge gap exists regarding the incidence of adverse events for JAK inhibitors compared to traditional systemic therapies used to treat poorly controlled atopic dermatitis as well as baseline rates in both atopic dermatitis and reference control populations. To address this gap, we analyzed data regarding adverse events of special interest for methotrexate, cyclosporine, and systemic corticosteroids and calculated the incidence of adverse events per 100 patient-years for these drugs. We also examined data regarding baseline incidence of adverse events in atopic dermatitis and control patients. We found that compared to upadacitinib and abrocitinib, traditional systemic therapies for atopic dermatitis demonstrated equal or higher incidence rates for malignancy (excluding non-melanoma skin cancer), non-melanoma skin cancer, major adverse cardiac events, and venous thromboembolism. Moreover, the use of upadacitinib and abrocitinib also exhibited either comparable or lower incidence of malignancy (excluding non-melanoma skin cancer), major adverse cardiac events, and venous thromboembolism, but higher rates of non-melanoma skin cancer, in comparison to baseline rates in atopic dermatitis or control patients. These findings indicate that JAK inhibitors should be positioned, at least based on safety, ahead of traditional systemic therapies for atopic dermatitis treatment.J Drugs Dermatol. 2022;21(12):1298-1303. doi:10.36849/JDD.7187.