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BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohns disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVies safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Purpose: Clozapine is an antipsychotic which was approved in 1989 for treatment-resistant schizophrenia in the United States (US). There were few randomized trials before its approval and potentially lethal clozapine adverse drug reactions (ADRs), such as agranulocytosis and myocarditis were identified by pharmacovigilance. VigiBase, the WHO global database, is a cornerstone of international pharmacovigilance efforts for ADR identification during post-marketing surveillance. This systematic review of the literature explores additional contributions to the knowledge of clozapine ADRs from recent VigiBase studies. Methods: Using the terms "clozapine AND VigiBase" we conducted an article search in PubMed on September 5, 2024. Of the 29 articles, 11 were excluded and 18 described in the Results section. Results: All clozapine ADRs were described in two VigiBase studies. One on pregnancy indicated no increased risk with clozapine compared with other antipsychotics; the other reported 191,557 clozapine ADRs, including 22,956 fatal outcomes through January 15, 2023, and paid attention to the reporting style of the top 4 reporting countries (the US, the United Kingdom, Canada and Australia). Infections were described in three VigiBase studies where clozapine treatment was associated with infections, respiratory aspiration, and pneumonia. Rapid titration can lead to localized clozapine-induced inflammations including myocarditis, pericarditis or pancreatitis, or generalized inflammations such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clozapine-induced inflammation was described in four VigiBase studies, two focused on all ages (myocarditis and DRESS) and two on youth (myocarditis and another on pericarditis and pancreatitis). Other specific ADRs were described in nine VigiBase studies (hematological malignancies, rhabdomyolysis, sialorrhea, seizures, diabetes mellitus, drug-induced parkinsonism, withdrawal symptoms, and suicidal behaviors). Conclusion: The spectrum of respiratory aspiration – aspiration pneumonia – pneumonia and other infections are significant causes of fatal outcomes in clozapine-treated patients. Clozapine had anti-suicidal effects versus other antipsychotics across all VigiBase labels of suicidal behavior. Plain Language Summary: Why was the review done? Marketers develop a package insert after a medical drug is licensed for use in each country. The package insert describes the known benefits and risks of the drug at the time it was licensed. After licensing, post-marketing studies are continued to look for possible undetected adverse drug reactions; this process is called pharmacovigilance. These pharmacovigilance studies should be done by the drug agencies in all countries. These national agencies send their reports to the international pharmacovigilance database, VigiBase. VigiBase is managed by the World Health Organization and is located in Uppsala, Sweden. Clozapine is a second-generation antipsychotic medication that was licensed in 1989 in the United States for treatment-resistant schizophrenia and then approved by other countries. In 1989 there was major concern about clozapine causing agranulocytosis (loss of white blood cells), so a hematological monitoring system was required in the United States. Later, myocarditis was associated with clozapine in pharmacovigilance studies. What did the authors do? They systematically reviewed VigiBase studies on clozapine adverse drug reactions and identified 18 studies that described clozapine adverse drug reactions in detail. What do these results mean? These VigiBase studies indicate that the respiratory aspiration – aspiration pneumonia – pneumonia spectrum, along with other infections, are significant causes of fatal outcomes in clozapine-treated patients, but this is not mentioned in any clozapine package insert. On the positive side, VigiBase data confirms other literature that clozapine may have specific anti-suicidal effects not present in other antipsychotics. [ABSTRACT FROM AUTHOR]

It has become increasingly common for patients to rely on the use of multiple prescription medications. The management of polypharmacy requires careful consideration for how drugs are metabolized and their potential for interaction with other drugs. Drug–drug interaction (DDI) assessments are typically performed in a stepwise manner during drug development, though knowledge gaps can exist at the time of approval. The US Food and Drug Administration can establish postmarketing requirements (PMRs) or postmarketing commitments (PMCs) to address these knowledge gaps. In this study, we systematically evaluated PMRs and PMCs established to new molecular entities (NMEs) at the time of initial approval between 2009 and 2023, for the assessment of pharmacokinetics‐based DDIs (i.e., drug metabolizing enzyme‐ and transporter‐related DDIs). We found that 22% of NMEs had at least one DDI‐related PMR or PMC, with a total of 263 that were pharmacokinetic based. Of these, 67% were for the assessment of drug metabolizing enzymes, which were established most frequently for their evaluation as a substrate, and 28% for transporters, which were established most frequently for their evaluation as an inhibitor. The 89% of PMRs and PMCs that were considered fulfilled had a revision to the United States prescribing information, the majority of which resulted in updated new instructions for use. This study highlights the value in conducting PMRs and PMCs early in the drug development process allowing broad patient inclusion at the time of initial drug approval. [ABSTRACT FROM AUTHOR]

Background: To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM). Methods: This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and body weight. Results: Data were collected from 3,067 subjects, and 3,022 subjects who received =1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg). Conclusion: Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population. [ABSTRACT FROM AUTHOR]

Sudden sensorineural hearing loss (SSNHL), a rare audiological condition that accounts for 1% of all cases of sensorineural hearing loss, can cause permanent hearing damage. Soon after the launch of global COVID-19 vaccination campaigns, the World Health Organization released a signal detection about SSNHL cases following administration of various COVID-19 vaccines. Post-marketing studies have been conducted in different countries using either pharmacovigilance or medico-administrative databases to investigate SSNHL as a potential adverse effect of COVID-19 vaccines. Here, we examine the advantages and limitations of each type of post-marketing study available. While pharmacoepidemiological studies highlight the potential association between drug exposure and the event, pharmacovigilance approaches enable causality assessment. The latter objective can only be achieved if an expert evaluation is provided using internationally validated diagnostic criteria. For a rare adverse event such as SSNHL, case information and quantification of hearing loss are mandatory for assessing seriousness, severity, delay onset, differential diagnoses, corrective treatment, recovery, as well as functional sequelae. Appropriate methodology should be adopted depending on whether the target objective is to assess a global or individual risk. [ABSTRACT FROM AUTHOR]

A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020. As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

We assessed the frequency that oncology drugs approved by the U.S. Food and Drug Administration (FDA) based on a single-arm study when there is already evidence of existing and available treatments. For this, we conducted a retrospective cross-sectional analysis of FDA-approved oncology drugs based on a single-arm study. All FDA announcements for all oncology drugs approved from May 2014 through June 2019 on a single-arm trial were included. We then performed a systematic search in PubMed, looking for studies on other drugs for the same indication as the FDA drug approval. For the 60 indications, we found 38 instances (63%) of existing therapies being used for the same indication. Of those, we found that 20 drugs were approved based upon a response rate lower than response rates of existing therapies in the same indication. Among oncology drugs that were FDA-approved based on a single-arm study, we found evidence of existing, available therapies being used for the same indication as the FDA-approved drug in the majority of indications (63%), and in one-third of all indications, the response rates for existing therapies were numerically better than the FDA-approved drug. These results suggest that there are inconsistencies in the standards set for oncology drug approvals, and many uncontrolled trials leading to drug approvals could have contemporary controls for which equipoise exists.

The helicase–primase inhibitor amenamevir (AMNV) was approved for herpes zoster in Japan in 2017. The authors conducted a 1‐month postmarketing observational study to evaluate the real‐world safety and efficacy (cutaneous improvement and pain resolution) of AMNV in patients with herpes zoster. Of the 3453 patients registered between March 2018 and December 2020, 3110 were included in the safety analyses. The mean age (±standard deviation) was 63.7 ± 17.5 years, with 57.9% of patients aged ≥65 years. Most patients had mild (53.3%) or moderate (41.0%) cutaneous lesions. Regarding pain, 43.9%, 25.6%, and 12.5% of patients had pain at the levels of 1–3, 4–6, and 7–10 on the numerical rating scale. In total, 30.0%, 27.2%, and 16.1% of patients were concomitantly treated with analgesics: acetaminophen, nonsteroidal anti‐inflammatory drugs, and Ca2+ channel α 2δ ligands, respectively, and 10.6% were treated with topical antiherpetic drugs. Adverse drug reactions occurred in 0.77% of patients, including four serious adverse drug reactions in four patients (hyponatremia, thrombocytopenia, rash, and rhabdomyolysis). Regarding important potential risks, renal disorder, cardiovascular events, and decreased platelets were observed in one, one, and two patients, respectively. Concerning efficacy, the cutaneous improvement rate (significantly improved or improved) was 95.5%, with significantly higher improvement rates in patients treated with AMNV for 7 days and in patients with less severe cutaneous lesions or less pain. Factors affecting the time to pain resolution were the severity of cutaneous lesions and pain at the start of AMNV treatment and older age. This study demonstrated that the AMNV is safe and effective in patients with herpes zoster in a real‐world clinical setting. [ABSTRACT FROM AUTHOR]

Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization's List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

IntroductionTumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting.MethodsUnsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age ( 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

This cross-sectional study estimates the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs.

Background Umeclidinium/vilanterol (UMEC/VI; ANORO ELLIPTA, GSK) is a commonly used dual bronchodilator. This study evaluated the safety and effectiveness of UMEC/VI in Korean patients with chronic obstructive pulmonary disease (COPD) over a 6-year period. Methods This was an open-label, multicentre, observational, post-marketing surveillance study. A total of 3,375 patients were enrolled consecutively in 52 hospitals, by 53 physicians, between July 2014 and July 2020. Patients who were administered UMEC/VI (fixed-dose 62.5 μg/25 μg) at least once and were monitored for safety and effectiveness were included in the analysis. Incidence and severity of adverse events (AEs) reported after administrating at least one dose of UMEC/VI were monitored, including unexpected adverse events (UAEs) and adverse drug reactions (ADRs). Effectiveness of UMEC/VI after 24 weeks of administration was also assessed using physician’s evaluation (effective, ineffective/no change, worsening, indeterminable) and lung function improvement. Results Of 3,375 patients, 3,086 were included in the safety assessment group (mean age±standard deviation: 69.76±8.80 years; 85.9% male [n=2,652]; 73.1% aged ≥65 years [n=2,255]). The overall incidence of AEs was 28.8% (n=890), of which 2.2% (n=67) were ADRs. Serious AEs and UAEs were reported in 181 (5.9%) and 665 (21.6%) patients, respectively, and two patients (

The World Health Organization estimates the number of people suffering from depression to be over 264 million. Current monoamine transmission modulating therapeutics, even with proper adherence and acceptable tolerability, are not effective for nearly one third of the patients, leading clinicians to explore other therapeutic options such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine infusions, and, more recently, glabellar botulinum toxin, BoNT, injections. The scale and mechanism of antidepressant action of BoNT is unclear and maybe hypothetically attributed to the disruption of proprioceptive facial feedback reinforcing negative emotions. Here we verify the antidepressant effect of botulinum toxin by analysis of over 40 thousand BoNT treatment reports out of thirteen million postmarketing safety reports in the FDA Adverse Event Reporting System, FAERS. The results of the analysis indicate that patients who received BoNT injections to treat hyperhidrosis, facial wrinkles, migraine prophylaxis, spasticity, and spasms, had a significantly lower number of depression reports when compared to patients undergoing different treatments for the same conditions. These findings suggest that the antidepressant effect of BoNT is significant, and, surprisingly, is observed for a broad range of injection sites.

ObjectivesTo report the results of the Nit-Occlud PDA prospective postapproval study (PAS) along with a comparison to the results of the pivotal and continued access trials.BackgroundThe Nit-Occlud PDA (PFM Medical, Cologne, Germany), a nitinol coil patent ductus arteriosus (PDA) occluder, was approved by the Food and Drug Administration in 2013.MethodsThe PAS enrolled a total of 184 subjects greater than 6 months of age, weighing at least 5 kg, with PDAs less than 4 mm by angiography at 11 centers. Patients were followed prospectively at 2 months, 12 months, and 24 months postprocedure. These outcomes were compared to the 357 subjects enrolled in the pivotal and continued access protocols. Efficacy and safety data were reported.ResultsAmong 184 subjects enrolled for the PAS between 2014 and 2017, 180 (97.8%) had successful device implantation. After 12 months, 98.7% (150/152) had trivial or no residual shunt by echocardiography and two subjects had only small residual shunts. There were three device embolizations that were all retrieved by snare without clinical consequence. Together with the pivotal and continued access study, 97.4% (449/461) had complete echocardiographic closure at 12 months in 541 enrolled subjects. The composite success was 94.4%. There were no mortalities and no serious device-related adverse events.ConclusionsThe Nit-Occlud PDA is a safe and effective device for closure of a small to moderate sized PDA. There were no serious device-related adverse events in a large cohort of three clinical trials.

Proton pump inhibitors, PPIs, are widely prescribed and sold globally. Although initially intended for time-limited treatment of acute disorders, such as gastric ulcers and esophagitis, PPIs are now commonly used for prolonged durations and are considered safe for over the counter access. Recent studies have raised concern over associations between PPI use and acute kidney injury, chronic kidney disease, end-stage renal disease, and electrolyte abnormalities. The growing concern over potentially serious adverse drug reactions warrants an evaluation of post marketing surveillance data. In this study of over ten million FDA Adverse Event Reporting System records, we provided evidence of kidney injury and electrolyte imbalances in an alarming number of patients taking PPIs. Additionally, we assessed differences between specific PPIs and observed significant electrolyte and renal abnormalities for each individual drug with varying magnitudes.

Purpose: Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real‐time, interactive, centralized statistical processing of individual‐level data from different data sets without transfer of sensitive personal data. Methods: We review IT‐architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. Results: In a review of all post‐authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. Conclusions: Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies. [ABSTRACT FROM AUTHOR]

Abstract Objective To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. Methods PROVE was a retrospective, non‐interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure‐freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment‐emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme‐inducing antiseizure medications (EIASMs). Results Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24‐month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. Significance In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

The meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix®; Pfizer Ltd, Sandwich, Kent, UK) is licensed in more than 80 countries worldwide for the prevention of meningococcal disease caused by serogroups A, C, W, and Y in individuals throughout their lifespans. This report summarizes safety data from the MenACWY-TT clinical development program and postmarketing experience. Within the clinical study program, reactogenicity data were based on 3 primary studies, including a large pooled analysis across multiple age groups, and long-term safety data were derived from 3 studies evaluating long-term antibody persistence. Postmarketing safety data through April 19, 2021, were collected and analyzed in connection with the MenACWY-TT Periodic Safety Update Report. Approximately 32 million doses of MenACWY-TT have been administered worldwide, with more than 21,530 additional individuals receiving MenACWY-TT as part of clinical trials. The safety profile of MenACWY-TT was consistent between the clinical study program and the postmarketing experience, as well as with other licensed meningococcal vaccines. The most commonly observed adverse events (AEs) were pyrexia/fever, headache, injection site pain/reactions, nausea/vomiting, and fatigue; serious AEs were rare relative to the number of doses administered. Several cases of serogroup replacement/lack of efficacy were observed in the 1-year postmarketing period but did not appear to be related to MenACWY-TT use. Extensive data derived from clinical trials and postmarketing experience indicate a consistently favorable safety profile for MenACWY-TT across a wide range of age groups. [ABSTRACT FROM AUTHOR]

Background: . The Vaccine Adverse Event Reporting System (VAERS) is the United States national passive vaccine safety surveillance system. We updated the data on the safety of single-antigen varicella vaccine (VAR) and assessed the safety of combination measles, mumps, rubella, and varicella vaccine (MMRV) licensed in the United States using VAERS data.Methods: US VAERS reports received after administration of VAR and MMRV during 2006-2020 were identified. Reports were analyzed by vaccine type, age, seriousness, most common adverse events (AEs), and concomitant vaccines. We reviewed medical records of selected reports of AEs of special interest and conducted empirical Bayesian data mining to identify disproportionally reported AEs.Results: During 2006-2020, approximately 132.8 million VAR doses were distributed; 40 684 reports were received in VAERS (30.6/100 000 doses distributed), with 4.1% classified as serious (1.3/100 000 doses distributed). Approximately 35.5 million MMRV doses were distributed; 13 325 reports were received (37.6/100 000 doses distributed) with 3.3% classified as serious (1.3/100 000 doses distributed). The most common adverse health events after both VAR and MMRV were injection site reactions (31% and 27%), rash (28% and 20%), and fever (12% and 14%), respectively. Vaccination errors accounted for 23% of reports after VAR administration and 41% after MMRV administration, but ≥95% of them did not describe an adverse health event. AEs associated with evidence of vaccine strain varicella-zoster virus (vVZV) infection included meningitis, encephalitis, herpes zoster, and 6 deaths (all in immunocompromised persons with contraindications for vaccination). No new or unexpected AE was disproportionally reported.Conclusions: No new or unexpected safety findings were detected for VAR and MMRV given as recommended, reinforcing the favorable safety profiles of these vaccines. Providers should obtain specimens for viral testing and strain-typing for serious AEs if they consider vVZV as the possible causative agent. [ABSTRACT FROM AUTHOR]

Background: Clinical trials demonstrate the efficacy and tolerability of medications targeting calcitonin gene-related peptide (CGRP) signaling for migraine prevention. However, these trials may not accurately reflect the real-world experiences of more diverse and heterogeneous patient populations, who often have higher disease burden and more comorbidities. Therefore, postmarketing safety surveillance is warranted. Regulatory organizations encourage marketing authorization holders to screen digital media for suspected adverse reactions, applying the same requirements as for spontaneous reports. Real-world data from social media platforms constitute a potential venue to capture diverse patient experiences and help detect treatment-related adverse events. However, while social media holds promise for this purpose, its use in pharmacovigilance is still in its early stages. Computational linguistics, which involves the automatic manipulation and quantitative analysis of oral or written language, offers a potential method for exploring this content., Objective: This study aims to characterize adverse events related to monoclonal antibodies targeting CGRP signaling on Reddit, a large online social media forum, by using computational linguistics., Methods: We examined differences in word frequencies from medication-related posts on the Reddit subforum r/Migraine over a 10-year period (2010-2020) using computational linguistics. The study had 2 phases: a validation phase and an application phase. In the validation phase, we compared posts about propranolol and topiramate, as well as posts about each medication against randomly selected posts, to identify known and expected adverse events. In the application phase, we analyzed posts discussing 2 monoclonal antibodies targeting CGRP signaling-erenumab and fremanezumab-to identify potential adverse events for these medications., Results: From 22,467 Reddit r/Migraine posts, we extracted 402 (2%) propranolol posts, 1423 (6.33%) topiramate posts, 468 (2.08%) erenumab posts, and 73 (0.32%) fremanezumab posts. Comparing topiramate against propranolol identified several expected adverse events, for example, "appetite," "weight," "taste," "foggy," "forgetful," and "dizziness." Comparing erenumab against a random selection of terms identified "constipation" as a recurring keyword. Comparing erenumab against fremanezumab identified "constipation," "depression," "vomiting," and "muscle" as keywords. No adverse events were identified for fremanezumab., Conclusions: The validation phase of our study accurately identified common adverse events for oral migraine preventive medications. For example, typical adverse events such as "appetite" and "dizziness" were mentioned in posts about topiramate. When we applied this methodology to monoclonal antibodies targeting CGRP or its receptor-fremanezumab and erenumab, respectively-we found no definite adverse events for fremanezumab. However, notable flagged words for erenumab included "constipation," "depression," and "vomiting." In conclusion, computational linguistics applied to social media may help identify potential adverse events for novel therapeutics. While social media data show promise for pharmacovigilance, further work is needed to improve its reliability and usability., (©Pengfei Zhang, Brad K Kamitaki, Thien Phu Do. Originally published in JMIR Formative Research (https://formative.jmir.org), 08.11.2024.)

PurposeTo analyze all recalls involving radiation oncology devices (RODs) from the US Food and Drug Administration (FDA)'s recall database, comparing these with non-radiation oncology device recalls to identify discipline-specific trends that may inform improvements in device safety.Methods and materialsRecall data on RODs from 2002 to 2015 were sorted into 4 product categories (external beam, brachytherapy, planning systems, and simulation systems). Outcomes included determined cause of recall, recall class (severity), quantity in commerce, time until recall termination (date FDA determines recall is complete), and time since 510(k) approval. Descriptive statistics were performed with linear regression of time-series data. Results for RODs were compared with those for other devices by Pearson χ2 test for categorical data and 2-sample Kolmogorov-Smirnov test for distributions.ResultsThere were 502 ROD recalls and 9534 other class II device recalls during 2002 to 2015. Most recalls were for external beam devices (66.7%) and planning systems (22.9%), and recall events peaked in 2011. Radiation oncology devices differed significantly from other devices in all recall outcomes (P≤.04). Recall cause was commonly software related (49% vs 10% for other devices). Recall severity was more often moderate among RODs (97.6% vs 87.2%) instead of severe (0.2% vs 4.4%; P

Background/Aims: Golimumab (GLM) is an anti-tumor necrosis factor-a drug approved for treating moderate-to-severe active ulcerative colitis (UC). A 52-week post-marketing surveillance (PMS) was initiated to evaluate its safety and effectiveness in patients with UC in Japan. We present an interim report of the ongoing PMS. Methods: Patients received 200 mg of subcutaneous GLM at week 0, 100 mg at week 2, and 100 mg 4 weekly thereafter. The safety analysis set included 392 patients with UC, and the effectiveness analysis set 387 patients. Safety and effectiveness were assessed at week 6. Results: Adverse drug reactions (ADRs) were reported in 8.2% (32/392) and serious ADRs in 4.6% (18/392). The most frequent ADRs were infection and infestation (3.3%), with herpes zoster being the most common. ADRs were significantly higher in patients with concomitant corticosteroid use (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.40-9.68). No significant difference in ADR incidence was observed between patients aged = 65 and < 65 years (OR, 1.23; 95% CI, 0.35-3.47). Six-week effectiveness of GLM was confirmed by a decrease in the partial Mayo score (-2.3; 95% CI, -2.6 to -2.1) and C-reactive protein levels (-0.64; 95% CI, -0.92 to -0.36), including in the biologics-experienced population. Conclusions: The safety and effectiveness of GLM at week 6 in a real-world setting were demonstrated in patients with UC in Japan. ADR patterns were consistent with previous reports with no new safety signals. Concomitant corticosteroid use may be associated with increased ADR incidence. The final results of the ongoing PMS are necessary for further evaluation. [ABSTRACT FROM AUTHOR]

Background/Aims Elobixibat, an ileal bile acid transporter (apical sodium-dependent bile acid transporter) inhibitor, was recently launched in Japan for the treatment of chronic idiopathic constipation. We conducted an interim analysis of post-marketing surveillance to evaluate the safety and efficacy of elobixibat in elderly patients with chronic constipation and compared the efficacy according to administration time. Methods Safety and efficacy outcomes were evaluated through patient interviews for 4 weeks. Results Adverse drug reactions (ADRs) were observed in 5.24% of the 1049 patients analyzed; diarrhea (2.19%) and abdominal pain (1.81%) were the most common. A serious ADR of death was reported in one patient (0.10%). The incidence of ADRs in the = 65-year old or = 75-year-old subpopulation was similar to that in the total patient population. Mean bowel movements per week significantly increased from 2.9 ± 2.5 at baseline to 5.0 ± 3.1 (P < 0.001) at Week 2 and 5.3 ± 2.6 (P < 0.001) at Week 4. The mean Bristol Stool Form Scale score significantly increased from 2.3 ± 1.4 at baseline to 3.8 ± 1.3 (P < 0.001) at Week 2 and 3.9 ± 1.1 at Week 4 (P < 0.001). Bowel movements significantly increased in the elderly population and subpopulations receiving elobixibat before breakfast, lunch, or dinner. The median time to bowel movement was 5 hours. Conclusion The results suggested that elobixibat was well-tolerated and efficacious in elderly patients with chronic constipation and can be administered before any meals. [ABSTRACT FROM AUTHOR]

Objective: To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. Methods: PROVE was a retrospective, non‐interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure‐freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment‐emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme‐inducing antiseizure medications (EIASMs). Results: Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24‐month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. Significance: In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months. [ABSTRACT FROM AUTHOR]

ObjectiveInsomnia is associated with increased risk for suicide. The Food and Drug Administration (FDA) has mandated that warnings regarding suicide be included in the prescribing information for hypnotic medications. The authors conducted a review of the evidence for and against the claim that hypnotics increase the risk of suicide.MethodThis review focused on modern, FDA-approved hypnotics, beginning with the introduction of benzodiazepines, limiting its findings to adults. PubMed and Web of Science were searched, crossing the terms "suicide" and "suicidal" with each of the modern FDA-approved hypnotics. The FDA web site was searched for postmarketing safety reviews, and the FDA was contacted with requests to provide detailed case reports for hypnotic-related suicide deaths reported through its Adverse Event Reporting System.ResultsEpidemiological studies show that hypnotics are associated with an increased risk for suicide. However, none of these studies adequately controlled for depression or other psychiatric disorders that may be linked with insomnia. Suicide deaths have been reported from single-agent hypnotic overdoses. A separate concern is that benzodiazepine receptor agonist hypnotics can cause parasomnias, which in rare cases may lead to suicidal ideation or suicidal behavior in persons who were not known to be suicidal. On the other hand, ongoing research is testing whether treatment of insomnia may reduce suicidality in adults with depression.ConclusionsThe review findings indicate that hypnotic medications are associated with suicidal ideation. Future studies should be designed to assess whether increases in suicidality result from CNS impairments from a given hypnotic medication or whether such medication decreases suicidality because of improvements in insomnia.

PurposeRadiation oncology relies on rapidly evolving technology and highly complex processes. The US Food and Drug Administration collects reports of adverse events related to medical devices. We sought to characterize all events involving radiation oncology devices (RODs) from the US Food and Drug Administration's postmarket surveillance Manufacturer and User Facility Device Experience (MAUDE) database, comparing these with non-radiation oncology devices.Methods and materialsMAUDE data on RODs from 1991 to 2015 were sorted into 4 product categories (external beam, brachytherapy, planning systems, and simulation systems) and 5 device problem categories (software, mechanical, electrical, user error, and dose delivery impact). Outcomes included whether the device was evaluated by the manufacturer, adverse event type, remedial action, problem code, device age, and time since 510(k) approval. Descriptive statistics were performed with linear regression of time-series data. Results for RODs were compared with those for other devices by the Pearson χ2 test for categorical data and 2-sample Kolmogorov-Smirnov test for distributions.ResultsThere were 4234 ROD and 4,985,698 other device adverse event reports. Adverse event reports increased over time, and events involving RODs peaked in 2011. Most ROD reports involved external beam therapy (50.8%), followed by brachytherapy (24.9%) and treatment planning systems (21.6%). The top problem types were software (30.4%), mechanical (20.9%), and user error (20.4%). RODs differed significantly from other devices in each outcome (P

The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms.

BackgroundCountries remain reluctant to adopt the 2012 World Health Organization recommendation for single low-dose (0.25 mg/kg) primaquine (SLD PQ) for Plasmodium falciparum transmission-blocking due to concerns over drug-related haemolysis risk, especially among glucose-6-phosphate dehydrogenase-deficient (G6PDd) people, without evidence demonstrating that it can be safely deployed in their settings. Pharmacovigilance methods provide a systematic way of collecting safety data and supporting the rollout of SLD PQ.MethodsThe Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT), comprising: (1) a standardized form to support the surveillance of possible adverse events following SLD PQ treatment; (2) a patient information card to enhance awareness of known adverse drug reactions of SLD PQ use; and (3) a database compiling recorded information, was developed and piloted. Data on patient characteristics, malaria diagnosis and treatment are collected. Blood samples are taken to measure haemoglobin (Hb) and test for G6PD deficiency. Active follow-up includes a repeat Hb measurement and adverse event monitoring on or near day 7. A 13-month prospective pilot study in two hospital facilities in Swaziland alongside the introduction of SLD PQ generated preliminary evidence on the feasibility and acceptability of PROMPT.ResultsPROMPT was well received by nurses as a simple, pragmatic approach to active surveillance of SLD PQ safety data. Of the 102 patients enrolled and administered SLD PQ, none were G6PDd. 93 (91.2 %) returned on or near day 7 for follow-up. Four (4.6 %) patients had falls in Hb ≥25 % from baseline, none of whom presented with signs or symptoms of anaemia. No patient's Hb fell below 7 g/dL and none required a blood transfusion. Of the 11 (11 %) patients who reported an adverse event over the study period, three were considered serious and included two deaths and one hospitalization; none were causally related to SLD PQ. Four non-serious adverse events were considered definitely, probably, or possibly related to SLD PQ.ConclusionImproved pharmacovigilance to monitor and promote the safety of the WHO recommendation is needed. The successful application of PROMPT demonstrates its potential as an important tool to rapidly generate locally acquired safety data and support pharmacovigilance in resource-limited settings.

PurposeTo explore whether privacy restrictions developed to protect patients have complicated research within a 15-year surveillance study conducted with US cancer registries.MethodsData from enrolling 27 cancer registries over a 10-year period were examined to describe the amount of time needed to obtain study approval. We also analyzed the proportion of patients that completed a research interview out of the total reported by the registries and examined factors thought to influence this measure.ResultsThe average length of the research review process from submission to approval of the research was 7 months (range,

• Near real-time safety surveillance of Covid-19 vaccines during the vaccine roll-out is necessary. • A web-based prospective cohort using patient reported outcomes is useful for vaccine surveillance. • mRNA vaccine Comirnaty® gave the least reactogenicity after the first dose. • Persons with a history of COVID-19 disease, female sex and younger age had an increased odds for experiencing reactogenicity after vaccination. To explore factors that are associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine in the Netherlands. A web-based prospective cohort design using patient reported outcomes (PROs). Any person who has been vaccinated with any brand of COVID-19 vaccine in the Dutch COVID immunization programme. 22,184 participants. Of these, 13,959 (62.9%) experienced reactogenicity in general and 11,979 (54.0%) systemic reactogenicity within 7 days after vaccination. Factors that are associated with the occurrence of reactogenicity after COVID-19 vaccination. Compared to the Comirnaty® vaccine, the highest odds ratio (OR) for developing reactogenicity was for the Vaxzevria® vaccine (OR 5.18) followed by Spikevax® (OR 2.16), and Janssen (OR 1.65). Participants with a history of COVID-19 disease had a 3.10 increased odds for reactogenicity. Women had a 2.08 increased odds compared to men. Older participants experienced less reactogenicity. Compared to the age group < 50, the ORs for the age groups 50–60, 61–79, and ≥80 were 0.36, 0.15, and 0.10 respectively. The use of an antipyretic drug, or a drug for nervous system disorders gave an increased odds of 1.34 and 1.16 respectively. A body mass index of 25.0–29.9 and over 30 was negatively associated with reactogenicity (OR 0.87 and OR 0.72 respectively). Comorbidities that were associated with reactogenicity were cardiac disorders (OR 1.26), respiratory disorders (OR 1.31), psychiatric disorders (1.37), reproductive disorders (OR 1.54), and eye disorders (OR 1.55). The factors associated with systemic reactogenicity were mostly comparable, but there were differences for comorbidities, drug use, and the strength of the regression coefficient. This extensive study with over 22,000 vaccine recipients in the Netherlands demonstrated that, taken into account all factors in the model, the Comirnaty® vaccine gave the least and the Vaxzevria® vaccine the most reactogenicity in general and systemic after the first dose. Also a person with a history of COVID-19 disease, female sex and younger age had an increased odds for experiencing reactogenicity after vaccination. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. As India has the second largest population of diabetic patients worldwide, availability of various treatment options for DME is essential. This postmarketing surveillance study was conducted to fulfill a commitment to the Regulatory Authority of India to examine the safety of dexamethasone intravitreal (DEX) implant over 1 year in Indian patients with DME receiving ≥1 DEX implant for DME-related visual impairment in clinical practice. Methods This observational, prospective, non-interventional study enrolled patients aged ≥18 years scheduled to receive DEX implant for DME-related visual impairment. Baseline demographics, medical history, date of last DEX implant injection, detailed information about adverse events (AEs), AEs of special interest (AESIs), serious AEs (SAEs), and adverse drug reactions (ADRs) reported during postinjection visits and investigator telephone calls were collected. Primary outcome measures were treatment-emergent AE (TEAE), AESI, SAE, and ADR occurrences. Results Of the enrolled patients (19 sites throughout India; n = 250), 84 had received DEX implant previously; mean (standard deviation; SD) duration between prior and study entry dose was 199.4 (156.0) days, and 91 (36.4%) had ≥1 prior ophthalmic condition. Over a mean of 182.6 (88.6) follow-up days (min–max: 0–364 days), 22 TEAEs were reported by 7 (2.8%) patients, 6 of whom had previously received DEX. AESIs of increased IOP (n = 3, 6 events) and glaucoma (n = 1, 1 event) were considered non-serious, of mild/moderate severity, and related to DEX treatment. Eyelid ptosis was reported in 1 patient (1 event). Nonocular AEs included cardiac AEs (n = 3, 4 events), pyrexia (n = 1, 2 events), and dyspnea (n = 1, 2 events). Three (1.2%) patients had 12 serious AEs; most were cardiac disorders; all were unrelated to DEX treatment. Two (0.8%) deaths were considered unrelated to treatment. Conclusions Based on voluntary reporting of adverse events in this surveillance study, DEX implant for treatment of DME-related visual impairment in the Indian population demonstrated a favorable safety profile with few treatment-related TEAEs (none were considered serious) during the 1-year follow-up. These data supplement previous findings and confirm the safety of DEX implant in this population during usual clinical practice. Trial registration World Health Organization Clinical Trials Registry: CTRI/2017/04/008396 . Registered 24 April 2017.

Objective. To identify the strategies employed by regulatory systems for the market surveillance and control of substandard, falsified, and unregistered medicines at the regional-global levels, especially regarding drug recall procedures. Method. An integrative literature review was performed. Searches were performed in MEDLINE via PubMed, Embase, and SciELO to select articles published from 2007 to 2019 in English, Portuguese, and Spanish, covering national regulatory system initiatives, with a focus on the recall of substandard, falsified, and unregistered medicines. Results. Of 483 articles initially identified, 21 global, regional, or national scope studies were selected. Prevention, detection, and response strategies, including drug recall, were grouped according to two broad market surveillance and control models (passive-reactive and proactive) used by regulatory systems. These models seem to combine passive and proactive, complementary or concurring actions that varied according to country development level and regulatory capacity. Although considered the most effective response for protection of populations, medicine recall was not implemented in a uniform manner in different regulatory systems as indicated by the studies. Conclusions. Addressing the complexity and magnitude of the problem of substandard, falsified, and unregistered medicines will demand effort, investment, and profound changes in the approaches, processes, and capacity of regulatory systems, with market surveillance and control strategies possibly converging toward a hybrid, multisectoral, multidisciplinary, global, and systemic model of human health protection. [ABSTRACT FROM AUTHOR]

AimPreclinical studies have suggested that nitinol-based compression anastomosis might be a viable solution to anastomotic leak following low anterior resection. A prospective multicentre open label study was therefore designed to evaluate the performance of the ColonRing(™) in (low) colorectal anastomosis.MethodThe primary outcome measure was anastomotic leakage. Patients were recruited at 13 different colorectal surgical units in Europe, the United States and Israel. Institutional review board approval was obtained.ResultsBetween 21 March 2010 and 3 August 2011, 266 patients completed the study protocol. The overall anastomotic leakage rate was 5.3% for all anastomoses, including a rate of 3.1% for low anastomoses. Septic anastomotic complications occurred in 8.3% of all anastomoses and 8.2% of low anastomoses.ConclusionNitinol compression anastomosis is safe, effective and easy to use and may offer an advantage for low colorectal anastomosis. A prospective randomized trial comparing ColonRing(™) with conventional stapling is needed.

Background and Aim: Cranfixer was approved in 2017 by the Food and Drug Administration of Iran as a skull flap fixation and also a burr hole cover. The effectiveness and safety of this commercial medical device were investigated in detail by the regulatory auditors. Methods and Materials/Patients: Cranfixer was used for ninety-five patients. Sixty patients were selected from a list if they had at least two follow-ups after surgery. The following variables were investigated: age, gender, number of Cranfixers, device loosening, infection, and prominence. In addition, a retrospective review was performed about the reason of surgery. Results: Flap loosening and infection were the major variables surveyed. On average, two Cranfixers were used for each patient. Patients’ median age was 44 years. There was no sex preference (50% male). The craniotomy occurred in the frontal (50%), occipital (3%), parietal (20%), and temporal (27%) lobes. Based on examination and CT imaging, no cases of loosening were observed. Just in one patient, one of two Cranfixers was infected (P

ObjectivesTo compare the performance of a targeted maximum likelihood estimator (TMLE) and a collaborative TMLE (CTMLE) to other estimators in a drug safety analysis, including a regression-based estimator, propensity score (PS)-based estimators, and an alternate doubly robust (DR) estimator in a real example and simulations.Study design and settingThe real data set is a subset of observational data from Kaiser Permanente Northern California formatted for use in active drug safety surveillance. Both the real and simulated data sets include potential confounders, a treatment variable indicating use of one of two antidiabetic treatments and an outcome variable indicating occurrence of an acute myocardial infarction (AMI).ResultsIn the real data example, there is no difference in AMI rates between treatments. In simulations, the double robustness property is demonstrated: DR estimators are consistent if either the initial outcome regression or PS estimator is consistent, whereas other estimators are inconsistent if the initial estimator is not consistent. In simulations with near-positivity violations, CTMLE performs well relative to other estimators by adaptively estimating the PS.ConclusionEach of the DR estimators was consistent, and TMLE and CTMLE had the smallest mean squared error in simulations.

Objective: Drug therapeutic failures (TFs) are included in pharmacovigilance reporting, as some authors consider them a type of adverse drug reaction. Given their high frequency in Colombia, we studied their importance as a cause of admission to an intensive care unit (ICU). Methods: This was a cross-sectional observational study. Clinical records of patients who arrived at the emergency service of a third-care level university hospital were reviewed. Information was collected by a resident in clinical toxicology, and each case was validated and analyzed by a research team using the algorithm proposed by Vaca González and Schumock and Thornton criteria for preventability to evaluate the existence of possible medication errors. Findings: In total, 697 clinical records were evaluated and 18 patients presented TFs (2.6%, 95% confidence interval 1.5%–4.1%) as the cause of admission to the ICU. The most frequent TFs were seizures (56%) and hypertension (28%). The most commonly associated medications were valproic acid (28%) and losartan (28%). Ten cases (56%) were associated with drug misuse and the same number of cases was preventable, according to Schumock and Thornton criteria. Conclusion: This is the first study assessing TFs as a cause of admission to the ICU in the Colombian population. The frequency of TFs in our study was similar to that described in the literature; being the most common cause the inappropriate drug use, particularly for drugs with complex kinetics, such as antiepileptic drugs.

BackgroundOn May 21, 2007, a safety alert was widely disseminated through the media and US Food and Drug Administration (FDA) MedWatch concerning a possible increased risk of ischemic myocardial infarction and cardiovascular death in people receiving the antidiabetic drug rosiglitazone.ObjectiveTo determine whether notification of patients and providers about an FDA safety warning influenced the decision to discontinue rosiglitazone therapy and the resulting effect on glycemic control.Study designRetrospective electronic medical record (EMR) review.MethodsEMR documentation review of 552 primary care patients with a prescription for rosiglitazone current on May 21, 2007, was conducted to determine the percentage that had rosiglitazone discontinued as a result of written notification about the FDA alert. We ascertained whether discontinuation was initiated by the physician or patient. We compared the change in glycosylated hemoglobin (A1C) values from baseline to follow-up between the group continuing on rosiglitazone and the group discontinuing therapy.ResultsOf 552 patients, 344 (62%) had rosiglitazone discontinued as a result of the warning. Discontinuation was initiated by the physician in 150 cases (43.6%), by the patient in 155 cases (45.1%), and was undetermined in 39 cases (11.3%). No significant difference was found in the mean change in A1C values from baseline to follow-up between the 2 groups.ConclusionsNotifying patients and providers about FDA safety alerts does influence clinical decision making. The lay media should partner with the FDA to responsibly communicate drug safety information in evidence-based, understandable terms that quantify real risk.

Background: Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. As India has the second largest population of diabetic patients worldwide, availability of various treatment options for DME is essential. This postmarketing surveillance study was conducted to fulfill a commitment to the Regulatory Authority of India to examine the safety of dexamethasone intravitreal (DEX) implant over 1 year in Indian patients with DME receiving ≥1 DEX implant for DME-related visual impairment in clinical practice.Methods: This observational, prospective, non-interventional study enrolled patients aged ≥18 years scheduled to receive DEX implant for DME-related visual impairment. Baseline demographics, medical history, date of last DEX implant injection, detailed information about adverse events (AEs), AEs of special interest (AESIs), serious AEs (SAEs), and adverse drug reactions (ADRs) reported during postinjection visits and investigator telephone calls were collected. Primary outcome measures were treatment-emergent AE (TEAE), AESI, SAE, and ADR occurrences.Results: Of the enrolled patients (19 sites throughout India; n = 250), 84 had received DEX implant previously; mean (standard deviation; SD) duration between prior and study entry dose was 199.4 (156.0) days, and 91 (36.4%) had ≥1 prior ophthalmic condition. Over a mean of 182.6 (88.6) follow-up days (min-max: 0-364 days), 22 TEAEs were reported by 7 (2.8%) patients, 6 of whom had previously received DEX. AESIs of increased IOP (n = 3, 6 events) and glaucoma (n = 1, 1 event) were considered non-serious, of mild/moderate severity, and related to DEX treatment. Eyelid ptosis was reported in 1 patient (1 event). Nonocular AEs included cardiac AEs (n = 3, 4 events), pyrexia (n = 1, 2 events), and dyspnea (n = 1, 2 events). Three (1.2%) patients had 12 serious AEs; most were cardiac disorders; all were unrelated to DEX treatment. Two (0.8%) deaths were considered unrelated to treatment.Conclusions: Based on voluntary reporting of adverse events in this surveillance study, DEX implant for treatment of DME-related visual impairment in the Indian population demonstrated a favorable safety profile with few treatment-related TEAEs (none were considered serious) during the 1-year follow-up. These data supplement previous findings and confirm the safety of DEX implant in this population during usual clinical practice.Trial Registration: World Health Organization Clinical Trials Registry: CTRI/2017/04/008396 . Registered 24 April 2017. [ABSTRACT FROM AUTHOR]

Purpose Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. Methods: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety‐related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS‐I review to identify potential for bias in the research design of each study. Results: We found that the estimated impacts of FDA labeling changes on several key outcomes—including adverse events—varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. Conclusions: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications. [ABSTRACT FROM AUTHOR]

Purpose: Vaccine hesitancy is among the top ten threats to global health, and access to precise data on adverse events following immunization (AEFIs) is imperative to alleviate public concerns surrounding vaccines. This study aimed to present the overall trends of AEFIs reported in South Korea. Materials and Methods: We evaluated the trends of AEFIs using the Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System database between January 2005 and December 2017. AEFIs were classified into five categories to evaluate associations between vaccines and AEFIs through a case-non-case study: neurologic reactions, general systemic reactions, local reactions, allergic reactions, and others. Results: Among 54378 reported adverse events (AEs) associated with all vaccines approved in South Korea, more than half (56.7%) occurred following influenza vaccination, followed by the pneumococcal (11.6%) and Bacillus Calmette-Guérin (BCG) vaccines (5.0%). After immunization with most vaccines, general systemic reactions were most common, followed by local and neurologic reactions. Adjusted reporting odds ratios were calculated for all neurologic, general, local, and allergic reactions: of all vaccines, rotavirus [neurologic 2.43, 95% confidence interval (CI), 2.25-2.62], BCG (general; 2.20, 95% CI, 1.91-2.53), BCG (local; 3.15, 95% CI, 2.69-3.68), and Japanese encephalitis (allergic 2.38, 95% CI, 1.98-2.87) vaccines showed the highest values. Conclusion: The majority of reported AEFIs were non-serious and mostly general systemic reactions. Sufficient knowledge on the AEFIs would secure public confidence on the safety of vaccines, thereby reducing public health burden from vaccine-preventable diseases. [ABSTRACT FROM AUTHOR]

Background: Since 2008, the US Food and Drug Administration (FDA) has required that drug manufacturers conduct postmarket cardiovascular outcomes trials (CVOTs) for approved type 2 diabetes mellitus (T2DM) drugs. The utility and impact of these studies in determining atherosclerotic cardiovascular risk was reviewed during an FDA Advisory Committee Meeting held on October 24, 2018. Drug manufacturers and patient advocates at this meeting contended that the FDA-required CVOT studies discouraged private sector investment into developing novel T2DM drugs. Here, we explore these contentions by reviewing private sector investment in T2DM drug development from 2000 through 2008, followed by a deductive analysis of how associated events—including the implementation of the CVOT requirement—may have precipitated any observed changes. Methods: We collected and analyzed industry-sponsored interventional trials for T2DM initiated between January 1, 2000, and December 31, 2017, and compared observed trends with those seen across all trials, specific diseases, and against patent filings of novel antidiabetic agents. Results: The analysis shows a marked decline in initiated T2DM clinical trials from 2008 through 2017. Possible influencing factors, including the 2008 financial crisis and a slow in the discovery of novel antidiabetic agents may have contributed, but could not fully account for this decline in T2DM studies. Conclusions: These observations are consistent with the statements made by industry representatives and patient advocates at the 2018 Advisory Committee meeting. As the FDA reconsiders postmarket requirements for T2DM products, these observations underscore the importance of considering more efficient postmarket study structures to assess cardiovascular safety beyond mandatory CVOTs. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the long-term effectiveness, safety, and methotrexate (MTX) dose-tapering patterns in patients with rheumatoid arthritis (RA) receiving adalimumab plus high-dose MTX. Methods: In this prospective, postmarketing study (2012-2017), conducted at 128 sites in Japan, biologic-naïve patients with RA (duration ≤2 years) previously treated with MTX for ≥3 months, initiated treatment with adalimumab and MTX (≥12mg/week). Effectiveness by Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP), safety, and MTX dose-tapering were assessed from baseline to 104 weeks. Results: In the effectiveness analysis set (n = 292), DAS28-CRP remission (<2.6) was achieved in 92.3% (n = 120/130) of patients at week 104. The proportions of patients receiving MTX dose <10mg/week increased to 32.3% (n = 50/155) and ≥12mg/week reduced to 52.9% (n = 82/155) by week 104. Per univariate regression analysis, MTX dose tapering was associated with longer adalimumab drug survival. Of 70 patients with joint X-rays available, 59 (84.3%) achieved D modified total Sharp score ≤1.0 at 104 weeks. In the safety analysis set (n = 300), 143 adverse drug reactions were reported in 92 patients (30.7%, non-serious; 24.7%, serious 8.7%). Conclusion: The long-term effectiveness and safety of adalimumab with high-dose MTX was confirmed in biologic-naïve patients with early RA in a real-world setting in Japan. Clinical Trial Registration: This study is registered at ClinicalTrials.gov (identifier: NCT01736189; retrospectively registered 29 November 2012, due to administrative reasons). [ABSTRACT FROM AUTHOR]

Materiovigilance is the coordinated system of identification, collection, reporting, and analysis of any untoward occurrences associated with the use of medical devices and protection of patient's health by preventing its recurrences. Postmarketing surveillance of medical devices has been initiated in many countries, but it is still not as developed and robust as that of medicines. Materiovigilance program of India was launched on July 6, 2015, at Indian Pharmacopeia Commission with objectives to track the adverse events associated with the use of medical devices, to generate safety data, create awareness among the different stakeholders, and recommend the best practices and interventions to improve the patient's safety.

OPZELURA™ (ruxolitinib cream) became the first approved topical Janus kinase inhibitor (JAKi) in the USA on September 21, 2021, for treatment of mild to moderate atopic dermatitis and on July 18, 2022 for nonsegmental vitiligo. This study aims to review postmarketing safety encompassing nearly 14,000 patient-years of treatment during the first year of market approval through September 20, 2022. The Incyte global safety database and the US Food and Drug Administration (FDA) Adverse Event Reporting System were queried for adverse event (AE) reports received for OPZELURA between September 21, 2021 and September 20, 2022. Search of these databases found 294 postmarketing individual case safety reports (ICSRs) containing 585 nonserious AEs, four serious AEs and no fatal AEs. Of the 294 ICSRs, 220 (75%) were received from spontaneous sources and 74 (25%) were received from noninterventional/solicited sources. Consumers reported 221 ICSRs (75%) and 73 (25%) were medically confirmed by a healthcare professional (i.e. nurse, pharmacist and physician). Gender was reported in 257 ICSRs; of these, 81 (32%) involved male patients and 176 (68%) involved female patients. Age was reported in 64 ICSRs (22%), with a median age of 39 years. The AEs (any unfavorable sign, symptom or disease) with frequency >2% out of all events included application site pain (16 events), dermatitis atopic, skin irritation (15 events each), scratch (14 events) and condition aggravated (13 events). Application site pain, skin irritation and scratch were mostly related to an initial issue with cream texture that was rapidly addressed. 'Dermatitis atopic' and 'condition aggravated' reflected worsening of the underlying condition or lack of improvement. The four serious AEs were skin cancer (two events), pericarditis and thrombocytopenia (one event each), all of which had insufficient information for assessment of relatedness to OPZELURA. Because indications for OPZELURA are inflammatory conditions, OPZELURA has been subject to the same class warnings as oral JAKi that include the risk of serious infections, mortality, malignancy, major adverse cardiovascular events and thrombosis, imposed by FDA subsequent to the ORAL Surveillance trial of tofacitinib in rheumatoid arthritis (Kragstrup et al. RMD Open, 2022; 8:e002236). Topical application of OPZELURA results in low systemic bioavailability of ruxolitinib, and serious AEs associated with oral JAKi were not reported with OPZELURA. Safety data from the first year of marketing confirm that OPZELURA is well tolerated, without significant systemic AEs, and with a low incidence of application site reactions. [ABSTRACT FROM AUTHOR]

The prevalence of safety-related postmarketing label modifications of medications for hematological malignancies is unknown. We identified 35 new drugs indicated for hematological malignancies approved by the US Food and Drug Administration between January 1999 and December 2014. Characteristics of supporting trials and safety-related label modifications from approval to December 2017 were collected from drug labels. Regulatory review and approval pathways were also collected. New drug approvals were supported by trials with a median of 167 patients (interquartile range 115–316). All drugs were approved based on surrogate endpoints. Twenty-seven drug approvals (77%) were not supported by randomized controlled trials. All drugs received orphan drug designation, and most were granted fast track designation, priority review, and accelerated approval (83, 74, and 60%, respectively). A total of 28 drugs (80%) had postmarketing safety-related label modifications. Additions to black box warnings, contraindications, warnings and precautions, and common adverse reactions were identified in 31, 11, 77, and 46% of drugs, respectively. Five drugs (14%) were permanently or temporarily withdrawn from the US market. Drugs for hematological malignancies are often approved based on limited evidence through expedited regulatory pathways with incomplete safety profiles. Hematologists should be vigilant for unrecognized side effects when prescribing newly approved drugs. [ABSTRACT FROM AUTHOR]

Aim: Lusutrombopag is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing invasive procedures. This real‐world surveillance assesses the safety and effectiveness of lusutrombopag in Japan. Methods: This ongoing, multicenter, prospective, real‐world surveillance is collecting data from case report forms between October 2016 and May 2021. Interim data up to September 2018 were used to evaluate safety (adverse events and adverse drug reactions [ADRs]) and effectiveness (proportion of patients avoiding preoperative platelet transfusion and change in platelet count from baseline). Results: The safety analysis set included 331 patients. The mean baseline platelet count was 46.2 ± 13.7 × 109/L. Of 377 invasive procedures, radiofrequency ablation (110 procedures, 29.2%) was the most frequent. The mean time from starting lusutrombopag treatment to invasive procedure was 12.3 days. Incidences of serious adverse events and ADRs were 8.76% and 3.32%, respectively. Six cases (1.81%) of portal vein thrombosis were considered serious adverse events; of these, four cases (1.21%) were classified as serious ADRs. Of 300 patients who underwent an invasive procedure (excluding those with platelet transfusion refractoriness), 282 (94.0%) avoided preoperative platelet transfusion. In patients with platelet measurements before and after lusutrombopag administration who did not undergo platelet transfusion, the mean maximum change in platelet count from baseline was 41.7 ± 31.4 × 109/L (range, −6 to 276; n = 286). All patients receiving second (n = 20) and third (n = 1) treatments avoided preoperative platelet transfusion without developing any ADRs. Conclusions: This real‐world surveillance further supports the safety and effectiveness of lusutrombopag in patients with chronic liver disease undergoing invasive procedures. [ABSTRACT FROM AUTHOR]