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Background On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. Methods This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Results Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). Conclusions In interim data on >6000 tolvaptan REMS patients

Introduction Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness. Methods This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians. Results A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1–1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred. Conclusion In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction. Trial Registration Clinicaltrials.gov identifier NCT01228682. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01947-9., Plain Language Summary Hospitalized patients often experience abnormally low blood sodium levels (hyponatremia), which can cause significant symptoms and poses a serious health risk (Wald et al. in Arch Intern Med 170:294–302, 2010). Yet, increasing sodium levels too rapidly in these patients can unintentionally cause osmotic demyelination syndrome, resulting in long-term neurologic damage or death. Tolvaptan was approved in the European Union to treat one type of hyponatremia caused by a hormonal imbalance known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Tolvaptan effectively increased patient sodium levels in clinical trials, but real-world data are needed to understand tolvaptan treatment more fully in everyday clinical practice. We evaluated patterns of use, efficacy, and safety of tolvaptan in patients treated in hospitals and after discharge for hyponatremia due to SIADH. Tolvaptan was correctly used to treat only hyponatremia caused by SIADH in nearly all of the 252 patients studied. Patient sodium levels increased in the first week of tolvaptan treatment and then stabilized. Hyponatremia symptoms, such as confusion, nausea, tiredness, and dizziness, were present in 48.4% of patients before treatment and in 18.3% after starting tolvaptan. Consistent with earlier studies, some patients (24.6%) experienced excessively rapid correction of hyponatremia. However, no subsequent neurologic problems or deaths were attributed to the rapid correction, which suggests that medical providers were carefully monitoring and managing sodium levels to prevent serious consequences. Our study indicates that tolvaptan is being used safely and effectively to treat hyponatremia due to SIADH in a patient population with complex medical needs. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01947-9.

A Development Safety Update Report (DSUR) is a comprehensive review of safety information collected during an annual reporting period for an investigational drug. The creation of a DSUR is a resource-intensive process, requiring effective communication among, and collaboration with, various functional stakeholders. To increase the efficiency and cost-effectiveness of generating a DSUR with the use of an electronic authoring platform. This computerized platform auto-populates the DSUR template using available source data. Requirements for the DSUR authoring tool were developed, and available data sources were mapped to respective sections of a company DSUR template. The DSUR authoring tool, mined, scanned, and extracted the relevant data from multiple-input source documents using Natural Language Processing logic. The data were then auto-populated into the template, as required by regulatory guidance ICH-E2F, with different text options based on questions and answers. The time- and cost-savings gained through automation were analyzed for DSURs authored during 2017–2019. The DSUR contains 31 sections (20 main sections and 11 sub-sections), of which 9 were fully automated, 12 were partially automated, and 10 were not automated in this release of the automation tool. Use of the DSUR automation tool resulted in a time-savings of approximately 25% per report, corresponding to a cost saving of US$4550 per report. Deployment of the automation tool reduced the time and cost required to manually produce DSURs, as well as improved the quality, compliance, and consistency of company-prepared DSURs. This tool enhanced the potential of the organization to generate larger volumes of DSURs in a timely manner, without requiring additional resources or compromising quality. This or a similar authoring automation tool could be employed in the future to generate other regulatory submission documents, which also require various source documents and cross-functional contributions.

Introduction Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure in North America and Europe, but it is often missed because of unstandardized diagnostic methods and criteria. This study aimed to develop and validate an automated algorithm to identify potential DILI cases in routine pharmacovigilance (PV) activities. Methods Post-marketing hepatic adverse events reported for a potentially hepatotoxic drug in a global PV database from 19 March 2017 to 18 June 2018 were assessed manually and with the automated algorithm. The algorithm provided case assessments by applying pre-specified criteria to all case data and narratives simultaneously. Results A total of 1456 cases were included for analysis and assessed manually. Sufficient data for algorithm assessment were available for 476 cases (32.7%). Of these cases, manual assessment identified 312 (65.5%) potential DILI cases while algorithm assessment identified 305 (64.1%) potential DILI cases. Comparison of manual and algorithm assessments demonstrated a sensitivity of 97.8% and a specificity of 79.3% for the algorithm. Given the prevalence of potential DILI cases in the population studied, the algorithm was calculated to have positive predictive value 56.3% and negative predictive value 99.2%. The time required for manual review compared to algorithm review suggested that application of the algorithm prior to manual screening would have resulted in a time savings of 42.2%. Conclusion An automated algorithm to identify potential DILI cases was developed and successfully implemented. The algorithm demonstrated a high sensitivity, a high negative predictive value, along with significant efficiency and utility in a real-time PV database. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01856-x.

Introduction Two risk minimization (RM) tools—a healthcare professional frequently asked questions (HCP-FAQs) brochure and a patient/caregiver information brochure (PCIB)—were developed for HCPs and for adolescents (aged ≥ 13 years) receiving aripiprazole for bipolar I mania and their caregivers. Objectives This study evaluated the effectiveness of these RM tools in improving the awareness and education of HCPs and patients/caregivers. Method The RM tools were distributed to HCPs (identified in agreement with the marketing authorization holder [MAH] and local regulatory authorities), who in turn distributed the PCIBs to patients/caregivers. A web-based survey was then conducted targeting HCPs and patients/caregivers. Results The response rate was low: 118 of 23,282 invited HCPs and 16 patients/caregivers completed the survey. Overall, 42% (49/118) of HCP respondents were aware of aripiprazole RM tools; of these, 59% (29/49) of HCPs read them at least once and 66% (19/29) of these used the RM tools while discussing the benefit–risk profile of aripiprazole with patients/caregivers. In total, 30 of the 118 HCPs (25%) were aware of the PCIB, and 26 distributed it to their patients/caregivers, whereas seven HCPs advised them to read the brochure. Overall, 15 of the 16 patients/caregivers were aware of the PCIB, and 13 read/referred to it. Of these, 12 found the PCIB useful, and five monitored their weight while receiving aripiprazole and reported potential risks immediately to their HCP. Conclusion The response rate to the survey was low, and the tools displayed limited utility and effectiveness in improving awareness and education in a small number of responders. Therefore, the aripiprazole risk management plan was amended, and the tools were discontinued. Electronic supplementary material The online version of this article (10.1007/s40264-018-0662-2) contains supplementary material, which is available to authorized users.

To evaluate how changes in infliximab dose influence resource utilization and expenditures for patients with rheumatoid arthritis (RA).A retrospective analysis using claims from January 1, 1999 through March 31, 2005 in the MedStat MarketScan databases for RA patients who had an increase, decrease, or no change in infliximab dose within 1 year of initiating therapy. Eligibility criteria included at least one claim with a diagnosis of RA and no biologic treatment within 6 months before the index infliximab claim, continuous health plan enrollment (commercial or Medicare) for 6 months before and 12 months after the index date, and three consecutive infliximab infusions. The index and final infliximab doses were estimated from claims data.Data were included for 1678 commercially insured patients and 616 Medicare-eligible patients; 45.4% and 39.3%, respectively, had an increase in dose, 24.7% and 43.2%, respectively, had a decrease in dose, and 29.9% and 17.5%, respectively, had no change in dose. Overall, resource utilization was higher in the increase-in-dose groups and lower in the no change-in-dose groups when compared with the decrease-in-dose groups for both cohorts. Medical costs were also highest for the increase-in-dose groups for both cohorts. Pharmacy expenditures for the no-change-in-dose groups were lower than the decrease-in-dose groups in both cohorts.An increase in dose was the most common dose change for the commercial cohort, while a decrease in dose was the most common dose change for the Medicare-eligible cohort. Patients with an increase in dose had the highest utilization and expenditures while those with no change in dose had the lowest levels. The nature of this utilization needs to be examined to better understand how dosing changes may influence medical utilization. Changes in dose were defined by the difference between the first and final doses and may not have captured changes in interim doses.