A Post-Authorization Safety Surveillance Study to Report Clinical Experience with Purified Factor IX Concentrate in Pediatric Patients with Hemophilia B.

Introduction: Purified factor IX (FIX) concentrate (IMMUNINE®, Takeda Manufacturing Austria AG, Vienna, Austria) is indicated for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia B. Data on the use of purified FIX concentrate in patients ≤6 years old with congenital hemophilia B are limited. Aim: Document real-world clinical experience with purified FIX concentrate in routine practice for pediatric patients with hemophilia B. Methods: This prospective post-authorization safety surveillance study enrolled patients ≤6 years old with moderate or severe hemophilia B (baseline FIX ≤5%) who were prescribed purified FIX concentrate, as determined by the treating physician. The planned observation period for each patient was either 12 months or ≥50 exposure days, whichever occurred first. The primary endpoints were the occurrence of treatment-related adverse events (AEs) and serious AEs (SAEs), and inhibitor development. Results: Thirteen male patients (mean ± standard deviation age, 3.80 ± 1.76 years) enrolled and received ≥1 treatment with purified FIX concentrate. Thirty-two AEs were reported in 6 patients; 4 were SAEs. No AEs were considered related to purified FIX concentrate. No patients developed inhibitory antibodies. Inhibitor testing was not conducted in 2 patients. Eighteen bleeding episodes were treated with purified FIX concentrate in 6 patients. Hemostatic efficacy was rated as either "excellent" or "good" in all patients with an available rating. Conclusion: No treatment-related AEs were reported, and purified FIX concentrate was shown to be effective in treating and preventing bleeding episodes in pediatric patients ≤6 years old with hemophilia B.

Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study.

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.

Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study.

OBJECTIVES: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. METHODS: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. RESULTS: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69-10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. DISCUSSION: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. CONCLUSION: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

Safety of recombinant activated factor VII for treatment of breakthrough bleeds in patients with congenital haemophilia A and inhibitors receiving emicizumab prophylaxis: Review of the real-world evidence.

BACKGROUND: Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real-world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. OBJECTIVES: The objective of this review is to identify and discuss real-world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. METHODS: A search of the following databases was conducted on 15 July 2022: BIOSIS Previews® , Current Contents Search® , Embase® , MEDLINE® . Search terms included 'real world', 'haemophilia A', and 'emicizumab'. RESULTS AND CONCLUSIONS: Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%-56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real-world studies, direct comparison of the results between studies is limited. However, real-world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa.

Safety and effectiveness of rasagiline in patients with Parkinson's disease in Japan: a post-marketing surveillance study.

BACKGROUND: Rasagiline is a monoamine oxidase B inhibitor for the treatment of Parkinson's disease (PD). This study assessed the safety and effectiveness of rasagiline in patients with PD in routine clinical practice in Japan. RESEARCH DESIGN AND METHODS: This multicenter, prospective, observational study (148 sites) enrolled patients (1 November 2018-31 October 2020) with PD. Patients received rasagiline orally 1 mg once daily; maximum observation period was 24 months. The incidence of adverse drug reactions (ADRs) was evaluated; effectiveness was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score. RESULTS: The safety analysis set comprised 961 patients (mean age, 72.50 years; 53.80% female; mean duration of PD, 6.82 years). Mean treatment duration was 14.74 months, with 42.25% receiving rasagiline for ≥ 19 months; 189 (19.67%) had ≥ 1 ADR. Common ADRs were dyskinesia (4.06%), orthostatic hypotension (2.29%), hallucination (1.87%), visual hallucination, nausea, fall (1.56% each), dizziness (1.35%), and somnolence (1.25%). Mean (standard deviation) UPDRS Part III total score was 28.5 (14.35) at baseline and 25.5 (14.98) at the final assessment. CONCLUSIONS: No new concerns in safety and effectiveness regarding rasagiline in Japanese patients with PD were raised. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03727139; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-184181.

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP.

INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide. AIM: To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP. METHODS: The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded. RESULTS: Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product. CONCLUSION: In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

Thirteen years of experience with eslicarbazepine acetate in the United Kingdom and Republic of Ireland: A safety perspective.

OBJECTIVE: Eslicarbazepine acetate (ESL) is a once-daily oral antiseizure medication. Its safety and tolerability from clinical trials have been mostly confirmed by real-world data. The main purpose of this report is to provide an overview of the safety profile of ESL in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Safety data were obtained from the UK and ROI post-marketing sources (October 2009-April 2022) by the marketing authorization holder. All individual reports were included in the Argus Safety™ database. All adverse events (AEs) were coded using MedDRA® version 24.1. Only valid cases (meeting the minimum pharmacovigilance reporting requirements) were included. RESULTS: During 13 years of ESL marketing, with cumulative estimated exposure of 2 210 395 patients-years, 183 reports were received. A total of 402 AEs were reported for the 155 valid reports. The most common reported AEs (≥6% of total reported), per system organ class (SOC), were: nervous system disorders (23.4%), injury, poisoning, and procedural complications (18.9%), general disorders and administration site conditions (12.9%), psychiatric disorders (12.7%) and gastrointestinal disorders (6.7%). The most frequently reported (≥2% of total reported) AEs were: seizure (4.5%), hyponatremia (4.2%), dizziness (2.7%), rash, fatigue (2.5% each), and somnolence (2.0%). Twenty-six percent of events were classified as serious (including six fatal cases). SIGNIFICANCE: The current analysis supports the known safety profile of ESL, as generally well-tolerated with most AEs being non-serious. The most common AEs were considered either expected according to the disease itself or to the reference safety information. ESL continues to be a relevant medication in the treatment of partial (focal-onset) epilepsy, as also confirmed by the 2022 NICE guidelines.

Safety and effectiveness of lusutrombopag in patients who have chronic liver disease with thrombocytopenia and undergoing invasive procedures: Real-world post-marketing surveillance in Japan.

AIM: Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases who are scheduled to undergo an invasive procedure. Here, we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. METHODS: This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. RESULTS: The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients who received one or more, two or more, and three or more treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients who were Child-Pugh class A, B, and C, respectively. The most common serious adverse drug reactions were portal vein thrombosis, pancytopenia, and white blood cell count decrease, reported in 14 (1.36%), three (0.29%), and two (0.19%) patients, respectively. The incidence of adverse drug reactions was not higher in patients with Child-Pugh class C or those undergoing retreatment cycles compared with other Child-Pugh classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. CONCLUSIONS: This surveillance study further supports the safety and effectiveness of lusutrombopag in a broad range of patients with chronic liver diseases undergoing planned invasive procedures. CLINICAL TRIAL REGISTRATION: JapicCTI-163432.

Post-marketing surveillance for the safety of the 9-valent human papillomavirus vaccine: a retrospective real-world study in China.

BACKGROUND: The 9-valent human papillomavirus (9vHPV) vaccine was introduced in China in 2018. This study was conducted to monitor the occurrence of new-onset autoimmune diseases (AIs) in Chinese women vaccinated with the 9vHPV vaccine and adverse pregnancy outcomes in infants born to mothers with inadvertent pregnancy exposure. RESEARCH DESIGN AND METHODS: Women who received the first dose of the 9vHPV vaccine at age 16-26 years in Ningbo between January 2019 and March 2021 were monitored in the Ningbo Regional Health Information Platform. New-onset cases of seven pre-specified AIs diagnosed within six months after vaccination were collected. Cases of stillbirth and 23 major congenital anomalies diagnosed within three months of birth in target infants were collected. RESULTS: A total of 102,670 doses of the 9vHPV vaccine were administered to 41,609 women who had received no other HPV vaccine. New-onset AIs were diagnosed in 36 women, comprising 21 Hashimoto's, 11 Graves', and 4 uveitis disease cases. Among 50 women with maternal vaccination exposure, no stillbirths were observed. One case of microtia was observed. CONCLUSIONS: In this first post-marketing surveillance of the 9vHPV vaccine in China, no safety signals were identified when putting the results in context to published data.

Real-world safety and effectiveness of adalimumab in patients with hidradenitis suppurativa: A 52-week analysis of a postmarketing surveillance study in Japan.

Adalimumab is a human monoclonal antibody against tumor necrosis factor-α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic recurrent inflammatory skin disease. We report the results of the final analysis of the postmarketing surveillance (PMS) study (ClinicalTrials.gov: NCT03894956), which evaluated the 52-week safety and efficacy of adalimumab for HS treatment in real-world clinical practice in Japan. This multicenter, prospective, open-label, observational study (March 2019 to May 2021) included patients with HS treated with subcutaneous adalimumab at doses following the package insert. The primary endpoint was safety, and the secondary endpoints were effectiveness, including HS clinical response (HiSCR), C-reactive protein (CRP), skin pain, and Dermatology Life Quality Index (DLQI). Of the 84 patients registered at 65 sites, 83 patients were included in the analyses. Adverse drug reactions (ADRs) were reported by 10 (12.0%) patients; two patients reported a serious ADR, including one patient with serious infection. Other safety events of special interest reported were liver disorder and dermatitis psoriasiform (one patient each). Almost all patients with ADRs were recovering or had recovered, except for one patient who experienced a serious ADR of liver disorder and died. At 12 weeks, 55.4% of patients achieved HiSCR; this increased to 60.5% and 62.8% at 24 and 52 weeks of adalimumab treatment, respectively. Significant reductions from baseline in CRP (P < 0.05), skin pain (P < 0.0001), and DLQI (P < 0.0001) were observed at all time points. The results from this PMS study demonstrated that long-term adalimumab treatment is well tolerated and effective in patients with HS in real-world clinical practice in Japan.

Preventive Pharmacovigilance: timely and precise prevention of adverse events through person-level patient screening and dose-level product surveillance.

The goal of pharmacovigilance (PV) is to prevent adverse events (AEs) associated with drugs and vaccines. Current PV programs are of a reactive nature and rest entirely on data science, i.e., detecting and analyzing AE data from provider/patient reports, health records and even social media. The ensuing preventive actions are too late for people who have experienced AEs and often overly broad, as responses include entire product withdrawals, batch recalls, or contraindications of subpopulations. To prevent AEs in a timely and precise manner, it is necessary to go beyond data science and incorporate measurement science into PV efforts through person-level patient screening and dose-level product surveillance. Measurement-based PV may be called 'preventive pharmacovigilance', the goal of which is to identify susceptible individuals and defective doses to prevent AEs. A comprehensive PV program should contain both reactive and preventive components by integrating data science and measurement science.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Safety and effectiveness of empagliflozin in clinical practice as monotherapy or with other glucose-lowering drugs in Japanese patients with type 2 diabetes: subgroup analysis of a 3-year post-marketing surveillance study.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin are increasingly prescribed as initial glucose-lowering drugs for type 2 diabetes (T2D), based on their cardiorenal benefits. However, information regarding the safety and the effectiveness of monotherapy with SGLT2 inhibitors in routine clinical practice is limited. RESEARCH DESIGN AND METHODS: We analyzed data from a prospective, 3-year, post-marketing surveillance study of empagliflozin in Japan. We evaluated adverse drug reactions (ADRs) (the primary endpoint) and glycemic effectiveness with or without other glucose-lowering drugs. RESULTS: 7931 T2D patients were treated with empagliflozin. At baseline, mean age was 58.7 years, 63.0% were male, and 1835 (23.14%) were not receiving other glucose-lowering drugs. ADRs occurred in 141 (7.68%) and 875 (14.62%) patients initiating empagliflozin as monotherapy or combination therapy, respectively. The most frequent ADRs of special interest with empagliflozin as monotherapy or combination therapy were urinary tract infections (0.82% and 1.14% of patients, respectively) and excessive/frequent urination (0.65%, 1.50%). At last observation, glycated hemoglobin level was reduced by a mean of 0.78% with empagliflozin monotherapy (from baseline mean of 7.55%) and 0.74% with combination therapy (baseline 8.16%). CONCLUSIONS: Empagliflozin is well tolerated and effective in clinical practice in Japan when initiated as monotherapy or combination therapy.

Safety and Effectiveness of Empagliflozin in Korean Patients with Type 2 Diabetes Mellitus: Results from a Nationwide Post-Marketing Surveillance.

BACKGROUND: To evaluate the safety and effectiveness of empagliflozin in routine clinical settings, we collected and assessed the clinical profiles of Korean patients with type 2 diabetes mellitus. METHODS: This was a post-marketing surveillance study of empagliflozin 10 and 25 mg. Information on adverse events and adverse drug reactions (ADRs) was collected as safety data sets. Available effectiveness outcomes, including glycosylated hemoglobin (HbA1c) level, fasting plasma glucose, body weight, and blood pressure, were assessed. RESULTS: The incidence rate of ADRs was 5.14% in the safety dataset (n=3,231). Pollakiuria, pruritis genital, and weight loss were the most common ADRs. ADRs of special interest accounted for only 1.18%, and there were no serious events that led to mortality or hospitalization. In the effectiveness data set (n=2,567), empagliflozin significantly reduced the mean HbA1c level and body weight during the study period by -0.68%±1.39% and -1.91±3.37 kg (both P<0.0001), respectively. In addition, shorter disease duration, absence of dyslipidemia, and higher baseline HbA1c levels were identified as the clinical features characteristic of a "responder" to empagliflozin therapy. CONCLUSION: Empagliflozin is a safe and potent glucose-lowering drug in routine use among Korean patients with type 2 diabetes mellitus. It is expected to have better glycemic efficacy in Korean patients with poorly controlled type 2 diabetes mellitus.

Long-term safety and effectiveness of vonoprazan for prevention of gastric and duodenal ulcer recurrence in patients on nonsteroidal anti-inflammatory drugs in Japan: a 12-month post-marketing surveillance study.

BACKGROUND: This study assessed the safety and effectiveness of vonoprazan for prevention of duodenal and gastric ulcer recurrence in patients on long-term nonsteroidal anti-inflammatory drugs (NSAIDs) in routine clinical practice. RESEARCH DESIGN AND METHODS: This 12-month, prospective, observational study (145 sites, Japan, September 2016-April 2020) analyzed patients with a history of gastric or duodenal ulcer who started once-daily vonoprazan and were receiving NSAIDs for pain. The primary outcome was the incidence of adverse drug reactions (ADRs). RESULTS: Most patients (86.7% [1099/1268]) received vonoprazan for at least 6 months. Most patients (98.6% [1250/1268]) received the 10-mg dose of vonoprazan, 38.3% (486/1268) received cyclooxygenase-2 inhibitors, and 61.7% (782/1268) received other NSAIDs. The overall incidence of ADRs was 0.71% (9/1268). Most commonly reported ADRs were gastrointestinal (0.32%), nervous system (0.16%), and hepatobiliary system (0.16%) disorders. The overall incidence of gastric or duodenal ulcer recurrence was 1.04% (95% CI 0.56-1.78). CONCLUSIONS: No new safety concerns were reported for vonoprazan for prevention of secondary ulcer or bleeding in patients receiving long-term NSAIDs. Vonoprazan was effective for preventing NSAID-related peptic ulcer recurrence in this real-world study. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03214198; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-163436.

Safety and effectiveness of empagliflozin and linagliptin fixed-dose combination therapy in Japanese patients with type 2 diabetes: final results of a one-year post-marketing surveillance study.

BACKGROUND: Fixed-dose combination (FDC) of the sodium-glucose co-transporter 2 inhibitor empagliflozin and the dipeptidyl peptidase-4 inhibitor linagliptin was approved for type 2 diabetes (T2D) treatment in Japan in 2018. We conducted a post-marketing surveillance study of empagliflozin/linagliptin FDC in routine clinical practice in Japan. RESEARCH DESIGN AND METHODS: This one-year, prospective, multicenter, observational study investigated the safety and effectiveness of empagliflozin/linagliptin FDC in Japanese patients with T2D. The primary outcome was incidence of adverse drug reactions (ADRs). RESULTS: Among 1146 patients, mean (SD) age was 63.8 (12.8) years and 22.08% were aged ≥75 years. Mean (SD) glycated hemoglobin (HbA1c) was 7.66% (1.21); fasting plasma glucose (FPG) was 142.90 mg/dl (43.75). ADRs were experienced by 32 (2.79%) patients (1 serious ADR); ADRs of important identified risk included urinary tract infection (7 patients [0.61%]), hypoglycemia (2 [0.17%]), ketoacidosis (0), genital infection (1 [0.09%]), and volume depletion (1 [0.09%]). Overall mean (SD) change from baseline in body weight, HbA1c, and FPG were -1.08 kg (3.21), -0.39% (1.11), and -7.90 mg/dl (39.12), respectively. CONCLUSIONS: Empagliflozin/linagliptin FDC was effective and generally well tolerated in Japanese patients with T2D; no new safety concerns were identified. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03761797) [Figure: see text] [Figure: see text].

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

Pharmacists' role in detection and evaluation of adverse drug reactions: Developing proactive systems for pharmacosurveillance.

PURPOSE: To identify current challenges in detection of medication-related symptoms, and review technology-based opportunities to increase the patient-centeredness of postmarketing pharmacosurveillance to promote more accountable, safer, patient-friendly, and equitable medication prescribing. SUMMARY: Pharmacists have an important role to play in detection and evaluation of adverse drug reactions (ADRs). The pharmacist's role in medication management should extend beyond simply dispensing drugs, and this article delineates the rationale and proactive approaches for pharmacist detection and assessment of ADRs. We describe a stepwise approach for assessment, best practices, and lessons learned from a pharmacist-led randomized trial, the CEDAR (Calling for Detection of Adverse Drug Reactions) project. CONCLUSION: Health systems need to be redesigned to more fully utilize health information technologies and pharmacists in detecting and responding to ADRs.

Sex differences: From preclinical pharmacology to clinical pharmacology.

Sex is a crucial variable to take into account in medical research. In this review, we attempted to present its importance at all stages of research and even during drug's post-marketing surveillance. Most preclinical research studies do not take sex into account while many diseases are known to present sexual dimorphism. However, a shift in thinking occurred since the January 2016 implementation of the US Institutes of Health recommendations to take sex into account in research. Nevertheless, in preclinical studies, the lack of sex-based statistical analyses persists. Moreover, in humans, women are often under-represented in some clinical trials, despite well-identified sexual dimorphism. In addition, some pathologies are subject to social representations of diseases considered "male" or "female" which can also lead to a delay in diagnosis and management for both sexes. Finally, many drug classes may be subject to sex differences in efficacy and safety. For example, women present more adverse events than men, mainly because of different pharmacokinetic parameters. Accounting sex as a variable from the preclinical phase is essential to improve the transposition of observed results and move towards personalized medicine.