Baloxavir marboxil is an oral anti-influenza drug that inhibits the cap-dependent endonuclease of the virus polymerase acidic protein. In clinical trials, baloxavir reduced the time to alleviation of influenza symptoms and time to resolution of fever in adults, adolescents, and children. The purpose of this study is to collect data on the safety and effectiveness of baloxavir when used in clinical practice. This postmarketing surveillance (clinicaltrials.jp; JapicCTI-183882), conducted at 688 Japanese hospitals or clinics (March 2018 to March 2019), enrolled patients of any age with influenza A or B infection who received a single, weight-based dose of baloxavir. Adverse drug reactions (ADRs) were seen in 11.2% of 3094 patients during the 7-day observation period; the most common ADR was diarrhea (6.1%). ADRs were more common in children aged 3000 patients suggests that baloxavir is well tolerated and effective regardless of patient age or influenza virus type.

Background Naldemedine is a peripherally acting μ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. Objectives To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. Methods Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (C_max) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. Results A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC_0–inf 1.78-fold and C_max 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC_0–inf 2.91-fold and 1.90-fold, and C_max 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC_0–inf by 83% and C_max by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. Conclusions Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Purpose: Alerts for bleeding events are included in the Japanese package inserts of some anti‐influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti‐influenza drugs. This large‐scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti‐influenza drugs and in untreated patients.Methods: This retrospective cohort study used a large‐scale Japanese employment‐based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders.Results: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti‐influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti‐influenza treatments (odds ratios for baloxavir were 0.90–0.99 compared to other therapies).Conclusions: Based on real‐world observation using a large‐scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti‐influenza drugs.

Ensitrelvir received approval in Japan for emergency use in the management of patients with coronavirus disease (COVID-19) in November 2022. A post-marketing surveillance (PMS) was conducted to evaluate the safety and effectiveness of ensitrelvir in Japanese real-world clinical practice, and the interim analysis results (data cutoff: July 20, 2023) have been published. This report describes the final analysis of the PMS for ensitrelvir in a Japanese clinical setting. A continuous survey method was used for this PMS (November 2022 to December 2023), and the observation period was 28 days from the start date of ensitrelvir administration. Patients with COVID-19 who received ensitrelvir for the first time and provided written informed consent to collect and use their data were included in this survey. The outcomes included patient characteristics, adverse drug reactions (ADRs), and time to resolution of COVID-19 symptoms. A total of 3760 and 3638 patients were included in the safety and effectiveness analysis sets, respectively. In the safety analysis set, the mean ± standard deviation age was 43.6 ± 17.7 years, 48.5 % were male, 97.5 % had mild COVID-19, and 73.4 % had a vaccination history. Of the 379 ADRs reported, 374 were not serious and 5 were serious. None of the ADRs resulted in sequelae or death. The median time to resolution of fever and all symptoms was 36.0 and 156.0 h, respectively. This PMS including >3000 patients suggested the safety of ensitrelvir for the treatment of patients with COVID-19 in Japan, with no new safety concern.

A single oral dose of baloxavir marboxil, a cap-dependent endonuclease inhibitor, is approved for patients with influenza A or B infection; however, real-world evidence is limited. We evaluated the effectiveness of baloxavir vs neuraminidase inhibitors in reducing the incidence of severe illness in influenza outpatients aged 5-11 years. In this retrospective cohort study, we analyzed individual-level data from patients treated with these antivirals, using a large, Japanese health insurance claims database (JMDC). Patients were included at the first date of diagnosis of the influenza virus infection (Day 1) in two influenza seasons. The primary outcome was the incidence of hospitalization from Day 2-14. Of 196,749 included patients (Season 2018/2019, n = 103,709; Season 2019/2020, n = 93,040), 20.9 % received baloxavir, 38.8 % received oseltamivir, 28.7 % received laninamivir, and 11.6 % received zanamivir. In each treatment group, 61-70 % patients had influenza A. The incidence of hospitalization from Day 2-14 was significantly lower for baloxavir than for oseltamivir, laninamivir, and zanamivir. The adjusted risk ratio (95 % CI) for oseltamivir, laninamivir, and zanamivir were 1.86 (1.30-2.68), 2.11 (1.37-3.25), and 1.90 (1.31-2.77), respectively, compared with baloxavir. Comparative incidence of hospitalizations between agents were unaffected by season or virus type. Using a large, Japanese health insurance claims database, a lower rate of hospitalization was demonstrated in children aged 5-11 years with an influenza virus infection when treated with baloxavir vs neuraminidase inhibitors. Thus, single dose, oral baloxavir may reduce the incidence of severe illness in these patients.