Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Evaluation of Oseltamivir Used to Prevent Hospitalization in Outpatients With Influenza: A Systematic Review and Meta-Analysis.

Importance: Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed. Objective: To assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients. Data Sources: PubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022. Study Selection: Included studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection. Data Extraction and Synthesis: In this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Main Outcomes and Measures: Hospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs. Results: Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6166 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.9% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.79; 95% CI, 0.48 to 1.29; RD, -0.17%; 95% CI, -0.23% to 0.48%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 1.01; 95% CI, 0.21 to 4.90) or in patients considered at greater risk of hospitalization (RR, 0.65; 0.33 to 1.28). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13 to 1.82) and vomiting (RR, 1.83; 95% CI, 1.28 to 2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46 to1.08). Conclusions and Relevance: In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.

Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis.

INTRODUCTION: Baloxavir marboxil (BXM), a newly developed cap-dependent endonuclease inhibitor, is widely used to treat influenza virus infections in inpatients and outpatients. A previous meta-analysis included only outpatients and patients suspected of having an influenza virus infection based on clinical symptoms. However, whether BXM or oseltamivir is safer and more effective for inpatients remains controversial. Therefore, we conducted a systematic review and meta-analysis validating the effectiveness and safety of BXM versus oseltamivir in inpatients with influenza virus. METHODS: The Scopus, EMBASE, PubMed, Ichushi, and CINAHL databases were systematically searched for articles published until January 2023. The outcomes were mortality, hospitalization period, incidence of BXM- or oseltamivir-related adverse events, illness duration, and changes of virus titers and viral RNA load in patients with influenza virus infections. RESULTS: Two randomized controlled trials with 1624 outpatients and two retrospective studies with 874 inpatients were enrolled. No deaths occurred in outpatients treated with BXM or oseltamivir. Among inpatients, BXM reduced mortality (p = 0.06) and significantly shortened hospitalization period (p = 0.01) compared to oseltamivir. In outpatients, BXM had a significantly lower incidence of adverse events (p = 0.03), reductions in influenza virus titers (p < 0.001) and viral RNA loads (p < 0.001), and a tendency to be a shorter illness duration compared with that of oseltamivir (p = 0.27). CONCLUSIONS: Our meta-analysis showed that BXM was safer and more effective in patients than oseltamivir; thus, supporting the use of BXM for the initial treatment of patients with proven influenza virus infection.

Treatment and prevention of influenza in geriatric patients.

INTRODUCTION: Older adults are the most vulnerable population to the effects of influenza. These patients have age-related characteristics that make response to both infection and therapeutics different than younger patients. AREAS COVERED: Influenza vaccination and antiviral therapy are the foundational approaches to preventing and treating influenza in geriatric patients. Older adults should receive one of the three enhanced vaccines before influenza season beings. There are five antivirals used in influenza. Geriatric patients have been under-enrolled in antiviral studies but have been included in small numbers. Oseltamivir has the most abundant evidence, including in the hospital and long-term care (LTC) facilities, and the strongest evidence for reducing mortality and complications. Peramivir offers the shortest time for symptom alleviation, while baloxavir is best tolerated. EXPERT OPINION: Oseltamivir has the most versatility in preventing and treating influenza in geriatric patients. Parenteral peramivir and zanamivir are second-line alternatives for complicated influenza when oseltamivir cannot be used. Single-dose peramivir and baloxavir are attractive alternatives to oseltamivir in uncomplicated influenza but will not increase in utilization until more evidence is available regarding mortality and complications, particularly in hospitalized and LTC patients. More studies, including comparative trials, are required to elucidate the role in therapy for each therapeutic in the geriatric population.

Neuraminidase is a host-directed approach to regulate neutrophil responses in sepsis and COVID-19.

BACKGROUND AND PURPOSE: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections. EXPERIMENTAL APPROACH: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models. KEY RESULTS: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage. CONCLUSION AND IMPLICATIONS: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections.

Systematic review and meta-analysis of the efficacy and safety of oseltamivir (Tamiflu) in the treatment of Coronavirus Disease 2019 (COVID-19).

Efforts are ongoing by researchers globally to develop new drugs or repurpose existing ones for treating COVID-19. Thus, this led to the use of oseltamivir, an antiviral drug used for treating influenza A and B viruses, as a trial drug for COVID-19. However, available evidence from clinical studies has shown conflicting results on the effectiveness of oseltamivir in COVID-19 treatment. Therefore, this systematic review and meta-analysis was performed to assess the clinical safety and efficacy of oseltamivir for treating COVID-19. The study was conducted according to the PRISMA guidelines, and the priori protocol was registered in PROSPERO (CRD42021270821). Five databases were searched, the identified records were screened, and followed by the extraction of relevant data. Eight observational studies from four Asian countries were included. A random-effects model was used to pool odds ratios (ORs), mean differences (MD), and their 95% confidence intervals (CI) for the study analysis. Survival was not significantly different between all categories of oseltamivir and the comparison groups analysed. The duration of hospitalisation was significantly shorter in the oseltamivir group following sensitivity analysis (MD -5.95, 95% CI -9.91--1.99 p = 0.003, heterogeneity I2 0%, p = 0.37). The virological, laboratory and radiological response rates were all not in favour of oseltamivir. However, the electrocardiographic safety parameters were found to be better in the oseltamivir group. However, more studies are needed to establish robust evidence on the effectiveness or otherwise of oseltamivir usage for treating COVID-19.

[Systematic review and Meta-analysis of Lianhua Qingwen preparations combined with Oseltamivir in treatment of influenza].

This study aims to explore the efficacy and safety of Lianhua Qingwen preparations combined with Oseltamivir in the treatment of influenza patients. PubMed, Cochrane Library, EMbase, SinoMed, CNKI, Wanfang, and VIP were searched for the randomized controlled trials(RCTs) involving the comparison between the influenza patients treated with Lianhua Qingwen preparations combined with Oseltamivir and those treated with Oseltamivir alone. Fever clearance time was taken as the primary outcome indicator. Clinical effective rate(markedly effective and effective), time to muscle pain relief, time to sore throat relief, time to cough relief, time to nasal congestion and runny nose relief, time to negative result of viral nucleic acid test, and adverse reactions were taken as the secondary outcome indicators. The data were extracted based on the outcome indicators and then combined. The Cochrane collaboration's tool for assessing risk of bias was used to evaluate the quality of a single RCT, and the grading of recommendations assessment, development and evaluations(GRADE) system to assess the quality of a single outcome indicator. RevMan 5.3 was employed to analyze data and test heterogeneity. Finally, 16 RCTs involving 1 629 patients were included for analysis. The Meta-analysis showed that Lianhua Qingwen preparations combined with Oseltamivir was superior to Oseltamivir alone in the treatment of influenza in terms of clinical effective rate(RR=1.16, 95%CI [1.12, 1.20], P<0.000 01), fever clearance time(SMD=-2.02, 95%CI [-2.62,-1.41], P<0.000 01), time to muscle pain relief(SMD=-2.50, 95%CI [-3.84,-1.16], P=0.000 2), time to sore throat relief(SMD=-1.40, 95%CI [-1.93,-0.85], P<0.000 01), time to cough relief(SMD=-1.81, 95%CI [-2.44,-1.19], P<0.000 01), time to nasal congestion and runny nose(SMD=-2.31, 95%CI [-3.61,-1.01], P=0.000 5), and time to negative result of viral nucleic acid test(SMD=-0.68, 95%CI [-1.19,-0.16], P=0.01). However, due to the low quality of the trials, the above conclusions need to be proved by more high-quality clinical studies. In addition, we still need to attach importance to the adverse reactions of the integrated application of Chinese and western medicines.

Acute intermittent porphyria: is oseltamivir safe in these patients?

A 40-year-old man attended the emergency room with abdominal pain and inappropriate behaviour associated with stress, and the consumption of alcohol and cannabis. Examination revealed hypertension (155/100 mmHg), tachycardia (95 beats per minute), abdominal pain and leucocytosis with neutrophilia, hyponatraemia and hypokalaemia. Urine was positive for nitrites, elevated bilirubin and cannabinoids. The patient was diagnosed with acute intermittent porphyria (AIP) and immediately treated. After initial treatment, the patient improved. However, he subsequently relapsed after initiating treatment with oseltamivir for a flu-like illness. Treatment was discontinued and the patient progressed favourably. AIP recurrence could have been mediated by oseltamivir; an association not previously described in the literature.

Clinical Efficacy and Safety of Chinese Patent Medicine Combined with Oseltamivir for the Treatment of Adult Influenza: A Systematic Review and Meta-Analysis.

Influenza is a sudden and serious viral breathing and lung-related infectious disease that causes significant deadliness and death worldwide. Now, the international treatment is oseltamivir. Chinese patent medicine (CPM) as a kind of different therapy is used in the treatment of influenza in China. The aim of this study was to interpret the clinical efficacy and safety of CPM combined with oseltamivir in the treatment of adult influenza by reviewing all relevant randomized controlled trials, and to provide new ideas and methods for the treatment of influenza. PubMed, Embase, Cochrane Library, SinoMed, CNKI, and Wanfang Database were searched from the date of beginning until 1 June 2021, for the references on treatment of influenza with CPM. According to standard information extraction tables, two people worked to find and aggregate information independently. Review Manager 5.2 was used to study data carefully and evaluate risk of bias. A total of nine trials of 906 patients were included. Based on the meta-analysis, compared to oseltamivir, CPM combined with oseltamivir had better effect in the time of defervescence [MD = -17.68, 95% CI (-25.93, -9.44), P < 0.0001], the time of symptom improvement [MD = -22.28, 95% CI (-26.77, -17.80), P < 0.00001], and the time of hospitalization [MD = -2.04, 95% CI (-3.45, -0.63), P = 0.005]. Related to safety [RR = 0.69, 95% CI (0.38, 1.23), P = 0.21], the experimental group had fewer adverse reactions than the control group, but there is no statistical significance. The findings show that CPM combined with oseltamivir in adult influenza has a better efficacy in shortening the time of defervescence and symptom improvement, reducing the time of hospitalization. However, publication bias is inevitable due to the low methodological quality check of the clinical research about diagnostic criteria, definition of adult influenza, and small number of articles, and further large sample sizes and multi-center clinical trials are needed to give better proof for its efficacy and safety.

Inhaled Zanamivir vs Oral Oseltamivir to Prevent Influenza-related Hospitalization or Death: A Nationwide Population-based Quasi-experimental Study.

BACKGROUND: Meta-analyses of individual patient data from randomized, controlled trials show that early oseltamivir treatment for influenza cut the risk of pneumonia and hospitalization by 44% and 63%, respectively. However, data on the effectiveness of inhaled zanamivir in preventing hospitalization and death are lacking. METHODS: This nationwide, population-based, cohort study included all outpatients treated with inhaled zanamivir or oral oseltamivir within 48 hours after a clinical diagnosis of influenza before and after the rollout of inhaled zanamivir as the first-line antiviral in Taiwan. The main outcome was influenza-related hospitalization or death within 14 days. Those who developed the outcome within 2 days were excluded from analyses. Propensity score stratification was used to control confounding from covariates. RESULTS: A total of 865 032 eligible influenza outpatients were included in the analysis. The risk of developing the main outcome (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], .96 to 1.06) did not differ between the inhaled zanamivir group (n = 595 897, 68.9%, the reference) and the oral oseltamivir group (n = 269 135, 31.1%). Prespecified analysis on high-risk subgroups further showed that inhaled zanamivir is not inferior to oral oseltamivir in either patients aged ≥65 years (aHR, 1.14; 95% CI: 1.05 to 1.25) or patients with chronic lung diseases (aHR, 1.23; 95% CI: 1.08 to 1.41). CONCLUSIONS: Inhaled zanamivir is not inferior to oral oseltamivir as outpatient treatment in preventing influenza-related hospitalization or death for patients whose conditions do not require hospitalization within 2 days.

Oseltamivir induced oral-only erythema multiforme.

Severe dermatologic and mucosal adverse reactions to oseltamivir are rare. To date, only two other case reports have described mucosal changes secondary to oseltamivir, but both cases were associated with concomitant skin changes. We report a case of a previously healthy 18-year-old-male who developed oral-only erythema multiforme after being treated with oseltamivir for influenza B. Given the frequency of which oseltamivir is prescribed, we highlight the importance of recognizing this uncommon but serious adverse reaction.

Drug-induced Neuropsychiatric Adverse Events Using Post-Marketing Surveillance.

BACKGROUND: Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated. RESULTS: A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast. CONCLUSION: Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

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.

Association of bleeding symptoms during influenza infection and administered drugs.

On March 1, 2019, the Ministry of Health, Labour and Welfare added bleeding symptoms to adverse reaction package inserts as a possible adverse event for a new anti-influenza drug, baloxavir marboxil, because 13 patients with bleeding symptoms were identified among influenza patients taking the drug. Nevertheless, aspects of the epidemiology of bleeding symptoms among influenza patients remain unclear. This study elucidated bleeding symptoms among influenza patients and hospitalized patients as severe cases. A survey was administered to all physicians in Japan during the 2019-2020 season for reporting of bleeding symptoms in influenza patients. The survey elicited information about outcomes, assuming associated underlying diseases and drugs in addition to administered drugs including acetaminophen and anti-influenza (antiviral) drugs. We received reports of 63 cases with bleeding symptoms, including 5 cases of hospitalized patients. Among all patients, 54% had been administered oseltamivir; 10% had been administered baloxavir marboxil. Among hospitalized patients, all had been administered acetaminophen; 40% of them had been administered oseltamivir, and one patient had been administered baloxavir marboxil. Accumulation of bleeding symptom cases is expected to be necessary to evaluate the association.

Oseltamivir-Induced Mania in a Patient With Influenza A.

ABSTRACT: Oseltamivir is an antiviral drug often preferred in treating viral infections. Its use has increased owing to annual influenza outbreaks and the COVID-19 pandemic. Although its adverse effects are often seen in the gastrointestinal system, it has other adverse effects that can prevent its use, for example, neuropsychiatric events. In this case report, we present a manic episode case caused by the use of oseltamivir.

Effect of triple antimicrobial therapy on electrocardiography parameters in patients with mild-to-moderate coronavirus disease 2019.

OBJECTIVE: The effects of treatment of coronavirus disease 2019 (COVID-19) with a triple combination composed of hydroxychloroquine, an an-tiviral, and an antibiotic on electrocardiography (ECG) parameters in patients with mild-to-moderate symptoms are not wholly understood. We aimed to explore the changes in ECG parameters after treatment with triple combination therapy in patients with mild-to-moderate symptomatic COVID-19. METHODS: This retrospective, single-center case series analyzed 91 patients with mild-to-moderate symptomatic COVID-19 at Ankara Gazi Mus-tafa Kemal State Hospital of Ankara City, Turkey, from April 1, 2020, to April 30, 2020. Forty-three patients were treated with hydroxychloroquine+oseltamivir+azithromycin (Group 1) and 48 patients were treated with hydroxychloroquine+oseltamivir+levofloxacin (Group 2). Heart rate, P wave duration, P wave dispersion, PR interval, QRS duration, corrected QT interval (QTc), QTc dispersion (QTD), delta QTc, Tp-e, Tp-e dispersion, and Tp-e/QTc ratio were all calculated from the baseline and posttreatment 12-lead ECG recordings. RESULTS: The QTc, QRS duration, Tp-e, PR interval, and P wave duration were significantly increased after treatment (p<0.001; p<0.001; p<0.001; p=0.001; p=0.001). The posttreatment C-reactive protein level was significantly lower than at baseline in Group 1 (p=0.014). At admission, 30% of patients had QT prolongation, and 4.3% of them had a QT duration >500 ms. Both Group 1 and Group 2 showed significant prolongation of the QTc interval (Group 1; p<0.001 vs. Group 2; p<0.001), QRS duration (Group 1; p=0.006 vs. Group 2; p=0.014), Tp-e (Group 1; p=0.036 vs. Group 2; p<0.001), and PR interval (Group 1; p=0.002 vs. Group2; p=0.05). The QTD was significantly decreased in Group 1 (p<0.001). None of the patients experienced any overt ventricular arrhythmia. CONCLUSION: To the best of our knowledge, this study is the first to investigate QT prolongation in a population of COVID-19 patients treated with triple combination therapy. We found that there was a significant decrease in the QTD after the treatment in patients who were taking triple therapy including azithromycin.

Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.

First case of acute cholestatic hepatitis attributed to oseltamivir in a young girl with ah1n1 influenza.

Abstract: Oseltamivir caryboxylase is a potent inhibitor of the enzyme neuramidase of the influenza virus particle and it is active against both influenza A and B viruses. Oseltamivir is indicated for therapy or post-exposure prevention of influenza A and B. Side effects are uncommon and include mild nausea, gastrointestinal upset, dizziness and headache. Despite its widespread use, oseltamivir has not been associated with clinically apparent liver injury. To the best of our knowledge, this is the first case report in the literature linking the development of acute hepatitis to the consumption of oseltamivir in a patient suffering from influenza H1N1 infection.

Oseltamivir-Associated Bradycardia in Critically Ill Patients.

BACKGROUND: Oseltamivir is frequently administered to critically ill patients with presumed influenza. It may modulate Na+, K+, and Ca2+ channels to produce bradycardia. OBJECTIVE: To evaluate the association between oseltamivir and bradycardia in critically ill patients and assess parameters associated with bradycardia. METHODS: This was a retrospective audit of 203 critically ill adults with presumed influenza receiving at least 2 doses of oseltamivir. The primary outcome was the occurrence of bradycardia, defined as a heart rate (HR) ≤59 beats per minute (BPM) while receiving oseltamivir or a decrease of ≥20 BPM compared with the lowest HR before initiating oseltamivir. RESULTS: A total of 88 (43.4%) patients manifested bradycardia, 59 with HR ≤59 BPM, 19 with HR decrease of ≥20 BPM, and 10 with both. The time from first dose to bradycardia was 51.4 ± 43 hours. In all, 48 (54.6%) patients received therapies for bradycardia, including increased inotropic/vasopressor dose, electrolyte replacement, electrocardiogram, discontinuation of other medications, cardiology consult, discontinuation of oseltamivir, and pacer placement. There were no significant differences between groups with bradycardia versus without in terms of demographics, laboratory values, hospital characteristics, or oseltamivir dosing. Multivariate logistic regression showed that bradycardia was associated with baseline HR, age, past medical history of neurological issues, and positive influenza status. Between hours 6 through 126, significant differences existed between groups in actual and lowest HR. CONCLUSION AND RELEVANCE: Oseltamivir was associated with clinically relevant bradycardia in critically ill patients. Clinicians should closely monitor HR in critically ill patients receiving oseltamivir.