Penelope Ward

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial

Summary Background Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza. Methods We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients. Findings 475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87·4 h [95% Cl 73·3–104·7], p=0·02) with oseltamivir 75 mg and by 35 h (30%, 81·8 h [68·2–100·0], p=0·01) with oseltamivir 150 mg than with placebo (116·5 h [101·5–137·8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74·5 h [68·2–98·0], p=0·02; 150 mg 70·7 h [54·0–89·4], p=0·01; placebo 117·5 h [103·0–143·8]). Oseltamivir was associated with higher symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated. Interpretation Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.

Oral oseltamivir treatment of influenza in children

Background. Oral oseltamivir administration is effective treatment for influenza in adults. This study was conducted to determine the efficacy, safety and tolerability of oseltamivir in children with influenza. Methods. In this randomized, double blind, placebo-controlled study, children 1 through 12 years with fever [≥100°F (≥38°C)] and a history of cough or coryza <48 h duration received oseltamivir 2 mg/kg/dose or placebo twice daily for 5 days. The primary efficacy endpoint was the time to resolution of illness including mild/absent cough and coryza mild/absent, return to normal activity and euthermia. Results. Of 695 enrolled children 452 (65%) had influenza (placebo, n = 235; oseltamivir, n = 217). Among infected children the median duration of illness was reduced by 36 h (26%) in oseltamivir compared with placebo recipients (101 h; 95% confidence interval, 89 to 118 vs. 137 h; 95% confidence interval, 125 to 150;P < 0.0001). Oseltamivir treatment also reduced cough, coryza and duration of fever. New diagnoses of otitis media were reduced by 44% (12%vs. 21%). The incidence of physician-prescribed antibiotics was significantly lower in influenza-infected oseltamivir (68 of 217, 31%) than placebo (97 of 235, 41%;P = 0.03) recipients. Oseltamivir therapy was generally well-tolerated, although associated with an excess frequency of emesis (5.8%). Discontinuation because of adverse events was low in both groups (1.8% with oseltamivir vs. 1.1% with placebo). Oseltamivir treatment did not affect the influenza-specific antibody response. Conclusions. Oral oseltamivir administration is an efficacious and well-tolerated therapy for influenza in children when given within 48 h of onset of illness.

Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza

BACKGROUND Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802

AbstractOseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible.The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours.Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases.The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested.Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects.These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza.

Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.

We determined the efficacy of postexposure prophylaxis (PEP) and treatment of ill index cases with oseltamivir, in an attempt to prevent influenza transmission in households, in a study conducted in 277 households with 298 index cases (62% with laboratory-confirmed influenza) and 812 contacts aged > or =1 year. Contacts were randomized by household to receive treatment (5 days; n=402), if illness developed, or PEP for 10 days (n=410), and the number of households with at least 1 contact developing laboratory-confirmed influenza was measured. PEP provided a protective efficacy of 58.5% (95% confidence interval [CI], 15.6%-79.6%; P=.0114) for households against proven influenza and 68.0% (95% CI, 34.9%-84.2%; P=.0017) for individual contacts, compared with treatment of index cases alone. No oseltamivir-resistant variants were detected in treated index cases or contacts. PEP of household contacts of those with influenza reduces the secondary spread of influenza in families when the initial household case is treated.

Long-Term Use of Oseltamivir for the Prophylaxis of Influenza in a Vaccinated Frail Older Population

OBJECTIVES To investigate the efficacy of once-daily oral oseltamivir for 6 weeks (Tamiflu) in prophylaxis against laboratory-confirmed clinical influenza in frail older subjects living in homes for seniors and to determine the safety and tolerability of long-term oseltamivir. DESIGN Double-blind, placebo-controlled, parallel-group, randomized, multicenter study. SETTING Thirty-one residential homes for seniors across United States and Europe. PARTICIPANTS Five hundred forty-eight frail older occupants (mean age 81 years, >80% vaccinated). INTERVENTION Prophylaxis with oseltamivir 75 mg or placebo once daily for 6 weeks, beginning when influenza was detected locally. MEASUREMENTS The primary efficacy endpoint was laboratory-confirmed clinical influenza. RESULTS Oseltamivir administration resulted in a 92% reduction in the incidence of laboratory-confirmed clinical influenza compared with placebo (placebo 12/272 (4.4%), oseltamivir 1/276 (0.4%); P = .002). Of subjects vaccinated against influenza, oseltamivir was 91% effective in preventing laboratory-confirmed clinical influenza (placebo 11/218 (5.0%), oseltamivir 1/222 (0.5%); P = .003). Oseltamivir use was associated with a significant reduction in the incidence of secondary complications (placebo 7/272 (2.6%), oseltamivir 1/276 (0.4%); P = .037). Although nearly all subjects were taking concomitant medication both before and during the study, oseltamivir was well tolerated. A similar incidence of adverse events, including gastrointestinal effects, occurred in both groups. There was no suppression of antibody response in oseltamivir recipients. CONCLUSION Oral oseltamivir 75 mg once daily for 6 weeks effectively prevented clinical influenza in vaccinated frail older subjects using significant concomitant medications in a residential care setting. The treatment was well tolerated and provided additional protection to that afforded by vaccination.

The Pharmacokinetics and Tolerability of the Oral Neuraminidase Inhibitor Oseltamivir (Ro 64–0796/GS4104) in Healthy Adult and Elderly Volunteers

The tolerability and pharmacokinetics of Ro 64–0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double‐blind, placebo‐controlled studies. Two studies involved healthy adult volunteers (18–55 years) (n = 48) who received single (20–1000 mg) or bid doses (50–500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (≥65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple‐dose exposure was predictable from single‐dose data, and steady‐state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice‐daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.

Clinical benefits with oseltamivir in treating Influenza in adult populations: Results of a pooled and subgroup analysis

BackgroundInfluenza is a potentially life-threatening illness that affects approximately 10% of the population annually, with resulting personal misery and societal disruption. Oseltamivir is a novel influenza treatment that has been extensively investigated. We describe a series of retrospective analyses investigating various measures of clinical efficacy across different populations of influenza-infected patients enrolled in studies of oseltamivir (Tamiflu®) that were conducted within the clinical development programme.MethodsAdolescents and adults (13–97 years, n = 4015) presenting within 36 hours of onset of influenza symptoms were randomised to receive oseltamivir 75mg or placebo twice daily for 5 days during local influenza outbreaks. Of these patients, 2413 had laboratory-confirmed influenza and are included in the analysis. Approximately 30% (n = 739) of patients were ‘high risk’; 20% were healthy elderly subjects (n = 488) and 10% (n = 251) were patients with chronic respiratory and/or cardiac conditions. The primary endpoint was time to alleviation of a seven-symptom cluster in influenza-infected patients. Supplementary analyses were conducted using a variety of illness definitions and symptom clusters to investigate the sensitivity of the assessment of overall efficacy to differing disease definitions and also to explore efficacy in important subpopulations.ResultsA total of 2413 patients had confirmed influenza infection (placebo: n = 1063; oseltamivir: n = 1350). Across all populations, the time to alleviation of illness was reduced by 19% (median duration 100.6 hours [95% CI 94.8–104.7]) compared with placebo (124.5 hours [95% CI 117.7–132.3], p < 0.0001). Oseltamivir recipients returned to normal health status, regained ability to perform usual activities and regained normal sleep patterns significantly faster than placebo recipients. The median duration of troublesome influenza symptoms was significantly reduced by oseltamivir treatment, e.g. fatigue by 29% and myalgia by 26% (both p < 0.0001). After 48 hours of treatment, 57% more placebo than oseltamivir recipients remained febrile, despite greater use of acetaminophen by placebo recipients. In addition, the median duration of acute febrile illness was significantly shortened by oseltamivir treatment compared with placebo in patients with cardiac disease (44.0 hours vs 64.7 hours, p = 0.026) or chronic obstructive airways disease (37.9 hours vs 53.8 hours, p = 0.004). Efficacy was similar among influenza A- and influenza B-infected patients. Oseltamivir was well tolerated, with transient gastrointestinal effects (observed in one in seven oseltamivir-treated patients compared with one in 12 patients on placebo) that only rarely resulted in study discontinuation.ConclusionsOral oseltamivir is a well tolerated and effective treatment for influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease.

Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin

ABSTRACT Twelve volunteers completed a two-sequence, three-way crossover study of a single 900-mg aspirin dose and multiple doses of 75 mg of oseltamivir in the absence and presence of 900 mg of aspirin. The plasma and urine results demonstrated no pharmacokinetic interaction between oseltamivir and aspirin.