Oseltamivir Phosphate by Mosby’s Drug Consult™ (2006)
INTRODUCTION
Pronounciation: oh-sel-tam’-i-vir foss’-fate
Ingredients: Oseltamivir Phosphate
FDA Approval Date: 1999-10-01
Foreign Brand Availability: Tamiflu (AUSTRALIA; US; CANADA; ENGLAND; FRANCE; HONG-KONG; IRELAND; ISRAEL; KOREA; PHILIPPINES; SINGAPORE)
Drug Class: Antivirals
Pregnancy Categories: C
Indications: Influenza
Off Label Uses: None found
Cost of Therapy: Influenza; 75 mg; Tamiflu Capsules; 2 capsules/day; 5 day supply
DESCRIPTION
Tamiflu (oseltamivir phosphate) is available as a capsule containing 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 12 mg/ml oseltamivir base. In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K 30, croscarmellose sodium, and sodium stearyl fumarate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes FD&C blue no. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains xanthan gum, monosodium citrate, sodium benzoate, sorbitol, saccharin sodium, titanium dioxide, and tutti-frutti flavoring.
Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino -5-amino-3(1-ethylpropoxy)-1-cyclohexene -1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt.
CLINICAL PHARMACOLOGY
MICROBIOLOGY
Mechanism of Action
Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
Antiviral Activity In Vitro
The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus were highly variable depending on the assay method used and the virus tested. The 50% and 90% inhibitory concentrations (IC50 and IC90) were in the range of 0.0008 uM to >35 uM and 0.004 uM to >100 uM, respectively (1 uM = 0.284 ug/ml). The relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established.
Drug Resistance
Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered in vitro by passage of virus in the presence of increasing concentrations of oseltamivir carboxylate. Genetic analysis of these isolates showed that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both.
In clinical studies of postexposure and seasonal prophylaxis, determination of resistance was limited by the low overall incidence rate of influenza infection and prophylactic effect of oseltamivir phosphate.
In clinical studies in the treatment of naturally acquired infection with influenza virus, 1.3% (4/301) of posttreatment isolates in adult patients and adolescents, and 8.6% (9/105) in pediatric patients aged 1-12 years showed emergence of influenza variants with decreased neuraminidase susceptibility to oseltamivir carboxylate.
Genotypic analysis of these variants showed a specific mutation in the active site of neuraminidase compared to pretreatment isolates. The contribution of resistance due to alterations in the viral hemagglutinin has not been fully evaluated.
Cross-Resistance
Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza mutants has been observed in vitro.
Due to limitations in the assays available to detect drug-induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made. However, 1 of the 3 oseltamivir-induced mutations in the viral neuraminidase from clinical isolates is the same as 1 of the 3 mutations observed in zanamivir-resistant virus.
Insufficient information is available to fully characterize the risk of emergence of oseltamivir phosphate resistance in clinical use.
Immune Response
No influenza vaccine interaction study has been conducted. In studies of naturally acquired and experimental influenza, treatment with oseltamivir phosphate did not impair normal humoral antibody response to infection.
PHARMACOKINETICS
Absorption and Bioavailability
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of the total exposure after oral dosing.
Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily (see DOSAGE AND ADMINISTRATION).
Coadministration with food has no significant effect on the peak plasma concentration (551 ng/ml under fasted conditions and 441 ng/ml under fed conditions) and the area under the plasma concentration time curve (6218 ng·h/ml under fasted conditions and 6069 ng·h/ml under fed conditions) of oseltamivir carboxylate.
Distribution
The volume of distribution (Vss) of oseltamivir carboxylate, following intravenous administration in 24 subjects, ranged between 23 and 26 liters.
The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.
Metabolism
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.
Elimination
Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1-3 hours in most subjects after oral administration. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6-10 hours in most subjects after oral administration. Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion occurs, in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces.
SPECIAL POPULATIONS
Renal Impairment
Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function.
Pediatric Patients
The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single dose pharmacokinetic study in pediatric patients aged 5-16 years (n=18) and in a small number of pediatric patients aged 3-12 years (n=5) enrolled in a clinical trial. Younger pediatric patients cleared both the prodrug and the active metabolite faster than adult patients resulting in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). The pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are similar to those in adult patients.
Geriatric Patients
Exposure to oseltamivir carboxylate at steady-state was 25-35% higher in geriatric patients (age range 65-78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric patients were similar to those seen in young adults. Based on drug exposure and tolerability, dose adjustments are not required for geriatric patients for either treatment or prophylaxis (see DOSAGE AND ADMINISTRATION, Special Dosage Instructions).
CLINICAL STUDIES
STUDIES IN NATURALLY OCCURRING INFLUENZA
Treatment of Influenza
Adult Patients
Two Phase 3 placebo-controlled and double-blind clinical trials were conducted: one in the US and one outside the US. Patients were eligible for these trials if they had fever >100°F, accompanied by at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community. In addition, all patients enrolled in the trials were allowed to take fever-reducing medications.
Of 1355 patients enrolled in these two trials, 849 (63%) patients were influenza-infected (age range 18-65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected patients, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type.
Oseltamivir phosphate was started within 40 hours of onset of symptoms. Subjects participating in the trials were required to self-assess the influenza-associated symptoms as “none”, “mild”, “moderate” or “severe”. Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as “none” or “mild”. In both studies, at the recommended dose of oseltamivir phosphate 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving oseltamivir phosphate compared to subjects receiving placebo. Subgroup analyses of these studies by gender showed no differences in the treatment effect of oseltamivir phosphate in men and women.
In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg of oseltamivir phosphate twice daily for 5 days.
Geriatric Patients
Three double-blind placebo-controlled treatment trials were conducted in patients ≥65 years of age in three consecutive seasons. The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5°F. Of 741 patients enrolled, 476 (65%) patients were influenza-infected. Of the 476 influenza-infected patients, 95% were infected with influenza Type A and 5% with influenza Type B.
In the pooled analysis, at the recommended dose of oseltamivir phosphate 75 mg twice daily for 5 days, there was a 1 day reduction in the median time to improvement in influenza-infected subjects receiving oseltamivir phosphate compared to those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies.
Pediatric Patients
One double-blind placebo-controlled treatment trial was conducted in pediatric patients aged 1-12 years (median age 5 years), who had fever (>100°F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. Of 698 patients enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected patients, 67% were infected with influenza A and 33% with influenza B.
The primary endpoint in this study was the time to freedom from illness, a composite endpoint which required 4 individual conditions to be met. These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity. Oseltamivir phosphate treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses of this study by gender showed no differences in the treatment effect of oseltamivir phosphate in males and females.
Prophylaxis of Influenza
The efficacy of oseltamivir phosphate in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. The primary efficacy parameter for all these studies was the incidence of laboratory confirmed clinical influenza. Laboratory confirmed clinical influenza was defined as oral temperature ≥99.0°F/37.2°C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a 4-fold increase in virus antibody titers from baseline.
In a pooled analysis of 2 seasonal prophylaxis studies in healthy unvaccinated adults (aged 13-65 years), oseltamivir phosphate 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2% (6/520) for the oseltamivir phosphate group.
In a seasonal prophylaxis study in elderly residents of skilled nursing homes, oseltamivir phosphate 75 mg once daily taken for 42 days reduced the incidence of laboratory confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the oseltamivir phosphate group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.
In a study of postexposure prophylaxis in household contacts (aged ≥13 years) of an index case, oseltamivir phosphate 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the oseltamivir phosphate group. Index cases did not receive oseltamivir phosphate in the study.
INDICATIONS AND USAGE
TREATMENT OF INFLUENZA
Oseltamivir phosphate is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year of age and older who have been symptomatic for no more than 2 days.
PROPHYLAXIS OF INFLUENZA
Oseltamivir phosphate is indicated for the prophylaxis of influenza in adult patients and adolescents 13 years and older.
Oseltamivir phosphate is not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control’s Immunization Practices Advisory Committee.
CONTRAINDICATIONS
Oseltamivir phosphate is contraindicated in patients with known hypersensitivity to any of the components of the product.
PRECAUTIONS
GENERAL
There is no evidence for efficacy of oseltamivir phosphate in any illness caused by agents other than influenza viruses Types A and B.
Use of oseltamivir phosphate should not affect the evaluation of individuals for annual influenza vaccination in accordance with guidelines of the Center for Disease Control and Prevention Advisory Committee on Immunization Practices.
Efficacy of oseltamivir phosphate in patients who begin treatment after 40 hours of symptoms has not been established.
Efficacy of oseltamivir phosphate in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.
Safety and efficacy of repeated treatment or prophylaxis courses have not been studied.
Efficacy of oseltamivir phosphate for treatment or prophylaxis has not been established in immunocompromised patients.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Oseltamivir phosphate has not been shown to prevent such complications.
Hepatic Impairment: The safety and pharmacokinetics in patients with hepatic impairment have not been evaluated.
Renal Impairment: Dose adjustment is recommended for patients with a serum creatinine clearance <30 ml/min (see DOSAGE AND ADMINISTRATION).
INFORMATION FOR THE PATIENT
Patients should be instructed to begin treatment with oseltamivir phosphate as soon as possible from the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a physician.
Patients should be instructed to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take oseltamivir phosphate at the usual times.
Oseltamivir phosphate is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Long-term carcinogenicity tests with oseltamivir are underway but have not been completed. However, a 26 week dermal carcinogenicity study of oseltamivir carboxylate in FVB/Tg.AC transgenic mice was negative. The animals were dosed at 40, 140, 400 or 780 mg/kg/day in two divided doses. The highest dose represents the maximum feasible dose based on the solubility of the compound in the control vehicle. A positive control, tetradecanoyl phorbol-13-acetate administered at 2.5 ug per dose 3 times per week gave a positive response.
Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test.
In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to females for 2 weeks before mating, during mating, and until day 6 of pregnancy. Males were dosed for 4 weeks before mating, during, and for 2 weeks after mating. There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure [AUC(0-24h)] of oseltamivir carboxylate.
PREGNANCY CATEGORY C
There are insufficient human data upon which to base an evaluation of risk of oseltamivir phosphate to the pregnant woman or developing fetus. Studies for effects on embryo-fetal development were conducted in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route. Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure in the rabbit. Pharmacokinetic studies indicated that fetal exposure was seen in both species. In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. There was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in the exposed offspring in these studies. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.
Because animal reproductive studies may not be predictive of human response and there are no adequate and well-controlled studies in pregnant women, oseltamivir phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS
In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk. Oseltamivir phosphate should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant.
PEDIATRIC USE
The safety and efficacy of oseltamivir phosphate in pediatric patients younger than 1 year of age have not been established.
GERIATRIC USE
The safety of oseltamivir phosphate has been established in clinical studies which enrolled 741 subjects (374 received placebo and 362 received oseltamivir phosphate). Some seasonal variability was noted in the clinical efficacy outcomes (see CLINICAL STUDIES, Studies in Naturally Occurring Influenza, Treatment of Influenza, Geriatric Patients).
Safety and efficacy have been demonstrated in elderly residents of nursing homes who took oseltamivir phosphate for up to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season (see CLINICAL STUDIES, Studies in Naturally Occurring Influenza, Prophylaxis of Influenza).
DRUG INTERACTIONS
Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low.
In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases.
Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic drugs, has no effect on plasma levels of oseltamivir or oseltamivir carboxylate.
Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Coadministration of probenecid results in an approximate 2-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid.
Coadministration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak.
In 6 subjects, multiple doses of oseltamivir did not affect the single-dose pharmacokinetics of acetaminophen.
ADVERSE REACTIONS
TREATMENT STUDIES IN ADULT PATIENTS
A total of 1171 patients who participated in adult Phase 3 controlled clinical trials for the treatment of influenza were treated with oseltamivir phosphate. The most frequently reported adverse events in these studies were nausea and vomiting. These events were generally of mild to moderate degree and usually occurred on the first 2 days of administration. Less than 1% of subjects discontinued prematurely from clinical trials due to nausea and vomiting.
Adverse events included are: all events reported in the treatment studies with frequency ≥1% in the oseltamivir 75 mg bid group.
Additional adverse events occurring in <1% of patients receiving oseltamivir phosphate for treatment included unstable angina, anemia, pseudomembranous colitis, humerus fracture, pneumonia, pyrexia, and peritonsillar abscess.
PROPHYLAXIS STUDIES
A total of 3434 subjects (adolescents, healthy adults, and elderly) participated in Phase 3 prophylaxis studies, of whom 1480 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing. Events reported more frequently in subjects receiving oseltamivir phosphate compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhea, dyspepsia, and upper respiratory tract infections. However, the difference in incidence between oseltamivir phosphate and placebo for these events was less than 1%. There were no clinically relevant differences in the safety profile of the 942 elderly subjects who received oseltamivir phosphate or placebo, compared with the younger population.
TREATMENT STUDIES IN PEDIATRIC PATIENTS
A total of 1032 pediatric patients aged 1-12 years (including 698 otherwise healthy pediatric patients aged 1-12 years and 334 asthmatic pediatric patients aged 6-12 years) participated in Phase 3 studies of oseltamivir phosphate given for the treatment of influenza. A total of 515 pediatric patients received treatment with oseltamivir phosphate oral suspension.
The most frequently reported adverse event was vomiting. Other events reported more frequently by pediatric patients treated with oseltamivir phosphate included abdominal pain, epistaxis, ear disorder, and conjunctivitis. These events generally occurred once and resolved despite continued dosing. They did not cause discontinuation of drug in the vast majority of cases.
The adverse event profile in adolescents is similar to that described for adult patients and pediatric patients aged 1-12 years.
OBSERVED DURING CLINICAL PRACTICE FOR TREATMENT
The following adverse reactions have been identified during postmarketing use of oseltamivir phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to oseltamivir phosphate exposure.
General: Rash, swelling of the face or tongue, toxic epidermal necrolysis.
Digestive: Hepatitis, liver function tests abnormal.
Cardiac: Arrhythmia.
Neurologic: Seizure, confusion.
Metabolic: Aggravation of diabetes.
OVERDOSAGE
At present, there has been no experience with overdose. Single doses of up to 1000 mg of oseltamivir phosphate have been associated with nausea and/or vomiting.
DOSAGE AND ADMINISTRATION
Oseltamivir phosphate may be taken with or without food (see CLINICAL PHARMACOLOGY, Pharmacokinetics). However, when taken with food, tolerability may be enhanced in some patients.
STANDARD DOSAGE
Treatment of Influenza
Adults and Adolescents
The recommended oral dose of oseltamivir phosphate for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily for 5 days. Treatment should begin within 2 days of onset of symptoms of influenza.
Pediatric Patients
An oral dosing dispenser with 30, 45, and 60 mg graduations is provided with the oral suspension; the 75 mg dose can be measured using a combination of 30 and 45 mg. It is recommended that patients use this dispenser. In the event that the dispenser provided is lost or damaged, another dosing syringe or other device may be used to deliver the following volumes: 2.5 ml (1/2 tsp) for children ≤15 kg; 3.8 ml (3/4 tsp) for >15 to 23 kg; 5.0 ml (1 tsp) for >23 to 40 kg; and 6.2 ml (1 1/4 tsp) for >40 kg.
Prophylaxis of Influenza
The recommended oral dose of oseltamivir phosphate for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 7 days. Therapy should begin within 2 days of exposure. The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to 6 weeks. The duration of protection lasts for as long as dosing is continued.
SPECIAL DOSAGE INSTRUCTIONS
Hepatic Impairment
The safety and pharmacokinetics in patients with hepatic impairment have not been evaluated.
Renal Impairment
For plasma concentrations of oseltamivir carboxylate predicted to occur following various dosing schedules in patients with renal impairment, see CLINICAL PHARMACOLOGY, Special Populations.
Treatment of Influenza: Dose adjustment is recommended for patients with creatinine clearance between 10 and 30 ml/min receiving oseltamivir phosphate for the treatment of influenza. In these patients it is recommended that the dose be reduced to 75 mg of oseltamivir phosphate once daily for 5 days. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.
Prophylaxis of Influenza: For the prophylaxis of influenza, dose adjustment is recommended for patients with creatinine clearance between 10 and 30 ml/min receiving oseltamivir phosphate. In these patients it is recommended that the dose be reduced to 75 mg of oseltamivir phosphate every other day or 30 mg oseltamivir phosphate oral suspension every day. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.
Pediatric Patients
The safety and efficacy of oseltamivir phosphate for prophylaxis in pediatric patients younger than 13 years of age have not been established. The safety and efficacy of oseltamivir phosphate for treatment in pediatric patients younger than 1 year of age have not been established.
Geriatric Patients
No dose adjustment is required for geriatric patients (see CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS).
HOW SUPPLIED
CAPSULES
Tamiflu capsules are supplied as 75 mg (75 mg free base equivalent of the phosphate salt) grey/light yellow hard gelatin capsules. “ROCHE” is printed in blue ink on the grey body and “75 mg” is printed in blue ink on the light yellow cap.
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
ORAL SUSPENSION
Tamiflu oral suspension is supplied as a white powder blend for constitution to a white tutti-frutti-flavored suspension.
Storage
Dry Powder: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Constituted Suspension: Store under refrigeration at 2-8°C (36-46°F). Do not freeze.
Revision Date
Developed: 01/13/2000
Revised: 01/12/2006
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