Oseltamivir (Systemic)
VA CLASSIFICATION Primary: AM890 Commonly used brand name(s): Tamiflu. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s). Category: Antiviral (Systemic) Indications General considerations Resistance Decreased neuraminidase susceptibility of influenza virus to oseltamivir carboxylate was demonstrated in 1.3% (4 out of 301 isolates) of adult and adolescent patients treated in clinical studies. {07} In similar studies with pediatric patients aged 1 to 12 years, 8.6% (9 out of 105) of patients showed decreased neuraminidase susceptibility of influenza to oseltamivir carboxylate. {07} The active site of neuraminidase showed specific mutation in genotypic analysis. No studies were performed to determine the role of alterations in the viral hemagglutinin. {01} In vitro studies demonstrate the development of reduced susceptibility of influenza A virus in the presence of increasing concentrations of oseltamivir carboxylate. Genetic analysis showed reduced susceptibility and is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. {01} Crossresistance Genotypic analysis demonstrates similar mutations in the viral neuraminidase from clinical isolates between oseltamivir-induced and zanamivir-resistant virus. An estimation of incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made due to limitations in the assays available. {01} Accepted Influenza A (treatment)Oseltamivir is indicated for the treatment of uncomplicated acute infection caused by influenza A virus in patients older than 1 year of age who have been symptomatic for no more than 2 days. {01} {04} {07} Influenza B (treatment)Oseltamivir is indicated for the treatment of uncomplicated acute infection caused by influenza B virus in patients older than 1 year of age who have been symptomatic for no more than 2 days. {01} {04} {07} Note: Individuals who normally receive influenza vaccination should continue with annual influenza vaccination in accordance with guidelines of the Center for Disease Controls and Prevention Advisory Committee on Immunization Practices. {01} The clinical trials conducted in influenza-infected patients included small numbers of patients with influenza B. Therefore, less evidence exists to support the efficacy in influenza B. {01} {04} Efficacy data in patients who initiate oseltamivir 40 or more hours after symptom onset have not been determined. {01} {04} Efficacy in patients with chronic cardiac disease and/or respiratory disease has not been established. {01} {04} Influenza (prophylaxis) 1 Oseltamivir is indicated for the prophylaxis of influenza in adults and adolescents 13 years of age and older. {05} {06} 1 Not included in Canadian product labeling. Pharmacology/Pharmacokinetics Physicochemical characteristics: Molecular weight Oseltamivir free base: 312.4 {01} {04} Oseltamivir phosphate: 410.4 {01} {04} Mechanism of action/Effect: Oseltamivir is an inhibitor of influenza virus neuraminidase, possibly altering particle aggregation and release {01} {04} . Absorption: Oral oseltamivir phosphate is readily absorbed then extensively converted to oseltamivir carboxylate, the active form, predominantly by hepatic esterases. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Less than 5% of an oral dose reaches the systemic circulation as oseltamivir phosphate. {01} {04} Distribution: Oseltamivir carboxylateVolume of distribution is 23 to 26 liters following intravenous administration in 24 subjects {01} Protein binding: Oseltamivir phosphateModerate (42%) {01} {04} Oseltamivir carboxylateVery low (< 3%) {01} {04} Biotransformation: Hepatic; Oseltamivir, ethyl ester prodrug, undergoes extensive hydrolysis to the active ester form, oseltamivir carboxylate. {01} {04} Half-life: Elimination 1 to 3 hours for oseltamivir and 6 to 10 hours for oseltamivir carboxylate. {01} Peak serum concentration: Results after multiple doses of 75 milligrams twice daily of oseltamivir phosphate: Oseltamivir phosphate65.2 nanograms/milliliter (ng/mL) Oseltamivir carboxylate348 ng/mL {01} Time to peak effect: 24 hours for a significant reduction in viral titers after initiation of oral treatment after inoculation with experimental influenza virus. {02} Elimination: RenalOseltamivir carboxylate is extensively eliminated by renal excretion (> 99%). {01} Renal clearance (18.8 L/hr) exceeds glomerular filtration rate (7.5 L/hr), indicating that tubular secretion occurs {04} . FecalElimination of an oral radiolabeled dose is < 20% in the feces. {01} Precautions to Consider Pregnancy/Reproduction Fertility Doses of oseltamivir administered to female rats 2 weeks before mating, during mating and until Day 6 of pregnancy were 50, 250, and 1500 milligrams/kilogram per day. Doses of oseltamivir were administered to male rats 4 weeks before mating, during, and for 2 weeks after mating. Oseltamivir lacked an effect on fertility, mating performance, or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure (area under the concentration curve 0 to 24 hours) of oseltamivir carboxylate. {01} Pregnancy Adequate and well-controlled studies in humans have not been done. In a rat study, minimal maternal toxicity was reported with 1500 milligrams/kilogram (mg/kg) per day orally and no maternal toxicities were reported with 50 and 250 mg/kg per day orally. In a rabbit study, slight and marked maternal toxicities were observed, respectively, with 150 and 500 mg/kg per day and no maternal toxicities with 50 mg/kg per day. In the rat and rabbit study there was a dose-dependent increase in the incidence rates of a variety of minor skeleton abnormalities and variants in the exposed offspring. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied. Oseltamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. {01} {04} FDA Pregnancy Category C {01} Breast-feeding It is not known whether oseltamivir is distributed into human breast milk. Oseltamivir and oseltamivir carboxylate are distributed into the milk of lactating rats. Oseltamivir should be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant. {01} {04} Pediatrics Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of oseltamivir in children greater than 1 year of age. Safety and efficacy have not been established in children less than 1 year of age. {07} Geriatrics Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oseltamivir in the elderly. {01} {04} Drug interactions and/or related problems The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)not necessarily inclusive ( » = major clinical significance): » Probenecid (concomitant administration results in an approximate two-fold increase in the active metabolite due to a decrease in active anionic tubular secretion in the kidney {04} ) Medical considerations/Contraindications The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate) not necessarily inclusive ( » = major clinical significance). Except under special circumstances, this medication should not be used when the following medical problem exists: » Hypersensitivity to oseltamivir or any component of the formulation Risk-benefit should be considered when the following medical problems exist Cardiac disease, chronic or Illness caused by agents other than influenza viruses Types A or B or Respiratory disease (efficacy has not been established {04} ) Hepatic impairment (safety and pharmacokinetics have not been evaluated {04} ) » Renal function impairment (safety has not been established in patients with renal failure, creatinine clearance below 10 milliliters/minute (mL/min); dosage adjustment is in patients with a creatinine clearance of less than 30 mL/min) {01} {04} Severe or unstable medical condition (safety and efficacy not established in the treatment of influenza in patients with any medical condition which might require hospitalization) {01} {04} Side/Adverse Effects The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)not necessarily inclusive: Those indicating need for medical attention Incidence less frequent Bronchitis (phlegm producing cough; wheezing ) {01} {04} Those indicating need for medical attention only if they continue or are bothersome Incidence more frequent Diarrhea {01} {04} {03} nausea {01} {04} {03} vomiting {01} {04} {03} Onset of nausea was predominately after the first dose and usually resolved within 1 to 2 days with continued dosing. {03} Incidence less frequent Abdominal pain {04} conjunctivitis {07} (redness, pain, swelling of eye, eyelid, or inner lining of eyelid ; burning, dry or itching eyes; discharge ; excessive tearing) primarily in pediatric patients cough {04} dizziness {04} ear disorder {07} primarily in pediatric patients epistaxis {07} (bloody nose; unexplained nosebleeds)primarily in pediatric patients fatigue {04} headache {04} insomnia {04} (trouble in sleeping) {01} Overdose For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ). Treatment of overdose To enhance eliminationThere is no data available on removal of oseltamivir or oseltamivir carboxylate by hemodialysis or hemoperfusion; however, greater than 99% of oseltamivir carboxylate is eliminated by renal excretion. {01} Specific treatmentTreatment is symptomatic. No specific antidote is available. Supportive carePatients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Patient Consultation As an aid to patient consultation, refer to Advice for the Patient, Oseltamivir (Systemic) . In providing consultation, consider emphasizing the following selected information ( » = major clinical significance): Before using this medication » Conditions affecting use, especially: Hypersensitivity to oseltamivir or any component of the formulation. {01} {04} Other medications, especially probenecid {04} . Renal function impairmentDosage adjustment is recommended in patients with a creatinine clearance of less than 30 mL/min. {01} {04} No recommended dose regimens are available for patients having routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease. {06} Proper use of this medication Supplying patient information about oseltamivir » For patients taking oseltamivir for treatment of influenza infection: Importance of taking medication within 2 days after onset of symptoms; taking medication either with food or on an empty stomach; however, taking with food may lessen the occurrence of stomach upset; compliance with full 5-day course of therapy For patients taking oseltamivir for prevention of influenza infection: Importance of taking medication within 2 days after exposure to influenza virus; taking medication either with food or on an empty stomach; however, taking with food may lessen the occurrence of stomach upset; taking medication for at least 7 days For patients taking oral suspension dosage form: Proper administration technique; not using after expiration date » Proper dosing Taking as soon as remembered, except if it is near the next dose (within 2 hours); not doubling the dose; informing doctor about missed doses. {01} {04} » Proper storage Precautions while using this medication Checking with physician if no improvement after finishing medication. Side/adverse effects » Signs of potential side effects, especially bronchitis {01} {04} General Dosing Information For influenza treatment: Oseltamivir must be started within 2 days after the onset of signs and symptoms of influenza (weakness, headache, fever, cough, and sore throat). Oseltamivir may be taken with or without food. Tolerability may be enhanced in some patients when taken with food. {01} {04} For influenza prophylaxis: Oseltamivir must be started within 2 days after exposure to person infected with influenza. Oseltamivir may be taken with or without food. Tolerability may be enhanced in some patients when taken with food. {06} Oral Dosage Forms Note: The available dosage form contains oseltamivir phosphate, but dosage and strength are expressed in terms of the base. OSELTAMIVIR PHOSPHATE CAPSULES Usual adult dose Influenza A (treatment) or Influenza B (treatment) Oral, 75 milligrams (mg) two times a day for 5 days. Oseltamivir should be initiated within 2 days of influenza symptoms. {01} {04} {07} Note: Renal Impairment: In patients with a creatinine clearance of less than 30 mL/min the recommended dose is 75 mg once daily for 5 days. Use of oseltamivir in patients with renal failure (creatinine clearance below 10 mL/min) has not been studied {04} . No recommended dose regimens are available for patients having routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease. {06} Influenza (prophylaxis) 1 Oral, 75 mg once a day for at least 7 days. Oseltamivir should be initiated within 2 days of influenza exposure. {06} Note: Renal Impairment: In patients with a creatinine clearance between 10 and 30 mL/min, the recommended dose is 75 mg once every other day. No recommended dose regimens are available for patients having routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease. {06} Usual pediatric dose Children less than 13 years of ageSafety and efficacy have not been established. {01} {04} {06} Usual geriatric dose See Usual adult dose {01} {04} Strength(s) usually available U.S. 75 mg (Rx) [ Tamiflu (croscarmellose sodium) (ethanol) (gelatin ) (povidone K 30) (pregelatinized starch) (purified water) ( sodium stearyl fumarate) (talc) ( titanium dioxide) (black iron oxide) (red iron oxide) (yellow iron oxide ) (FD & C Blue #2 (imprint on capsule))] {01} Canada 75 mg (Rx) [ Tamiflu (corn starch) (croscarmellose sodium) (gelatin) (iron oxides) (povidone K 30) (sodium stearyl fumarate) (talc) (titanium dioxide)] {04} Packaging and storage: Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F). {01} {04} Auxiliary labeling: Continue medication for full time of treatment OSELTAMIVIR PHOSPHATE FOR ORAL SUSPENSION Usual adult dose See Oseltamivir Phosphate Capsules. Usual pediatric dose Influenza A (treatment) or Influenza B (treatment) For patients 1 year of age or older: Patients weighing more than 40 kgOral, 75 mg two times a day for five days beginning within two days of the onset of the symptoms of influenza. {07} Patients weighing 24 to 40 kgOral, 60 mg two times a day for five days beginning within two days of the onset of the symptoms of influenza. {07} Patients weighing 16 to 23 kgOral, 45 mg two times a day for five days beginning within two days of the onset of the symptoms of influenza. {07} Patients weighing less than or equal to 15 kgOral, 30 mg two times a day for five days beginning within two days of the onset of the symptoms of influenza. {07} For patients up to 1 year of age: Safety and efficacy have not been established. {07} Note: In patients with a creatinine clearance between 10 and 30 mL per minute, the recommended dose is 75 mg once a day for five days. No recommended dosing regimens are available for patients with end-stage renal disease who are undergoing routine hemodialysis or continuous peritoneal dialysis. {07} Influenza (prophylaxis) 1 For patients 13 years of age or older: Prophylaxis following close contact with an infected individualOral, 75 mg once a day for at least seven days. Therapy should be initiated within two days following exposure. {07} Prophylaxis during a community outbreakOral, 75 mg once a day for up to six weeks. {07} For patients up to 13 years of age: Safety and efficacy have not been established. {07} Note: In patients with a creatinine clearance between 10 and 30 mL per minute, the recommended dose is 75 mg once every other day. No recommended dosing regimens are available for patients with end-stage renal disease who are undergoing routine hemodialysis or continuous peritoneal dialysis. {07} Usual geriatric dose See Oseltamivir Phosphate Capsules Size(s) usually available: U.S. 12 mg per mL (Rx) [ Tamiflu ( xanthan gum) (monosodium citrate) (sodium benzoate) (sorbitol) (saccharin sodium) (titanium dioxide ) (tutti-frutti flavoring)] {07} Canada Not commercially available. Packaging and storage: Prior to reconstitution, store between 15 and 30 °C (59 and 86 °F). {07} After reconstitution, store the suspension between 15 and 30 °C (59 and 86 °F) or refrigerated between 2 and 8 °C (36 and 46 °F). {07} Protect from freezing. {07} Preparation of dosage form: It is recommended that the oral suspension be reconstituted as follows by the pharmacist prior to dispensing to the patient: #149; Tap the closed bottle several times to loosen the powder. {07} #149; Measure 52 mL of water in a graduated cylinder. {07} #149; Add the total amount of water for reconstitution to the bottle and shake the closed bottle well for 15 seconds. {07} #149; Remove the child-resistant cap and push the bottle adapter into the neck of the bottle. {07} #149; Close the bottle with the child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and the child-resistant status of the cap. {07} Stability: After reconstitution, the oral suspension should be used within 10 days. {07} Auxiliary labeling: Do not freeze. Shake well before using. Take by mouth only (use oral dispenser included with medication). Note: Include patient package insert and oral dispenser when dispensing. {07} Developed: 01/13/2000 Revised: 01/10/2001 References - Product Information: Tamiflu™ oseltamivir phosphate. F. HoffmannLa Roche Ltd., Basel, Switzerland, 10/1999.
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- Product Information: Tamiflu™, oseltamivir phosphate. Roche Laboratories, Nutley, NJ, (PI revised 11/2000) reviewed 12/2000.
- Product Information: Tamiflu™, oseltamivir phosphate. Roche Laboratories, Nutley, NJ, (PI revised 12/2000) reviewed 01/2001.
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