Oseltamivir (Systemic) by USP DI® Drug Info. for the Health Care Pro. - 26th Ed. (2006)
Introduction
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
Oseltamivir is not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control’s Immunization Practices Advisory Committee.
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. 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. 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.
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.
Cross - resistance—
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.
Accepted
Influenza (treatment) — Oseltamivir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. ,,
Influenza (prophylaxis) — Oseltamivir is indicated for the prophylaxis of influenza in patients 1 year and older.
According to the Canadian manufacturer, oseltamivir is indicated for the prevention of influenza illness in adults and adolescents 13 years and older following close contact with an infected individual (the index case). The decision to administer oseltamivir for prophylaxis to close contacts should be based on the knowledge that influenza is circulating in the area and the index case demonstrates characteristic symptoms of influenza.
Acceptance not established
There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses Types A and B.
Efficacy of oseltamivir in patients who begin treatment after 40 hours of symptoms has not been established.
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established.
Efficacy of oseltamivir for treatment or prophylaxis has not been established in immunocompromised patients.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight —
Oseltamivir free base: 312.4
Oseltamivir phosphate: 410.4
Mechanism of action/Effect:
Oseltamivir is an inhibitor of influenza virus neuraminidase, possibly altering particle aggregation and release .
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.
Distribution:
Oseltamivir carboxylate—Volume of distribution is 23 to 26 liters following intravenous administration in 24 subjects
Protein binding:
Oseltamivir phosphate - Moderate (42%)
Oseltamivir carboxylate - Very low (< 3%)
Biotransformation:
Hepatic; Oseltamivir, ethyl ester prodrug, undergoes extensive hydrolysis to the active ester form, oseltamivir carboxylate.
Half-life:
Elimination - 1 to 3 hours for oseltamivir and 6 to 10 hours for oseltamivir carboxylate.
Peak serum concentration:
Results after multiple doses of 75 milligrams twice daily of oseltamivir phosphate:
Oseltamivir phosphate - 65.2 nanograms/milliliter (ng/mL)
Oseltamivir carboxylate - 348 ng/mL
Time to peak effect:
24 hours for a significant reduction in viral titers after initiation of oral treatment after inoculation with experimental influenza virus.
Elimination:
Renal - Oseltamivir carboxylate is extensively eliminated by renal excretion (> 99%).
Renal clearance (18.8 L/hr) exceeds glomerular filtration rate (7.5 L/hr), indicating that tubular secretion occurs .
Fecal - Elimination of an oral radiolabeled dose is < 20% in the feces.
Precautions to Consider
Carcinogenicity
Long-term tests with oseltamivir are underway and have not yet been completed. However, a 26-week dermal carcinogenicity study of oseltamivir carboxylate in which FVB/Tg./AC transgenic mice were dosed at 40, 140, 400 or 780 mg per kg of body weight per day was negative.
Mutagenicity
Oseltamivir was 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.
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.
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.
FDA Pregnancy Category C
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.
Pediatrics
Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of oseltamivir in children 1 year of age and greater. Safety and efficacy have not been established in children less than 1 year of age.
Geriatrics
Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oseltamivir in the elderly.
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 )
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)
Hepatic impairment — (safety and pharmacokinetics have not been evaluated)
>> Renal function impairment — (safety has not been established in patients with renal failure, creatinine clearance below 10 milliliters/minute (mL/min); dosage adjustment is recommended in patients with a creatinine clearance of less than 30 mL/min)
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)
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)
Incidence rare
Angina, unstable (arm, back or jaw pain; chest pain or discomfort; chest tightness or heaviness; fast or irregular heartbeat; shortness of breath); humerus fracture ; peritonsillar abscess (sore throat, tender glands of jaw and throat, facial swelling, drooling, headache, fever, hoarseness); pseudomembranous colitis (abdominal or stomach cramps; pain; bloating; abdominal tenderness; diarrhea, watery and severe, which may also be bloody; fever; increased thirst; nausea or vomiting; unusual tiredness or weakness; unusual weight loss)
Incidence not determined — Observed during clinical practice; estimates of frequency can not be determined
Allergy (dizziness; fast heartbeat; shortness of breath; skin rash or itching over the entire body; sweating; weakness; wheezing); anaphylactic/anaphylactoid reactions (cough; difficulty swallowing; dizziness; fast heartbeat; hives; itching, puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath; skin rash; tightness in chest; unusual tiredness or weakness; wheezing); arrhythmia (dizziness; fainting; fast, slow, or irregular heartbeat); erythema multiforme (blistering, peeling, loosening of skin; chills; cough; diarrhea; fever; itching; joint or muscle pain; red irritated eyes; sore throat; sores, ulcers, or white spots in mouth or on lips; unusual tiredness or weakness); hepatitis (dark urine; general tiredness and weakness; light-colored stools; nausea and vomiting; upper right abdominal pain; yellow eyes and skin); seizure (convulsions; muscle spasm or jerking of all extremities; sudden loss of consciousness; loss of bladder control); Stevens-Johnson syndrome (blistering, peeling, loosening of skin; chills; cough; diarrhea; itching; joint or muscle pain; red irritated eyes; red skin lesions, often with a purple center; sore throat; sores, ulcers, or white spots in mouth or on lips; unusual tiredness or weakness); swelling of the face or tongue ; toxic epidermal necrolysis (blistering, peeling, loosening of skin; chills; cough; diarrhea; itching; joint or muscle pain; red irritated eyes; red skin lesions, often with a purple center; sore throat; sores, ulcers, or white spots in mouth or on lips; unusual tiredness or weakness); urticaria (hives or welts; itching; redness of skin; skin rash)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Diarrhea nausea vomiting —Onset of nausea was predominately after the first dose and usually resolved within 1 to 2 days with continued dosing.
Incidence less frequent
Abdominal pain ; conjunctivitis (redness, pain, swelling of eye, eyelid, or inner lining of eyelid; burning, dry or itching eyes; discharge; excessive tearing) — primarily in pediatric patients; cough ; dizziness ; ear disorder —primarily in pediatric patients; epistaxis (bloody nose; unexplained nosebleeds)—primarily in pediatric patients; fatigue ; headache ; insomnia (trouble in sleeping)
Incidence rare
Anemia (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness); pneumonia (chest pain; cough; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest; wheezing); pyrexia (fever)
Incidence not determined — Observed during clinical practice; estimates of frequency can not be determined
Aggravation of diabetes (blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; loss of consciousness; nausea; stomachache; sweating; troubled breathing; unexplained weight loss; vomiting); confusion (mood or mental changes); dermatitis (blistering, crusting, irritation, itching, or reddening of skin; cracked, dry, scaly skin; swelling); eczema (skin rash encrusted, scaly and oozing); rash
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center.
Clinical effects of overdose
Single doses of up to 1000 mg of oseltamivir have been associated with nausea and/or vomiting.
Treatment of overdose
To enhance elimination—There 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.
Specific treatment—Treatment is symptomatic. No specific antidote is available.
Supportive care—Patients 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
Other medications, especially probenecid.
Other medical problems, especially renal function impairment
Proper use of this medication
Importance of informing patient that oseltamivir is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control
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 10 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.
>> 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, humerus fracture, peritonsillar abscess, pseudomembranous colitis, or unstable angina
Signs of potential side effects observed during clinical practice, especially allergy, anaphylactic/anaphylactoid reactions, arrhythmia, erythema multiforme, hepatitis, seizure, Stevens-Johnson syndrome, swelling of the face or tongue, toxic epidermal necrolysis, or urticaria
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.
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.
For oral suspension—An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral suspension. The 75 mg dose can be measure using a combination of 30 mg and 45 mg. The pharmacist should recommend the use of this dispenser. However, if this dispenser is lost or damaged, another dosing syringe or other device may be used to administer the following volumes:
• 2.5 mL (1/2 teaspoon [tsp]) for children ≤15 kg
• 3.8 mL (3/4 tsp) for >15 to 23 kg
• 5 mL (1 tsp) for >23 to 40 kg
• 6.2 mL (1 1/4 tsp) for >40 kg
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 and adolescent (≥13 years) dose
Influenza (treatment) —
Oral, 75 milligrams (mg) two times a day for 5 days. Oseltamivir should be initiated within 2 days of onset of influenza symptoms.
For adult patients who cannot swallow a capsule—See Oseltamivir Phosphate for Oral Suspension
Note: Renal Impairment: In patients with a creatinine clearance between 10 and 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 . No recommended dose regimens are available for patients having routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.
Influenza (prophylaxis) —
Oral, 75 mg once a day for at least 10 days following close contact with an infected individual. Oseltamivir should be initiated within 2 days of influenza exposure. Recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once a day. Duration of protection lasts as long as dosing is continued.
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.
Usual adult and adolescent prescribing limits
Safety and efficacy have been demonstrated for up to 6 weeks.
Usual pediatric dose
Children less than 1 year of age—Safety and efficacy have not been established.
Children 1 year of age and older—See Oseltamivir Phosphate for Oral Suspension
Usual geriatric dose
See Usual adult dose
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)].
Canada —
75 mg (Rx) [Tamiflu (corn starch; croscarmellose sodium; gelatin; iron oxides; povidone K 30; sodium stearyl fumarate; talc; titanium dioxide)].
Packaging and storage:
Store at 25 °C (77 °F); excursions permitted to 15 to 30 °C (59 to 86 °F).
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 (treatment) —
For infants and children 1 year of age or older or adult patients who cannot swallow a capsule:
check table 1
Oseltamivir therapy should begin within 2 days of exposure.
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.
Influenza (prophylaxis) —
For infants and children 1 year of age or older following close contact with an infected individual:
check table 2
Oseltamivir therapy should begin within 2 days of exposure.
Note: In patients with a creatinine clearance between 10 and 30 mL per minute, the recommended dose is 30 mg oral suspension once per day. No recommended dosing regimens are available for patients with end-stage renal disease who are undergoing routine hemodialysis or continuous peritoneal dialysis.
Usual pediatric limits
Prophylaxis in children 1 to 12 years of age following close contact with an infected individual has not been evaluated for longer than 10 days duration.
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)].
Canada —
Not commercially available.
Packaging and storage:
Prior to reconstitution, store between 15 and 30 °C (59 and 86 °F). 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). Protect from freezing.
Preparation of dosage form:
It is recommended that the oral suspension be reconstituted as follows by the pharmacist prior to dispensing to the patient:
• Tap the closed bottle several times to loosen the powder.
• Measure 23 mL of water in a graduated cylinder.
• Add the total amount of water for reconstitution to the bottle and shake the closed bottle well for 15 seconds.
• Remove the child-resistant cap and push the bottle adapter into the neck of the bottle.
• 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.
Stability:
After reconstitution, the oral suspension should be used within 10 days.
Auxiliary labeling:
• Refrigerate - 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.
Not included in Canadian product labeling.
Revision Date
Developed: 01/13/2000
Revised: 01/12/2006
References
Product Information: TAMIFLU™ oseltamivir phosphate. F. Hoffmann - La Roche Ltd., Basel, Switzerland, 10/1999.
Hayden FG, Lobo M, Treanor JJ et al: Efficacy and tolerability of oral GS4104 for early treatment of experimental influenza in humans (abstract). 37th ICAAC Program Addendum: September 28, 1997;14.
Hayden FG, Treanor JJ, Fritz RS et al: Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA 1999; 282:1240 - 1246.
Product Information: TAMIFLU™, oseltamivir phosphate. Hoffmann-La Roche Ltd., Mississauga, Ontario, Canada, (PI revised 12/1999) reviewed 8/2000.
FDA Talk Paper: FDA Approves TAMIFLU for Another Indication - Prevention of Influenza. United States Food and Drug Administration, U.S. Department of Health and Human Services, Rockville, MD, 11/2000.
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.
Product Information: TAMIFLU®, oseltamivir phosphate. Roche Laboratories, Nutley, NJ, (PI revised 12/2005) reviewed 01/2006.
Product Information: TAMIFLU®, oseltamivir phosphate. Hoffmann-La Roche Limited, Mississauga, Ontario, (PI revised 07/2004) reviewed 01/2006.
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