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Tamiflu®
(oseltamivir phosphate)
CAPSULES AND FOR ORAL SUSPENSION
Drug Uses
Tamiflu is used for the treatment of
uncomplicated acute illness due to influenza infection.
How Taken
You may take Tamiflu with or without food.
However, when taken with food, your tolerability to Tamiflu may be enhanced. The
recommended oral dose of Tamiflu is 75 mg twice daily for 5 days. You should
begin treatment within 2 days of onset of symptoms of influenza.
Warnings/Precautions
Tamiflu is not a substitute for a flu
vaccination. You should continue receiving an annual flu vaccination. It is not
known whether this medicine is excreted in human milk. You should therefore, use
this drug only if the potential benefit justifies the potential risk to the
breast-fed infant.
Missed Dose
If you miss a dose, use it as soon as you
remember. If it is near the time for the next dose, skip the missed dose and
resume your usual dosing schedule. Do not double the dose to catch up.
Possible Side Effects
You may experience some common, less
serious side effects: nausea (without vomiting), vomiting, diarrhea, abdominal
pain, dizziness, headache, cough, insomnia, fatigue.
Storage
Store Tamiflu under refrigeration at 36º
to 46ºF (2º to 8ºC). Do not freeze.
Overdose
Symptoms of a Tamiflu overdose are nausea
and/or vomiting. Seek medical attention if an overdose is suspected.
More Information
You should begin treatment with Tamiflu 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.
TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45
mg, or 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 30 mg capsule shell contains gelatin,
titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell
contains gelatin, titanium dioxide, and black iron oxide. The 75 mg 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 sorbitol, monosodium citrate, xanthan gum, titanium
dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium.
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.
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 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 µM to > 35 µM and 0.004 µM to > 100 µM, respectively (1 µM=0.284
µg/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.
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. Resistance mutations selected in
vitro in neuraminidase are I222T and H274Y in influenza A N1 and I222T and R292K
in influenza A N2. Mutations E119V, R292K and R305Q have been selected in avian
influenza A neuraminidase N9. Mutations A28T and R124M have been selected in the
hemagglutinin of influenza A H3N2 and mutation H154Q in the hemagglutinin of a
reassortant human/avian virus H1N9.
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 to 12 years showed
emergence of influenza variants with decreased neuraminidase susceptibility in
vitro to oseltamivir carboxylate. Mutations in influenza A resulting in
decreased susceptibility were H274Y in neuraminidase N1 and E119V and R292K in
neuraminidase N2. Insufficient information is available to fully characterize
the risk of emergence of TAMIFLU resistance in clinical use.
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 TAMIFLU.
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, two of the three
oseltamivir-induced mutations (E119V, H274Y and R292K) in the viral
neuraminidase from clinical isolates occur at the same amino acid residues as
two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir-resistant
virus.
Immune Response
No influenza vaccine interaction study has been conducted. In studies of
naturally acquired and experimental influenza, treatment with TAMIFLU did not
impair normal humoral antibody response to infection.
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