Oseltamivir phosphate (Tamiflu) is the ethyl ester pro-drug of
oseltamivir carboxylate, an analogue of neur-aminic (sialic) acid that is a
reversible competitive antagonist of influenza A and B neuraminidase.
Neur-aminidase, like hemagglutinin, is a viral surface glyco-protein that interacts
with host cell receptors containing terminal neuraminic acid residues. The
binding of hemagglutinin to its cellular receptors initiates viral penetration
and promotes the fusion of the viral enve-lope to the plasma membrane.
Neuraminidase then de-stroys these hemagglutinin receptors by breaking the bond
between the terminal neuraminic acid residue and its adjacent oligosaccharide.
The cleavage of hemagglu-tinin receptors is required for the release of progeny
virus from the host cell. It also facilitates the spread of infection by
allowing viral particles to penetrate the neuraminic acid–rich respiratory
mucus and by pre-venting the clumping of virus that results from the bind-ing
of hemagglutinins to neuraminic acid residues on neighboring viral particles. Inhibition of neuraminidase activity prevents the release of progeny
virus and inhibits viral spread. The active site of neuraminidase is highly conserved in influenza A and B viruses;
thus, oseltamivir and other neuraminidase inhibitors (e.g., zanamivir) are
effective against a variety of influenza strains.
Influenza virus resistant to
oseltamivir has not been found in naturally acquired isolates but has been
iso-lated from influenza patients who have undergone treatment with this drug.
These resistant strains contain mutations in the active site of neuraminidase
and are generally less virulent and infective than nonresistant virus. In vitro
passage of influenza virus in the presence of oseltamivir carboxylate can
produce mutations in hemagglutinin that decrease the overall dependence of
viral replication on neuraminidase; however, the clinical relevance of this
resistance mechanism is unknown.
oseltamivir phosphate is rapidly ab-sorbed and converted by hepatic esterases
to oseltamivir carboxylate. Approximately 80% of an oral dose reaches the
systemic circulation as oseltamivir carboxylate, with peak plasma
concentrations achieved within 2.5 to 5 hours. The plasma elimination half-life
of oseltamivir carboxylate is 7 to 9 hours. Elimination of the parent drug and
its active metabolite occurs primarily by active tubular secretion and
Oseltamivir is approved for
the treatment of uncompli-cated acute influenza in patients aged 1 year and
older. It decreases the duration of illness by 1 to 1.5 days when treatment is
initiated within 48 hours of the onset of symptoms. Oseltamivir is also
indicated for the prophy-laxis of influenza in individuals aged 13 and older.
It re-duces infection rates to approximately 10 to 25% of that found in
untreated populations; however, it is not in-tended to substitute for the early
vaccination recom-mended by the CDC. Oseltamivir can be used as post-exposure
prophylaxis in household contacts of infected patients, with infection rates of
treated patients around 10% of placebo control levels.
The most frequently reported
adverse effects of os-eltamivir are nausea and vomiting. These events are
usu-ally mild to moderate, occur during the first 1 to 2 days of treatment, and
can be lessened by taking the drug with food. Bronchitis, insomnia, and vertigo
may also occur.
Oseltamivir may not be
indicated for use in certain individuals. Its efficacy in patients with chronic
cardiac or respiratory disease has not been established. In clin-ical trials,
no difference in the incidence of complica-tions was seen between treatment and
control groups. The efficacy of oseltamivir has not been demonstrated in
immunocompromised patients, patients who begin treatment after 40 hours of
symptoms, or patients given repeated prophylactic courses of therapy. Dosage
ad-justment is recommended for individuals with renal in-sufficiency; the drug’s
safety in patients with hepatic in-sufficiency is unknown.
No formal drug interaction
studies of oseltamivir have been performed. Oseltamivir and its carboxylate
metabolite do not interact with the cytochrome P450 system. Although probenecid
decreases the elimination of oseltamivir, dosage adjustment is not required
during coadministration of these drugs because of oseltamivir’s margin of
safety. Oseltamivir does not interfere with an-tibody production in response to
the influenza vaccine.