TAMIFLU®
Oseltamivir capsule 75 mg
Antiviral
Composition
Active ingredient
Oseltamivir phosphate
Capsules containing 98.5mg oseltamivir
phosphate equivalent to 75mg of oseltamivir.
Excipients
Polyvidone K30, pre-gelatinized starch,
croscarmellose sodium, talc, sodium stearyl
fumarate.
Appearance
Size 2 hard gelatin capsule with a grey
opaque body and a light yellow opaque cap, containing a white
to yellow-white powder.
Properties and Effects
Mechanism of action
Oseltamivir phosphate is a pro-drug of a
potent and selective inhibitor of influenza virus
neuraminidase enzymes. Viral neuraminidase is essential for
the release of recently formed virus particles from infected
cells, and the further spread of infectious virus.
The active metabolite of oseltamivir
inhibits neuraminidases of influenza viruses of both types A
and B. Concentrations of the active metabolite required to
inhibit the enzyme activity by 50% (IC50) are in the low
nanomolar range. The active metabolite also inhibits influenza
virus growth in-vitro and inhibits influenza virus replication
and pathogenicity in-vivo.
The active metabolite reduces shedding
of both influenza A and B virus by inhibiting the release of
infectious virus from infected cells.
Efficacy
Clinical efficacy of Tamiflu has been
demonstrated in human experimental infection studies and phase
III studies in naturally occurring influenza.
In studies in naturally acquired and
experimental influenza, treatment with Tamiflu did not impair
normal humoral antibody response to infection. Antibody
response to inactivated vaccine is not expected to be affected
by treatment with Tamiflu.
In phase III clinical trials, patients
were treated with Tamiflu for up to 40 hours after reported
onset of symptoms. In these studies, 97% of patients were
infected with influenza A and 3% with influenza B. Tamiflu
treatment significantly reduced the duration of clinically
relevant signs and symptoms of influenza by 32 hours. Disease
severity in patients with confirmed influenza taking Tamiflu
was also reduced by 38% compared to placebo. Moreover, Tamiflu
reduced the incidence of complications associated with
influenza treated with antibiotic therapy in otherwise healthy
young adults by approximately 50%. These complications include
bronchitis, pneumonia, sinusitis and otitis media. In phase
III clinical trials there was clear evidence of efficacy in
the secondary endpoints related to antiviral activity in terms
of both reduction of duration of virus shedding and reduction
in the AUC of viral titres.
Data from a partially recruited study in
the elderly population have shown that Tamiflu 75mg bid for
five days was associated with a reduction in median duration
of illness that was clinically relevant, and similar to that
seen in the adult treatment studies. In a separate partially
recruited study, patients aged >13 years with influenza and
co-existing chronic cardiac and/or respiratory disease
received the same regimen of either Tamiflu or placebo. No
difference in the median time to alleviation of all symptoms
was seen between patients taking Tamiflu or placebo, however
the duration of febrile illness was reduced by approximately
one day by receipt of Tamiflu. The proportion of patients
shedding virus on days 2 and 4 was also markedly reduced by
active treatment. There was no difference in the safety
profile of Tamiflu in the at-risk populations compared to the
general adult population.
Viral Resistance
The risk of emergence of drug resistance
in clinical use has been extensively examined. The incidence
of resistance to the active metabolite in viral isolates from
clinical studies is up to 1.5% in influenza A. Patients with
viruses displaying reduced sensitivity, cleared virus normally
and showed no clinical deterioration. All resistant genotypes
are disadvantaged compared to the corresponding wild-type
isolate and are likely to be less contagious in man. There is
no evidence for resistance in influenza B in vitro or in
clinical isolates.
Pharmacokinetics
Absorption
Oseltamivir is readily absorbed from the
gastrointestinal tract after oral administration of
oseltamivir phosphate and is extensively converted
predominantly by hepatic esterases to the active metabolite.
Plasma concentrations of the active metabolite are measurable
within 30 minutes, reach near maximal levels in 2 to 3 hours
post dose, and substantially exceed (>20 fold) those of the
prodrug. At least 75% of an oral dose reaches the systemic
circulation as the active metabolite. Plasma concentrations of
active metabolite are proportional to dose and are unaffected
by co-administration with food (See Dosage and
Administration).
Distribution
The mean volume of distribution (Vss) of
the active metabolite is approximately 23 litres in
humans.
The active moiety reaches all key sites
of influenza infection as shown by studies in the ferret, rat
and rabbit. In these studies, anti-viral concentrations of the
active metabolite were seen in the lung, bronchioalveolar
lavage, nasal mucosa, middle ear and trachea following oral
administration of doses of oseltamivir phosphate.
The binding of the active metabolite to
human plasma protein is negligible (approximately 3%). The
binding of the prodrug to human plasma protein is 42%. These
levels are insufficient to cause significant drug
interactions.
Metabolism
Oseltamivir phosphate is extensively
converted to the active metabolite by esterases located
predominantly in the liver. Neither oseltamivir nor the active
metabolite are substrates for, or inhibitors of, cytochrome
P450 isoforms (See Interactions).
Elimination
Absorbed oseltamivir is primarily (>
90%) eliminated by conversion to the active metabolite. The
active metabolite is not further metabolised and is eliminated
in the urine. Peak plasma concentrations of the active
metabolite decline with a half-life of 6 to 10 hours in most
subjects.
The active substance 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 in addition to glomerular filtration
occurs. Less than 20% of an oral radiolabeled dose is
eliminated in faeces .
Pharmacokinetics in Special Clinical
Situations
Patients with renal
impairment
Administration of 100 mg of Tamiflu
twice daily for five days to patients with various degrees of
renal impairment showed that exposure to the active metabolite
is inversely proportional to declining renal function. Dose
adjustment is recommended for patients with creatinine
clearance below 30 mL/min. There are no data available in
patients with renal failure (creatinine clearance < 10
mL/min), therefore caution is advised when administering
Tamiflu to those patient populations (See Precautions and
Special dosage instructions).
Patients with hepatic
impairment
In-vitro studies have shown that
exposure to oseltamivir is not expected to be increased
significantly nor is exposure to the active metabolite
expected to be significantly decreased in patients with
hepatic impairment (See Special dosage
instructions).
Elderly
Exposure to the active metabolite at
steady state was 25-35% higher in elderly (age range 65- 78)
compared to young adults who were given comparable doses of
Tamiflu. Half-lives observed in the elderly were similar to
those seen in young adults. On the basis of active ingredient
exposure and tolerability, dosage adjustments are not required
for elderly patients (See Special dosage
instructions).
Children
The pharmacokinetics of Tamiflu have
been evaluated in a small group of children 5 to 18 years of
age after administration of a single 2 mg/kg oral dose given
as an oral powder for reconstitution. The pharmacokinetic data
showed that younger children cleared both the pro-drug and the
active metabolite faster than older children resulting in
lower exposure for a given mg/kg dose. In children 5- 8 years
old, 2 mg/kg gives comparable exposure to that achieved in
adults receiving a single 75 mg capsule dose (approximately 1
mg/kg). With advancing age, the difference in exposure between
children and adults (per mg/kg dose) became less, such that
exposure in children over 12 years of age was similar to that
in adults.
Indications
Tamiflu is indicated for the treatment
of influenza in adults and children 12 years and
older.
Dosage and Administration
Standard Dosage
The recommended oral dose of Tamiflu is
75 mg twice daily, for 5 days. Treatment should begin within
the first or second day of onset of symptoms of influenza.
Tamiflu may be taken with or without food (See
Pharmacokinetics). However, taking with food may enhance
tolerability in some patients.
Special Dosage Instructions
Patients with renal
impairment
No dose adjustment is necessary for
patients with creatinine clearance above 30 mL/min. In
patients with a creatinine clearance of less than 30 mL/min,
it is recommended that the dose is reduced to 75 mg of Tamiflu
once daily for 5 days. Tamiflu has not been studied in
patients with renal failure (creatinine clearance below 10
mL/min), therefore caution is advised when administering
Tamiflu to those patient populations (See Pharmacokinetics in
special clinical situations and Precautions).
Patients with hepatic
impairment
No dose adjustment is required for
patients with hepatic dysfunction (See Pharmacokinetics in
special clinical situations).
Elderly
No dose adjustment is required for
elderly patients (See Pharmacokinetics in special clinical
situations).
Children
The safety and efficacy of Tamiflu in
children under 12 years has not been established. Limited
paediatric pharmacokinetic information is available (See
Pharmacokinetics in special clinical situations).
Contraindications
Hypersensitivity to oseltamivir
phosphate or any of the components of the product.
Warnings
None.
Precautions
There are limited studies in patients
older than 65 years of age and in patients at special risk of
influenza complications.
Efficacy of Tamiflu in 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 hospitalisation.
Dose adjustment is recommended for
patients with creatinine clearance below 30 mL/min. There are
no data available in patients with renal failure (creatinine
clearance below 10 mL/min), therefore caution is advised when
administering Tamiflu to those patient populations. (See
Pharmacokinetics in special clinical situations and special
dosage instructions).
Pregnancy, Nursing Mothers
Pregnancy Category C
In animal reproductive studies in rats
and rabbits, no teratogenic effect was observed. Fertility and
reproductive toxicity studies have been conducted in rats.
There was no evidence of an effect on fertility at any dose of
oseltamivir studied. Foetal exposure in rats and rabbits was
approximately 15- 20% of that of the mother.
At present, insufficient data are
available in pregnant women taking Tamiflu to enable an
evaluation of the potential for oseltamivir phosphate to cause
fetal malformations or fetal toxicity. Tamiflu should
therefore be used during pregnancy only if the potential
benefit justifies the potential risk to the foetus.
In lactating rats, oseltamivir and the
active metabolite are secreted in the milk. It is not known
whether oseltamivir or the active metabolite are secreted in
human milk, but extrapolation of the animal data provides
estimates of 0.01 mg/day and 0.3 mg/day for the respective
compounds. Tamiflu should therefore be used only if the
potential benefit for the lactating mother justifies the
potential risk for the nursing infant.
Undesirable Effects
Experience from Clinical
Trials
In a total of 1887 patients (including
patients on placebo, 75mg bid Tamiflu and 150mg bid Tamiflu)
in adult phase III studies in the treatment of influenza, the
most frequently reported adverse events were nausea and
vomiting. These events were transient and generally occurred
with first dosing. These events did not lead to patient
discontinuation of study medication in the vast majority of
instances. At the recommended dose of 75mg twice daily, three
patients withdrew because of nausea and the same number
withdrew because of vomiting.
In adult phase III treatment studies, some
adverse events occurred more frequently in patients taking
Tamiflu compared to those taking placebo. The adverse events
that occurred with an incidence of 1%, are shown in
Table 1. This summary includes healthy young adults and at
risk patients (patients at higher risk of developing
complications associated with influenza e.g. elderly patients
and patients with chronic cardiac or respiratory disease.
Those events reported more frequently, irrespective of
causality, in patients taking Tamiflu compared with placebo
were nausea, vomiting, bronchitis, insomnia and
vertigo.
|
Table
1: Summary of Adverse Events in the Treatment of
Naturally Acquired Influenza with Dose of 75 mg bid
Occurring in 1% of Patients. |
| |
Placebo
|
Ro 64-0796
75 mg bid |
| |
N=716 |
N=724 |
|
Nausea (without
vomiting) |
40 |
(5.6 %) |
72 |
(9.9%) |
|
Vomiting* |
21 |
(2.9%) |
68 |
(9.4 %) |
|
Diarrhoea |
70 |
(9.8%) |
48 |
(6.6%) |
|
Bronchitis |
15 |
(2.1%) |
17 |
(2.3%) |
|
Abdominal
pain |
16 |
(2.2%) |
16 |
(2.2%) |
|
Dizziness |
25 |
(3.5%) |
15 |
(2.1%) |
|
Headache |
14 |
(2.0%) |
13 |
(1.8%) |
|
Cough |
12 |
(1.7%) |
9 |
(1.2%) |
|
Insomnia |
6 |
(0.8%) |
8 |
(1.1%) |
|
Vertigo |
3 |
(0.4%) |
7 |
(1.0%) |
|
Fatigue |
7 |
(1.0%) |
7 |
(1.0%) |
