tamiflu
Generic Name: (
oseltamivir phosphate)
Dosage Type: powder, for suspension tamiflu
Generic Name: (
oseltamivir phosphate)
Dosage Type: capsule Organization: Roche Pharmaceuticals
DESCRIPTION
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. The structural formula is as follows:
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.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption and Bioavailability
Oseltamivir is readily absorbed from the gastrointestinal
tract after oral administration of oseltamivir phosphate and is extensively
converted predominantly by hepatic esterases to oseltamivir carboxylate.
At least 75% of an oral dose reaches the systemic circulation as oseltamivir
carboxylate. Exposure to oseltamivir is less than 5% of the total
exposure after oral dosing (see Table 1).
Table 1 Mean (% CV) Pharmacokinetic
Parameters of Oseltamivir and Oseltamivir Carboxylate After a Multiple
75 mg Capsule Twice Daily Oral Dose (n=20)
| Parameter |
Oseltamivir |
Oseltamivir Carboxylate |
|---|
| Cmax (ng/mL) |
65.2 (26) |
348 (18) |
| AUC0-12h (ng·h/mL) |
112 (25) |
2719 (20) |
Plasma concentrations of oseltamivir carboxylate
are proportional to doses up to 500 mg given twice daily (see DOSAGE AND ADMINISTRATION).
Coadministration with food has
no significant effect on the peak plasma concentration (551 ng/mL
under fasted conditions and 441 ng/mL under fed conditions) and the
area under the plasma concentration time curve (6218 ng·h/mL
under fasted conditions and 6069 ng·h/mL under fed conditions)
of oseltamivir carboxylate.
Distribution
The volume of distribution (Vss) of oseltamivir
carboxylate, following intravenous administration in 24 subjects,
ranged between 23 and 26 liters.
The binding
of oseltamivir carboxylate to human plasma protein is low (3%). The
binding of oseltamivir to human plasma protein is 42%, which is insufficient
to cause significant displacement-based drug interactions.
Metabolism
Oseltamivir is extensively converted to oseltamivir
carboxylate by esterases located predominantly in the liver. Neither
oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor
of, cytochrome P450 isoforms.
Elimination
Absorbed oseltamivir is primarily (>90%) eliminated
by conversion to oseltamivir carboxylate. Plasma concentrations of
oseltamivir declined with a half-life of 1 to 3 hours in most subjects
after oral administration. Oseltamivir carboxylate is not further
metabolized and is eliminated in the urine. Plasma concentrations
of oseltamivir carboxylate declined with a half-life of 6 to 10 hours
in most subjects after oral administration. Oseltamivir carboxylate
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 occurs, in addition to glomerular filtration.
Less than 20% of an oral radiolabeled dose is eliminated in feces.
Special Populations
Renal Impairment
Administration of 100 mg of oseltamivir phosphate
twice daily for 5 days to patients with various degrees of renal impairment
showed that exposure to oseltamivir carboxylate is inversely proportional
to declining renal function. Oseltamivir carboxylate exposures in
patients with normal and abnormal renal function administered various
dose regimens of oseltamivir are described in Table 2.
Table 2 Oseltamivir Carboxylate
Exposures in Patients With Normal and Reduced Serum Creatinine Clearance
| Parameter |
Normal Renal Function |
Impaired Renal Function |
|---|
|
75 mg qd |
75 mg bid |
150 mg bid |
Creatinine Clearance
<10 mL/min |
Creatinine Clearance
>10 and <30 mL/min |
|
|
|
|
CAPD |
Hemodialysis |
|
|
|
|
|
|
|
30 mg weekly |
30 mg alternate HD cycle |
75 mg daily |
75 mg
alternate days |
30 mg daily |
|---|
| AUC normalized to 48 hours. |
|
|
| Cmax |
259* |
348* |
705* |
766 |
850 |
1638 |
1175 |
655 |
| Cmin |
39* |
138* |
288* |
62 |
48 |
864 |
209 |
346 |
| AUC48 |
7476* |
10876* |
21864* |
17381 |
12429 |
62636 |
21999 |
25054 |
Pediatric Patients
The pharmacokinetics of oseltamivir and oseltamivir
carboxylate have been evaluated in a single dose pharmacokinetic study
in pediatric patients aged 5 to 16 years (n=18) and in a small number
of pediatric patients aged 3 to 12 years (n=5) enrolled in a clinical
trial. Younger pediatric patients cleared both the prodrug and the
active metabolite faster than adult patients resulting in a lower
exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent
total clearance decreases linearly with increasing age (up to 12 years).
The pharmacokinetics of oseltamivir in pediatric patients over 12
years of age are similar to those in adult patients.
Geriatric Patients
Exposure to oseltamivir carboxylate at steady-state
was 25% to 35% higher in geriatric patients (age range 65 to 78 years)
compared to young adults given comparable doses of oseltamivir. Half-lives
observed in the geriatric patients were similar to those seen in young
adults. Based on drug exposure and tolerability, dose adjustments
are not required for geriatric patients for either treatment or prophylaxis
(see DOSAGE AND ADMINISTRATION: Special
Dosage Instructions).
INDICATIONS AND USAGE
Treatment of Influenza
TAMIFLU 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.
Prophylaxis of Influenza
TAMIFLU is indicated for the prophylaxis of influenza
in patients 1 year and older.
TAMIFLU is not
a substitute for early vaccination on an annual basis as recommended
by the Centers for Disease Control and Prevention Advisory Committee
on Immunization Practices.
Description of Clinical Studies: Studies in Naturally Occurring
Influenza
Treatment of Influenza
Adult Patients
Two phase III placebo-controlled and double-blind
clinical trials were conducted: one in the USA and one outside the
USA. Patients were eligible for these trials if they had fever >100°F,
accompanied by at least one respiratory symptom (cough, nasal symptoms
or sore throat) and at least one systemic symptom (myalgia, chills/sweats,
malaise, fatigue or headache) and influenza virus was known to be
circulating in the community. In addition, all patients enrolled in
the trials were allowed to take fever-reducing medications.
Of 1355 patients enrolled in these two trials, 849 (63%)
patients were influenza-infected (age range 18 to 65 years; median
age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected
patients, 95% were infected with influenza A, 3% with influenza B,
and 2% with influenza of unknown type.
TAMIFLU
was started within 40 hours of onset of symptoms. Subjects participating
in the trials were required to self-assess the influenza-associated
symptoms as "none", "mild", "moderate" or "severe". Time to improvement
was calculated from the time of treatment initiation to the time when
all symptoms (nasal congestion, sore throat, cough, aches, fatigue,
headaches, and chills/sweats) were assessed as "none" or "mild". In
both studies, at the recommended dose of TAMIFLU 75 mg twice daily
for 5 days, there was a 1.3 day reduction in the median time to improvement
in influenza-infected subjects receiving TAMIFLU compared to subjects
receiving placebo. Subgroup analyses of these studies by gender showed
no differences in the treatment effect of TAMIFLU in men and women.
In the treatment of influenza, no increased efficacy
was demonstrated in subjects receiving treatment of 150 mg TAMIFLU
twice daily for 5 days.
Geriatric Patients
Three double-blind placebo-controlled treatment
trials were conducted in patients =65 years of age in three
consecutive seasons. The enrollment criteria were similar to that
of adult trials with the exception of fever being defined as >97.5°F.
Of 741 patients enrolled, 476 (65%) patients were influenza-infected.
Of the 476 influenza-infected patients, 95% were infected with influenza
type A and 5% with influenza type B.
In the
pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily
for 5 days, there was a 1 day reduction in the median time to improvement
in influenza-infected subjects receiving TAMIFLU compared to those
receiving placebo (p=NS). However, the magnitude of treatment effect
varied between studies.
Pediatric Patients
One double-blind placebo-controlled treatment trial
was conducted in pediatric patients aged 1 to 12 years (median age
5 years), who had fever (>100°F) plus one respiratory symptom
(cough or coryza) when influenza virus was known to be circulating
in the community. Of 698 patients enrolled in this trial, 452 (65%)
were influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected
patients, 67% were infected with influenza A and 33% with influenza
B.
The primary endpoint in this study was the
time to freedom from illness, a composite endpoint which required
4 individual conditions to be met. These were: alleviation of cough,
alleviation of coryza, resolution of fever, and parental opinion of
a return to normal health and activity. TAMIFLU treatment of 2 mg/kg
twice daily, started within 48 hours of onset of symptoms, significantly
reduced the total composite time to freedom from illness by 1.5 days
compared to placebo. Subgroup analyses of this study by gender showed
no differences in the treatment effect of TAMIFLU in males and females.
Prophylaxis of Influenza
Adult Patients
The efficacy of TAMIFLU in preventing naturally
occurring influenza illness has been demonstrated in three seasonal
prophylaxis studies and a postexposure prophylaxis study in households.
The primary efficacy parameter for all these studies was the incidence
of laboratory-confirmed clinical influenza. Laboratory-confirmed clinical
influenza was defined as oral temperature =99.0°F/37.2°C
plus at least one respiratory symptom (cough, sore throat, nasal congestion)
and at least one constitutional symptom (aches and pain, fatigue,
headache, chills/sweats), all recorded within 24 hours, plus either
a positive virus isolation or a fourfold increase in virus antibody
titers from baseline.
In a pooled analysis
of two seasonal prophylaxis studies in healthy unvaccinated adults
(aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days
during a community outbreak reduced the incidence of laboratory-confirmed
clinical influenza from 4.8% (25/519) for the placebo group to 1.2%
(6/520) for the TAMIFLU group.
In a seasonal
prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU
75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed
clinical influenza from 4.4% (12/272) for the placebo group to 0.4%
(1/276) for the TAMIFLU group. About 80% of this elderly population
were vaccinated, 14% of subjects had chronic airway obstructive disorders,
and 43% had cardiac disorders.
In a study of
postexposure prophylaxis in household contacts (aged =13 years)
of an index case, TAMIFLU 75 mg once daily administered within 2 days
of onset of symptoms in the index case and continued for 7 days reduced
the incidence of laboratory-confirmed clinical influenza from 12%
(24/200) in the placebo group to 1% (2/205) for the TAMIFLU group.
Index cases did not receive TAMIFLU in the study.
Pediatric Patients
The efficacy of TAMIFLU in preventing naturally
occurring influenza illness has been demonstrated in a randomized,
open-label, postexposure prophylaxis study in households that included
children aged 1 to 12 years, both as index cases and as family contacts.
All index cases in this study received treatment. The primary efficacy
parameter for this study was the incidence of laboratory-confirmed
clinical influenza in the household. Laboratory-confirmed clinical
influenza was defined as oral temperature =100°F/37.8°C
plus cough and/or coryza recorded within 48 hours, plus either a positive
virus isolation or a fourfold or greater increase in virus antibody
titers from baseline or at illness visits. Among household contacts
1 to 12 years of age not already shedding virus at baseline, TAMIFLU
for Oral Suspension 30 mg to 60 mg taken once daily for 10 days reduced
the incidence of laboratory-confirmed clinical influenza from 17%
(18/106) in the group not receiving prophylaxis to 3% (3/95) in the
group receiving prophylaxis.
CONTRAINDICATIONS
TAMIFLU is contraindicated in patients with known
hypersensitivity to any of the components of the product.
PRECAUTIONS
General
There is no evidence for efficacy of TAMIFLU in
any illness caused by agents other than influenza viruses Types A
and B.
Use of TAMIFLU should not affect the
evaluation of individuals for annual influenza vaccination in accordance
with guidelines of the Centers for Disease Control and Prevention
Advisory Committee on Immunization Practices.
Efficacy of TAMIFLU in patients who begin treatment after 40 hours
of symptoms has not been established.
Efficacy
of TAMIFLU in the treatment of 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 hospitalization.
Safety and efficacy
of repeated treatment or prophylaxis courses have not been studied.
Efficacy of TAMIFLU for treatment or prophylaxis has
not been established in immunocompromised patients.
Serious bacterial infections may begin with influenza-like symptoms
or may coexist with or occur as complications during the course of
influenza. TAMIFLU has not been shown to prevent such complications.
Hepatic Impairment
The safety and pharmacokinetics in patients with
hepatic impairment have not been evaluated.
Renal Impairment
Dose adjustment is recommended for patients with
a serum creatinine clearance <30 mL/min (see DOSAGE AND ADMINISTRATION).
Serious Skin/Hypersensitivity Reactions
Rare cases of anaphylaxis and serious skin reactions
including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and
erythema multiforme have been reported in post-marketing experience
with TAMIFLU. TAMIFLU should be stopped and appropriate treatment
instituted if an allergic-like reaction occurs or is suspected.
Neuropsychiatric Events
There have been postmarketing reports (mostly from
Japan) of self-injury and delirium with the use of TAMIFLU in patients
with influenza. The reports were primarily among pediatric patients.
The relative contribution of the drug to these events is not known.
Patients with influenza should be closely monitored for signs of abnormal
behavior throughout the treatment period.
Information for Patients
Patients should be instructed to 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.
Patients should be instructed to take any missed doses as soon as
they remember, except if it is near the next scheduled dose (within
2 hours), and then continue to take TAMIFLU at the usual times.
TAMIFLU is not a substitute for a flu vaccination. Patients
should continue receiving an annual flu vaccination according to guidelines
on immunization practices.
Drug Interactions
The concurrent use of TAMIFLU with live attenuated
influenza vaccine (LAIV) intranasal has not been evaluated. However,
because of the potential for interference between these products,
LAIV should not be administered within 2 weeks before or 48 hours
after administration of TAMIFLU, unless medically indicated. The concern
about possible interference arises from the potential for antiviral
drugs to inhibit replication of live vaccine virus. Trivalent inactivated
influenza vaccine can be administered at any time relative to use
of TAMIFLU.
Information derived from pharmacology
and pharmacokinetic studies of oseltamivir suggests that clinically
significant drug interactions are unlikely.
Oseltamivir is extensively converted to oseltamivir carboxylate by
esterases, located predominantly in the liver. Drug interactions involving
competition for esterases have not been extensively reported in literature.
Low protein binding of oseltamivir and oseltamivir carboxylate suggests
that the probability of drug displacement interactions is low.
In vitro studies demonstrate that neither oseltamivir
nor oseltamivir carboxylate is a good substrate for P450 mixed-function
oxidases or for glucuronyl transferases.
Cimetidine,
a non-specific inhibitor of cytochrome P450 isoforms and competitor
for renal tubular secretion of basic or cationic drugs, has no effect
on plasma levels of oseltamivir or oseltamivir carboxylate.
Clinically important drug interactions involving competition
for renal tubular secretion are unlikely due to the known safety margin
for most of these drugs, the elimination characteristics of oseltamivir
carboxylate (glomerular filtration and anionic tubular secretion)
and the excretion capacity of these pathways. Coadministration of
probenecid results in an approximate twofold increase in exposure
to oseltamivir carboxylate due to a decrease in active anionic tubular
secretion in the kidney. However, due to the safety margin of oseltamivir
carboxylate, no dose adjustments are required when coadministering
with probenecid.
Coadministration with amoxicillin
does not alter plasma levels of either compound, indicating that competition
for the anionic secretion pathway is weak.
In six subjects, multiple doses of oseltamivir did not affect the
single-dose pharmacokinetics of acetaminophen.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity tests with oseltamivir
are underway but have not been completed. However, a 26-week dermal
carcinogenicity study of oseltamivir carboxylate in FVB/Tg.AC transgenic
mice was negative. The animals were dosed at 40, 140, 400 or 780 mg/kg/day
in two divided doses. The highest dose represents the maximum feasible
dose based on the solubility of the compound in the control vehicle.
A positive control, tetradecanoyl phorbol-13-acetate administered
at 2.5 µg per dose three times per week gave a positive response.
Oseltamivir was found to be 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.
In a fertility and early embryonic development study in rats, doses
of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to
females for 2 weeks before mating, during mating and until day 6 of
pregnancy. Males were dosed for 4 weeks before mating, during and
for 2 weeks after mating. There were no effects on fertility, mating
performance or early embryonic development at any dose level. The
highest dose was approximately 100 times the human systemic exposure
(AUC0-24h) of oseltamivir carboxylate.
Pregnancy
Pregnancy Category C
There are insufficient human data upon which to
base an evaluation of risk of TAMIFLU to the pregnant woman or developing
fetus. Studies for effects on embryo-fetal development were conducted
in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500
mg/kg/day) by the oral route. Relative exposures at these doses were,
respectively, 2, 13, and 100 times human exposure in the rat and 4,
8, and 50 times human exposure in the rabbit. Pharmacokinetic studies
indicated that fetal exposure was seen in both species. In the rat
study, minimal maternal toxicity was reported in the 1500 mg/kg/day
group. In the rabbit study, slight and marked maternal toxicities
were observed, respectively, in the 150 and 500 mg/kg/day groups.
There was a dose-dependent increase in the incidence rates of a variety
of minor skeletal abnormalities and variants in the exposed offspring
in these studies. However, the individual incidence rate of each skeletal
abnormality or variant remained within the background rates of occurrence
in the species studied.
Because animal reproductive
studies may not be predictive of human response and there are no adequate
and well-controlled studies in pregnant women, TAMIFLU should be used
during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers
In lactating rats, oseltamivir and oseltamivir carboxylate
are excreted in the milk. It is not known whether oseltamivir or oseltamivir
carboxylate is excreted in human milk. TAMIFLU should, therefore,
be used only if the potential benefit for the lactating mother justifies
the potential risk to the breast-fed infant.
Geriatric Use
The safety of TAMIFLU has been established in clinical
studies which enrolled 741 subjects (374 received placebo and 362
received TAMIFLU). Some seasonal variability was noted in the clinical
efficacy outcomes (see INDICATIONS AND USAGE: Description of
Clinical Studies: Studies in Naturally Occurring Influenza: Treatment
of Influenza: Geriatric Patients).
Safety and efficacy have been demonstrated in elderly
residents of nursing homes who took TAMIFLU for up to 42 days for
the prevention of influenza. Many of these individuals had cardiac
and/or respiratory disease, and most had received vaccine that season
(see INDICATIONS AND USAGE: Description of Clinical Studies: Studies in
Naturally Occurring Influenza: Prophylaxis of Influenza: Adult Patients).
Pediatric Use
The safety and efficacy of TAMIFLU in pediatric
patients younger than 1 year of age have not been studied. TAMIFLU
is not indicated for either treatment or prophylaxis of influenza
in pediatric patients younger than 1 year of age because of uncertainties
regarding the rate of development of the human blood-brain barrier
and the unknown clinical significance of non-clinical animal toxicology
data for human infants (see ANIMAL TOXICOLOGY).
ANIMAL TOXICOLOGY
In a 2-week study in unweaned rats, administration
of a single dose of 1000 mg/kg oseltamivir phosphate to 7-day-old
rats resulted in deaths associated with unusually high exposure to
the prodrug. However, at 2000 mg/kg, there were no deaths or other
significant effects in 14-day-old unweaned rats. Further follow-up
investigations of the unexpected deaths of 7-day-old rats at 1000
mg/kg revealed that the concentrations of the prodrug in the brains
were approximately 1500-fold those of the brains of adult rats administered
the same oral dose of 1000 mg/kg, and those of the active metabolite
were approximately 3-fold higher. Plasma levels of the prodrug were
10-fold higher in 7-day-old rats as compared with adult rats. These
observations suggest that the levels of oseltamivir in the brains
of rats decrease with increasing age and most likely reflect the maturation
stage of the blood-brain barrier. No adverse effects occurred at 500
mg/kg/day administered to 7- to 21-day-old rats. At this dosage, the
exposure to prodrug was approximately 800-fold the exposure expected
in a 1-year-old child.
ADVERSE REACTIONS
Treatment Studies in Adult Patients
A total of 1171 patients who participated in adult
phase III controlled clinical trials for the treatment of influenza
were treated with TAMIFLU. The most frequently reported adverse events
in these studies were nausea and vomiting. These events were generally
of mild to moderate degree and usually occurred on the first 2 days
of administration. Less than 1% of subjects discontinued prematurely
from clinical trials due to nausea and vomiting.
Adverse events that occurred with an incidence of =1% in 1440
patients taking placebo or TAMIFLU 75 mg twice daily in adult phase
III treatment studies are shown in Table 3. This summary includes
945 healthy young adults and 495 "at risk" patients (elderly patients
and patients with chronic cardiac or respiratory disease). Those events
reported numerically more frequently in patients taking TAMIFLU compared
with placebo were nausea, vomiting, bronchitis, insomnia, and vertigo.
Prophylaxis Studies in Adult Patients
A total of 4187 subjects (adolescents, healthy adults
and elderly) participated in phase III prophylaxis studies, of whom
1790 received the recommended dose of 75 mg once daily for up to 6
weeks. Adverse events were qualitatively very similar to those seen
in the treatment studies, despite a longer duration of dosing (see Table 3). Events reported more frequently in subjects receiving TAMIFLU
compared to subjects receiving placebo in prophylaxis studies, and
more commonly than in treatment studies, were aches and pains, rhinorrhea,
dyspepsia and upper respiratory tract infections. However, the difference
in incidence between TAMIFLU and placebo for these events was less
than 1%. There were no clinically relevant differences in the safety
profile of the 942 elderly subjects who received TAMIFLU or placebo,
compared with the younger population.
Table 3 Most Frequent Adverse Events in Studies
in Naturally Acquired Influenza in Patients 13 Years of Age and Older
|
Treatment |
Prophylaxis |
|---|
| Adverse Event |
Placebo
N=716 |
Oseltamivir
75 mg bid
N=724 |
Placebo/No Prophylaxis*
N=1688 |
Oseltamivir
75 mg qd
N=1790 |
|---|
|
|
| Nausea (without vomiting) |
40 |
(6%) |
72 |
(10%) |
56 |
(3%) |
129 |
(7%) |
| Vomiting |
21 |
(3%) |
68 |
(9%) |
16 |
(1%) |
39 |
(2%) |
| Diarrhea |
70 |
(10%) |
48 |
(7%) |
40 |
(2%) |
50 |
(3%) |
| Bronchitis |
15 |
(2%) |
17 |
(2%) |
22 |
(1%) |
15 |
(1%) |
| Abdominal pain |
16 |
(2%) |
16 |
(2%) |
25 |
(1%) |
37 |
(2%) |
| Dizziness |
25 |
(3%) |
15 |
(2%) |
21 |
(1%) |
24 |
(1%) |
| Headache |
14 |
(2%) |
13 |
(2%) |
306 |
(18%) |
326 |
(18%) |
| Cough |
12 |
(2%) |
9 |
(1%) |
119 |
(7%) |
94 |
(5%) |
| Insomnia |
6 |
(1%) |
8 |
(1%) |
15 |
(1%) |
22 |
(1%) |
| Vertigo |
4 |
(1%) |
7 |
(1%) |
4 |
(<1%) |
4 |
(<1%) |
| Fatigue |
7 |
(1%) |
7 |
(1%) |
163 |
(10%) |
139 |
(8%) |
Adverse events included are: all events reported
in the treatment studies with frequency =1% in the oseltamivir
75 mg bid group.
Additional adverse events
occurring in <1% of patients receiving TAMIFLU for treatment included
unstable angina, anemia, pseudomembranous colitis, humerus fracture,
pneumonia, pyrexia, and peritonsillar abscess.
Treatment Studies in Pediatric Patients
A total of 1032 pediatric patients aged 1 to 12
years (including 698 otherwise healthy pediatric patients aged 1 to
12 years and 334 asthmatic pediatric patients aged 6 to 12 years)
participated in phase III studies of TAMIFLU given for the treatment
of influenza. A total of 515 pediatric patients received treatment
with TAMIFLU for Oral Suspension.
Adverse events
occurring in =1% of pediatric patients receiving TAMIFLU treatment
are listed in Table 4. The most frequently reported adverse
event was vomiting. Other events reported more frequently by pediatric
patients treated with TAMIFLU included abdominal pain, epistaxis,
ear disorder, and conjunctivitis. These events generally occurred
once and resolved despite continued dosing. They did not cause discontinuation
of drug in the vast majority of cases.
The
adverse event profile in adolescents is similar to that described
for adult patients and pediatric patients aged 1 to 12 years.
Prophylaxis in Pediatric Patients
Pediatric patients aged 1 to 12 years participated
in a postexposure prophylaxis study in households, both as index cases
(134) and as contacts (222). Gastrointestinal events were the most
frequent, particularly vomiting. The adverse events noted were consistent
with those previously observed in pediatric treatment studies (see Table 4).
Table 4 Most
Frequent Adverse Events Occurring in Children Aged 1 to 12 Years in
Studies in Naturally Acquired Influenza
|
Treatment Trials* |
Household Prophylaxis Trial† |
|---|
| Adverse Event |
Placebo
N=517 |
Oseltamivir
2
mg/kg bid
N=515 |
No Prophylaxis‡
N=87 |
Prophylaxis
with Oseltamivir
QD‡
N=99 |
|---|
|
|
| Vomiting |
48 |
(9%) |
77 |
(15%) |
2 |
(2%) |
10 |
(10%) |
| Diarrhea |
55 |
(11%) |
49 |
(10%) |
- |
|
1 |
(1%) |
| Otitis media |
58 |
(11%) |
45 |
(9%) |
2 |
(2%) |
2 |
(2%) |
| Abdominal pain |
20 |
(4%) |
24 |
(5%) |
- |
|
3 |
(3%) |
| Asthma (including aggravated) |
19 |
(4%) |
18 |
(3%) |
1 |
(1%) |
1 |
(1%) |
| Nausea |
22 |
(4%) |
17 |
(3%) |
1 |
(1%) |
4 |
(4%) |
| Epistaxis |
13 |
(3%) |
16 |
(3%) |
- |
|
1 |
(1%) |
| Pneumonia |
17 |
(3%) |
10 |
(2%) |
2 |
(2%) |
- |
|
| Ear disorder |
6 |
(1%) |
9 |
(2%) |
- |
|
- |
|
| Sinusitis |
13 |
(3%) |
9 |
(2%) |
- |
|
- |
|
| Bronchitis |
11 |
(2%) |
8 |
(2%) |
2 |
(2%) |
- |
|
| Conjunctivitis |
2 |
(<1%) |
5 |
(1%) |
- |
|
- |
|
| Dermatitis |
10 |
(2%) |
5 |
(1%) |
- |
|
- |
|
| Lymphadenopathy |
8 |
(2%) |
5 |
(1%) |
- |
|
- |
|
| Tympanic membrane disorder |
6 |
(1%) |
5 |
(1%) |
- |
|
- |
|
| Age |
Prophylaxis (10 days) |
|---|
| 1-2 years |
30 mg QD |
| 3-5 years |
45 mg QD |
| 6-12 years |
60 mg QD |
Adverse events included in Table 4 are: all events
reported in the treatment studies with frequency =1% in the
oseltamivir 75 mg bid group.
Observed During Clinical Practice
The following adverse reactions have been identified
during postmarketing use of TAMIFLU. Because these reactions are reported
voluntarily from a population of uncertain size, it is not possible
to reliably estimate their frequency or establish a causal relationship
to TAMIFLU exposure.
Body as a Whole: Swelling
of the face or tongue, allergy, anaphylactic/anaphylactoid reactions
Dermatologic: Dermatitis, rash, eczema, urticaria, erythema
multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis (see PRECAUTIONS)
Digestive: Hepatitis, liver function
tests abnormal
Cardiac: Arrhythmia
Neurologic: Seizure, confusion
Metabolic: Aggravation of diabetes
OVERDOSAGE
At present, there has been no experience with overdose.
Single doses of up to 1000 mg of TAMIFLU have been associated with
nausea and/or vomiting.
DOSAGE AND ADMINISTRATION
TAMIFLU may be taken with or without food (see CLINICAL PHARMACOLOGY:
Pharmacokinetics). However, when taken with
food, tolerability may be enhanced in some patients.
Standard Dosage – Treatment of Influenza
Adults and Adolescents
The recommended oral dose of TAMIFLU for treatment
of influenza in adults and adolescents 13 years and older is 75 mg
twice daily for 5 days. Treatment should begin within 2 days of onset
of symptoms of influenza.
Pediatric Patients
TAMIFLU is not indicated for treatment of influenza
in pediatric patients younger than 1 year.
The
recommended oral dose of TAMIFLU for pediatric patients 1 year and
older is shown in Table 5. TAMIFLU for Oral Suspension may also
be used by patients who cannot swallow a capsule. For pediatric patients
who cannot swallow capsules, TAMIFLU for Oral Suspension is the preferred
formulation. If the for Oral Suspension product is not available,
TAMIFLU Capsules may be opened and mixed with sweetened liquids such
as regular or sugar-free chocolate syrup.
Table 5 Oral Dose of TAMIFLU for Treatment of Influenza in Pediatric
Patients by Weight
| Body Weight (kg) |
Body Weight (lbs) |
Recommended Dose for 5 Days |
Number of Bottles of TAMIFLU for Oral
Suspension Needed to Obtain the Recommended Doses for a 5 Day Regimen |
Number of TAMIFLU Capsules Needed to
Obtain the Recommended Doses for a 5 Day Regimen |
| =15 kg |
=33 lbs |
30 mg twice daily |
1 |
10 TAMIFLU Capsules (30 mg) |
| >15 kg to 23 kg |
>33 lbs to 51 lbs |
45 mg twice daily |
2 |
10 TAMIFLU Capsules (45 mg) |
| >23 kg to 40 kg |
>51 lbs to 88 lbs |
60 mg twice daily |
2 |
20 TAMIFLU Capsules (30 mg) |
| >40 kg |
>88 lbs |
75 mg twice daily |
3 |
10 TAMIFLU Capsules (75 mg) |
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 measured using a combination of 30 mg and 45 mg. It is
recommended that patients use this dispenser. In the event that the
dispenser provided is lost or damaged, another dosing syringe or other
device may be used to deliver the following volumes: 2.5 mL (1/2 tsp)
for children =15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0
mL (1 tsp) for >23 to 40 kg, and 6.2 mL (1 1/4 tsp) for >40 kg.
Standard Dosage – Prophylaxis of Influenza
Adults and Adolescents
The recommended oral dose of TAMIFLU for prophylaxis
of influenza in adults and adolescents 13 years and older following
close contact with an infected individual is 75 mg once daily for
at least 10 days. Therapy should begin within 2 days of exposure.
The recommended dose for prophylaxis during a community outbreak of
influenza is 75 mg once daily. Safety and efficacy have been demonstrated
for up to 6 weeks. The duration of protection lasts for as long as
dosing is continued.
Pediatric Patients
The safety and efficacy of TAMIFLU for prophylaxis
of influenza in pediatric patients younger than 1 year of age have
not been established.
The recommended oral
dose of TAMIFLU for pediatric patients 1 year and older following
close contact with an infected individual is shown in Table 6. TAMIFLU for Oral Suspension may also be used by patients who cannot
swallow a capsule. For pediatric patients who cannot swallow capsules,
TAMIFLU for Oral Suspension is the preferred formulation. If the for
Oral Suspension product is not available, TAMIFLU Capsules may be
opened and mixed with sweetened liquids such as regular or sugar-free
chocolate syrup.
Table 6 Oral Dose of TAMIFLU for Prophylaxis of Influenza in Pediatric
Patients by Weight
| Body Weight (kg) |
Body Weight (lbs) |
Recommended Dose for 10 Days |
Number of Bottles of TAMIFLU
for Oral Suspension Needed to Obtain the Recommended Doses for a 10
Day Regimen |
Number of TAMIFLU Capsules
Needed to Obtain the Recommended Doses for a 10 Day Regimen |
|---|
| =15 kg |
=33 lbs |
30 mg once daily |
1 |
10 TAMIFLU Capsules (30 mg) |
| >15 kg to 23 kg |
>33 lbs to 51 lbs |
45 mg once daily |
2 |
10 TAMIFLU Capsules (45 mg) |
| >23 kg to 40 kg |
>51 lbs to 88 lbs |
60 mg once daily |
2 |
20 TAMIFLU Capsules (30 mg) |
| >40 kg |
>88 lbs |
75 mg once daily |
3 |
10 TAMIFLU Capsules (75 mg) |
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 measured using a combination of 30 mg and 45 mg. It is
recommended that patients use this dispenser. In the event that the
dispenser provided is lost or damaged, another dosing syringe or other
device may be used to deliver the following volumes: 2.5 mL (1/2 tsp)
for children =15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0
mL (1 tsp) for >23 to 40 kg, and 6.2 mL (1 1/4 tsp) for >40 kg.
Prophylaxis in pediatric patients following close contact
with an infected individual is recommended for 10 days. Prophylaxis
in patients 1 to 12 years of age has not been evaluated for longer
than 10 days duration. Therapy should begin within 2 days of exposure.
Special Dosage Instructions
Hepatic Impairment
The safety and pharmacokinetics in patients with
hepatic impairment have not been evaluated.
Renal Impairment
For plasma concentrations of oseltamivir carboxylate
predicted to occur following various dosing schedules in patients
with renal impairment, see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Special Populations.
Treatment of Influenza
Dose adjustment is recommended for patients with
creatinine clearance between 10 and 30 mL/min receiving TAMIFLU for
the treatment of influenza. In these patients it is recommended that
the dose be reduced to 75 mg of TAMIFLU once daily for 5 days. No
recommended dosing regimens are available for patients undergoing
routine hemodialysis and continuous peritoneal dialysis treatment
with end-stage renal disease.
Prophylaxis of Influenza
For the prophylaxis of influenza, dose adjustment
is recommended for patients with creatinine clearance between 10 and
30 mL/min receiving TAMIFLU. In these patients it is recommended that
the dose be reduced to 75 mg of TAMIFLU every other day or 30 mg TAMIFLU
every day. No recommended dosing regimens are available for patients
undergoing routine hemodialysis and continuous peritoneal dialysis
treatment with end-stage renal disease.
Geriatric Patients
No dose adjustment is required for geriatric patients
(see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations and PRECAUTIONS).
Preparation of TAMIFLU for Oral Suspension
It is recommended that TAMIFLU for Oral Suspension
be constituted 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 constitution to the bottle
and shake the closed bottle well for 15 seconds.
- Remove the child-resistant cap and push bottle adapter into
the neck of the bottle.
- Close bottle with child-resistant cap tightly. This will assure
the proper seating of the bottle adapter in the bottle and child-resistant
status of the cap.
NOTE: SHAKE THE TAMIFLU FOR ORAL SUSPENSION WELL
BEFORE EACH USE.
The constituted TAMIFLU for
Oral Suspension (12 mg/mL) should be used within 10 days of preparation;
the pharmacist should write the date of expiration of the constituted
suspension on a pharmacy label. The patient package insert and oral
dispenser should be dispensed to the patient.
Emergency Compounding of an Oral Suspension from TAMIFLU Capsules
(Final Concentration 15 mg/mL)
The following directions are provided for use only
during emergency situations. These directions are not intended to
be used if the FDA-approved, commercially manufactured TAMIFLU for
Oral Suspension is readily available from wholesalers or the manufacturer.
Compounding an oral suspension with this procedure will
provide one patient with enough medication for a 5-day course of treatment
or a 10-day course of prophylaxis.
Commercially
manufactured TAMIFLU for Oral Suspension (12 mg/mL) is the preferred
product for pediatric and adult patients who have difficulty swallowing
capsules or where lower doses are needed. In the event that TAMIFLU
for Oral Suspension is not available, the pharmacist may compound
a suspension (15 mg/mL) from TAMIFLU (oseltamivir phosphate) Capsules
75 mg using either of two vehicles: Cherry Syrup (Humco®) or
Ora-Sweet® SF (sugar-free) (Paddock Laboratories). Other vehicles
have not been studied. This compounded suspension
should not be used for convenience or when the FDA-approved TAMIFLU
for Oral Suspension is commercially available.
First, calculate the Total Volume of an oral suspension
needed to be compounded and dispensed for each patient. The Total
Volume required is determined by the weight of each patient. Refer
to Table 7.
Table 7 Volume of an Oral Suspension (15 mg/mL) Needed to be Compounded
Based Upon the Patient's Weight
| Body Weight (kg) |
Body Weight (lbs) |
Total Volume to Compound per patient (mL) |
|---|
| =15 kg |
=33 lbs |
30 mL |
| 16 to 23 kg |
34 to 51 lbs |
40 mL |
| 24 to 40 kg |
52 to 88 lbs |
50 mL |
| =41 kg |
=89 lbs |
60 mL |
Second, determine the number of capsules and the
amount of vehicle (Cherry Syrup or Ora-Sweet SF) that are needed to
prepare the Total Volume (calculated from Table 7: 30 mL, 40 mL, 50 mL, or 60 mL) of compounded
oral suspension (15 mg/mL). Refer to Table 8.
Table 8 Number of TAMIFLU 75 mg Capsules
and Amount of Vehicle (Cherry Syrup OR Ora-Sweet SF) Needed to Prepare
the Total Volume of a Compounded Oral Suspension (15 mg/mL)
| Total Volume of Compounded Oral Suspension
needed to be Prepared |
30 mL |
40 mL |
50 mL |
60 mL |
|---|
| Required number
of TAMIFLU 75 mg Capsules |
6 capsules (450 mg
oseltamivir) |
8 capsules (600 mg
oseltamivir) |
10 capsules (750
mg oseltamivir) |
12 capsules (900
mg oseltamivir) |
| Required volume of vehicle |
|
|
|
|
| Cherry Syrup
(Humco) OR Ora-Sweet SF (Paddock
Laboratories) |
29 mL |
38.5 mL |
48 mL |
57 mL |
Third, follow the procedure below for compounding
the oral suspension (15 mg/mL) from TAMIFLU Capsules 75 mg
- Carefully separate the capsule body and cap and transfer the
contents of the required number of TAMIFLU 75 mg Capsules into a clean
mortar.
- Triturate the granules to a fine powder.
- Add one-third (1/3) of the specified amount of vehicle and triturate
the powder until a uniform suspension is achieved.
- Transfer the suspension to an amber glass or amber polyethyleneterephthalate
(PET) bottle. A funnel may be used to eliminate any spillage.
- Add another one-third (1/3) of the vehicle to the mortar, rinse
the pestle and mortar by a triturating motion and transfer the vehicle
into the bottle.
- Repeat the rinsing (Step 5) with the remainder of the vehicle.
- Close the bottle using a child-resistant cap.
- Shake well to completely dissolve the active drug and to ensure
homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: The active drug, oseltamivir phosphate, readily dissolves
in the specified vehicles. The suspension is caused by some of the
inert ingredients of TAMIFLU Capsules which are insoluble in these
vehicles.)
- Put an ancillary label on the bottle indicating "Shake Gently
Before Use". [This compounded suspension should be gently shaken prior
to administration to minimize the tendency for air entrapment, particularly
with the Ora-Sweet SF preparation.]
- Instruct the parent or guardian that any remaining material
following completion of therapy must be discarded by either affixing
an ancillary label to the bottle or adding a statement to the pharmacy
label instructions.
- Place an appropriate expiration date label according to storage
condition (see below).
STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION
Refrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2°
to 8°C (36° to 46°F).
Room Temperature: Stable for five days
(5 days) when stored at room temperature, 25°C (77°F).
Note: The storage conditions are based on stability studies
of compounded oral suspensions, using the above mentioned vehicles,
which were placed in amber glass and amber polyethyleneterephthalate
(PET) bottles. Stability studies have not been conducted with other
vehicles or bottle types.
Place a pharmacy
label on the bottle that includes the patient's name, dosing
instructions, and drug name and any other required information to
be in compliance with all State and Federal Pharmacy Regulations. Refer to Table 9 for the proper dosing instructions.
Note: This compounding procedure results
in a 15 mg/mL suspension, which is different from the commercially
available TAMIFLU for Oral Suspension, which has a concentration of
12 mg/mL.
Table 9 Dosing Chart for Pharmacy-Compounded
Suspension from TAMIFLU Capsules 75 mg
| Body Weight (kg) |
Body Weight
(lbs) |
Dose
(mg) |
Volume per Dose
15 mg/mL |
Treatment Dose (for 5 days) |
Prophylaxis Dose (for 10 days) |
|---|
| Note: 1
teaspoon = 5 mL |
| =15 kg |
=33 lbs |
30 mg |
2 mL |
2 mL two times a day |
2 mL once daily |
| 16 to 23 kg |
34 to 51 lbs |
45 mg |
3 mL |
3 mL two times a day |
3 mL once daily |
| 24 to 40 kg |
52 to 88 lbs |
60 mg |
4 mL |
4 mL two times a day |
4 mL once daily |
| =41 kg |
=89 lbs |
75 mg |
5 mL |
5 mL two times a day |
5 mL once daily |
Consider dispensing the suspension with a graduated
oral syringe for measuring small amounts of suspension. If possible,
mark or highlight the graduation corresponding to the appropriate
dose (2 mL, 3 mL, 4 mL, or 5 mL) on the oral syringe for each patient.
The dosing device dispensed with the commercially available TAMIFLU
for Oral Suspension should NOT be used with the compounded suspension
since they have different concentrations.
HOW SUPPLIED
TAMIFLU Capsules
30-mg capsules (30 mg free base equivalent of the
phosphate salt): light yellow hard gelatin capsules. "ROCHE" is printed
in blue ink on the light yellow body and "30 mg" is printed in blue
ink on the light yellow cap. Available in blister packages of 10 (NDC
0004-0802-85).
45-mg capsules (45 mg free base
equivalent of the phosphate salt): grey hard gelatin capsules. "ROCHE"
is printed in blue ink on the grey body and "45 mg" is printed in
blue ink on the grey cap. Available in blister packages of 10 (NDC
0004-0801-85).
75-mg capsules (75 mg free base
equivalent of the phosphate salt): grey/light yellow hard gelatin
capsules. "ROCHE" is printed in blue ink on the grey body and "75
mg" is printed in blue ink on the light yellow cap. Available in blister
packages of 10 (NDC 0004-0800-85).
Storage
Store the capsules at 25°C (77°F); excursions
permitted to 15° to 30°C (59° to 86°F). [See USP
Controlled Room Temperature]
TAMIFLU for Oral Suspension
Supplied as a white powder blend for constitution
to a white tutti-frutti–flavored suspension. Available in glass
bottles containing approximately 33 mL of suspension after constitution.
Each bottle delivers 25 mL of suspension equivalent to 300 mg oseltamivir
base. Each bottle is supplied with a bottle adapter and 1 oral dispenser
(NDC 0004-0810-95).
Storage
Store dry powder at 25°C (77°F); excursions
permitted to 15° to 30°C (59° to 86°F). [See USP
Controlled Room Temperature]
Store constituted
suspension under refrigeration at 2° to 8°C (36° to
46°F). Do not freeze.
Humco® is a
registered trademark of Humco Holding Group, Inc.
Ora-Sweet® SF is a registered trademark of Paddock Laboratories
Distributed by:
Roche Pharmaceuticals
Roche Laboratories Inc.
340 Kingsland
Street
Nutley, New Jersey 07110–1199
Licensor:
Gilead Sciences, Inc.
Foster City, California 94404
27899418
Rev. July 2007
Copyright©
1999-2007 by Roche Laboratories Inc. All rights reserved.
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Revised: 08/2007Roche Pharmaceuticals