NEW ZEALAND DATA SHEET

Tamiflu (oseltamivir)
1. PRODUCT NAME
Tamiflu 75mg capsules
Tamiflu 45 mg capsules
Tamiflu 30 mg capsules
Tamiflu 6mg/mL powder for oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Tamiflu 30mg capsules
Each capsule contains 39.4 mg oseltamivir phosphate equal to 30mg oseltamivir
Tamiflu 45mg capsules
Each capsule contains 59.1 mg oseltamivir phosphate equal to 45mg oseltamivir
Tamiflu 75mg capsules
Each capsule contains 98.5 mg oseltamivir phosphate equal to 75mg oseltamivir
Tamiflu 6mg/mL powder for oral suspension
Each mL of reconstituted suspension contains 0.5122 g oseltamivir phosphate which when
constituted with 55 mL water makes 65 mL of 6mg/mL oseltamivir. One bottle of
reconstituted suspension (65 ml) contains 390 mg of oseltamivir.
Excipients with known effect
Tamiflu 6mg/mL powder for oral suspension
5 ml oseltamivir suspension delivers 0.9 g of sorbitol.
7.5 ml oseltamivir suspension delivers 1.3 g of sorbitol.
10 ml oseltamivir suspension delivers 1.7 g of sorbitol.
12.5 ml oseltamivir suspension delivers 2.1 g of sorbitol.

For the full list of excipients, see section 6.1 List of excipients.

3. PHARMACEUTICAL FORM
Tamiflu 30 mg hard capsules
The hard capsule consists of a light yellow opaque body bearing the imprint “ROCHE” and a
light yellow opaque cap bearing the imprint “30 mg”. Imprints are blue.
Tamiflu 45 mg hard capsules
The hard capsule consists of a grey opaque body bearing the imprint “ROCHE” and a grey
opaque cap bearing the imprint “45 mg”. Imprints are blue.
Tamiflu 75 mg hard capsules
The hard capsule consists of a grey opaque body bearing the imprint “ROCHE” and a light
yellow opaque cap bearing the imprint “75 mg”. Imprints are blue.
Tamiflu 6mg/mL powder for oral suspension
The powder is a granulate or clumped granulate with a white to light yellow colour.

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4. CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
Tamiflu is indicated for the treatment of influenza in adults and children 2 weeks of age and
older who have been symptomatic for no more than 2 days (see section 4.4 Special warnings
and precautions for use).

Tamiflu is indicated for the prophylaxis of influenza in adults and children >1 years of age.
Vaccination is the preferred method of routine prophylaxis against infection with influenza
virus.
4.2 DOSE AND METHOD OF ADMINISTRATION
Dosage
Tamiflu may be taken with or without food (see section 5.2 Pharmacokinetic properties).
However, Tamiflu taken with food may enhance tolerability in some patients.
Standard dosage
Treatment of influenza
Treatment should begin within the first or second day of onset of symptoms of influenza.

Adults and adolescents

The recommended oral dose of Tamiflu for adults and adolescents ≥13 years is 75 mg twice
daily, for 5 days. Adults and adolescents ≥13 years of age can take Tamiflu capsules. Patients
unable to swallow capsules may receive the appropriate dose of Tamiflu oral suspension or
home-prepared or pharmacy-compounded Tamiflu capsules (see Patients unable to swallow
capsules) to achieve a 75 mg dose.

Infants and Children ≥ 1 to < 13 years of age

The recommended weight adjusted dosing regimens of Tamiflu for children ≥1 year of age
are:

Body weight Recommended dose for 5 Volume of 6 mg/mL oral

days suspension
< 15 kg 30 mg twice daily 5.0 mL twice daily
> 15 to 23 kg 45 mg twice daily 7.5 mL twice daily
> 23 kg to 40 kg 60 mg twice daily 10.0 mL twice daily
> 40 kg 75 mg twice daily 12.5 mL twice daily

Infants and children ≥ 1-year-old may receive the required Tamiflu dose in the form of
capsules. Patients unable to swallow capsules may receive the appropriate dose of Tamiflu
oral suspension or home-prepared or pharmacy-compounded Tamiflu capsules (see Patients
unable to swallow capsules).

Infants 2 weeks to <1 year of age:

The recommended oral dose of Tamiflu for infants 2 weeks to less than 1 year of age is 3 mg/kg
twice daily, for 5 days. These dosing recommendations are not intended for infants who have
a post-conceptual age of less than 36 weeks.

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The recommended oral dose of Tamiflu for infants 2 weeks to less than 1 year of age is*:
Body weight Recommended dose Amount of 6mg/mL
for 5 days oral suspension
3 kg 9 mg twice daily 1.5 mL twice daily
4 kg 12 mg twice daily 2.0 mL twice daily
5 kg 15 mg twice daily 2.5 mL twice daily
6 kg 18 mg twice daily 3.0 mL twice daily
7 kg 21 mg twice daily 3.5 mL twice daily
8 kg 24 mg twice daily 4.0 mL twice daily
9kg 27 mg twice daily 4.5 mL twice daily
10kg 30 mg twice daily 5.0 mL twice daily
* This table is not intended to contain all possible weights for this population. For all infants
2 weeks to less than 1 year of age, 3mg/kg should be used to determine dose regardless of the
weight of the patient.
It is recommended that Tamiflu powder for oral suspension be reconstituted by a pharmacist
prior to dispensing to the patient (see section 6.6 Special precautions for disposal and other
handling).
Prophylaxis of influenza
Adults and adolescents
The recommended oral dose of Tamiflu for adults and adolescents ≥ 13 years for prophylaxis
of influenza following close contact with an infected individual is 75 mg once daily for 10
days. Adults and adolescents ≥ 13 years of age can take capsules. Therapy should begin
within two 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 six weeks. The duration of protection lasts for as long as dosing is continued.

Adults and adolescents 13 years of age and older who are unable to swallow capsules may
receive the appropriate dose of Tamiflu oral suspension or home-prepared or pharmacy-
compounded Tamiflu capsules (see Patients unable to swallow capsules).

Infants and Children ≥ 1 to < 13 years of age

The recommended weight-adjusted prophylactic oral dosing regimens of Tamiflu for children
≥ 1 year of age are:

Body weight Recommended dose for 10 Volume of 6 mg/mL oral

days suspension
< 15 kg 30 mg once daily 5.0 mL once daily
> 15 to 23 kg 45 mg once daily 7.5 mL once daily
> 23 kg to 40kg 60 mg once daily 10.0 mL once daily
> 40 kg 75 mg once daily 12.5 mL once daily

Infants and children ≥ 1-year-old may receive the required Tamiflu dose in the form of
capsules but those who are unable to swallow capsules may receive the appropriate dose of
Tamiflu oral suspension or home-prepared or pharmacy-compounded Tamiflu capsules (see
below, Patients unable to swallow capsules).

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It is recommended that Tamiflu powder for oral suspension be reconstituted by a pharmacist
prior to dispensing to the patient (see section 6.6 Special precautions for disposal and other
handling).

Patients unable to swallow capsules

When commercially manufactured Tamiflu powder for oral suspension is not readily
available, adults, adolescents, children and infants (≥ 1 year of age) who are unable to
swallow capsules may receive appropriate doses of Tamiflu either prepared at home by
caregivers or prepared by a pharmacist.
Home-prepared, extemporaneous preparation of capsules
This procedure describes the preparation of a 15 mg/mL solution.
Adults and adolescents (13 years and older)
Adults and adolescents who are unable to swallow capsules may receive a 75 mg dose of
Tamiflu by following the instructions below.
1. Hold one Tamiflu 75 mg capsule over a small bowl, carefully pull the capsule open and
pour the powder into the bowl,
2. Add a suitable, small amount (1 teaspoon maximum) of sweetened food product such as
regular or sugar-free chocolate syrup, honey, light brown or table sugar dissolved in water,
dessert toppings, sweetened condensed milk, apple sauce or yogurt to mask the bitter taste
of the medication.
3. Stir the mixture well and give the entire contents to the patient. The mixture must be
swallowed immediately after its preparation. If there is some mixture left inside the bowl,
rinse the bowl with a small amount of water and have the patient drink this remaining
mixture. It is not necessary to administer any undissolved white powder as this is inert
material.

Children (1 year and older); 15 mg/mL solution

Children who are unable to swallow capsules and require a dose different to that available in
capsule form may receive appropriate doses of Tamiflu by following the instructions below.

1. Hold one Tamiflu 75 mg capsule over a small bowl, carefully pull the capsule open and
pour the powder into the bowl.

2. Using a graduated syringe, add 5 mL water to the powder. Stir for about two minutes.

3. Draw up into the syringe the correct amount of mixture from the bowl (see table below).
The recommended dose is body weight dependent

Push down on the plunger of the syringe, to empty its entire contents into a second bowl.
Discard any unused mixture.

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 Body weight Recommended dose Amount of Tamiflu mixture for
one dose
(15 mg/mL)
≤ 15 kg 30 mg 2 mL
> 15 to 23 kg 45 mg 3 mL
> 23 kg to 40kg 60 mg 4 mL
> 40 kg 75 mg 5 mL
Note: This compounding procedure results in a 15 mg/mL mixture, which is different from the
commercially available Tamiflu Oral Suspension.

4. In the second bowl, add a suitable, small amount (1 teaspoon maximum) of sweetened
food product such as regular or sugar-free chocolate syrup, honey (only for children one
year or older), light brown or table sugar dissolved in water, dessert toppings, sweetened
condensed milk, apple sauce or yogurt to the mixture to mask the bitter taste of the
medication.

5. Stir this mixture well and give the entire contents of the second bowl to the patient. This
mixture must be swallowed immediately after its preparation. If there is some mixture left
inside the bowl, rinse the bowl with a small amount of water and have the patient drink
this remaining mixture.

Pharmacy-compounded oral suspension from Tamiflu capsules (final concentration 6

mg/mL) for adults, adolescents, children and infants ≥ 2 weeks of age
Commercially manufactured Tamiflu for oral suspension (6 mg/mL) is the preferred product
for paediatric patients > 2 weeks of age 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 (6 mg/mL) from Tamiflu capsules.

This procedure describes the preparation of a 6 mg/mL suspension, which will provide one
patient with enough medication for a 5-day course of treatment or a 10-day course of
prophylaxis.

The pharmacist may compound a suspension (6 mg/mL) from Tamiflu 75 mg capsules using
water containing 0.05% w/v sodium benzoate added as a preservative.

First, calculate the total volume needed to be compounded and dispensed to provide a 5-day
course of treatment or a 10-day course of prophylaxis for the patient. The total volume of
compounded Tamiflu 6 mg/mL suspension required is determined by the weight of the
patient according to the recommendation in the table below:

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Volume of pharmacy compounded suspension (6 mg/mL) required for a 5 day course
based on the patient’s weight

Body Weight (kg) Total Volume to Compound per Patient Weight (mL)
up to 5kg 25mL
>5 to 6 kg 30 mL
>6 – 15 kg 50 mL
> 15 - 23 kg 75 mL
> 23 - 40 kg 100mL
> 40 kg 125 mL

Second, determine the number of capsules and the amount of vehicle (water containing
0.05% w/v sodium benzoate added as a preservative) that is needed to prepare the total
volume (calculated from the table above: 25 mL, 50 mL, 75 mL, 100 mL or 125 mL) of
compounded Tamiflu 6 mg/mL suspension as shown in the table below:

Total Volume Required Number of Tamiflu Required Volume

of Compounded 75 mg Capsules of Vehicle
Suspension (mg of oseltamivir)
to be Prepared
25 mL 2 capsules 24.5 mL
(150 mg)
50 mL 4 capsules 49.5 mL
(300 mg)
75 mL 6 capsules 74 mL
(450 mg)
100 mL 8 capsules 98.5 mL
(600 mg)
125 mL 10 capsules 123.5 mL
(750 mg)

Third, follow the procedure below for compounding the suspension (6 mg/mL) from Tamiflu
capsules:
1. Transfer the contents of the stated amount of Tamiflu capsules into the bottle and add
the stated amount of sodium benzoate solution (see Table above).
2. Close the bottle with the cap and shake for two minutes.
3. Put an ancillary label on the bottle indicating “Shake Gently Before Use”.
4. Instruct the parent or caregiver to discard any remaining solution after the patient has
completed the full course of therapy.
5. Place an appropriate expiration date label according to storage condition (see below).
Storage of the Pharmacy-compounded suspension (6 mg/mL)
Room temperature storage conditions: stable for 3 weeks (21 days) when stored at room
temperature ‘do not store above 25°C’.

Refrigerated storage conditions: stable for 6 weeks when stored at 2 - 8 ºC

Pharmacy-compounded Tamiflu suspension should not be frozen.

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Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, use
by date, medicine name and any other required information to be in compliance with local
pharmacy regulations.

The appropriate dose must be mixed by the caregiver with an equal quantity of sweet liquid
food, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or
fudge sauce) to mask the bitter taste.

Special dosage instructions

Patients with renal impairment
Treatment of influenza
In adults, no dose adjustment is necessary for patients with creatinine clearance above 60
mL/min. In patients with a creatinine clearance of > 30 – 60 mL/min, it is recommended that
the dose be reduced to 30 mg of Tamiflu twice daily for 5 days. In patients with a creatinine
clearance of 10 - 30 mL/min, it is recommended that the dose is reduced to 30 mg of Tamiflu
once daily for 5 days. In patients undergoing routine haemodialysis, an initial dose of 30 mg
of Tamiflu can be administered prior to the start of dialysis if influenza symptoms develop
during the 48 hours between dialysis sessions. To maintain plasma concentrations at a
therapeutic level, a dose of 30 mg should be administered after every haemodialysis session.
For peritoneal dialysis, a dose of 30 mg of Tamiflu administered prior to the start of dialysis
followed by further 30 mg doses administered every 5 days is recommended for treatment
(see section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). The
pharmacokinetics of oseltamivir have not been studied in patients with end stage renal
disease (i.e. creatinine clearance of < 10 mL/min) not undergoing dialysis. Hence, dosing
recommendation cannot be provided for this group.

Prophylaxis of influenza
In adults, no dose adjustment is necessary for patients with creatinine clearance above 60
mL/min. In patients with a creatinine clearance of > 30 – 60 mL/min, it is recommended that
the dose be reduced to 30 mg of Tamiflu once daily. In patients with creatinine clearance
between 10 - 30 mL/min receiving Tamiflu, it is recommended that the dose be reduced to 30
mg every other day. In patients undergoing routine haemodialysis, an initial dose of 30 mg of
Tamiflu can be administered prior to the start of dialysis. To maintain plasma concentrations
at a therapeutic level, a dose of 30 mg should be administered after every alternate
haemodialysis session. For peritoneal dialysis, an initial dose of 30 mg of Tamiflu
administered prior to the start of dialysis followed by further 30 mg doses administered every
7 days is recommended for prophylaxis (see section 5.2 Pharmacokinetic properties,
Pharmacokinetics in special populations). The pharmacokinetics of oseltamivir have not been
studied in patients with end stage renal disease (i.e. creatinine clearance of < 10 mL/min) not
undergoing dialysis. Hence, dosing recommendation cannot be provided for this group.

Children with renal impairment

There is insufficient clinical data available in children with renal impairment to be able to
make any dosing recommendation.
Patients with hepatic impairment
No dose adjustment is required for patients with hepatic dysfunction in the treatment or
prophylaxis of influenza (see section 5.2 Pharmacokinetic properties, Pharmacokinetics in
special populations). No studies have been carried out in paediatric patients with hepatic
impairment.

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Immunocompromised patients
Treatment of Influenza
Treatment of adult immunocompromised patients, 18 years of age and older, for a duration of
10 days has been evaluated (see sections 4.8 Undesirable Effects and 5.0 Pharmacological
Properties). No dose adjustment is necessary (see “Treatment of Influenza” in Section 4.2
Dose and Method of Administration).
Prophylaxis of Influenza

Seasonal prophylaxis in immunocompromised patients ≥ 1 year of age is recommended for

12 weeks. No dose adjustment is necessary (see “Prophylaxis of Influenza” in Section 4.2
Dose and Method of Administration).
Use in the elderly
No dose adjustment is required for elderly patients in the treatment or prophylaxis of
influenza (see section 5.2 Pharmacokinetic properties).
Paediatric use
The efficacy of Tamiflu in infants less than 2 weeks of age has not been established (see
section 5.2 Pharmacokinetic properties). Pharmacokinetic data indicates that a dosage of 3
mg/kg twice daily in infants 2 weeks to less than 1 year of age provides plasma
concentrations of the pro-drug and active metabolite that are anticipated to be clinically
efficacious with a safety profile comparable to that seen in older children and adults.

4.3 CONTRAINDICATIONS
Tamiflu is contraindicated in patients with known hypersensitivity to oseltamivir phosphate
or any component of the product.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Convulsion and delirium like neuropsychiatric events have been reported during Tamiflu
administration in patients with influenza, predominately in children and adolescents. In rare
cases, these events resulted in accidental injury. The contribution of Tamiflu to those events
is unknown and these have also been reported in patients with influenza who were not taking
Tamiflu (see section 4.8 Undesirable effects).

Patients, especially children and adolescents, should be closely monitored for signs of
abnormal behaviour.

There is no evidence for efficacy of Tamiflu in any illness caused by agents other than
influenza viruses types A and B.

Sorbitol
Tamiflu powder for oral suspension contains sorbitol. For subjects with hereditary fructose
intolerance, Tamiflu powder for oral suspension is not recommended. Sorbitol may have a
laxative effect or cause diarrhoea.

A bottle of 13 g Tamiflu 6 mg/mL powder for oral suspension contains 11.142 g of sorbitol.
30 mg oseltamivir suspension delivers 0.9 g of sorbitol.
45 mg oseltamivir suspension delivers 1.3 g of sorbitol.
60 mg oseltamivir suspension delivers 1.7 g of sorbitol.

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75 mg oseltamivir suspension delivers 2.1 g of sorbitol.
Use in Renal Impairment
For dose adjustments in patients with renal impairment refer to the Special dosage
instructions and Pharmacokinetics in special populations sections.
Paediatric use
See sections 4.2 Dose and method of administration and 5.2 Pharmacokinetic properties.
Effects on Laboratory Tests
Elevated liver enzymes have been reported in patients with influenza-like illness receiving
oseltamivir (see section 4.8 Undesirable Effects, Post-marketing experience).
Pharmaceutical Precautions
Direct contact of oseltamivir phosphate with the skin and eyes should be avoided as it is a
potential skin sensitiser and eye irritant.

4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS
Information derived from pharmacology and pharmacokinetic studies of oseltamivir
phosphate suggest that clinically significant interactions with other medicines are unlikely.

Oseltamivir phosphate is extensively converted to the active compound by esterases, located

predominantly in the liver. Interactions involving competition for esterases have not been
extensively reported in the literature. Low protein binding of oseltamivir and the active
metabolite do not suggest the probability of displacement interactions.

In vitro studies demonstrated that neither oseltamivir phosphate nor the active metabolite is a
good substrate for P450 mixed-function oxidases or for glucuronyl transferases (see section
5.2 Pharmacokinetic properties). There is no mechanistic basis for an interaction with oral
contraceptives.

Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal
tubular secretion of basic or cationic agents has no effect on plasma levels of oseltamivir or
its active metabolite.

Clinically important interactions involving competition for renal tubular secretion are
unlikely due to the known safety margin for most of these medicines, the elimination
characteristics of the active metabolite (glomerular filtration and anionic tubular secretion)
and the excretion capacity of these pathways. Co-administration of probenecid results in
approximate 2-fold increase in exposure to the active metabolite due to a decrease in active
tubular secretion in the kidney. However, due to the wide safety margin of the active
metabolite, no dose adjustments are required when co-administering with probenecid.

Co-administration with amoxicillin does not alter plasma levels of either compound,
indicating that competition for the anionic secretion pathway is weak.

Co-administration with paracetamol does not alter plasma levels of oseltamivir, its active
metabolite, or paracetamol.

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No pharmacokinetic interactions between oseltamivir or its major metabolite have been
observed when co-administering oseltamivir with paracetamol, acetyl-salicylic acid,
cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates),
warfarin, rimantadine or amantadine.

In phase III treatment and prophylaxis clinical studies, Tamiflu has been administered with
commonly used medicines such as ACE inhibitors (enalapril, captopril), thiazide diuretics
(bendrofluazide) antibiotics (penicillin, cephalosporin, azithromycin, erythromycin and
doxycycline), H2-receptor blockers (ranitidine, cimetidine), beta-blockers (propranolol),
xanthines (theophylline), sympathomimetics (pseudoephedrine), opioids (codeine),
corticosteroids, inhaled bronchodilators and analgesic agents (aspirin, ibuprofen and
paracetamol). No change in adverse event profile or frequency has been observed as a result
of co-administration of Tamiflu with these compounds.

4.6 FERTILITY, PREGNANCY AND LACTATION

Pregnancy
Category B1
In animal reproductive studies in rats and rabbits, no teratogenic effect was observed. Foetal
exposure in rats and rabbits was approximately 15 - 20% of that of the mother.

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 foetus.

No controlled clinical trials have been conducted on the use of Tamiflu in pregnant women;
however, there is evidence from post-marketing and observational studies showing benefit of
the current dosing regimen in this patient population. Results from pharmacokinetic analyses
indicate lower exposure to the active metabolite, however dose adjustments are not
recommended for pregnant women in the treatment or prophylaxis of influenza (see section
5.2 Pharmacokinetic properties, Pharmacokinetics in Special Populations). A large amount
of data from pregnant women exposed to oseltamivir (more than 1000 exposed outcomes
during the first trimester) from post-marketing reports and observational studies in
conjunction with animal studies indicate no direct or indirect harmful effects with respect to
pregnancy or embryonal/foetal development.

Labour and Delivery

The safe use of oseltamivir during labour and delivery has not been established.

Breast-feeding
In lactating rats, oseltamivir and the active metabolite are secreted in milk. Very limited
information is available on children breast-fed by mothers taking Tamiflu and on excretion of
oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active
metabolite were detected in breast milk; however, the levels were low, which would result in
a sub-therapeutic dose to the infant. Based on this information, the pathogenicity of the
circulating influenza virus strain and the underlying condition of the lactating woman,
administration of oseltamivir may be considered if the potential benefit for the lactating
mother justifies the potential risk of exposure of the medicine to the nursing infant.
Fertility
Based on preclinical data, there is no evidence that Tamiflu has an effect on male or female
fertility (see section 5.3 Preclinical safety data).

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4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
No studies on the effects on the ability to drive and to use machines have been performed.
The pharmacological activity and adverse events reported to date do not indicate such an
effect is likely.

4.8 UNDESIRABLE EFFECTS

Experience from clinical trials
The overall safety profile of Tamiflu is based on data from 2646 adults/adolescents and 859
paediatric patients with influenza, and on data from 1943 adult/adolescent and 148 paediatric
patients receiving Tamiflu for the prophylaxis of influenza in clinical trials. In
adult/adolescent treatment studies, the most frequently reported adverse drug reactions
(ADRs) were nausea, vomiting and headache. The majority of these ADRs were reported on
a single occasion, occurred on either the first or second treatment day and resolved
spontaneously within 1 – 2 days. In adult/adolescent prophylaxis studies, the most frequently
reported ADRs were nausea, vomiting, headache and pain. In children, the most commonly
reported ADR was vomiting. In the majority of patients, these events did not lead to
discontinuation of Tamiflu.
Tabulated summary of adverse drug reactions from clinical trials
Adverse drug reactions from clinical trials are listed according to the MedDRA system organ
class. The corresponding frequency category for each adverse drug reaction (Table 1) is
based on the following convention: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Treatment and Prophylaxis of Influenza in Adults and Adolescents
In adult/adolescent treatment and prophylaxis studies, ADRs that occurred the most
frequently (≥ 1%) at the recommended dose (75 mg twice daily for 5 days for treatment and
75 mg once daily for up to 6 weeks for prophylaxis), and whose incidence is at least 1%
higher on Tamiflu compared to placebo, are shown in Table 1.

The population included in the influenza treatment studies comprised of otherwise healthy
adults/adolescents and patients “at risk” (patients at higher risk of developing complications
associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory
disease). In general, the safety profile in the patients “at risk” was qualitatively similar to that
in otherwise healthy adults/adolescents.

The safety profile reported in the subjects that received the recommended dose of Tamiflu for
prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the
treatment studies (see Table 1), despite a longer duration of dosing in the prophylaxis studies.

Table 1: Summary of Adverse Reactions in ≥ 1% of adult and adolescent patients that

received oseltamivir for treatment or prophylaxis of influenza, in clinical studies
(difference to placebo ≥ 1%)

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 Treatment Frequency
Prophylaxis
System Organ Class Studies categorya
Tamiflu Tamiflu
Adverse Drug Reaction (75 mg twice (75 mg twice
daily) daily)
n = 2646 n = 1943
Gastrointestinal
Disorders
Nausea 10% 8% very common
Vomiting 8% 2% common
Neurological and
Nervous
System Disorders
Headache 2% 17% very common
General Disorders
Pain < 1% 4% common
a
Frequency category is reported only for the Tamiflu group.

Treatment and Prophylaxis of Influenza in Elderly

There were no clinically relevant differences in the safety profile of the 942 subjects, 65 years
of age and older who received Tamiflu or placebo, compared with the younger population
(aged up to 65 years).
Treatment and Prophylaxis of Influenza in Immunocompromised Patients
In a double blind study for the treatment of influenza, a total of 199 adult immunocompromised
patients (evaluable for safety) were randomized to receive Tamiflu for 10 days: 98 patients
received the standard dose (75 mg twice daily) and 101 patients received the double dose (150
mg twice daily). The safety profile of Tamiflu observed in this study was consistent with that
observed in previous clinical trials where Tamiflu was administered for treatment of influenza
in non-immunocompromised patients (otherwise healthy patients or “at risk” patients [i.e.,
those with respiratory and/or cardiac co-morbidities]). Both doses were well tolerated, with the
percentage of patients reporting adverse events being lower in the standard dose group
compared to the double dose group (49.0% vs 59.4 %, respectively). (See section 5.0
Pharmacological Properties, Clinical Trials).
In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1
– 12 years old, the safety profile in the 238 subjects receiving Tamiflu was consistent with that
previously observed in Tamiflu prophylaxis clinical trials.
Treatment and prophylaxis of influenza in infants and children > 1 year of age
A total of 1481 paediatric patients (including otherwise healthy children aged 1 – 12 years
old and asthmatic children aged 6 – 12 years old) participated in clinical studies investigating
the use of Tamiflu in the treatment of influenza. A total of 859 paediatric patients received
treatment with Tamiflu suspension.

The ADRs that occurred in ≥ 1% of children aged 1 – 12 years receiving Tamiflu in the
clinical trials for treatment of naturally acquired influenza (n = 859), and whose incidence is
at least 1% higher on Tamiflu compared to placebo (n = 622), is vomiting (16% on
oseltamivir vs. 8% on placebo). Amongst the 148 children who received the recommended
dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), and
in a separate 6-week paediatric prophylaxis study (n = 49), vomiting was the most frequent

Tamiflu 190502 12
ADR (8% on Tamiflu vs. 2% in the no prophylaxis group). Tamiflu was well tolerated in
these studies and the adverse events noted were consistent with those previously observed in
paediatric treatment studies.

Treatment of influenza in infants 2 weeks to less than 1 year of age

In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of
oseltamivir therapy in 124 influenza infected infants 2 weeks to less than 1 year of age, the
safety profile was similar among age cohorts with vomiting, diarrhoea and nappy rash being
the most frequently reported adverse events (see section 5.2 Pharmacokinetic properties,
Pharmacokinetics in special populations). Insufficient data are available for infants who have
a post-conceptual age of less than 36 weeks.

Safety information available on Tamiflu administered fir the treatment of influenza in

children less than 1 year of age from prospective and retrospective observational trials
(compromising more 2400 children of that age class), epidemiological database research and
post-marketing reports suggest that the safety profile in children less than 1 year of age is
similar to the established safety profile of children aged 1 year and above.
Post-Marketing Experience
The following adverse events have been identified during post-marketing use of Tamiflu.
Because these events are reported voluntarily from a population of uncertain size, it is not
possible to reliably estimate their frequency and/or establish a causal relationship to Tamiflu
exposure.

Skin and subcutaneous tissue disorders: hypersensitivity reactions such as allergic skin
reactions including dermatitis, rash, eczema and urticaria, erythema multiforme, allergy,
anaphylactic/anaphylactoid reactions, face oedema, Stevens-Johnson-Syndrome and toxic
epidermal necrolysis have been reported.

Hepatobiliary disorders: hepatitis and elevated liver enzymes have been reported in patients
with influenza-like illness receiving oseltamivir.

Psychiatric disorders/Nervous system disorders: convulsion and delirium (including

symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions,
hallucinations, agitation, anxiety and nightmares) have been reported during Tamiflu
administration in patients with influenza, predominately in children and adolescents. These
events often had an abrupt onset and rapid resolution. In rare cases, these events resulted in
accidental injury, and some resulted in a fatal outcome, however, the contribution of Tamiflu
to those events is unknown. Such neuropsychiatric events have also been reported in patients
with influenza who were not taking Tamiflu. Three separate large epidemiological studies
confirmed that influenza-infected patients receiving Tamiflu are at no higher risk of developing
neuropsychiatric events in comparison to influenza-infected patients not receiving antivirals.
Patients with influenza should be closely monitored for signs of abnormal behaviour
throughout the treatment period.
Gastrointestinal disorders: gastrointestinal bleeding was observed after the use of Tamiflu.
In particular, haemorrhagic colitis was reported and subsided when the course of influenza
abated or treatment with Tamiflu was interrupted.

Blood and lymphatic system disorders: thrombocytopenia.

Tamiflu 190502 13
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare
professionals are asked to report any suspected adverse reactions
https://nzphvc.otago.ac.nz/reporting/

4.9 OVERDOSE
Reports of overdose with Tamiflu have been received from clinical trials and during post-
marketing experience. In the majority of cases reporting overdose, no adverse events were
reported.

Adverse events reported following overdose were similar in nature and distribution to
those observed with therapeutic doses of Tamiflu described in Adverse Effects.

For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800 764 766).

5. PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code:
J05AH02
Mechanism of Action
Oseltamivir phosphate is a pro-drug of oseltamivir carboxylate, a potent and selective
inhibitor of influenza virus neuraminidase enzymes. Viral neuraminidase is important both
for viral entry into uninfected cells and for the release of recently formed virus particles from
infected cells, and the further spread of infectious virus.

Oseltamivir carboxylate inhibits the neuraminidases of influenza viruses of both types A and
B. Concentrations of oseltamivir carboxylate required to inhibit the enzyme activity by 50%
(IC50) are in the low nanomolar range. Oseltamivir carboxylate also inhibits influenza virus
infection and replication in-vitro and inhibits influenza virus replication and pathogenicity in-
vivo.

Oseltamivir carboxylate reduces shedding of both influenza A and B virus by inhibiting the
release of infectious virus from infected cells.
Clinical trials
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.

Trials in naturally occurring influenza

In phase III clinical trials conducted in the 1997 - 1998 Northern Hemisphere influenza
season, 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

Tamiflu 190502 14
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 these 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 treatment study in the elderly population have shown that Tamiflu 75 mg twice
daily for five days was associated with a reduction in median duration of illness that was
clinically relevant, and similar to that seen in the younger adult treatment studies. In a
separate 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.
Treatment of influenza in children
One double-blind placebo controlled treatment trial was conducted in otherwise healthy
children (65% influenza positive) aged 1 to 12 years (mean age 5.3), who had fever ( 100
F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be
circulating in the community. In this study 67% of influenza-infected patients were infected
with influenza A and 33% with influenza B. Tamiflu treatment, started within 48 hours of
onset of symptoms, significantly reduced the duration of illness by 35.8 hours compared to
placebo. Duration of illness was defined as time to alleviation of cough, nasal congestion,
resolution of fever, and return to normal health and activity. The proportion of patients
developing acute otitis media was reduced by 40% in children receiving Tamiflu (29/183) vs
placebo (53/200). Children receiving Tamiflu returned to normal health and activity almost 2
days earlier than those receiving placebo.

A second study was completed in 334 asthmatic children aged 6 to 12 years old of which
53.6% were influenza-positive. In the oseltamivir-treated group the median duration of illness
was not reduced significantly. By day 6 (the last day of treatment) FEV1 had increased by
10.8% in the oseltamivir-treated group compared to 4.7% on placebo (p = 0.0148) in this
population.

Treatment of influenza in immunocompromised adults

A randomized, double blind study, to evaluate safety and characterize the effects of oseltamivir
on the development of resistant influenza virus (primary analysis) in influenza-infected adult
immunocompromised patients, included 151 patients evaluable for efficacy of oseltamivir
(secondary analysis, not powered). The study included solid organ transplant [SOT] patients,
haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell
count <500 cells/mm3, patients on systemic immunosuppressive therapy, and those with
haematological malignancy. These patients were randomized to be treated, within 96 hours of

Tamiflu 190502 15
symptoms onset, with standard dose (73 patients) or double dose (78 patients) of oseltamivir,
for a duration of 10 days.
The median time to resolution of symptoms (TTRS) was similar between the standard dose
group (103 hours [90% CI 75.4-110.0]) and double dose group (104 hours [90% CI 65.8-
131.0]). The proportion of patients with secondary infections in the standard dose group and
double dose group was comparable (8.2% vs 5.1%).
The TTRS in all oseltamivir-treated adult immunocompromised patients (combined from
both dose groups) was shorter when compared to matched placebo-treated otherwise healthy
(reduced by 14 hours) and “at risk” patients (reduced by 60 hours), from previous studies.
Trials for prophylaxis of influenza
Prophylaxis of influenza in adults and adolescents
The efficacy of Tamiflu in preventing naturally occurring influenza illness has been
demonstrated in three seasonal prophylaxis studies and two post exposure 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 ºF/37.2 ºC 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
18 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 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 post-exposure prophylaxis study, household
contacts (aged  13 years) who had no laboratory evidence of influenza at baseline, and who
were living with an index case subsequently shown to have had influenza infection, were
randomized to treatment (the ITTIINAB population). In this population Tamiflu 75 mg
administered once daily within 2 days of onset of symptoms in the index case and continued
for 7 days, reduced the incidence of laboratory confirmed clinical influenza in the contacts
from 12% (24/200) in the placebo group to 1% (2/205) for the Tamiflu group (risk reduction
91.9%, p < 0.001). For the study population as a whole (the ITT population), including
contacts of index cases in whom influenza infection was not confirmed, the incidence of
laboratory confirmed clinical influenza was reduced from 7.4% (34/462) in the placebo group
to 0.8% (4/493) for the Tamiflu group (risk reduction 89%, p < 0.001). Index cases did not
receive Tamiflu in the study. In the ITT population 13.9%of contacts in the placebo group
and 11.4% of contacts in the Tamiflu group had been vaccinated.

The efficacy of Tamiflu in preventing naturally occurring influenza illness in adults and
children has also been demonstrated in a post exposure prophylaxis study conducted in
households in which index cases with rapid onset of fever, cough and/or coryza received
twice daily treatment with Tamiflu for 5 days. The primary efficacy parameter for this study
was the percentage of households with at least one secondary case of febrile laboratory

Tamiflu 190502 16
confirmed influenza illness. A laboratory confirmed case was defined as a febrile illness
(oral/otic temperature ≥ 100.0 ºF/37.8 ºC) plus cough and/or coryza, confirmed to be
influenza by either detection of viral shedding within 2 days before or after the time that the
fever was reported, and/or a fourfold increase in influenza virus antibody titers from baseline
to the day 30 sample. Household contacts were randomized (by household) to receive either
once daily prophylaxis with oseltamivir for 10 days (Group P) or to receive treatment for 5
days upon the emergence of influenza-like illness (Group T).

In households with an infected index case and where there was no laboratory evidence of
influenza among the contacts at baseline (ITTIINAB), there was a 78.8% (p = 0.0008)
reduction in households with infected contacts in Group T 22% (20/89) versus Group P 5%
(4/84). In the population as a whole (ITT), including contacts of index cases in whom
influenza infection was not confirmed, the prophylactic efficacy protection was 62.7% (p =
0.0042), Group T 20% (27/137) versus Group P 7% (10/137). A significant number of
children aged 1 - 12 participated in this study, both as index cases and as contacts. In the
ITTIINAB population of paediatric contacts, there was an 80.1% (p = 0.0206) reduction in
the incidence of laboratory confirmed influenza in Group T 21% (15/70) versus Group P 4%
(2/47). A similar reduction in clinical influenza was seen in the subset of paediatric contacts
that also had paediatric index cases.
Prophylaxis of influenza in children
The efficacy of Tamiflu in preventing naturally occurring influenza illness has been
demonstrated in a postexposure prophylaxis study in households that included children aged
1 to 12 years, both as index cases and as family contacts. The primary efficacy parameter for
this study was the incidence of laboratory-confirmed clinical influenza. In this study, Tamiflu
oral suspension 30 mg to 75 mg once daily taken for 10 days among children who were not
already shedding virus at baseline reduced the incidence of laboratory-confirmed clinical
influenza from 21% (15/70) in the group not receiving prophylaxis to 4% (2/47) in the group
receiving prophylaxis.
Prophylaxis of influenza in immunocompromised patients
A double-blind, placebo controlled study was conducted for seasonal prophylaxis of
influenza in 475 immunocompromised subjects, including 18 children 1 – 12 years old.
Laboratory-confirmed clinical influenza, as defined by RT-PCR plus oral temperature  37.2
°C/99.0 °F plus cough and/or coryza, all recorded within 24 hours, was evaluated. Among
subjects who were not already shedding virus at baseline, Tamiflu reduced the incidence of
laboratory-confirmed clinical influenza from 3.0% (7/231) in the group not receiving
prophylaxis to 0.4% (1/232) in the group receiving prophylaxis (see Table 2).

Tamiflu 190502 17
Table 2: Incidence of influenza infection in immunocompromised patients

Population Placebo Tamiflu Treatment 95% CI for p-value c

n/N 75 mg once effect a difference in
(%) daily proportions
n/N between
(%) treatmentsb
Overall 7/238 5/237 28.3% -2.3% to 4.1% 0.772
ITT (2.9%) (2.1%)
ITTII 7/238 2/237 71.3% -0.6% to 5.2% –
(2.9%) (0.8%)
ITTIINAB 7/231 1/232 85.8% 0.1% to 5.7% –
(3.0%) (0.4%)
a
Treatment effect = (1 – Relative Risk)*100%; b Calculated using Newcombe’s method of combining Wilson
score intervals without continuity correction; c Comparison of Placebo versus Tamiflu using Fisher’s exact test
ITTII = intent-to-treat index-infected ITTIINAB = intent-to-treat index-infected, not infected at baseline.

Viral resistance
Reduced sensitivity of viral neuraminidase
Clinical studies: The risk of emergence of influenza viruses with reduced susceptibility or
resistance to oseltamivir has been examined during Roche-sponsored clinical studies (see Table
3). Patients who were found to carry oseltamivir-resistant virus generally did so transiently
and showed no worsening of the underlying symptoms. In some paediatric patients,
oseltamivir-resistant virus was detected for a prolonged period compared to patients carrying
oseltamivir-sensitive virus; however, these patients showed no prolongation of influenza
symptoms.
An overall higher incidence of oseltamivir-resistance was observed in adult
immunocompromised patients, treated with standard dose or double dose of oseltamivir for a
duration of 10 days [14.9% (10/67) in standard dose group and 2.8% (2/71) in double dose
group], compared to data from studies with oseltamivir-treated otherwise healthy adult patients.
The majority of patients that developed resistance were transplant recipients (8/10 patients in
the standard dose group and 2/2 patients in the double dose group). Most of the patients with
oseltamivir-resistant virus were infected with influenza type A and had prolonged viral
shedding.
Table 3: Incidence of Oseltamivir Resistance in Clinical Studies
Patients with Resistance Mutations (%)
Patient Population Phenotyping* Genotyping and
Phenotyping*
Adults and Adolescents 21/2377 (0.88%) 27/2391 (1.12%)

Children (1 – 12 years) 19/464 (4.1%) 25/464 (5.4%)

* Full genotyping was not performed in all studies.

Tamiflu 190502 18
Prophylaxis of Influenza
In clinical studies conducted in post-exposure (7 days), post-exposure within household groups
(10 days) and seasonal (42 days) prophylaxis of influenza in immunocompetent persons, there
was no evidence for emergence of drug resistance associated with the use of Tamiflu. There
was no resistance observed during a 12-week seasonal prophylaxis study in
immunocompromised subjects.

Clinical and surveillance data: Natural mutations associated with reduced susceptibility to
oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients
without exposure to oseltamivir. For example, in 2008 the oseltamivir resistance-associated
substitution H275Y was found in > 99 % of circulating 2008 H1N1 influenza isolates in
Europe, while the 2009 H1N1 influenza (“swine flu”) was almost uniformly susceptible to
oseltamivir. Resistant strains have also been isolated from both immunocompetent and
immunocompromised patients treated with oseltamivir. The susceptibility to oseltamivir and
the prevalence of such viruses appears to vary seasonally and geographically. Oseltamivir
resistance has also been reported in patients with pandemic H1N1 influenza in connection
with both therapeutic and prophylactic regimens.

The rate of emergence of resistance may be higher in the youngest age groups, and in
immunocompromised patients. Oseltamivir-resistant viruses isolated from oseltamivir-
treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been
found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be
viral sub-type specific.

Prescribers should consider available information on influenza virus drug susceptibility

patterns for each season when deciding whether to use Tamiflu (for the latest information,
please refer to WHO and/or local government websites).
5.2 PHARMACOKINETIC PROPERTIES
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 pro-drug. 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 section 4.2 Dose and Method of
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, bronchoalveolar lavage, nasal mucosa, middle ear and trachea following oral
administration of doses of oseltamivir phosphate.

Tamiflu 190502 19
The binding of the active metabolite to human plasma protein is negligible (approximately
3%). The binding of the pro-drug to human plasma protein is 42%. These levels are
insufficient to cause significant 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 section 4.5 Interactions with other Medicines
and other Forms of 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 radiolabelled dose is eliminated in
faeces.
Pharmacokinetics in special populations
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.

A population pharmacokinetic model describing the impact of creatinine clearance (CrCL) on

oseltamivir and oseltamivir carboxylate pharmacokinetics was developed and qualified for
simulation using 80 subjects with varying degrees of renal function. Subjects had dense
pharmacokinetic profiles and were identified from three clinical studies; a study in subjects
with either normal renal function or mild, moderate or severe renal impairment (WP15648)
and two studies in healthy subjects receiving a range of single (WP15517) or multiple doses
of oseltamivir (WP15525). Simulations were performed and suitable regimens using
available capsule formulations were selected on the basis to provide oseltamivir carboxylate
exposures considered safe and efficacious in clinical trials.

Refer to section 4.2 Dose and method of administration for recommended dosing for patients
with severe, moderate and mild renal impairment.

Two clinical studies were performed to evaluate the pharmacokinetic, safety and tolerability
of oseltamivir and oseltamivir carboxylate in end stage renal disease patients undergoing
haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In study
PP15974 patients undergoing either CAPD or HD received a single 75 mg capsule of
oseltamivir, whereas in study NP16472 patients received 30 mg oseltamivir oral suspension
for 6.5 weeks, with CAPD patients receiving a single dose per week and HD patients a dose
after alternate dialysis sessions. In order to assist in determining appropriate dosing
recommendations in HD, a population pharmacokinetic model for HD was constructed and
qualified for simulation. Suitable regimens using available capsule formulations were
selected on their basis to achieve oseltamivir carboxylate plasma trough levels in subjects

Tamiflu 190502 20
with normal renal function dosed at 75 mg twice daily for treatment, or 75 mg oseltamivir
given orally once daily for prophylaxis.

Refer to section 4.2 Dose and method of administration for recommended dosing for patients
with end stage renal disease undergoing haemodialysis and continuous ambulatory peritoneal
dialysis.
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 significantly decreased in patients with
hepatic impairment (see section 4.2 Dose and method of administration).
Elderly
Exposure to the active metabolite at steady state was 25 to 35% higher in elderly (age range
65 to 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 exposure
and tolerability, dosage adjustments are not required for elderly patients for either the
treatment or prophylaxis of influenza (see section 4.2 Dose and method of administration).
Pregnant Women
A pooled population pharmacokinetic analysis indicates that the Tamiflu dosage regimen
described in Dosage and Administration results in lower exposure (30% on average across all
trimesters) to the active metabolite in pregnant women compared to non-pregnant women.
The lower predicted exposure however, remains above inhibitory concentrations (IC95
values) and at a therapeutic level for a range of influenza virus strains. In addition, there is
evidence from observational studies showing benefit of the current dosing regimen in this
patient population. Therefore, dose adjustments are not recommended for pregnant women in
the treatment or prophylaxis of influenza (see sections 4.4 Special warnings and precautions
for use and 4.6 Fertility, pregnancy and lactation).

Immunocompromised Patients
Population pharmacokinetic analysis indicates that treatment of adult immunocompromised
patients with oseltamivir (as described in Section 2.2. Dosage and Administration) results in
an increased exposure (of up to 50%) to the active metabolite when compared to adult non-
immunocompromised patients. However, due to the wide safety margin of the active
metabolite, no dose adjustments are required in adult immunocompromised patients.
Infants and Children ≥ 1 year of age
The pharmacokinetics of Tamiflu have been evaluated in a single dose pharmacokinetic
studies in children aged 1 to 16 years. Multiple dose pharmacokinetics were studied in a
small number of children aged 3 to 12 enrolled in a clinical trial. The rate of clearance of the
active metabolite, corrected for bodyweight, was faster in younger children, than in adults,
resulting in lower exposure in these children for a given mg/kg dose. Doses of 2 mg/kg and
unit doses of 30 and 45 mg, administered to children in the appropriate categories according
to the recommendation in section 4.2 yield oseltamivir carboxylate exposures comparable to
those achieved in adults receiving a single 75 mg capsule dose (approximately 1 mg/kg). The
pharmacokinetics of oseltamivir in children over 12 years of age are similar to those in adults.

Infants 2 weeks to less than 1 year of age

The pharmacokinetics, pharmacodynamics and safety of Tamiflu have been evaluated in two
open-label studies including influenza infected infants 2 weeks to less than 1 year of age

Tamiflu 190502 21
(n=124). The rate of clearance of the active metabolite, corrected for body weight, decreases
with ages below one year. Metabolite exposures are also more variable in the youngest
infants. The available data indicates that the exposure following a 3 mg/kg dose in infants 2
weeks to less than 1 year of age provided pro-drug and metabolite exposures anticipates to be
efficacious with a safety profile comparable to that seen in older children and adults using the
approved dose. The reported adverse events were consistent with the established safety
profile in older children.

5.3 PRECLINICAL SAFETY DATA

Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity and genotoxicity.

Carcinogenicity
Three studies for carcinogenic potential (2-year rat and mouse studies with oseltamivir, and a
6 month transgenic Tg:AC mouse assay performed with the active metabolite) were negative.

Teratology studies have been conducted in rats and rabbits at doses up to 1500 mg/kg/day
and 500 mg/kg/day, respectively. No effects on embryo-foetal development were observed.

Genotoxicity
Oseltamivir and the active metabolite were negative in the standard battery of genotoxicity
assays

Impairment of Fertility
A rat fertility study up to a dose of 1500 mg/kg/day demonstrated no adverse effects on either
sex.

Reproductive Toxicity
In pre-/post-natal rat studies, prolonged parturition was noted at 1500 mg/kg/day: the safety
margin between human exposure and the highest no effect dose (500 mg/kg/day) in rats is
480-fold for oseltamivir and 44-fold for the active metabolite, respectively. Foetal exposure
in the rats and rabbits was approximately 15 to 20% of that of the mother.

Other
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Limited data
indicate that oseltamivir and the active metabolite are excreted in human milk. Extrapolation
of the animal data provides estimates of 0.01 mg/day and 0.3 mg/day for the respective
compounds.

A potential for skin sensitisation to oseltamivir was observed in a “maximisation” test in

guinea pigs. Approximately 50% of the animals treated with the unformulated active
ingredient showed erythema after challenging the induced animals. Reversible irritancy of the
rabbits’ eyes was detected.

Very high oral single doses of oseltamivir phosphate had no effect in adult rats, however,
such doses resulted in toxicity in juvenile seven-day-old rat pups, including death. These
effects were seen at doses of 657 mg/kg/day and higher. No adverse effects were seen
following a single dose of 500 mg/kg, nor with chronic dosing of 500 mg/kg/day from day 7
to day 21 post-partum.

Tamiflu 190502 22
6. PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Tamiflu 30 mg hard capsules
Capsule core
Starch
Purified talc
Povidone
Croscarmellose sodium
Sodium stearyl fumarate
Capsule shell
Gelatin (animal origin)
Yellow iron oxide
Red iron oxide
Titanium dioxide
Printing ink
Opacode blue S-1-4118
Tamiflu 45 mg hard capsules
Capsule core
Starch
Purified talc
Povidone
Croscarmellose sodium
Sodium stearyl fumarate
Capsule shell
Gelatin
Black iron oxide
Titanium dioxide
Printing ink
Opacode S-1-4118
Tamiflu 75 mg hard capsules
Capsule core
Starch
Purified talc
Povidone
Croscarmellose sodium
Sodium stearyl fumarate
Capsule shell
Gelatin
Yellow iron oxide
Red iron oxide
Titanium dioxide
Printing ink
Opacode S-1-4118

Tamiflu 190502 23
Tamiflu 6mg/mL powder for oral suspension
Sorbitol
Monosodium citrate
Xanthan gum
Sodium benzoate
Saccharin sodium
Titanium dioxide

Tutti frutti flavour (including maltodextrins [maize], propylene glycol, arabic gum and
natural identical flavouring substances [mainly consisting of banana, pineapple and peach
flavour]).

6.2 INCOMPATIBILITIES
Not applicable.

6.3 SHELF LIFE

Tamiflu 30mg, 45mg and 75 mg capsules
10 years
Tamiflu 6mg/mL powder for oral suspension
4 years
Reconstituted solution
Not refrigerated - 10 days stored at or below 25°C.
Refrigerated - 17 days stored at 2° to 8°C (Refrigerate, do not freeze).

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Tamiflu 30mg, 45mg and 75 mg capsules
Store at or below 25°C
Tamiflu 6mg/mL powder for oral suspension
Store at or below 25°C
For storage conditions after reconstitution of the medicine, see section 6.3 Shelf life.
6.5 NATURE AND CONTENTS OF CONTAINER >
Tamiflu 30mg*, 45mg* and 75 mg capsules
Available in blister packages of 10 capsules.

*Tamiflu 30 mg and 45 mg capsules are currently not available.

Tamiflu 6mg/mL powder for oral suspension
Available in 100 mL bottle pack with 13 g of white to yellow white powder, a bottle adaptor,
a plastic oral dispenser and a measuring plastic cup. After reconstitution with 55 mL of water,
the usable volume of oral suspension allows the retrieval of 10 doses of 30 mg oseltamivir.
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING
Disposal
The release of medicines into the environment should be minimised. Medicines should not
be disposed of via wastewater and disposal through household waste should be avoided.
Unused or expired medicine should be returned to a pharmacy for disposal.

Tamiflu 190502 24
Handling
Preparation of Tamiflu 6 mg/mL powder for oral suspension
It is recommended that Tamiflu powder for oral suspension be constituted by the pharmacist
prior to dispensing to the patient (see section 4.2 Dose and method of administration):

1. Tap the closed bottle several times to loosen the powder.

2. Measure 55 mL of water. Use the measuring cup (where provided) and fill it to the indicated
level.
3. Add all 55 mL of water for constitution to the bottle and shake the closed bottle well for 15
seconds. The final constituted volume is 65 mL
4. Remove the child-resistant cap and push bottle adapter into neck of bottle.
5. 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.

7. MEDICINE SCHEDULE
Tamiflu 30mg and 45mg capsules; and Tamiflu 6mg/mL powder for oral suspension:
Prescription Only Medicine.

Tamiflu 75mg capsules: Pharmacist Only Medicine for the treatment or prophylaxis of
influenza in adults and children aged 13 years and older who have been exposed to the
influenza virus.

For children 12 years of age and under, Tamiflu 75mg capsules is a Prescription Only
Medicine for the treatment or prevention of influenza.

8. SPONSOR
Roche Products (New Zealand) Limited
PO Box 109113 Newmarket
Auckland 1149
NEW ZEALAND

Medical enquiries: 0800 276 243

9. DATE OF FIRST APPROVAL

Tamiflu 30 mg capsules – 26 November 2009
Tamiflu 45mg capsules – 26 November 2009
Tamiflu 75 mg capsules 21 January 2000
Tamiflu 6mg/mL powder for oral solution – 1 November 2012

10. DATE OF REVISION OF THE TEXT

30 May 2019

Summary of Changes Table

Section Changed Summary of new information

4.2 Addition of “Treatment of influenza” and “Prophylaxis of influenza”.
Update to table titled “Volume of pharmacy compounded suspension (6
mg/mL) required for a 5 day course based on the patient’s weight.

Tamiflu 190502 25
 4.8 Update to “Treatment and Prophylaxis of Influenza in
Immunocompromised Patients”.

5.1 Addition of “Treatment of influenza in immunocompromised adults”.

5.2 Addition of “Immunocompromised Patients”.

Tamiflu 190502 26