- Community outbreak: 75 mg once daily for up to 6

TAMIFLU® ‫ﮢﯿﻤﯿﻔﻠﻮ‬ weeks (2.3)

• Pediatric patients 1 to 12 years of age: Based on
(oseltamivir) weight once daily for 10 days (2.3)
- Community outbreak: Based on weight once daily
for up to 6 weeks (2.3)
HIGHLIGHTS OF PRESCRIBING
INFORMATION • Renally impaired adult patients (creatinine clearance
Only TAMIFLU 75mg capsule is registered in >30-60 mL/min): Reduce to 30 mg once daily (2.4)
Pakistan. • Renally impaired adult patients (creatinine clearance
These highlights do not include all the information >10-30 mL/min): Reduce to 30 mg once every other
needed to use TAMIFLU safely and effectively. See day (2.4)
full prescribing information for TAMIFLU. • ESRD patients on hemodialysis: Reduce to 30 mg
immediately and then 30 mg after alternate
TAMIFLU® (oseltamivir phosphate) capsules, for hemodialysis cycles for the recommended duration of
oral use prophylaxis (2.4)
• ESRD patients on CAPD: Reduce to 30 mg
-------------- INDICATIONS AND USAGE -------------- immediately and then 30 mg once weekly for the
TAMIFLU is an influenza neuraminidase inhibitor recommended duration of prophylaxis (2.4)
(NAI) indicated for:
• Treatment of acute, uncomplicated influenza A and B --------DOSAGE FORMS AND STRENGTHS --------
in patients 2 weeks of age and older who have been • Capsules: 75 mg
symptomatic for no more than 48 hours. (1.1)
• Prophylaxis of influenza A and B in patients 1 year ---------------- CONTRAINDICATIONS ----------------
and older. (1.2) Patients with known serious hypersensitivity to
Limitations of Use: oseltamivir or any of the components of TAMIFLU (4)
• Not a substitute for annual influenza vaccination. (1.3)
• Consider available information on influenza drug --------- WARNINGS AND PRECAUTIONS----------
susceptibility patterns and treatment effects when • Serious skin/hypersensitivity reactions such as
deciding whether to use. (1.3) Stevens-Johnson Syndrome, toxic epidermal
• Not recommended for patients with end-stage renal necrolysis and erythema multiforme: Discontinue
disease not undergoing dialysis. (1.3) TAMIFLU and initiate appropriate treatment if
allergic-like reactions occur or are suspected. (5.1)
--------- DOSAGE AND ADMINISTRATION --------- • Neuropsychiatric events: Patients with influenza,
Treatment of influenza including those receiving TAMIFLU, particularly
• Adults and adolescents (13 years and older): 75 mg pediatric patients, may be at an increased risk of
twice daily for 5 days (2.2) confusion or abnormal behavior early in their illness.
• Pediatric patients 1 to 12 years of age: Based on Monitor for signs of abnormal behavior. (5.2)
weight twice daily for 5 days (2.2)
• Pediatric patients 2 weeks to less than 1 year of age: ---------------- ADVERSE REACTIONS ----------------
3mg/kg twice daily for 5 days (2.2) Most common adverse reactions (>1% and more
• Renally impaired adult patients (creatinine clearance common than with placebo):
>30-60 mL/min): Reduce to 30 mg twice daily for • Treatment studies – Nausea, vomiting, headache. (6.1)
5 days (2.4) • Prophylaxis studies – Nausea, vomiting, headache,
• Renally impaired adult patients (creatinine clearance pain. (6.1)
>10-30 mL/min): Reduce to 30 mg once daily for ---------------- DRUG INTERACTIONS ----------------
5 days (2.4) Live attenuated influenza vaccine (LAIV), intranasal:
• ESRD patients on hemodialysis: Reduce to 30 mg Avoid administration of LAIV within 2 weeks before or
immediately and then 30 mg after every hemodialysis 48 hours after TAMIFLU use, unless medically
cycle. Treatment duration not to exceed 5 days (2.4) indicated. (7)
• ESRD patients on CAPD: Reduce to a single 30 mg
dose immediately (2.4)
Prophylaxis of influenza Revised: 08/2019
• Adults and adolescents (13 years and older): 75 mg
once daily for at least 10 days (2.3)

Page - 1 - of 23
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Treatment of Influenza
TAMIFLU is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients
2 weeks of age and older who have been symptomatic for no more than 48 hours.
1.2 Prophylaxis of Influenza
TAMIFLU is indicated for the prophylaxis of influenza A and B in patients 1 year and older.
1.3 Limitations of Use
• TAMIFLU is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for
Disease Control and Prevention Advisory Committee on Immunization Practices.

• Influenza viruses change over time. Emergence of resistance substitutions could decrease drug effectiveness. Other
factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers
should consider available information on influenza drug susceptibility patterns and treatment effects when deciding
whether to use TAMIFLU [see Microbiology (12.4)].
• TAMIFLU is not recommended for patients with end-stage renal disease not undergoing dialysis [see Dosage and
Administration (2.4) and Use in Specific Populations (8.6)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosage and Administration Overview
Administer TAMIFLU for the treatment of influenza in patients 2 weeks of age or older [see Dosage and Administration
(2.2)] or for prophylaxis of influenza in patients 1 year and older [see Dosage and Administration (2.3)] using:

• TAMIFLU capsules
The capsules may be taken with or without food; however, tolerability may be enhanced if TAMIFLU is taken with food.
Adjust the TAMIFLU dosage in patients with moderate or severe renal impairment [see Dosage and Administration
(2.4)].
TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup,
corn syrup, caramel topping, or light brown sugar (dissolved in water). During emergency situations and when neither
the age-appropriate strengths of TAMIFLU capsules to mix with sweetened liquids are available, then a pharmacist may
prepare an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.6)].
2.2 Recommended Dosage for Treatment of Influenza
Initiate treatment with TAMIFLU within 48 hours of influenza symptom onset.
Adults and Adolescents (13 years of age and older)
The recommended oral dosage of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is
75 mg twice daily (one 75 mg capsule) for 5 days.

Pediatric Patients (2 weeks of age through 12 years of age)

Table 1 displays the recommended oral dosage of TAMIFLU for treatment of influenza in pediatric patients 2 weeks of
age through 12 years of age and provides information about prescribing the capsule or the formulation for oral
suspension.
2.3 Recommended Dosage for Prophylaxis of Influenza
Initiate post-exposure prophylaxis with TAMIFLU within 48 hours following close contact with an infected individual.
Initiate seasonal prophylaxis with TAMIFLU during a community outbreak.
Adults and Adolescents (13 years of age and older)
The recommended dosage of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and older is
75 mg orally once daily (one 75 mg capsule once daily) for at least 10 days following close contact with an infected
individual and up to 6 weeks during a community outbreak. In immunocompromised patients, TAMIFLU may be
continued for up to 12 weeks [see Use in Specific Populations (8.9)]. The duration of protection lasts for as long as
TAMIFLU dosing is continued.

Pediatric Patients (1 year to 12 years of age)

Table 1 displays the recommended oral dosage of TAMIFLU for prophylaxis of influenza in pediatric patients 1 year to
12 years of age based on body weight and provides information about prescribing the capsule or the formulation for oral
suspension. Prophylaxis in pediatric patients is recommended for 10 days following close contact with an infected
individual and up to 6 weeks during a community outbreak [see Use in Specific Populations (8.4) and Clinical Studies
(14.2)].
Table 1 TAMIFLU Dosage Recommendations in Pediatric Patients for Treatment and Prophylaxis of
Influenza

Volume of
Number of
Oral Number of
Bottles of
Treatment Dosage Prophylaxis Dosage Suspension Capsules to
Weight Oral
for 5 days for 10 days* (6 mg/mL) Dispense
Suspension to
for each (Strength)‡
Dispense
Dose†
Patients from 2 Weeks to less than 1 Year of Age

Any weight 3 mg/kg twice daily Not applicable 0.5 mL/kg§ 1 bottle Not applicable

Patients 1 to 12 Years of Age Based on Body Weight

10 capsules
15 kg or less 30 mg twice daily 30 mg once daily 5 mL 1 bottle
(30 mg)
10 capsules
15.1 kg to 23 kg 45 mg twice daily 45 mg once daily 7.5 mL 2 bottles
(45 mg)
20 capsules
23.1 kg to 40 kg 60 mg twice daily 60 mg once daily 10 mL 2 bottles
(30 mg)
10 capsules
40.1 kg or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles
(75 mg)
* The recommended duration for post-exposure prophylaxis is 10 days and the recommended duration for community
outbreak (seasonal/pre-exposure) prophylaxis is up to 6 weeks (or up to 12 weeks in immunocompromised patients). The
amount supplied (e.g., number of bottles or capsules) for seasonal prophylaxis may be greater than for post-exposure
prophylaxis.
† Use an oral dosing dispensing device that measures the appropriate volume in mL with the oral suspension.
‡ TAMIFLU for oral suspension is the preferred formulation for patients who cannot swallow capsules.
§ For patients less than 1 year of age, provide an appropriate dosing device that can accurately measure and administer
small volumes.
2.4 Dosage in Patients with Renal Impairment
Table 2 displays the dosage recommendations for the treatment and prophylaxis of influenza in adults with various stages
of renal impairment (estimated creatinine clearance of less than or equal to 90 mL per minute). Dosage modifications are
recommended in adults with an estimated creatinine clearance less than or equal to 60 mL per minute [see Use in
Specific Population (8.6) and Clinical Pharmacology (12.3)].
Table 2 Recommended Dosage Modifications for Treatment and Prophylaxis of Influenza in Adults with Renal
Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment Recommended Treatment Recommended Prophylaxis

(Creatinine Clearance) Regimen* Regimen*†
Mild
75 mg twice daily for 5 days 75 mg once daily
(>60-90 mL/minute)
Moderate
30 mg twice daily for 5 days 30 mg once daily
(>30-60 mL/minute)
Severe
30 mg once daily for 5 days 30 mg every other day
(>10-30 mL/minute)
30 mg immediately and then 30 mg
after every hemodialysis cycle 30 mg immediately and then 30 mg
ESRD Patients on Hemodialysis
(≤ 10 mL/minute) (treatment duration not to exceed 5 after alternate hemodialysis cycles
days)
ESRD Patients on Continuous
A single 30 mg dose administered 30 mg immediately and then 30 mg
Ambulatory Peritoneal Dialysis‡
immediately once weekly
(≤10 mL/minute)
ESRD Patients not on Dialysis TAMIFLU is not recommended TAMIFLU is not recommended
* Capsules or oral suspension can be used for 30 mg dosing.
† The recommended duration for post-exposure prophylaxis is at least 10 days and the recommended duration for
community outbreak (seasonal/pre-exposure) prophylaxis is up to 6 weeks (or up to 12 weeks in immunocompromised
patients).
‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

2.5 Emergency Preparation of Oral Suspension from 75 mg TAMIFLU Capsules

The following directions are provided for use only during emergency situations and when FDA-approved, commercially
manufactured TAMIFLU for oral suspension is not available from wholesalers or the manufacturer.
The following emergency preparation instructions will provide one patient with enough TAMIFLU for a 5-day course of
treatment of influenza or a 10-day course of prophylaxis of influenza:

Step #1: Determine the dosage of TAMIFLU for the patient [see Dosage and Administration (2.2, 2.3, and 2.4)] then
determine the total volume of oral suspension needed to be prepared (see Table 3).

Table 3 Emergency Preparation: Volume of Prepared Oral Suspension (6 mg per mL) Based Upon TAMIFLU
Dose

Total Volume to Prepare per

TAMIFLU Dose*
Patient
15 mg or less 37.5 mL
30 mg 75 mL
45 mg 100 mL
 60 mg 125 mL
75 mg 150 mL
* If the TAMIFLU dose is between the doses listed, use the
greater listed dose to determine the total volume of prepared
oral suspension.

Step #2: Preparation must be performed with only one of the following vehicles (other vehicles have not been studied):
Cherry Syrup (Humco), Ora-Sweet SF (sugar-free) (Paddock Laboratories), or simple syrup. Determine the number of
capsules and the amount of water and vehicle needed to prepare the total volume (see Table 3) of prepared oral
suspension (6 mg per mL) for a complete treatment or prophylaxis course (see Table 4).

Table 4 Emergency Preparation: Number of TAMIFLU 75 mg Capsules and Amount of Water and Vehicle
Needed to Prepare the Total Volume of a Prepared Oral Suspension (6 mg per mL)

Total Volume of Prepared Oral

37.5 mL 75 mL 100 mL 125 mL 150 mL
Suspension
Number of TAMIFLU 75 mg
3 (225 mg) 6 (450 mg) 8 (600 mg) 10 (750 mg) 12 (900 mg)
Capsules (Total Strength)*
Amount of Water 2.5 mL 5 mL 7 mL 8 mL 10 mL
Volume of Vehicle
Cherry Syrup (Humco) OR
34.5 mL 69 mL 91 mL 115 mL 137 mL
Ora-Sweet SF (Paddock
Laboratories) OR simple syrup
*Includes overage to ensure all doses can be delivered

Step #3: Follow the instructions below for preparing the 75 mg TAMIFLU capsules to produce the oral suspension
(6 mg per mL):

a. Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 4).
Constitution in other bottle types is not recommended because there is no stability data with other bottle types.
b. Carefully separate the capsule body and cap and pour the contents of the required number of TAMIFLU 75 mg
capsules into the PET or glass bottle.
c. Gently swirl the suspension to ensure adequate wetting of the TAMIFLU powder for at least 2 minutes.
d. Slowly add the specified amount of vehicle to the bottle.
e. Close the bottle using a child-resistant cap and shake well for 30 seconds to completely dissolve the active drug
and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. The active drug,
oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by inert ingredients
of TAMIFLU capsules which are insoluble in these vehicles.
f. Put an ancillary label on the bottle indicating “Shake Well Before Use.”
g. Instruct the parent or caregiver that any unused suspension remaining in the bottle 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.
 h. Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, drug name and any
other required information to be in compliance with all State and Federal Pharmacy Regulations. Place an
appropriate expiration date on the label according to storage conditions below.
i. Include the recommended dosage on the pharmacy label as per Tables 1 and 2 [see Dosage and Administration
(2.2, 2.3, and 2.4)].
j. Store the prepared oral suspension in glass or PET bottles either:
• In a refrigerator [2° to 8°C (36° to 46°F)]: Stable for 5 weeks when stored in a refrigerator.
• At room temperature [25°C (77°F)]: Stable for 5 days when stored at room temperature.

3 DOSAGE FORMS AND STRENGTHS

TAMIFLU Capsules:
• 75-mg (75 mg free base equivalent of the phosphate salt): grey/light yellow, hard gelatin, with “ROCHE” is printed
in blue ink on the grey body and “75 mg” printed in blue ink on the light yellow cap.

4 CONTRAINDICATIONS
TAMIFLU is contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the
product. Severe allergic reactions have included anaphylaxis and serious skin reactions including toxic epidermal
necrolysis, Stevens-Johnson Syndrome, and erythema multiforme [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Serious Skin/Hypersensitivity Reactions
Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and
erythema multiforme have been reported in postmarketing experience with TAMIFLU. Stop TAMIFLU and institute
appropriate treatment if an allergic-like reaction occurs or is suspected. The use of TAMIFLU is contraindicated in
patients with known serious hypersensitivity to TAMIFLU [see Contraindications (4) and Adverse Reactions (6.2)].
5.2 Neuropsychiatric Events
There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting
in fatal outcomes, in patients with influenza who were receiving TAMIFLU [see Adverse Reactions (6.2)]. Because these
events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be
uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients and often had
an abrupt onset and rapid resolution. The contribution of TAMIFLU to these events has not been established. Influenza
can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations,
delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of
encephalitis or encephalopathy but can occur without obvious severe disease. Closely monitor TAMIFLU-treated
patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and
benefits of continuing TAMIFLU for each patient.
5.3 Risk of Bacterial Infections
There is no evidence for efficacy of TAMIFLU in any illness caused by pathogens other than influenza viruses. 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.
Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.
5.4 Fructose Intolerance in Patients with Hereditary Fructose Intolerance
Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg TAMIFLU for oral
suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary
fructose intolerance and may cause dyspepsia and diarrhea.
5.4 Effects on ability to drive and use machines
Tamiflu has no effect on your ability to drive or use machines
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed below and elsewhere in the labeling:
• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Neuropsychiatric events [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Adverse Reactions from Treatment and Prophylaxis Trials in Adult and Adolescent Subjects (13 years of age and older)
The overall safety profile of TAMIFLU is based on data from 2,646 adult and adolescent subjects that received the
recommended dosage of 75 mg orally twice daily for 5 days for treatment of influenza and 1,943 adult and adolescent
subjects that received the recommended dosage of 75 mg orally once daily for up to 6 weeks for prophylaxis of influenza
in clinical trials.
The most common adverse reactions in the pooled treatment and pooled prophylaxis trials in adults and adolescents are
displayed in Table 5. The majority of these adverse reactions were reported on a single occasion, occurred on either the
first or second treatment day and resolved spontaneously within 1-2 days. This summary includes otherwise healthy
adults/adolescents and subjects “at risk” (subjects 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 subjects
“at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.

Table 5 Adverse Reactions Occurring in ≥1% of Adults and Adolescents (13 years of age and older) in
Treatment and Prophylaxis Trials*

System Organ Class Treatment Trials Prophylaxis Trials

Adverse Reaction TAMIFLU TAMIFLU
Placebo Placebo
75 mg twice daily 75 mg once daily
(n = 1977) (n = 1586)
(n = 2646) (n = 1943)
Gastrointestinal Disorders
Nausea 10% 6% 8% 4%
Vomiting 8% 3% 2% 1%
Nervous System Disorders
Headache 2% 1% 17% 16%
General Disorders
Pain <1% <1% 4% 3%
* Adverse reactions that occurred in ≥1% of TAMIFLU-treated adults and adolescents and ≥1% greater in TAMIFLU-
treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials.
Adverse Reactions from Treatment and Prophylaxis Trials in Pediatric Subjects (1 year to 12 years of age)
A total of 1,481 pediatric subjects (including otherwise healthy pediatric subjects aged 1 year to 12 years and asthmatic
pediatric subjects aged 6 to 12 years) participated in clinical trials of TAMIFLU for the treatment of influenza. A total of
859 pediatric subjects received treatment with TAMIFLU for oral suspension either at a 2 mg per kg twice daily for 5
days or weight-band dosing. Vomiting was the only adverse reaction reported at a frequency of >1% in subjects receiving
TAMIFLU (16%) compared to placebo (8%).
Amongst the 148 pediatric subjects aged 1 year to 12 years who received TAMIFLU at doses of 30 to 60 mg once daily
for 10 days in a post-exposure prophylaxis study in household contacts (n = 99), and in a separate 6–week seasonal
influenza prophylaxis safety study (n = 49), vomiting was the most frequent adverse reaction (8% on TAMIFLU versus
2% in the no prophylaxis group).
Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age)
Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open-label
studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including
premature infants at least 36 weeks post conceptional age) exposed to TAMIFLU at doses ranging from 2 to 3.5 mg per
kg of the formulation for oral suspension twice daily orally for 5 days. The safety profile of TAMIFLU was similar
across the age range studied, with vomiting (9%), diarrhea (7%) and diaper rash (7%) being the most frequently reported
adverse reactions, and was generally comparable to that observed in older pediatric and adult subjects.
Adverse Reactions from the Prophylaxis Trial in Immunocompromised Subjects
In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 year to
12 years of age, the safety profile in the 238 subjects receiving TAMIFLU 75 mg once daily was consistent with that
previously observed in other TAMIFLU prophylaxis clinical trials [see Clinical Studies (14.2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

General disorders and administration site conditions: Swelling of the face or tongue, allergy,
anaphylactic/anaphylactoid reactions, hypothermia
Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-
Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)]
Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis
Cardiac Disorders: Arrhythmia
Hepatobiliary Disorders: Hepatitis, abnormal liver function tests
Nervous System Disorders: Seizure
Metabolism and Nutrition Disorders: Aggravation of diabetes
Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety,
altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

7 DRUG INTERACTIONS
7.1 Influenza Vaccines
Live Attenuated Influenza Vaccine
The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated.
However, because of the potential for TAMIFLU to inhibit replication of live vaccine virus and possibly reduce the
efficacy of LAIV, avoid administration of LAIV within 2 weeks before or 48 hours after TAMIFLU administration,
unless medically indicated.
Inactivated Influenza Vaccine
Inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.
7.2 Drugs Without Clinically Significant Drug Interaction with TAMIFLU
No dose adjustments are needed for either oseltamivir or the concomitant drug when coadministering oseltamivir with
amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium
carbonates), rimantadine, amantadine, or warfarin [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
There are no adequate and well-controlled studies with TAMIFLU in pregnant women to inform a drug-associated risk of
adverse developmental outcomes. Available published epidemiological data suggest that TAMIFLU, taken in any
trimester, is not associated with an increased risk of birth defects. However, these studies individually are limited by
small sample sizes, use of different comparison groups, and some lacked information on dose, which preclude a
definitive assessment of the risk [see Data and Clinical Pharmacology (12.3)]. In animal reproduction studies with
oseltamivir, no adverse developmental effects were observed at clinically relevant exposures (see Data).

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or
fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birth weight and small for
gestational age.
Data
Human Data
Published prospective and retrospective observational studies of more than 5,000 women exposed to TAMIFLU during
pregnancy, including more than 1,000 women exposed in the first trimester, suggest that the observed rate of congenital
malformations was not increased above the rate in the general comparison population, regardless of when therapy was
administered during the gestational period. However, individually, none of these studies had adequate sample sizes and
some lacked information on dose, which preclude a definitive assessment of the risk.
Animal Data
Oseltamivir was administered orally during organogenesis to pregnant rats (at 50, 250, or 1500 mg/kg/day on gestation
days 6 to 17) and rabbits (at 50, 150, or 500 mg/kg/day on gestation days 6 to 18). In rats, embryo-fetal effects consisting
of an increased incidence of minor skeletal malformations were observed at a maternally toxic dose (1500 mg/kg/day),
resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 190 times human exposures at the
maximum recommended human dose (MRHD) of TAMIFLU (75 mg twice a day). In the rabbit study, embryo-fetal
effects consisting of an increased incidence of minor skeletal abnormalities and variants were observed at maternally
toxic doses (≥150 mg/kg/day) resulting in systemic exposures (based on AUC for oseltamivir carboxylate) ≥8 times
human exposures at the MRHD of TAMIFLU.

In prenatal and postnatal development studies in rats, oseltamivir was administered orally (at 50, 250, 500, or 1500
mg/kg/day) from organogenesis through late gestation, delivery, and lactation (gestation day 6 to postpartum/lactation
day 20). Prolonged parturition duration and reduced offspring viability were observed at a maternally toxic dose (1500
mg/kg/day). No adverse maternal or offspring effects were observed at doses ≤500 mg/kg/day, resulting in systemic drug
exposures (based on AUC for oseltamivir carboxylate) 44 times human exposures at the MRHD of TAMIFLU.
8.2 Lactation
Risk Summary
Based on limited published data, oseltamivir and oseltamivir carboxylate have been shown to be present in human milk
at low levels considered unlikely to lead to toxicity in the breastfed infant. Postmarketing experience has not reported any
information to suggest serious adverse effects of oseltamivir exposure via breast milk in infants. It is not known if
oseltamivir affects human milk production. The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for TAMIFLU and any potential adverse effects on the breastfed child from the
drug or from the underlying maternal condition.
8.4 Pediatric Use
Treatment of Influenza
The safety and efficacy of TAMIFLU for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age
has been established [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]
and is based on:

• 13 to 17 years of age: Safety and efficacy in adolescent patients 13 to 17 years of age was supported by adequate
and well-controlled trials in adults and adolescents and younger pediatric patients and safety data in adolescents
treated with TAMIFLU in a study of treatment and prophylaxis.
• 1 year to 12 years of age: Safety and efficacy in pediatric patients 1 year to 12 years of age was supported by
results of one double-blind, placebo-controlled trial in 452 pediatric patients with influenza in whom TAMIFLU
2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset [see Clinical Studies
(14.1)]. Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric
patients 6 to 12 years of age with known asthma. Efficacy could not be established in pediatric patients with
asthma.
• 2 weeks to less than 1 year of age: Safety and efficacy in pediatric patients 2 weeks to less than 1 year of age is
supported by adequate and well-controlled trials in adults and older pediatric patients and two open-label trials of
TAMIFLU (2 to 3.5 mg per kg twice daily for 5 days) in 136 pediatric subjects 2 weeks to less than 1 year of
age. In these two trials, the oseltamivir plasma concentrations in these subjects were similar to or higher than the
oseltamivir plasma concentrations observed in older pediatric subjects and adults [see Clinical Pharmacology
(12.3) and Clinical Studies (14.1)].

The safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not
been established.

Prophylaxis of Influenza
The safety and efficacy of TAMIFLU for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has
been established [see Dosage and Administration (2.3), Clinical Pharmacology (12.3), and Clinical Studies (14.2)] and
is based on:
• 13 to 17 years of age: Prophylaxis in adolescent patients 13 to 17 years of age is supported by one randomized,
placebo-controlled post-exposure household prophylaxis trial of TAMIFLU 75 mg taken orally once daily for 7
days in household contacts including 207 adolescents [see Clinical Studies (14.2)].
• 1 year to 12 years of age: TAMIFLU for prophylaxis in pediatric patients 1 year to 12 years of age is supported
by one randomized, open-label, post-exposure household prophylaxis trial including pediatric subjects 1 year to
12 years of age who received 30 to 60 mg of TAMIFLU for oral suspension (supplied as powder) taken orally
 once daily for 10 days [see Clinical Studies (14.2)]. Additional safety information was provided in a 6-week
seasonal prophylaxis (community outbreak) safety study in 49 patients 1 year to 12 years of age.

The safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established for pediatric patients less
than 1 year of age.
8.5 Geriatric Use
Treatment of Influenza
Of the 4,765 adults in clinical trials of TAMIFLU for the treatment of influenza, 948 (20%) were 65 years and older,
while 329 (7%) were 75 years and older. In three double-blind, placebo-controlled trials in the treatment of influenza in
patients at least 65 years old, that enrolled 741 subjects (374 received placebo and 362 received TAMIFLU), no overall
differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and younger subjects [see Clinical
Studies (14.1)].
Prophylaxis of Influenza
Of the 4,603 adults in clinical trials of TAMIFLU for the prophylaxis of influenza, 1,046 (23%) were 65 years and older,
while 719 (16%) were 75 years and older. In a randomized, placebo-controlled trial in elderly residents of nursing homes
who took TAMIFLU for up to 42 days for the prophylaxis of influenza (TAMIFLU n=276, placebo n=272), no overall
differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and younger subjects [see Clinical
Studies (14.2)].
8.6 Renal Impairment
Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal
function which may increase the risk of TAMIFLU-associated adverse reactions. Therefore, dosage adjustment is
recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-
stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment [see Dosage and
Administration (2.4)]. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis [see Indications
and Usage (1.3) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics
in patients with severe hepatic impairment have not been evaluated [see Clinical Pharmacology (12.3)].
8.8 Use in Patients with Chronic Conditions
Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease
was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to
alleviation of all symptoms, was not established, but no new safety signals were identified [see Clinical Studies (14.1)].

No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently
severe or unstable to be considered at imminent risk of requiring hospitalization.

8.9 Immunocompromised Patients

Efficacy of TAMIFLU for the treatment or prophylaxis of influenza has not been established in immunocompromised
patients [see Clinical Studies (14.2)]. Safety of TAMIFLU has been demonstrated for up to 12 weeks for prophylaxis of
influenza in immunocompromised patients [see Adverse Reactions (6.1)].
10 OVERDOSAGE
Reports of overdoses with TAMIFLU have been received from clinical trials and during postmarketing experience. In the
majority of cases reporting overdose, no adverse reactions were reported. Adverse reactions reported following overdose
were similar in nature to those observed with therapeutic doses of TAMIFLU [see Adverse Reactions (6)].
11 DESCRIPTION
TAMIFLU (oseltamivir phosphate), an influenza neuraminidase inhibitor (NAI), is available as:
• Capsules containing 75 mg of oseltamivir for oral use, in the form of oseltamivir phosphate, and
In addition to the active ingredient, each capsule contains croscarmellose sodium, povidone K30, pregelatinized starch,
sodium stearyl fumarate and talc. The 75 mg capsule shell contains black iron oxide, gelatin, red iron oxide, titanium
dioxide, and yellow iron oxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant.

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:

O COOC2H5
3
4
5
HN
NH2 . H3PO4
O

12 CLINICAL PHARMACOLOGY
Pharmacotherapeutic group: Antivirals for systemic use, neuraminidase inhibitors ATC code: J05AH02

12.1 Mechanism of Action

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].
12.3 Pharmacokinetics
Absorption and Bioavailability
Oseltamivir is absorbed from the gastrointestinal tract after oral administration of TAMIFLU (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 and less than 5% of the oral dose reaches the systemic
circulation as oseltamivir (see Table 6).

Table 6 Mean (% CV) Pharmacokinetic Parameters of Oseltamivir and Oseltamivir Carboxylate Following
Multiple Dosing of 75 mg Capsules Twice Daily (n=20)

Parameter Oseltamivir Oseltamivir Carboxylate

 Cmax (ng/mL) 65 (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 (about 6.7
times the maximum recommended TAMIFLU dosage) [see Dosage and Administration (2)].

Coadministration with food had 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
(TAMIFLU is not available as an IV formulation), 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.

Elimination
Absorbed oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite, 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 unchanged in urine. Plasma concentrations of
oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.
Metabolism
Oseltamivir is extensively converted to the active metabolite, oseltamivir carboxylate, by esterases located predominantly
in the liver. Oseltamivir carboxylate is not further metabolized. Neither oseltamivir nor oseltamivir carboxylate is a
substrate for, or inhibitor of, cytochrome P450 isoforms.

Excretion
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 (via organic anion transporter) occurs in addition to glomerular
filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces.

Specific Populations
Renal Impairment
Administration of 100 mg of TAMIFLU twice daily (about 1.3 times the maximum recommended dosage) for 5 days to
subjects with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely
proportional to declining renal function.

Population-derived pharmacokinetic parameters were determined for patients with varying degrees of renal function
including ESRD patients on hemodialysis. Median simulated exposures of oseltamivir carboxylate for recommended
treatment and prophylaxis regimens are provided in
Table 7. The pharmacokinetics of oseltamivir have not been studied in ESRD patients not undergoing dialysis [see
Indications and Usage (1.3), and Use in Specific Populations (8.6)].

Table 7 Simulated Median Treatment Exposure Metrics of Oseltamivir Carboxylate in Patients with Normal
Renal Function, with Renal Impairment and ESRD Patients on Hemodialysis

Renal Function/ Normal Mild Moderate Severe ESRD

Impairment Creatinine Creatinine Creatinine Creatinine Creatinine Clearance
Clearance Clearance Clearance Clearance <10 mL/min on
90- 60-90 mL/min 30-60 mL/min 10-30 mL/min Hemodialysis
140 mL/min (n=45) (n=13) (n=11) (n=24)
(n=57)
Recommended Treatment Regimens
PK exposure 75 mg twice 75 mg twice 30 mg twice 30 mg once daily 30 mg every HD cycle
parameter daily daily daily
Cmin (ng/mL) 145 253 180 219 221
Cmax (ng/mL) 298 464 306 477 1170
AUC48 (ng∙h/mL)* 11224 18476 12008 16818 23200
Recommended Prophylaxis Regimens
PK exposure 75 mg once 75 mg once 30 mg once 30 mg every 30 mg alternate HD
parameter daily daily daily other day cycle
Cmin (ng/mL) 39 62 57 70 42
Cmax (ng/mL) 213 311 209 377 903
AUC48 (ng∙hr/mL)* 5294 8336 6262 9317 11200
*AUC normalized to 48 hours.

In continuous ambulatory peritoneal dialysis (CAPD) patients, the peak concentration of oseltamivir carboxylate
following a single 30 mg dose of oseltamivir or once weekly oseltamivir was approximately 3-fold higher than in
patients with normal renal function who received 75 mg twice daily. The plasma concentration of oseltamivir carboxylate
on Day 5 (147 ng/mL) following a single 30 mg dose in CAPD patients is similar to the predicted Cmin (160 ng/mL) in
patients with normal renal function following 75 mg twice daily. Administration of 30 mg once weekly to CAPD patients
resulted in plasma concentrations of oseltamivir carboxylate at the 168-hour blood sample of 63 ng/mL, which were
comparable to the Cmin in patients with normal renal function receiving the approved regimen of 75 mg once daily (40
ng/mL).
Hepatic Impairment
In clinical studies, oseltamivir carboxylate exposure was not altered in subjects with mild or moderate hepatic
impairment [see Use in Specific Populations (8.7)].
Pregnant Women
A pooled population pharmacokinetic analysis indicates that the TAMIFLU dosage regimen resulted in lower exposure
to the active metabolite in pregnant women (n=59) compared to non-pregnant women (n=33). However, this predicted
exposure is expected to have activity against susceptible influenza virus strains and there are insufficient
pharmacokinetics and safety data to recommend a dose adjustment for pregnant women [see Use in Specific Populations
(8.1)].
Pediatric Subjects (1 year to 12 years of age)
The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single-dose pharmacokinetic
study in pediatric subjects aged 5 to 16 years (n=18) and in a small number of pediatric subjects aged 3 to 12 years (n=5)
enrolled in a clinical trial. Younger pediatric subjects cleared both the prodrug and the active metabolite faster than adult
subjects 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 subjects over
12 years of age are similar to those in adult subjects [see Use in Specific Populations (8.4)].
Pediatric Subjects (2 weeks to less than 1 year of age)
The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in two open-label studies of
pediatric subjects less than one year of age (n=122) infected with influenza. Apparent clearance of the active metabolite
decreases with decreasing age in subjects less than 1 year of age; however the oseltamivir and oseltamivir carboxylate
exposure following a 3 mg/kg dose in subjects under 1 year of age is expected to be within the observed exposures in
adults and adolescents receiving 75 mg twice daily and 150 mg twice daily [see Use in Specific Populations (8.4)].
Geriatric Patients
Exposure to oseltamivir carboxylate at steady-state was 25 to 35% higher in geriatric subjects (age range 65 to 78 years)
compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric subjects 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 Use in Specific Populations (8.5)].
Drug Interaction Studies
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.
Coadministration of probenecid results in an approximate two-fold 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.
No clinically relevant pharmacokinetic interactions have been observed when coadministering oseltamivir with
amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium
carbonates), rimantadine, amantadine, or warfarin.
12.4 Microbiology
Mechanism of Action
Oseltamivir phosphate is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir
carboxylate. Oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase affecting release of viral particles.
The median IC50 values of oseltamivir against influenza A/H1N1, influenza A/H3N2, and influenza B clinical isolates
were 2.5 nM (range 0.93-4.16 nM, N=74), 0.96 nM (range 0.13-7.95 nM, N=774), and 60 nM (20-285 nM, N=256),
respectively, in a neuraminidase assay with a fluorescently labeled MUNANA substrate.
Antiviral Activity
The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was
determined in cell culture. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell
culture were highly variable depending on the assay method used and the virus tested. The 50% and 90% effective
concentrations (EC50 and EC90) were in the range of 0.0008 micromolar to greater than 35 micromolar and
0.004 micromolar to greater than 100 micromolar, respectively (1 micromolar=0.284 microgram per mL). The
relationship between the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition
of influenza virus replication in humans has not been established.
Resistance
Cell culture studies: Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered
by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir carboxylate. Reduced
susceptibility of influenza virus to inhibition by oseltamivir carboxylate may be conferred by amino acid substitutions in
the viral neuraminidase and/or hemagglutinin proteins.
Clinical studies: Reduced susceptibility isolates have been obtained during treatment with oseltamivir and from sampling
during community surveillance studies. Changes in the viral neuraminidase that have been associated with reduced
susceptibility to oseltamivir carboxylate are summarized in Table 8. The clinical impact of this reduced susceptibility
is unknown.
Hemagglutinin (HA) substitutions selected in cell culture and associated with reduced susceptibility to oseltamivir include
(influenza virus subtype-specific numbering) A11T, K173E, and R453M in H3N2; and H99Q in influenza B virus
(Yamagata lineage). In some cases, HA substitutions were selected in conjunction with known NA resistance substitutions
and may contribute to reduced susceptibility to oseltamivir; however, the impact of HA substitutions on antiviral activity
of oseltamivir in humans is unknown and likely to be strain-dependent.
 Table 8 Neuraminidase Amino Acid Substitutions Associated with Reduced Susceptibility to Oseltamivir

Amino Acid Substitution*

Influenza A N1 (N1 numbering in brackets)

I117V (I117V), E119V (E119V), R152K (R152K), Y155H (Y155H), F173V (F174V), D198G/N (D199G/N),
I222K/R/T/V (I223K/R/T/V), S246G/N (S247G/N), G248R+I266V (G249R+I267V), H274Y (H275Y), N294S
(N295S), Q312R+I427T (Q313R+I427T), N325K (N325K), R371K (R368K)

Influenza A N2

E41G, E119I/V, D151V, I222L/V, Q226H, SASG245-248 deletion, S247P, R292K, N294S

Influenza B (B numbering in brackets)

E119A (E117A), P141S (P139S), G142R (G140R), R152K (R150K), D198E/N/Y (D197E/N/Y), I222L/T/V
(I221L/T/V), A246D/S/T (A245D/S/T), H274Y (H273Y), N294S (N294S), R371K (R374K), G402S (G407S)

* All numbering is N2, except where indicated.

Selection of influenza A viruses resistant to oseltamivir can occur at higher frequencies in children. Oseltamivir
treatment-associated resistance in pediatric treatment studies has been detected at frequencies of 27 to 37% and 3 to 18%
(3/11 to 7/19 and 1/34 to 9/50 post-treatment isolates, respectively) for influenza A/H1N1 virus and influenza A/H3N2
virus, respectively.

In immunocompromised adults and pediatrics (1 year of age and older), selection of influenza viruses resistant to
oseltamivir can occur at higher frequencies than in the otherwise healthy population. In a treatment study of
immunocompromised subjects, treatment-associated genotypic resistance was detected in 27% (8/30), 12% (6/52), and
0% (0/42) of influenza A/H1N1, A/H3N2, and B virus infections, respectively. Treatment-emergent resistance was
observed at a higher frequency in hematopoietic stem cell transplant recipients (32%; 6/19).

The frequency of resistance selection to oseltamivir and the prevalence of such resistant virus vary seasonally and
geographically.

Circulating seasonal influenza strains expressing neuraminidase resistance-associated substitutions have been observed in
individuals who have not received oseltamivir treatment. The oseltamivir resistance-associated substitution H275Y was
found in more than 99% of US-circulating 2008 H1N1 influenza virus isolates. The 2009 H1N1 influenza virus (“swine
flu”) was almost uniformly susceptible to oseltamivir; however, the frequency of circulating resistant variants can change
from season to season. Prescribers should consider available information from the CDC on influenza virus drug
susceptibility patterns and treatment effects when deciding whether to use TAMIFLU.

Cross-resistance
Cross-resistance between oseltamivir and zanamivir has been observed in neuraminidase biochemical assays. The
H275Y (N1 numbering) or N294S (N2 numbering) oseltamivir resistance-associated substitutions observed in the N1
neuraminidase subtype, and the E119V or N294S oseltamivir resistance-associated substitutions observed in the N2
subtype (N2 numbering), are associated with reduced susceptibility to oseltamivir but not zanamivir. The Q136K and
K150T zanamivir resistance-associated substitutions observed in N1 neuraminidase, or the S250G zanamivir resistance-
associated substitutions observed in influenza B virus neuraminidase, confer reduced susceptibility to zanamivir but not
oseltamivir. The R292K oseltamivir resistance-associated substitution observed in N2, and the I222T, D198E/N, R371K,
or G402S oseltamivir resistance-associated substitutions observed in influenza B virus neuraminidase, confer reduced
susceptibility to both oseltamivir and zanamivir. These examples do not represent an exhaustive list of cross resistance-
associated substitutions and prescribers should consider available information from the CDC on influenza drug
susceptibility patterns and treatment effects when deciding whether to use TAMIFLU.

No single amino acid substitution has been identified that could confer cross-resistance between the neuraminidase
inhibitor class (oseltamivir, zanamivir) and the M2 ion channel inhibitor class (amantadine, rimantadine). However, a
virus may carry a neuraminidase inhibitor-associated substitution in neuraminidase and an M2 ion channel inhibitor-
associated substitution in M2 and may therefore be resistant to both classes of inhibitors. The clinical relevance of
phenotypic cross-resistance evaluations has not been established.

Immune Response
No influenza vaccine/oseltamivir 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.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug oseltamivir phosphate up to
400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form oseltamivir carboxylate induced no statistically
significant increases in tumors over controls. The mean maximum daily exposures to the prodrug in mice and rats were
approximately 130- and 320-fold, respectively, greater than those in humans at the recommended clinical dose based on
AUC comparisons. The respective safety margins of the exposures to the active oseltamivir carboxylate were 15- and 50-
fold.
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 mating, 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 in this study was approximately 115
times the human systemic exposure (AUC0-24h) of oseltamivir carboxylate that occurs after administration of the
maximum recommended human dose.
14 CLINICAL STUDIES
14.1 Treatment of Influenza
Adults
Two randomized, placebo-controlled, double-blind clinical trials of TAMIFLU were conducted in adults between 18 and
65 years old, one in the U.S. and one outside the U.S., for the treatment of acute uncomplicated influenza. Eligible
subjects had fever of at least 100ºF, 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. Subjects were randomized to receive oral TAMIFLU or placebo for 5 days.
All enrolled subjects were allowed to take fever-reducing medications.
Of 1,355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (median age 34 years; 52%
male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3%
with influenza B, and 2% with influenza of unknown type.
Study medication was started within 40 hours of onset of symptoms and administered twice daily for 5 days. Subjects
were required to self-assess the influenza-associated symptoms (nasal congestion, sore throat, cough, aches, fatigue,
headaches, and chills/sweats) twice daily as “none,” “mild,” “moderate,” or “severe”. Time to improvement was
calculated from the time of treatment initiation to the time when all symptoms were assessed as “none” or “mild”. In both
trials, there was a 1.3-day reduction in the median time to improvement in influenza-infected subjects who received
TAMIFLU 75 mg twice a day for 5 days compared to subjects who received placebo. Subgroup analyses 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 who received higher doses of
TAMIFLU.
Adolescents and Adults with Chronic Cardiac or Respiratory Disease
A double-blind, placebo-controlled, multicenter trial was unable to demonstrate efficacy of TAMIFLU (75 mg twice
daily for 5 days) in the treatment of influenza in adult and adolescent subjects (13 years or older) with chronic cardiac
(excluding chronic idiopathic hypertension) or respiratory diseases, as measured by time to alleviation of all symptoms.
However, in patients treated with TAMIFLU there was a more rapid cessation of febrile illness. No difference in the
incidence of influenza complications was observed between the treatment and placebo groups in this population.
Geriatric Subjects
Three double-blind placebo-controlled treatment trials were conducted in subjects who were at least 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 higher than 97.5°F. Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected; of these, 95% were
infected with influenza type A and 5% with influenza type B.
In the pooled analysis, there was a 1-day reduction in the median time to improvement in influenza-infected subjects who
received TAMIFLU 75 mg twice daily for 5 days compared to those who received placebo (p=NS) [see Use in Specific
Populations (8.5)]. Some seasonal variability was noted in the clinical efficacy outcomes.
Pediatric Subjects (1 year to 12 years of age)
One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 year to 12 years (median
age 5 years) who had fever (at least 100ºF) plus one respiratory symptom (cough or coryza) when influenza virus was
known to be circulating in the community. Of 698 subjects enrolled in this trial, 452 (65%) were influenza-infected (50%
male; 68% Caucasian). Of the 452 influenza-infected subjects, 67% were infected with influenza A and 33% with
influenza B.
Efficacy in this trial was determined by the time to alleviation or resolution of influenza signs and symptoms, measured
by a composite endpoint that required the following four individual conditions be met: i) alleviation of cough, ii)
alleviation of coryza, iii) resolution of fever, and iv) parental opinion of a return to normal health and activity.
TAMIFLU treatment of 2 mg per kg twice daily, started within 48 hours of onset of symptoms, reduced the total
composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses by gender showed no
differences in the treatment effect of TAMIFLU in male and female pediatric subjects.
Pediatric Subjects (2 weeks to less than 1 year of age)
Two open-label trials evaluated the safety and pharmacokinetics of oseltamivir and oseltamivir carboxylate in influenza-
infected pediatric subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post
conceptional age). Subjects received TAMIFLU at doses ranging from 2 to 3.5 mg per kg twice daily for 5 days
depending on subject age. These clinical trials were not designed to evaluate clinical efficacy or virologic response.
Of the 136 subjects under the age of 1 year enrolled and dosed in the trials, the majority of the subjects were male (55%),
white (79%), non-Hispanic (74%), full term (76%) and infected with influenza A (80%). Pharmacokinetic data indicated
that a dose of 3 mg per kg twice daily in pediatric subjects 2 weeks to less than 1 year of age provided TAMIFLU
concentrations similar to or higher than those observed in older pediatric subjects and adults receiving the approved dose
and provided the basis for approval [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].
14.2 Prophylaxis of Influenza
Adult and Adolescent Subjects (13 years of age and older)
The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal
prophylaxis (community outbreak) clinical trials and one post-exposure prophylaxis trial in household contacts. The
efficacy endpoint for all of these trials was the incidence of laboratory-confirmed clinical influenza defined as meeting
all the following criteria (all signs and symptoms must have been recorded within 24 hours):
• oral temperature greater than or equal to 99.0°F (37.2°C),
• at least one respiratory symptom (cough, sore throat, nasal congestion),
• at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), and
• either a positive virus isolation or a four-fold increase in virus antibody titers from baseline.
In a pooled analysis of two seasonal prophylaxis trials 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 5% (25/519) for the placebo group to 1% (6/520) for the TAMIFLU group.
In the seasonal (community outbreak) prophylaxis trial in elderly residents of skilled nursing homes, about 80%, 43%,
and 14% of the subjects were vaccinated, had cardiac disorders, and had chronic airway obstructive disorders,
respectively. In this trial, subjects were randomized to TAMIFLU 75 mg once daily or placebo taken orally for 42 days.
The incidence of laboratory-confirmed clinical influenza was 4% (12/272) in the placebo-treated subjects compared to
less than 1% (1/276) in the TAMIFLU-treated subjects.
In the post-exposure prophylaxis trial in household contacts (aged 13 years or older) of an index influenza case,
TAMIFLU 75 mg once daily or placebo taken orally was administered within 48 hours of onset of symptoms in the index
case and continued for 7 days (index cases did not receive TAMIFLU treatment). The incidence of laboratory-confirmed
clinical influenza was 12% (24/200) in the placebo-treated subjects compared to 1% (2/205) in the TAMIFLU-treated
subjects.
Pediatric Subjects (1 year to 12 years of age)
The efficacy of TAMIFLU in preventing naturally occurring influenza illness was demonstrated in a randomized, open-
label post-exposure prophylaxis trial in household contacts that included pediatric subjects aged 1 year to 12 years, both
as index cases and as family contacts. All index cases in this trial received TAMIFLU for oral suspension 30 to 60 mg
taken orally once daily for 10 days. The efficacy parameter was the incidence of laboratory-confirmed clinical influenza
in the household. Laboratory-confirmed clinical influenza was defined as meeting all of the following criteria:
• oral temperature at least 100°F (37.8°C),
• cough and/or coryza recorded within 48 hours, and
• either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at
illness visits.
Among household contacts 1 year to 12 years of age not already shedding virus at baseline, the incidence of laboratory-
confirmed clinical influenza was lower in the group who received TAMIFLU prophylaxis [3% (3/95)] compared to the
group who did not receive TAMIFLU prophylaxis [17% (18/106)].
Immunocompromised Subjects
A double-blind, placebo-controlled trial was conducted for seasonal prophylaxis of influenza in
475 immunocompromised subjects (including 18 pediatric subjects 1 year to 12 years of age) who had received solid
organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87). Median time since
transplant for solid organ transplant recipients was 1,105 days for the placebo group and 1,379 days for the TAMIFLU
group. Median time since transplant for hematopoietic stem cell transplant recipients was 424 days for the placebo group
and 367 days for the TAMIFLU group. Approximately 40% of subjects received influenza vaccine prior to entering the
study. The primary efficacy endpoint was the incidence of confirmed clinical influenza, defined as oral temperature
higher than 99.0°F (37.2°C) plus cough and/or coryza, all recorded within 24 hours, plus either a positive virus culture or
a four-fold increase in virus antibody titers from baseline. Subjects received treatment with TAMIFLU 75 mg or placebo
once daily by mouth for 12 weeks. The incidence of confirmed clinical influenza was 3% (7/238) in the placebo group
compared with 2% (5/237) in the TAMIFLU group; this difference was not statistically significant. A secondary analysis
was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza infection.
Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza
infection was 3% (7/231) in the placebo group and <1% (1/232) in the TAMIFLU group.
16 HOW SUPPLIED/STORAGE AND HANDLING
TAMIFLU Capsules
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.

Nature and Contents of Container

Triplex blister pack (PVC/PE/PVDC, sealed with aluminium foil).
Available in blister packages of 10

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].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Serious Skin/Hypersensitivity Reactions
Advise patients and/or caregivers of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions.
Instruct patients and/or caregiver to stop TAMIFLU and seek immediate medical attention if an allergic-like reaction
occurs or is suspected [see Warnings and Precautions (5.1)].

Neuropsychiatric Events
Advise patients and/or caregivers of the risk of neuropsychiatric events in TAMIFLU-treated patients with influenza and
instruct patients to contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU [see
Warnings and Precautions (5.2)].
Important Dosing Information
Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms, within
48 hours of onset of symptoms. Similarly, instruct patients to start taking TAMIFLU for prevention as soon as possible
after exposure [see Dosage and Administration (2)]. Instruct patients 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.
Influenza Vaccines
Instruct patients that TAMIFLU is not a substitute for receiving an annual flu vaccination. Patients should continue
receiving an annual flu vaccination according to guidelines on immunization practices. Because of the potential for
TAMIFLU to inhibit replication of live attenuated influenza vaccine (LAIV) and possibly reduce efficacy of LAIV,
avoid administration of LAIV within 2 weeks or 48 hours after TAMIFLU administration, unless medically necessary
[see Drug Interactions (7.1)].
Fructose Intolerance
Inform patients with hereditary fructose intolerance that one dose of 75 mg TAMIFLU oral suspension (supplied as
powder) delivers 2 grams of sorbitol. Inform patients with hereditary fructose intolerance that this is above the daily
maximum limit of sorbitol and may cause dyspepsia and diarrhea [see Warnings and Precautions (5.4)].
SPECIAL INSTRUCTIONS
• Always tell your health care provider if you are taking any other medicine.
• If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, please consult your
doctor, pharmacist or other health care provider for advice before taking this medicine. Do not share medicines prescribed
for you with any other person.
• Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you
are not sure.
• Your doctor will tell you how long your treatment with this medicine will last. If you have the impression that the effect
of this medicine is too strong or too weak, tell your doctor or pharmacist.
• You will not be expected to give yourself this medicine. It will be given to you by a person who is qualified to do so.
• In the event of overdosage, consult your doctor or pharmacist. If neither is available, contact the nearest hospital or
poison center.
• Not all side effects reported for this medicine are included in this leaflet. Should your general health worsen or if you
experience any untoward effects while taking this medicine, please consult your health care provider for advice.
• In case of any adverse events or safety queries please contact pakistan.drug_safety@roche.com. If you have a scientific
query related to one of Roche's products, please contact us at pakistan.medical_information@roche.com
• If you get side effects, talk to your doctor or pharmacist. You can also report side effects to DRAP through MED Vigilance
E-Reporting System of DRAP available online at https://primaryreporting.who-umc.org/PK
• Store all medicines out of reach of children.
• Do not use this medicine if you notice any visible signs of deterioration.
• Return all unused medicine to your pharmacist.
• Do not dispose of unused medicine in drains or sewerage systems (e.g. toilets).

INCOMPATIBILITIES
Not applicable.

SHELF LIFE
10 years

DRUG PRODUCT SPECIFICATIONS

Innovator’s Specification

PACK SIZE

Presentation Pack Size

75 mg Capsule 10s

MARKETING AUTHORIZATION / REGISTRATION HOLDER

Roche Pakistan Ltd
1st Floor, 37-B, Block 6, P.E.C.H.S, Shahrah-e-Faisal, Karachi
Drug Sale Licensee: Roche Pakistan Limited

MANUFACTURER

Name of manufacturing site Address of site Manufacturing step

Delpharm Milano S.r.l. Via Carnevale 1, 20054 Segrate (MI), Manufacturer
Italy
IMPORTER
Imported and marketed by Roche Pakistan Ltd, 1st Floor, 37-B, Block 6, P.E.C.H.S., Shahrah-e-Faisal, Karachi.

REGISTRATION NUMBER / MARKETING AUTHORISATION NUMBER

039619 (Tamiflu 75mg Capsules)

DATE OF FIRST MARKET AUTHORIZATION

18th October 2005

DATE OF REVISION OF THE TEXT

Current of October 2024, Updated as per US PI August 2019

Only TAMIFLU 75mg capsule is registered in Pakistan.