Submission Control Number: 125025

Manufactured under license from Gilead Sciences Inc.

(r)

Trade-Mark of F. Hoffmann-La Roche AG, used under license

(c) Copyright 1999-2008 by Hoffmann-La Roche Limited CDS Version 4.0, 5.0

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 7 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 20 ACTION AND CLINICAL PHARMACOLOGY 20 STORAGE AND STABILITY 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION 24

PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 25 DETAILED PHARMACOLOGY 28 MICROBIOLOGY 29 TOXICOLOGY 31 REFERENCES 44

PART III: CONSUMER INFORMATION. 45

PRTAMIFLU(r) Oseltamivir phosphate

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

TAMIFLU (oseltamivir phosphate) is contraindicated in patients with known hypersensitivity to any of the components of the product. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Use of TAMIFLU in children under 1 year of age is contraindicated. TAMIFLU may be safely administered only once the blood-brain barrier is fully developed (see TOXICOLOGY: Multiple Dose Toxicity)

WARNINGS AND PRECAUTIONS

General

No increased efficacy was demonstrated in adult subjects receiving 150 mg TAMIFLU (oseltamivir phosphate) twice daily for 5 days compared to those receiving 75 mg twice daily for the treatment of influenza. There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza viruses Types A and B. Data on treatment of influenza B are limited. Efficacy of TAMIFLU in patients who begin treatment after 48 hours of symptoms has not been established. Efficacy of TAMIFLU in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization. Safety and efficacy of repeated treatment or prevention courses have not been studied. Efficacy of TAMIFLU for treatment or prevention of influenza in immunocompromised patients has not been established.

Endocrine and Metabolism

A bottle of 30 g TAMIFLU powder for oral suspension contains 25.713 g of sorbitol. One dose of 45 mg oseltamivir administered twice daily delivers 2.6 g of sorbitol which is unsuitable for subjects with hereditary fructose intolerance.

Hepatic

There have been post-marketing reports of elevated liver enzymes and hepatotoxicity including fulminant hepatits/hepatic failure, in some cases with fatal outcome, where a causal relationship with oseltamivir could not be excluded, especially in patients with pre-existing liver disease. The safety, efficacy and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been studied (see DOSAGE AND ADMINISTRATION: Dosage Adjustment, Hepatic Impairment).

Neuropsychiatric

There have been post-marketing reports (mostly from Japan) of delirium and self-injury, in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU. Because these events were reported voluntarily during clinical practice, estimate of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients. The contribution of TAMIFLU to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behaviour. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient (see ADVERSE REACTIONS: Post-Market Adverse Drug Reactions, Neurologic, Psychiatric). Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, 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.

Renal

Renal Impairment:

No dosing recommendation is available for patients undergoing routine hemodialysis and continuous peritoneal dialysis with end stage renal disease and for patients

with creatinine clearance <= 10 mL/min (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION: Dosage Adjustment).

Resistance

In clinical studies of naturally acquired infection, the cumulative incidence of oseltamivir- resistant virus by phenotyping alone or by phenotyping and genotyping was 0.32% (4/1245) or 0.4% (5/1245) respectively in adult/adolescent patients. In children with naturally acquired influenza virus infection, resistance was determined in 6 clinical studies WV15731 (0%; 0/5), WV15758 (8%; 15/183), WV15759/WV15871 (0%, 0/60), JV16284 (19%, 8/43), WV16193 (0%, 0/147), NV16871 (8%, 2/26). From the data obtained in these studies, the cumulative incidence of oseltamivir resistance in pediatric patients aged 1 to 12 years was 4.1% (19/464) based on phenotyping and 5.4% (25/464) based on phenotyping and genotyping (full genotyping was not performed on all patients). The patients cleared the virus normally and showed no clinical deterioration. There has been no evidence for emergence of drug resistance associated with the use of TAMIFLU in clinical studies conducted to date in post-exposure (7 days), post-exposure within the household groups (10 days) and seasonal (42 days) prophylaxis of influenza (see MICROBIOLOGY: Resistance). Insufficient information is available to fully characterize the risk of emergence of resistance to TAMIFLU in clinical use. (see MICROBIOLOGY: Resistance).

Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions have been reported since marketing in patients treated with TAMIFLU (see Post-Market Adverse Reactions).

Special Populations

Pregnant Women:

At present, insufficient data are available in pregnant women taking TAMIFLU to enable an evaluation of the potential for TAMIFLU to cause fetal malformations or fetal toxicity. TAMIFLU should therefore be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Studies for effects on embryo-fetal development were conducted in rats (50, 250 and 1500 mg/kg/day) and rabbits (50, 150 and 500 mg/kg/day) by the oral route. Relative exposures at these doses were, respectively, 2, 13 and 100 times human exposure in the rat and 4, 8 and 50 times human exposure in the rabbit. Pharmacokinetic studies indicated that fetal exposure was seen in both species. In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. An increased incidence of abortion was seen in the 500 mg/kg/day group. There was a dose-dependent increase in the incidence rates of a variety of minor skeletal individual abnormalities and variants in the exposed offspring in these studies. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied. In view of the isolated nature of this finding it was considered to be of doubtful toxicological significance. For the results of administration of oseltamivir to juvenile rats see WARNINGS AND PRECAUTIONS, Nursing Women.

Nursing Women:

It is not known whether oseltamivir or the active metabolite are excreted in human milk. In lactating rats, oseltamivir and the active metabolite are excreted in the milk. TAMIFLU should not be used by mothers who are nursing children under one year of age due to the potential risk to the nursing infant. Administration of oseltamivir to juvenile rats resulted in a high mortality rate along with high exposure to the brain. Oseltamivir may be safely administered only once the blood-brain barrier is fully developed (see TOXICOLOGY: Multiple Dose Toxicity).

Pediatrics (< 1 year of age)

: TAMIFLU should not be used in children under 1 year of age (see TOXICOLOGY: Multiple Dose Toxicity). The safety and efficacy of TAMIFLU in infants younger than 1 year of age have not been established (see CLINICAL TRIALS).

Geriatrics (>= 65 years of age): >=

Efficacy of TAMIFLU in the treatment of elderly patients has not been evaluated. Safety data in 372 elderly patients (

65 years old) showed no overall difference between these subjects and younger adults. Based on drug exposure and tolerability, dosage adjustments are not anticipated for elderly patients (see ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Geriatrics).

Safety has been demonstrated in elderly residents of nursing homes who took TAMIFLU for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season (see CLINICAL TRIALS).

DRUG INTERACTIONS

Overview

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 demonstrated that neither oseltamivir nor the active metabolite are good substrates for P450 mixed-function oxidases or for glucuronyl transferases.

Drug-Drug Interactions

Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic drugs, has no effect on plasma levels of oseltamivir or its active metabolite. Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of the active metabolite (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Co-administration of probenecid results in an approximate two-fold increase in exposure to the active metabolite due to a decrease in active anionic 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. Other drugs excreted via anionic tubular secretion have not been evaluated. Co-administration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak. In six subjects, co-administration with acetaminophen did not alter plasma levels of oseltamivir, its active metabolite, or acetaminophen. Co-administration with paracetamol does not alter plasma levels of oseltamivir, its active metabolite, or paracetamol. No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when co-administering oseltamivir with paracetamol, acetyl-salicylic acid, cimetidine or with antacids (Magnesium and aluminum hydroxides and calcium carbonates). In phase III treatment and prophylaxis clinical studies, TAMIFLU (oseltamivir phosphate) has been administered with commonly used drugs such as ACE inhibitors (enalapril, captopril), thiazide diuretics (bendrofluazide), antibiotics (penicillin), H2-receptor blockers (cimetidine), and analgesic agents (acetylsalicylic acid, 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.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbs have not been established.

Drug-Laboratory Tests

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Hepatic Impairment:

The safety, efficacy and pharmacokinetics in patients with severe hepatic impairment have not been studied. No studies have been carried out in pediatric patients with hepatic impairment.

Infants:

The safety and efficacy of TAMIFLU (oseltamivir phosphate) in infants younger than 1 year of age have not been established. TAMIFLU should not be used in children under 1 year of

age (see TOXICOLOGY: Multiple Dose Toxicity). Administration of TAMIFLU to infants younger than 1 year of age is contraindicated (see CONTRAINDICATIONS). For information on renal impairment and elderly patients see Dosage Adjustment section.

Recommended Dose - Treatment of Influenza

Treatment should begin no more than two days after the onset of symptoms of influenza.

Adults and Adolescents (>= 13 years):

The recommended oral dose of TAMIFLU capsules for the treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily, for 5 days.

Pediatrics (1 to 12 years):

The recommended oral dose of TAMIFLU oral suspension for pediatric patients 1 year and older is shown in the table below. TAMIFLU oral suspension may also be used by adult patients who cannot swallow a capsule. If TAMIFLU oral suspension is not available, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup. For children old enough to safely swallow capsules, the 30 and 45 mg capsules can also be taken as outlined in the table below.

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg.

Recommended Dose - Prevention of Influenza

Therapy should begin within 2 days of exposure after the onset of symptoms in the index case and continue for at least ten days. Viral shedding may continue for up to 14 days in children and elderly after the onset of influenza illness. Therefore, if the index case is a child or an elderly person, therapy with TAMIFLU for prevention may continue for up to 14 days. Patients should be instructed to complete the entire course of therapy.

Adults and adolescents (>= 13 years):

The recommended oral dose of TAMIFLU for prevention of influenza following close contact with an infected individual (the index case) is 75 mg once daily.

Pediatrics (1 to 12 years):

The recommended dose of TAMIFLU oral suspension for prevention in pediatric patients 1 year and older is shown in the table below. TAMIFLU oral suspension may also be used by adult patients who cannot swallow a capsule. If TAMIFLU oral suspension

is not available, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup. For children old enough to safely swallow capsules, the 30 and 45 mg capsules can also be taken as outlined in the table below.

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg.

Dosage Adjustment

Hepatic Impairment:

No dose adjustment is required in adult patients with mild or moderate hepatic impairment (See ACTIONS AND CLINICAL, PHARMACOLOGY: Special Populations and Conditions, Hepatic Impairment).

Renal Impairment:

No dose adjustment is necessary for patients with creatinine clearance above 30 mL/min.

No dosing recommendation is available for patients undergoing routine hemodialysis and continuous peritoneal dialysis with end stage renal disease and for patients with creatinine clearance <= 10 mL/min (see ACTION AND CLINICAL PHARMACOLOGY: Special Populations and Conditions, Renal Impairment).

Treatment of Influenza:

In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 75 mg of TAMIFLU once daily for 5 days.

Prevention of influenza:

In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 75 mg of TAMIFLU every other day, or alternatively, one 30 mg capsule or 30 mg suspension once daily.

Elderly Patients

: No dose adjustment is required for elderly patients (See WARNINGS AND PRECAUTIONS: Special Populations, Geriatrics).

Missed Dose

The missed dose should be taken as soon as remembered, then the regular dosing schedule should be continued. Two doses of TAMIFLU should not be taken at the same time.

Administration

TAMIFLU may be taken with or without food (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics, Absorption). However, taking with food may enhance tolerability in some patients.

Reconstitution of Oral Suspension:

It is recommended that TAMIFLU powder for oral suspension be reconstituted by the pharmacist prior to dispensing to the patient.

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

2. Measure 52 mL of water in a graduated cylinder.

3. Add the total amount of water for reconstitution to the bottle and shake the closed bottle well for 15 seconds.

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.

Dispense with patient information leaflet and oral dispenser. It is recommended to write the date of expiration of the reconstituted suspension on the bottle label. (The shelf life of the reconstituted suspension is 10 days if stored at room temperature (not above 25degC) or 17 days if stored in a refrigerator (2degC - 8degC)). A bottle of 30 g TAMIFLU powder for oral suspension contains 25.713 g of sorbitol. One dose of 45 mg oseltamivir administered twice daily delivers 2.6 g of sorbitol which is unsuitable for subjects with hereditary fructose intolerance (see WARNINGS AND PRECAUTIONS: Endocrine and Metabolism).

Note: Shake the TAMIFLU oral suspension well before each use.

Emergency Compounding of an Oral Suspension from TAMIFLU Capsules (Final Concentration 15 mg/mL)

The following directions are provided for use only during emergency situations. These directions are not intended to be used if the Health Canada-approved, commercially manufactured TAMIFLU for Oral Suspension is readily available from wholesalers or the manufacturer. Compounding an oral suspension with this procedure will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis. Commercially manufactured TAMIFLU for Oral Suspension (12 mg/mL) is the preferred product for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are needed. In the event that TAMIFLU for Oral Suspension is not available, the pharmacist may compound a suspension (15 mg/mL) from TAMIFLU (oseltamivir phosphate) Capsules 75 mg using the vehicle Ora-Sweet(r) SF (sugar-free) (Paddock Laboratories). Other vehicles have not been studied. This compounded suspension should not be used for

convenience or when the Health Canada-approved TAMIFLU for Oral Suspension is commercially available.

First, calculate the Total Volume of an oral suspension needed to be compounded and dispensed for each patient. The Total Volume required is determined by the weight of each patient. Refer to Table 3.

Table 3: Volume of an Oral Suspension (15 mg/mL) Needed to be Compounded Based Upon the Patient's Weight

Second, determine the number of capsules and the amount of vehicle (Ora-Sweet SF) that are needed to prepare the Total Volume (calculated from Table 3: 30 mL, 40 mL, 50 mL, or 60 mL) of compounded oral suspension (15 mg/mL). Refer to Table 4.

Table 4: Number of TAMIFLU 75 mg Capsules and Amount of Vehicle (Ora-Sweet SF) Needed to Prepare the Total Volume of a Compounded Oral Suspension (15 mg/mL)

Third, follow the procedure below for compounding the oral suspension (15 mg/mL) from TAMIFLU Capsules 75 mg:

1. Carefully separate the capsule body and cap and transfer the contents of the required number of TAMIFLU 75 mg Capsules into a clean mortar.

2. Triturate the granules to a fine powder.

3. Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.

4. Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.

5. Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.

6. Repeat the rinsing (Step 5) with the remainder of the vehicle.

7. Close the bottle using a child-resistant cap.

8. Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. (Note: The active drug, oseltamivir phosphate, readily dissolves in the specified vehicle. The suspension is caused by some of the inert ingredients of TAMIFLU Capsules which are insoluble in the vehicle.)

9. Put an ancillary label on the bottle indicating "Shake Gently Before Use". [This compounded suspension should be gently shaken prior to administration to minimize the tendency for air entrapment.]

10. Instruct the parent or guardian that any remaining material following completion of therapy must be discarded by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.

11. Place an appropriate expiration date label according to storage condition (see below).

STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION: Compounded with Ora-Sweet(r)SF: Stable for 5 weeks (35 days) when stored at 25degC. Note: The storage conditions are based on stability studies of compounded oral suspensions, using the above mentioned vehicle, which were placed in amber glass and amber polyethyleneterephthalate (PET) bottles. Stability studies have not been conducted with other vehicles or bottle types. Place a pharmacy label on the bottle that includes the patient's name, dosing instructions, and drug name and any other required information to be in compliance with all Provincial and Federal Pharmacy Regulations. Refer to Table 5 for the proper dosing instructions.

Note: This compounding procedure results in a 15 mg/mL suspension, which is different from the commercially available TAMIFLU for Oral Suspension, which has a concentration of 12 mg/mL.

Table 5: Dosing Chart for Pharmacy-Compounded Suspension from TAMIFLU Capsules 75 mg

Note: 1 teaspoon = 5 mL

Consider dispensing the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 mL, 3 mL, 4 mL, or 5 mL) on the oral syringe for each patient. The dosing device dispensed with the commercially available TAMIFLU for Oral Suspension should NOT be used with the compounded suspension since they have different concentrations.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended. At present there has been no experience with overdose. Single doses of up to 1000 mg of TAMIFLU (oseltamivir phosphate) have been associated with nausea and/or vomiting.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

TAMIFLU (oseltamivir phosphate) is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active metabolite, oseltamivir carboxylate. The active metabolite is a selective inhibitor of influenza A and B virus neuraminidase enzymes which are glycoproteins found on the virion surface. 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 in the body. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. Oseltamivir is readily absorbed after oral administration and converted by hepatic esterases to its active metabolite. The mean volume of distribution (Vss) of the active metabolite is approximately 23 L. The active metabolite is not further metabolized and is eliminated in the urine. The half-life of elimination of this metabolite is 6 to 10 hours. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h), indicating that tubular secretion in addition to glomerular filtration occurs. The prodrug which reaches the systemic circulation (less than 5%) is eliminated by renal excretion also. The binding of oseltamivir to human plasma protein is 42% and that of the active metabolite is negligible, approximately 3%. Exposure to the active metabolite is inversely proportional to declining renal function.

Pharmacokinetics

Absorption:

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of TAMIFLU and is extensively converted predominantly by hepatic esterases to the active metabolite. At least 75% of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the prodrug is less than 5% relative to the active metabolite. Plasma concentrations of active metabolite are proportional to dose and are not significantly affected by co-administration with food (see DOSAGE AND ADMINISTRATION).

Distribution: The mean volume of distribution (Vss) of the active metabolite is approximately 23 litres in humans. The binding of oseltamivir to human plasma protein is 42% and that of the active metabolite is negligible, approximately 3%.

Metabolism:

Oseltamivir 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.

Excretion

: Absorbed oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite. The active metabolite is not further metabolized 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 drug 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 feces.

Special Populations and Conditions

Pediatrics:

The pharmacokinetics of oseltamivir have been evaluated in single dose pharmacokinetic studies in pediatric patients aged 1 to 16 years. Multiple dose pharmacokinetics were studied in a small number of pediatric patients aged 3-12 years enrolled in a clinical trial. Younger pediatric patients cleared both the prodrug and the active metabolite faster than adults resulting in lower exposure for a given mg/kg dose. Doses of 2 mg/kg give 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 pediatric patients over 12 years of age are similar to those in adults.

TAMIFLU should not be used in children under 1 year of age (see TOXICOLOGY: Multiple Dose Toxicity).

Geriatrics:

Exposure to the active metabolite at steady-state was 25% to 35% higher in elderly patients (age range 65 to 78) compared to young adults given comparable doses of TAMIFLU. Half-lives observed in the elderly patients were similar to those seen in young adults. On the basis of drug exposure and tolerability, dosage adjustments are not required for elderly patients for either treatment or prevention (see DOSAGE AND ADMINISTRATION: Dosage Adjustment).

Hepatic Impairment:

The safety, efficacy and pharmacokinetics of TAMIFLU in patients with severe hepatic impairment have not been studied (See WARNINGS AND PRECAUTIONS: Hepatic). In a clinical study of adult patients with moderate hepatic impairment (N=11), compared with healthy volunteers (N=23), metabolic conversion of oseltamivir into the active metabolite oseltamivir carboxylate was not significantly altered (See DOSAGE AND ADMINISTRATION: Dosage Adjustment, Hepatic Impairment). No studies have been carried out in pediatric patients with hepatic impairment.

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.

No dosing recommendation is available for patients undergoing routine hemodialysis and continuous peritoneal dialysis with end stage renal disease and for patients with creatinine clearance <= 10 mL/min.

Treatment of Influenza:

In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 75 mg of TAMIFLU once daily for 5 days.

Prevention of influenza:

In patients with a creatinine clearance of 10 - 30 mL/min, it is recommended that the dose be reduced to 75 mg of TAMIFLU every other day, or alternatively, one 30 mg capsule or 30 mg suspension every day (See DOSAGE AND ADMINISTRATION: Dosage Adjustment, Renal Impairment).

STORAGE AND STABILITY

TAMIFLU (oseltamivir phosphate) Capsules

: Store at 15 to 30degC.

TAMIFLU Powder for Oral Suspension

: Store dry powder at 15 to 25oC. Store reconstituted suspension:

1. at room temperature (not above 25degC). Discard unused portion within 10 days of reconstitution.

or in a refrigerator (2degC - 8degC). Discard unused portion within 17 days of reconstitution. Do not freeze reconstituted suspension.

TAMIFLU Pharmacy-Compounded Suspension

: Store reconstituted suspension:

(a) compounded with Ora-Sweet(r)SF: Stable for 5 weeks (35 days) when stored at 25degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TAMIFLU (oseltamivir phosphate) 30 mg, 45 mg and 75 mg Capsules

Composition

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg or 75 mg oseltamivir for oral use in the form of oseltamivir phosphate. In addition to the active ingredient, each capsule contains corn starch, croscarmellose sodium, povidone K30, sodium stearyl fumarate and talc. The 30 mg capsule shell contains gelatin, red iron oxide, yellow iron oxide and titanium dioxide. The 45 mg capsule shell contains gelatin, black iron oxide and titanium dioxide. The 75 mg capsule shell contains gelatin, black iron oxide, red iron oxide, yellow iron oxide and titanium dioxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as a colorant.

Availability

TAMIFLU 30 mg capsules are available as light yellow hard gelatin capsules. "ROCHE" is printed in blue ink on the light yellow body and "30 mg" is printed in blue ink on the light yellow cap. TAMIFLU 45 mg capsules are available as grey hard gelatin capsules. "ROCHE" is printed in blue ink on the grey body and "45 mg" is printed in blue ink on the grey cap. TAMIFLU 75 mg capsules are available as 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. All three capsules strengths are available in blister packages of 10.

TAMIFLU Powder for Oral Suspension

Composition

TAMIFLU powder for oral suspension contains 900 mg oseltamivir as oseltamivir phosphate per bottle, which when reconstituted contains 12 mg/mL oseltamivir. The nonmedicinal ingredients are: monosodium citrate, saccharin sodium, sodium benzoate, sorbitol, titanium dioxide, tutti- frutti flavoring and xanthan gum.

Availability

TAMIFLU powder for oral suspension is available as a white powder blend for reconstitution to a white tutti-frutti-flavored suspension. Available in 100 mL glass bottles with a bottle adapter and 1 oral dispenser *. Net contents after reconstitution: 75 mL containing oseltamivir phosphate equivalent to 900 mg oseltamivir base. *Oral dosing dispenser manufactured by F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name

oseltamivir phosphate

Chemical Name

Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-

cyclohexene-1-carboxylate, phosphate (1:1) Molecular Formula C16H28N2O4 (free base)

Molecular Weight

312.4 for oseltamivir free base and 410.4 for oseltamivir

phosphate salt

Structural Formula

Physical Form

White crystalline solid

Solubility

Freely soluble in water and methanol, slightly soluble in dimethylformamide and ethanol, and practically insoluble in acetone, 2-propanol and non-polar organic solvents.

pKa and pH values

pKa: 7.75

Partition Co-efficient

1-octanol/aqueous phosphate buffer: logP=0.36

Melting Point

192-195degC with degradation

CLINICAL TRIALS

Treatment of Influenza

Adult Patients:

Phase III clinical trials evaluated the safety and efficacy of TAMIFLU (oseltamivir phosphate) for the treatment of naturally occurring influenza during a period when influenza virus was known to be circulating in the community. A total of 1418 patients received any treatment (TAMIFLU or placebo) of whom 476 patients received 75 mg TAMIFLU twice daily for 5 days. Patients started treatment with TAMIFLU within 40 hours after reported onset of symptoms. The primary efficacy parameter was the time to alleviation of all symptoms. The population used in the primary analyses was the intent-to-treat-infected (ITTI) population. This population included only subjects who received at least one dose of study treatment and who had laboratory confirmed influenza. An intent-to-treat (ITT) population included all subjects who took at least one dose of study medication, regardless of whether they proved to have influenza. The results for two pivotal studies are shown in the table below.

Table 6: Median Time (Hours) to Alleviation of All Symptoms in the ITTI and ITT Populations

ITT intent-to-treat

ITTI intent-to-treat infected

difference between medians

Treatment with TAMIFLU significantly reduced the duration by 1.3 days, of clinically relevant symptoms of influenza. The seven symptoms assessed were: feverish feeling, muscle aches or myalgia, headache, sore throat, cough, overall discomfort, and nasal stuffiness or runny nose.

Pediatric Patients:

One double-blind placebo controlled treatment trial was conducted in pediatric patients, aged 1 to12 years (mean age 5.3), who had fever (>100degF) 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. Treatment with TAMIFLU, started within 48 hours of onset of symptoms, significantly reduced the duration of illness by 1.5 days compared to placebo. Duration of illness was defined as time to alleviation of cough, alleviation of coryza, resolution of fever, and return to normal health and activity.

Pediatric patients receiving TAMIFLU returned to normal health and activity almost 2 days earlier than those receiving placebo.

Prevention of Influenza

Adult Patients:

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been proven in four separate trials which are summarized below and in Table 4.

In a phase III study (WV15799) in adult and adolescent contacts of a household case of influenza, 75 mg of TAMIFLU once daily, started within 2 days of onset of symptoms in the household case and continued for 7 days, significantly reduced the incidence of influenza illness occurring in the contacts by 92% (p value = < 0.001). In a double blind placebo controlled study (WV15673) conducted in unvaccinated otherwise healthy adults 18-65 years of age, 75 mg of TAMIFLU administered once daily significantly reduced the incidence of clinical influenza by 76% (p value = 0.0006) during a community outbreak of influenza. The subjects in this study received TAMIFLU for a period of 42 days. No additional benefit was demonstrated in this study using 75 mg of TAMIFLU twice daily. In a double blind placebo controlled study (WV15825) in elderly residents of nursing homes, many of whom had chronic cardiac disease and/or respiratory disease, 80% received vaccine in the season of the study. The vaccine was a good match for circulating strains. The administration of 75 mg of TAMIFLU once daily significantly reduced the incidence of clinical influenza illness in these patients by 92% (p value = 0.0015). In the same study, TAMIFLU significantly reduced the incidence of influenza associated bronchitis, pneumonia and sinusitis by 86% (p value = 0.037). The subjects in this study received TAMIFLU for a period of 42 days. In all three of these clinical trials, approximately 1% of subjects taking TAMIFLU for prevention developed influenza during the dosing period. In a fourth phase III study (WV16193) it was demonstrated that TAMIFLU effectively prevents the secondary spread of influenza within households. In this study, the index case was treated with TAMIFLU and household contacts were randomized (by household) to receive either prophylaxis (P) with TAMIFLU or treatment (T) with TAMIFLU upon emergence of influenza- like illness. In households with infected index cases where subjects who were already shedding virus at baseline were excluded (ITTIINAB population) there was a 78.8% (p =0.0008) reduction in the incidence of laboratory-confirmed influenza in P versus T. Amongst contacts, the outcome was analogous to that seen for households with a significantly lower number of infected contacts in P versus T (84.5% reduction, p =0.0002, ITTIINAB population). No virus shedding was detected in any subject in the prophylaxis group while 7% of contact in the treatment group (ITTIINAB) shed virus. TAMIFLU also significantly reduced the incidence of virus shedding and successfully prevented virus transmission in families.

Table 7: Clinical Summary of Prevention Studies

*Pediatric dosing adjusted according to age

* * Number of households ITT=Intent to treat

ITTIINAB=Intent to treat, index infected, not infected at baseline

Pediatric Patients:

In the post-exposure prophylaxis study in the family (WV16193; see 'Adult Prevention Studies') there were 215 pediatric contact cases (>1 to 12 years of age). There was an even distribution of boys and girls with the majority being Caucasian. The mean age was 8 years (range 1 to 12). The data from this subset of pediatric patients was examined to determine if oseltamivir was effective in the prevention of influenza infection in this setting. When subjects who were already shedding virus at baseline were excluded (ITTIINAB population, 117), 17 pediatric contacts became infected, 2 in the prophylaxis group and 15 in the treatment group (see Table 4). The protective efficacy in the pediatric contacts was similar to that achieved in the overall population in this study.

The dosing schedule in this study was by age. The majority of children received the now recommended schedule of treatment by weight in children (see DOSAGE AND ADMINISTRATION). There were, however, some children who were under- or over-dosed (23% and 9%, respectively) in this study.

DETAILED PHARMACOLOGY

Animal Pharmacology

Oseltamivir phosphate produced effects in the non-clinical safety pharmacology studies only at oral doses well in excess of any clinically relevant therapeutic levels. These effects in the rat, were reduced gastrointestinal transit and gastric emptying at 1000 mg/kg. In the rodent toxicology studies these effects were not reported as any sign of gastrointestinal disturbance. Additionally, there were increases in excretion of electrolytes at 100 and 1000 mg/kg and increased urine production at 1000 mg/kg. Increases in electrolyte excretion were reported in a 27-week rat toxicology study at 1000 mg/kg/day and attributed to a high phosphate intake due to the salt of the test material. In the same study less pronounced effects were seen at 200 mg/kg/day, while in another rat toxicology study no significant effects were seen at 100 mg/kg/day. A statistically significant increase in response to a painful stimulus was seen but this was neither time nor dose related and therefore not thought to be of pharmacological significance. The intravenous infusion of the active metabolite at 2, 15 and 100 mg/kg cumulatively produced statistically significant changes in heart rate, QT and QTc interval, QRS duration and pCO2 when compared with time matched controls in the anaesthetized dog. The effects on heart rate and pCO2 were at isolated time points and the decrease in QRS duration was not accompanied by any other relevant physiological changes and so not likely to be due to the drug treatment. The statistical differences in QT and QTc interval between the active metabolite and vehicle treated groups was seen in the predose and just after the start of the infusion suggesting no pharmacological significance. Because of this, significance was tested for by comparing percentage changes from predose values within the active metabolite treatment group. There were no significant differences detected. However, on comparison with the absolute values significant differences were seen during the infusion of the 100 mg/kg/dose. To clarify this situation a further test was performed in an isolated sheep Purkinje fibre study where no significant effects were observed on cardiac action potential parameters. Other than these findings, no additional effects were seen on the cardiovascular and respiratory dynamics of the anaesthetized dog. In conclusion, oseltamivir phosphate produced significant pharmacological effects only at doses much greater than would be of clinical relevance. It is therefore concluded that oseltamivir phosphate and the active metabolite produced no clinically relevant pharmacological effects on the central nervous, cardiovascular, respiratory, gastrointestinal, smooth muscle, renal, hepatic and immune systems tested.

Human Pharmacology

QT/QTc:

A retrospective analysis of ECGs from 8 clinical pharmacology studies (n=182 subjects including 30 placebo) concluded that TAMIFLU (oseltamivir phosphate) does not cause prolongation of QT intervals in humans. Although some individuals were found to have some alterations in QTc measurements, none were of clinical significance and the frequency was similar among placebo and subjects treated with TAMIFLU.

In a study on ECG intervals in which healthy volunteers received daily doses of either 75, 225 or 450 mg TAMIFLU b.i.d. orally for 5 days, treatment with TAMIFLU had no impact on any ECG parameters

MICROBIOLOGY

Virology: Oseltamivir was also tested for its effect on human T cell proliferation in vitro. Both antigen specific T cell lines and peripheral blood lymphocytes were isolated from whole blood. There was a slight but significant inhibition of influenza specific T cell line proliferation in the presence of 1 and 10 uM active metabolite, while there was no effect on antigen stimulation of peripheral blood lymphocytes. This slight effect (<20 %) on T cell proliferation is unlikely to compromise the long-term immune status of the patient with respect to subsequent influenza infection. The active metabolite inhibits neuraminidases of influenza viruses of both types A and B. Inhibitory concentrations in vitro are in the low nanomolar range. The 50% inhibitory concentration (IC50) was in the range of 0.1 to 2.6 nM. The relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established. The active metabolite also inhibits influenza virus infection and replication in vitro and inhibits influenza virus replication and pathogenicity in animal models.

Resistance: In vitro

Extensive in vitro work has been completed with the active metabolite. Resistance to this compound does not arise readily in vitro. Several different resistance mutations in the viral neuraminidase have been selected in vitro in Roche studies or reported in the published literature. Resistance mutations tend to be viral sub-type specific. The degree of reduced sensitivity differs markedly for different mutations from 2 fold for I222V in N1 to 30,000 fold for R292K in N2. Influenza A virus H1N1 strains are associated with a histidine to tyrosine change at position 274 (H274Y) on the enzyme. In H3N2 subtypes the genetic alteration of interest is an arginine to lysine at position 292 (R292K) on the enzyme. In vitro these mutant viruses exhibit reduced growth potential compared to wild-type virus.

In vivo

In vivo experiments of infectivity and pathogenicity have been conducted with mutated viruses in mice and ferrets. These experiments have demonstrated that the H274Y H1N1 mutant and the R292K H3N2 mutant have reduced ability to infect susceptible animals compared to wild-type virus and that infection is not associated with clinical evidence of pathogenicity in the ferret. Correlation of in vitro resistance patterns to resistance in vivo are not known. Viruses with resistant neuraminidase genotypes have varying degrees of loss of fitness compared to wild-type. During the clinical program, resistance to therapy was assessed by neuraminidase enzyme inhibition assays and by genotyping of the neuraminidase enzyme itself. In addition, the potential for virus resistance mediated by changes in hemagglutinin was evaluated genotypically. The R292K mutation was the most commonly selected mutation in the in vitro studies and was also the predominant mutation occurring clinically (occurrence restricted to N2 subtype). The exception to the predictive pattern of in vitro experiments to the clinical emergence of resistance was the occurrence of E119V (glutamic acid to valine at position 119 on the enzyme) in influenza N2, that had not been seen previously in vitro. Characterisation of a clinical isolate carrying this mutation demonstrated that the mutation effected a reduction in infectivity/pathogenicity and is therefore unlikely to be of clinical concern. In the patients in whom resistant virus were selected the emergence of resistant virus did not appear to give a more severe or prolonged infection or illness as measured by a composite symptom score. The potential for emergence of virus resistant to treatment continues to be evaluated. In clinical studies and viruses from TAMIFLU-treated patients, mutations in N1 neuraminidase giving resistance/reduced sensitivity to oseltamivir carboxylate are H274Y and in one instance N294S and E119V, R292K and in one instance each N294S and SASG245-248del in N2 neuraminidase. In influenza B neuraminidase one instance of G402S giving a 4 fold decrease in sensitivity has been reported and one instance of D198N (10 fold decrease) in an immunocompromised child has been reported. The estimated incidence of oseltamivir-resistant virus in the adult/adolescent population is 0.32% (4/1245) by phenotyping alone and 0.4% (5/1245) by genotyping and phenotyping (full genotyping was not performed on all studies) and 4.1% (19/464) or 5.4% (25/464) respectively for pediatric patients aged 1 to 12 years. Insufficient information is available to fully characterize the risk of emergence of resistance to TAMIFLU in clinical use. In the prophylactic trials with naturally acquired influenza infection, only 32 from 2155 drug treated individuals became productively infected with influenza virus (i.e. culture positive). Viral neuraminidase sensitivities were successfully determined from samples of 20 of these patients and none were found to be carrying resistant virus. Cross resistance: Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza mutants has been observed in vitro. Due to the limitations in the assays available to detect drug-induced shifts in virus susceptibility due to mutations in the viral hemagglutinin, an estimate of the incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made. However, one of the three oseltamivir-induced mutations in the viral neuraminidase from clinical isolates is the same as one of the three mutations in the viral neuraminidase from clinical isolates observed in zanamivir-resistant virus. Insufficient information is available to fully characterize the risk of emergence of resistance or cross-resistance to TAMIFLU (oseltamivir phosphate) in clinical use.

TOXICOLOGY

Acute Dose Toxicity

Acute oral administration was well tolerated by male and female adult rodents (mice and rats) and unweaned 14-day old male and female rats at 2000 mg/kg (~1000-fold the highest clinical dose). An intravenous range-finding study in mice (n=1/sex/dose) produced convulsions immediately after intravenous dosing with 250 mg/kg. The male died and the female recovered after 40 minutes. The maximum non-lethal dose of 100 mg/kg was confirmed in a further five males and five females observed for two weeks. Other than some evidence of a local reaction in the tail of two females, there were no significant adverse effects in this group.

Multiple Dose Toxicity

In multiple dose rat studies, doses up to 500 mg/kg/day (2 weeks), 650 mg/kg/day (4 weeks), and 200 mg/kg/day (27 weeks) were generally well tolerated, with no significant toxicologic effects. A dose of 1000 mg/kg/day in a two-week range-finding rat study in unweaned 7-9 day old rats resulted in a high rate of mortality (18/24) associated with unusually high exposure to the pro- drug; no adverse effects were observed at 500 mg/kg/day in this study. This dose level gave an exposure to the brain of approximately 800-fold that estimated for the brains of 1 year old children. In a single-dose investigatory study of this observation in 7-, 14-, 24- and 42-day-old rats, a dose of 1000 mg/kg resulted in brain exposure to the pro-drug that indicated respectively 1500-, 650- and 2-fold the exposure found in the brain of adult (42-day-old) rats. These data suggest that oseltamivir may be safely administered only once the blood-brain-barrier is fully developed. In multiple dose rat studies, the highest doses examined (>=1000 mg/kg/day) also induced two renal changes. One consisted of cortico-medullary mineralisation in the proximal tubules due to the imbalance of the calcium/phosphate ratio in the diet caused by dosing high levels of a phosphate salt. The second was a mild enhancement of chronic progressive nephropathy; rats are specifically sensitive to both these changes. A dose of 1000 mg/kg/day in the rat results in approximately 70 and 520 times the clinical exposure in humans, to the active metabolite and prodrug, respectively. In clinical studies, there was no biochemical evidence of renal effects in humans. Marked gastrointestinal irritation was observed in marmosets at 2000 mg/kg/day, but not in four- and 39-week studies at 2 x 500 mg/kg/day. Emesis occurred at 500 mg/kg/day and above in marmosets, probably related to the concentration of the oral formulation. A reduction in incidence was associated with dividing the doses and halving the concentrations administered. This effect was seen at approximately 100 and 200 times the exposure values following clinical use in human, of the active metabolite and prodrug, respectively. In the 39-week marmoset study, one 2 x 25 mg/kg/day group and two 2 x 100 mg/kg/day group animals were sacrificed prematurely. All three showed evidence of osteomalacia before dosing commenced, at autopsy and at the histopathological examination of the bones. No animal in the 2 x 500 mg/kg/day group was affected. Review of the clinical safety database, including the elderly, failed to reveal any biochemical evidence of skeletal effects in humans.

Reproduction and Teratology

Fertility, teratology and pre- and post-natal studies were conducted to cover all phases of the reproductive process. There was no evidence of adverse effects on fertility or embryo-foetal development up to the highest dose of 1500 mg/kg/day in rats, or for teratogenicity testing in rabbits up to 500 mg/kg/day. These dose levels were associated with maternal toxicity. In rabbits mortalities occurred at 750 and 1500 mg/kg/day during a non-pregnant tolerance study. Some rabbits were sacrificed in the teratology range-finding and main studies at 500 mg/kg/day due to abortions associated with maternal toxicity. In the regulatory pre- and post-natal study in rats, maternal deaths occurred (9/25) at or immediately prior to delivery in the 1500 mg/kg/day group; prolonged parturition was also observed. Two further studies were therefore undertaken; although only 1/125 maternal deaths at parturition were seen in the combined 1500 mg/kg/day groups, extension of parturition was confirmed by these studies. It was concluded that the drug alone was not responsible for the maternal deaths in the first pre- and post-natal study. At 1500 mg/kg/day in the rat teratology study, there was a slightly increased incidence of incomplete ossification of the 3rd sternebra in the exposed offspring, when compared to controls. Statistical significance was achieved, however, the majority of incidences occurred in one litter, where a general reduction in ossification was observed. In view of the isolated nature of this finding it was considered to be of doubtful toxicological significance.

Mutagenicity and Carcinogenicity

There was no evidence of mutagenic potential in any study (doses up to 5000ug/plate), with or without metabolic activation. Separate bacterial cell gene mutation (Ames) tests were conducted for the pro-drug and active metabolite. A mouse lymphoma cell mutation test examined the active metabolite. The pro-drug was tested in a chromosome analysis assay with human lymphocytes, and in an in vivo micronucleus test in mice (oral dose of up to 2000 mg/kg). All the study systems were verified as sensitive by positive controls, and all the results were negative. Two year rat and mouse studies and a six month transgenic Tg: AC mouse assay performed with the active metabolite were negative. The tables presented on the following pages provide the findings of the main toxicology, reproductive, mutagenicity and various special studies performed with oseltamivir phosphate.

Table 8: Acute Dose Toxicity

Table 9: Multiple Dose Toxicity

Table 9: Multiple Dose Toxicity

Table 9: Multiple Dose Toxicity

Table 9: Multiple Dose Toxicity

Table 9: Multiple Dose Toxicity

Table 10: Reproductive Toxicity Studies

Table 10: Reproductive Toxicity Studies

Table 10: Reproductive Toxicity Studies

+ = Mechanistic investigations (all dosed Day 6 of pregnancy to Day 21 of lactation) a = dosed from Day 6 to 17 of pregnancy

Table 11: Mutagenicity Studies

Table 12: Special Studies

REFERENCES

1. Bardsley-Elliot A and Noble S. Oseltamivir. Drugs 1999; 58(5):851-860.

2. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. NEJM 1999; 341(18):1336-43.

3. Hayden FG, Treanor J, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: Randomized, controlled trials for prevention and treatment. JAMA 1999; 282(13):1240-1246.

4. He G, et al. Summary of the clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite (Ro 64-0802). Clinical Pharmacokinetics. 1999; 37:471-84.

5. Massarella JW, He G, et al. The pharmacokinetics and tolerability of the influenza neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adults and elderly volunteers. J Clin Pharmacol. 2000; 40:836-43.

6. Nicholson KG, Aoki FY, Osterhaus ADME, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. The Lancet 2000; 355:1845- 50.

7. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA 2000; 283:1016-24.

8. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20:127-33.

9. Welliver R, Monto AS, et al. Effectiveness of oseltamivir in preventing influenza in household contact: a randomized controlled trial. JAMA 2001; 285:748-54.

10. Peters PH, et al. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 2001; 49:1025-1031.

11. Hayden F.G., Belshe R, Villanueva C, et al. Management of influenza in households: A prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004, 189:440-449.

IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PRTAMIFLU(r) (oseltamivir phosphate)

This leaflet is part III of a three-part "Product Monograph" published when TAMIFLU was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about TAMIFLU. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the flu is:

The flu, or influenza, is an infection caused by influenza viruses. It is most common in the fall and

winter. The flu is highly contagious. The virus usually enters the body through the mouth, nose or

eyes. When a person with the flu coughs or sneezes,

the virus becomes airborne and can be inhaled by anyone nearby.

Flu occurs in local outbreaks which happen once or twice per year, usually in the winter.

What the difference is between the flu and a cold:

Both the flu and a cold are viral infections and can cause symptoms such as coughing and sore throat. A cold is a minor viral infection of the nose and throat. The flu however is usually more severe, has rapid onset of symptoms, and is associated with higher fever and aches and pains.

What the medication is used for:

TAMIFLU is a prescription medication (a viral neuraminidase inhibitor) used to treat or prevent the

onset of flu.

What it does:

TAMIFLU works by inhibiting an enzyme necessary for the flu virus to spread through your body.

In two large clinical treatment trials, flu patients who took TAMIFLU recovered 1.3 days (30%) faster than flu patients who did not take TAMIFLU. TAMIFLU should also alleviate your symptoms, and help you feel better soon.

In a large clinical trial for prevention of flu in families with children 13 years and older, TAMIFLU,

started within 2 days of the first family member getting sick and taken for 7 days, prevented over 90% of the flu illnesses in the rest of the family.

When TAMIFLU should not be used:

• Do not use TAMIFLU if you are allergic or sensitive to oseltamivir phosphate or any ingredient in this formulation (See What the nonmedicinal ingredients are)

• TAMIFLU should not be used in children under 1 year of age.

What the medicinal ingredient is:

TAMIFLU is available as capsules containing 30 mg,

45 mg or 75 mg of the active ingredient oseltamivir as oseltamivir phosphate.

The suspension contains 12 mg/mL of the active ingredient oseltamivir as oseltamivir phosphate.

What the nonmedicinal ingredients are:

TAMIFLU capsules contain the following nonmedicinal ingredients: corn starch, croscarmellose sodium, gelatin, iron oxides, povidone K 30, sodium stearyl fumarate, talc, titanium dioxide and FD&C Blue No. 2.

TAMIFLU suspension contains the following nonmedicinal ingredients: monosodium citrate, saccharin sodium, sodium benzoate, sorbitol, titanium dioxide, tutti-frutti flavoring and xanthan gum.

What dosage forms it comes in:

30 mg, 45 mg and 75 mg capsules

TAMIFLU 30 mg capsules are available as light yellow capsules with "Roche" printed in blue ink on one side and "30 mg" printed in blue ink on the other.

TAMIFLU 45 mg capsules are available as grey capsules with "Roche" printed in blue ink on one side and "45 mg" printed in blue ink on the other.

TAMIFLU 75 mg capsules are available as a grey/light-yellow capsule with "Roche" printed in blue ink on one side and "75 mg" printed in blue ink on the other.

TAMIFLU is also available as a liquid suspension. The suspension will be prepared by your pharmacist and will be a thick white fruit-flavored liquid.

WARNINGS AND PRECAUTIONS

BEFORE you use TAMIFLU talk to your doctor or pharmacist if:

• you ever had a bad reaction to oseltamivir phosphate (TAMIFLU) or any of the inactive ingredients

• you have hereditary fructose intolerance

• you are allergic to other medicines, food and dyes

• you are taking any other medicines, including those not prescribed by your doctor

• you have any type of kidney disease

• you are pregnant, plan on becoming pregnant, or are breast-feeding.

This information will help your doctor and you decide whether you should use TAMIFLU and what extra care may need to be taken while you are on the medicine.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor about all medications (prescription and non-prescription) that you are taking, or plan on taking.

weakness, runny or stuffy nose, sore throat and cough.

Usual dose:

TAMIFLU should be taken twice daily (once in the morning and once in the evening) for five days.

It is important that you begin your treatment with TAMIFLU as soon as possible from the first appearance of your flu symptoms. If flu symptoms, most notably fever, do not begin to improve in the first day or two after you start your treatment with TAMIFLU, speak with your doctor.

TAMIFLU can be taken with food. As with many medicines, if taken with a light snack, milk, or a meal, possible stomach upset may be reduced.

You must complete the entire treatment recommended by your doctor, even if you are feeling better.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than prescribed by your doctor. Never share TAMIFLU with anyone, even if they have the same symptoms.

If your doctor has prescribed TAMIFLU liquid suspension, follow the directions below to ensure proper dosing.

PROPER USE OF THIS MEDICATION

Your doctor has prescribed TAMIFLU after diagnosing your flu condition. Other people may not benefit from taking this medicine, even though their problems may seem similar to yours. Do not give your TAMIFLU to anyone else.

TAMIFLU is not a substitute for the flu shot. If you are at high risk of developing complications, you should continue to get your flu shot as recommended by your doctor. You might be surprised to find that you are still susceptible to flu even though you got your annual flu shot.

Treatment with TAMIFLU (adults, adolescents and children (>= 1 year))

Treatment with TAMIFLU should begin no more

than two days

after flu symptoms have started to appear. Typical symptoms of flu include sudden onset of fever, headache, tiredness, muscular

1. Shake closed bottle well for about 5 seconds before each use.

2. Remove child-resistant cap.

3. Before inserting the tip of the dispenser into bottle adapter, push the plunger completely down toward the tip of the dispenser. Insert tip firmly into opening of the bottle adapter.

4. Turn the entire unit (bottle and dispenser) upside down.

5. Pull the plunger out slowly until the desired amount of medication is withdrawn into the dispenser (see

figure).

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

Dispense directly into mouth.

Close bottle with child-resistant cap after each use.

Disassemble oral dispenser, rinse under running tap water and air dry prior to next use.

Emergency Home Preparation of an Oral Suspension from TAMIFLU Capsules:

When TAMIFLU oral suspension is not available, and if directed by your doctor or pharmacist, you may mix the contents of TAMIFLU capsules with sweetened liquids to prepare an oral suspension for children, immediately before dosing.

Please follow your doctor's (pharmacist's) instructions carefully to ensure proper dosing:

• Holding one capsule over a small bowl, carefully pull the capsule open and pour the complete contents of the capsule into the bowl.

• Add a small amount of a sweetened liquid such as chocolate syrup (regular or sugar- free) that the child will consume completely.

• Stir the mixture and give the entire dose to the child.

• Rinse the bowl with a bit of sweetened liquid and administer the rinse to the child.

Prevention with TAMIFLU (adults, adolescents and children (>= 1 year))

Therapy should begin within 2 days after coming into contact with someone with flu symptoms. Typically, about one in ten get the flu during an outbreak, although this varies. If someone close to you (like someone living in your home) has the flu your chance of getting it yourself is higher (around one in five).

Usual dose:

TAMIFLU should be taken once daily for 10 days or longer as recommended by your doctor if you have contacted someone who has flu. It is important that you begin your treatment with TAMIFLU as soon as possible after you are exposed.

TAMIFLU can be taken with food. As with many medicines, if taken with a light snack, milk, or a meal, possible stomach upset may be reduced.

The duration of dosing was tailored by your doctor. You must complete the entire course of therapy that your doctor has prescribed for you.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than prescribed by your doctor.

Overdose:

At present there has been no experience with overdose. In cases of overdose or suspected overdose,

contact the poison control centre or your doctor immediately.

Missed Dose:

If you forget to take a dose of TAMIFLU take it as soon as possible, then just carry on with the regular

times you take your medication. Do not take double the amount if you miss one dose.

If you have missed several doses, inform your doctor and follow the advice given to you. Do not change your dose of TAMIFLU unless instructed to do so by your doctor.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Unwanted effects are possible with all medicines. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking TAMIFLU.

TAMIFLU is generally well tolerated. The most common/possible unwanted effects are:

nausea

vomiting

abdominal pain

headache

Taking TAMIFLU with food may reduce possible stomach upset.

Severe skin and hypersensitivity reactions have been reported since the marketing of TAMIFLU. Symptoms of skin reactions include flushing, rash, itching or swelling. Symptoms of hypersensitivity reactions include dizziness or breathing problems.

Cases of liver toxicity have also been reported, symptoms of which include, yellowing of skin or eyes and dark urine.

People with the flu, particularly children and adolescents, may be at an increased risk of seizures, confusion, delirium, hallucinations, agitation, anxiety or other abnormal behaviour early during their illness. These events may occur shortly after beginning TAMIFLU or may occur when flu is not treated. These events are uncommon but may result in self-injury to the patient, sometimes fatal. Therefore, patients should be observed for signs of unusual behaviour and a healthcare professional should be contacted immediately if the patient shows any signs of unusual behaviour.

Some unwanted effects may go away during treatment as your body adjusts to the medicine.

If you are concerned about these or any other unexpected effects while on TAMIFLU, talk with

your doctor or pharmacist.

This is not a complete list of side effects. For any unexpected effects while taking TAMIFLU, contact your doctor or pharmacist.

HOW TO STORE IT

Keep this medication out of the reach of children.

Store away from heat.

Keep TAMIFLU capsules in their original labeled container at room temperature at 15 to 30degC and keep them in a dry place.

Keep TAMIFLU liquid suspension in its original labeled container in a refrigerator at 2 to 8degC. Do not freeze. The pharmacist will write the date of expiration on the bottle label.

Do not use this medicine after the expiry date on the package.

This leaflet does not provide all known information about TAMIFLU. If you have any questions or concerns about your treatment, please speak with your doctor or pharmacist.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone; 866-234-2345 By toll-free fax: 866-678-6789

Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada

Tunney's Pasture, AL 070lC Ottawa ON KIA OK9

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: www.rochecanada.com or by contacting the sponsor, Hoffmann-La Roche Limited, at 1-888-762-4388.

This leaflet was prepared by Hoffmann-La Roche Limited, Mississauga, L5N 6L7.

Oral dosing dispenser manufactured by F. Hoffmann- La Roche Ltd., 4070 Basel, Switzerland

TAMIFLU is manufactured under license from Gilead Sciences Inc. TAMIFLU is a registered Trade-Mark of F. Hoffmann-La Roche AG, used under license

Last revised: December 2, 2008