TAMIFLU 45 MG

Body weight

Recommended

dosage for

10 days of

treatment*

Which capsule should

be taken?

Less or equal

to 15 kg

30 mg

once daily

1 capsule of 30 mg

once daily

More than 15 kg

up to 23 kg

45 mg

once daily

1 capsule of 45 mg

once daily

More than 23 kg

up to 40 kg

60 mg

once daily

2 capsules of 30 mg

once daily

More than 40 kg

75 mg

once daily

1 capsule of 75 mg or

1 capsule of 30 mg

+ 1 capsule of 45 mg

once daily

* In the event of an outbreak of influenza in the community,

preventive treatment with Tamiflu can be taken for a period of up

to 6 weeks. Consult your attending doctor regarding for how long

the medicine should be taken.

Adults (from 13 years of age and above):

∙ Treatment

Start treatment immediately upon the first appearance of influenza

symptoms (up to 48 hours). The recommended dosage is 75 mg

Tamiflu twice daily for 5 days.

∙ Prevention

Start preventive treatment immediately after exposure to the

disease and/or as soon as you suspect you have been infected.

The recommended dosage is 75 mg Tamiflu once daily. The doctor

will recommend the length of time that the medicine has to be

taken for. Generally, when taking preventive treatment after close

contact with a person with influenza, the recommended length of

time will be at least 10 days.

In the event of an outbreak of influenza in the community, preventive

treatment with Tamiflu can be taken for up to 6 weeks

In patients suffering from kidney insufficiency (Creatinine clearance

10-60 mL/min), the dosages have to be adjusted.

During treatment with Tamiflu, if there is no improvement in the

influenza symptoms or there is a deterioration or development of

new symptoms, consult the attending doctor.

Do not exceed the recommended dosage.

Swallow the medicine with water.

In special circumstances and only with the instruction of your doctor

or pharmacist:

The capsule can be opened and its entire contents swallowed in

the following way:

∙ Take the required dose of Tamiflu capsules: 30, 45, 60 or 75 mg.

∙ Open the capsule carefully and pour the complete contents into

a cup or small bowl.

∙ Add a small amount, 1-2 teaspoons, of sweetened liquid or

food, e.g.: cocoa diluted with water, chocolate syrup, ice cream,

molasses, raspberry or maple syrup.

∙ Stir the mixture well and swallow the full amount.

Repeat the entire process in the same way each time you have to

take the required dose of Tamiflu.

ATTENTION:

For treatment of influenza: Start the treatment immediately upon

the first appearance of influenza symptoms (up to 48 hours).

Preventative treatment: Start immediately after exposure to the

disease and/or as soon as you suspect you have been infected

If you took an overdose or if a child has accidentally swallowed

the medicine, refer immediately to a hospital emergency room, and

bring the package of the medicine with you.

Take this medicine at set intervals, as determined by the attending

doctor. If you forgot to take this medicine at the scheduled time,

take a dose as soon as you remember; but never take two doses

together or at intervals of less than two hours! If you forgot to

take a several doses of this medicine, refer to the attending doctor

and follow his instructions.

Even if there is an improvement in your health, do not stop treatment

with the medicine without consulting the doctor.

Do not take medicines in the dark! Check the label and the dose

each time you take the medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult

the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Tamiflu

may cause side effects in some users.

Do not be alarmed by the list of side

effects. You may not suffer from any

of them.

Stop the treatment and refer to a

doctor immediately if you have an

allergic skin reaction or severe rash.

Stop the treatment and refer for medical

help if you develop any of the following symptoms:

∙ skin rash or urticaria

∙ blisters and peeling skin

∙ blisters or sores in the mouth

∙ itching

∙ swelling of the face, eyes, lips, tongue or throat

∙ breathing difficulties

∙ chest pain or tightness

Behavioral change. Refer to a doctor immediately if you suffer from

confusion, speech difficulty, hallucinations, restlessness, seizures,

abnormal behavior, anxiety, excessive nervousness, nightmares,

fear of self-harm (mainly among children).

Additional side effects:

Common side effects in adults and children over one year of age

are effects related to the gastrointestinal system, e.g.: Nausea,

vomiting, diarrhea, abdominal pains and headaches. These effects

are common at the start of treatment and generally resolve as

treatment continues. Taking the medicine with food may reduce

the chance of getting these side effects.

Less common side effects in adults, e.g.: Dizziness, headaches,

fatigue, sleeping difficulties, bronchitis, gastrointestinal bleeding,

cough, vertigo.

Less common side effects in children and infants over one year

of age, e.g.: Ear inflammations and other ear disorders, eye

inflammation, pneumonia, sinusitis, bronchitis, gastrointestinal

bleeding, aggravation of existing asthma, skin inflammation and

swelling of the lymph nodes.

Side effects of unknown frequency, e.g.: Mild to severe liver function

impairment, skin sensitivity, heart rhythm disorder and worsening

of diabetes.

Parents must inform the attending doctor about any side effect, as

well as any additional medicine being given to the child!

In the event that you experience side effects not mentioned in this

leaflet or if there a change in your general feeling, consult with the

doctor immediately.

Side effects can be reported to the Ministry of Health via the

online side effects report form available at the homepage of

the Ministry of Health www.health.gov.il or via the following

link: https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine, should be

kept in a safe place out of the reach of children and/or infants in

order to avoid poisoning. Do not induce vomiting unless explicitly

instructed to do so by the doctor

Do not use the medicine after the expiry date (exp. date) that

appears on the package. The expiry date refers to the last day

of that month.

Do not store above 25°C.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains

Pregelatinized starch, talc, povidone K 30, croscarmellose sodium,

sodium stearyl fumarate, titanum dioxide, iron oxide yellow, iron

oxide red, iron oxide black, gelatin, printing ink.

What the medicine looks like and the contents of the

package:

Tamiflu 30 mg capsules are yellow, with "ROCHE 30 mg" caption

imprinted on them in blue.

Tamiflu 45 mg capsules are gray, with "ROCHE 45 mg" caption

imprinted on them in blue.

Tamiflu 75 mg capsules are gray and yellow, with "ROCHE 75 mg"

caption imprinted on them in blue.

The capsules are available in tray (blister) packages containing

10 capsules.

License holder: Roche Pharmaceuticals (Israel) Ltd.

address: P.O.B. 6391, Hod Hasharon 4524079

Manufacturer: F. Hoffmann-La Roche Ltd., Basel, Switzerland

This leaflet was checked and approved by the Ministry of Health

on August 2015

Registration number of the medicine in the National Drug Registry

of the Ministry of Health:

Tamiflu capsules 30 mg: 138.02.31733

Tamiflu capsules 45 mg: 138.03.31734

Tamiflu capsules 75 mg: 118.79.29952

The format of this leaflet was determined by the Ministry of Health,

and its content was checked and approved by it in August 2015

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

(The medicine is dispensed with a doctor’s prescription only)

TAMIFLU

®

30 mg, 45 mg, 75 mg

Capsules

Each capsule contains:

Oseltamivir 30 mg, 45 mg, 75 mg

* For information on inactive ingredients, see section 6 "Further

Information".

Read this leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine, if you

have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment.

Do not pass it on to others. It may harm them, even if it seems to

you that their medical condition is similar.

This medicine is not intended to treat infants under one year of

age.

Important information for your review:

∙ Tamiflu is intended for treatment and prevention of influenza.

∙ Start the treatment immediately upon first appearance of influenza

symptoms (up to 48 hours).

1. WHAT IS THE MEDICINE INTENDED FOR?

Tamiflu is intended for the treatment of influenza in adults and

children over one year of age, who have been presenting influenza

symptoms for less than two days.

Tamiflu is intended to prevent influenza among adults and children

over one year of age (30 mg, 45 mg).

The medicine is available in the following forms:

- Tamiflu capsules 75 mg: only for adults and children weighing

more than 40 kg.

- Tamiflu capsules 30 mg and 45 mg, for adults and children one

year of age and older.

Therapeutic group:

Tamiflu is an antiviral medicine belonging to the “neuraminidase

inhibitors” group. This medicine prevents spread of the influenza

virus in the body. Tamiflu attacks the influenza virus itself, thereby

preventing or treating the influenza.

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

you have a known sensitivity to the active ingredient, Oseltamivir,

or to any of the ingredients of the medicine mentioned in section

6 "Further information".

Special warnings regarding use of the medicine:

Do not use this medicine without consulting a doctor before starting

treatment:

- if you are taking other medicines.

- if you are suffering from impaired function of the kidney, the

heart, the respiratory system, or from any other serious health

condition.

- if you have received an anti-influenza vaccination by nasal

administration within the two weeks preceding commencement

of treatment with Tamiflu or if you are due to receive an anti-

influenza vaccination by nasal administration 48 hours after

treatment with Tamiflu.

- if you are sensitive to any food or medicine, inform the doctor

before taking the medicine.

It is unknown whether treatment with Tamiflu is:

- effective in patients who took the medicine more than two days

after appearance of the influenza symptoms

- effective for treatment of influenza in patients with chronic heart

and respiratory problems

- effective for treatment and prevention of influenza in patients with

a weak immune system

- safe and effective in preventing influenza in children under one

year of age

Tamiflu is not intended for the treatment or prevention of viral

infections other than influenza, even if they are accompanied by

flu-like symptoms.

The signs that generally characterize

influenza are fever above 37.8°C,

cough, sore throat, stuffed or runny

nose, headache, muscle aches, and

extreme fatigue. Influenza is usually

worse than a regular cold and may

last longer than a cold.

Tamiflu does not prevent bacterial

infections that may develop with

influenza.

Use of Tamiflu does not offset the need for an annual anti-influenza

vaccination for potential recipients.

Patients with influenza, especially children and adolescents, may be

at an increased risk of seizures, confusion or abnormal behavior in

the early stages of influenza. These events can occur at the start of

Tamiflu treatment for influenza or when influenza is not treated.

These events are not common, but since they may lead to self-

injury, the parent or patient should refer to the attending doctor

immediately upon appearance of signs of abnormal behavior (see

section 4 "Side effects").

Cases of allergic skin reactions have been reported after taking

Tamiflu. If you develop an allergic skin reaction or severe rash,

stop the treatment and refer to the attending doctor (see section

4 "Side effects").

Tamiflu and other medicines

If you are taking, or have recently taken, other medicines, including

non-prescription medicines or nutritional supplements, tell the

doctor or pharmacist. In particular, inform the doctor or pharmacist if

you received an anti-influenza vaccination by nasal administration

within the two weeks preceding commencement of treatment with

Tamiflu or if you are due to receive an anti-influenza vaccination by

nasal administration 48 hours after treatment with Tamiflu.

Use of Tamiflu and food

Do not chew! Swallow the medicine with water.

The medicine can be taken with or without food. However, taking

the medicine with food may lower the chance of gastrointestinal

side effects (e.g., nausea and vomiting).

Pregnancy and breastfeeding

- Consult with the doctor if you are pregnant or are planning to

become pregnant. It is not known how Tamiflu may affect your

baby. Tamiflu can only be used during pregnancy if the benefits

of treatment justify the possible risk to your unborn baby.

- Consult with the doctor if you are breastfeeding or plan to

breastfeed. It is not known if Tamiflu passes into breast milk. The

doctor will decide if you can take Tamiflu when breastfeeding.

Driving and operating machinery

Use of this medicine does not impair ability to drive a car or operate

machinery.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions.

Check with the doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by the doctor

only. The usual dosage is generally:

Children - 1 year of age and older:

∙ Treatment

Start treatment immediately upon the first appearance of influenza

symptoms (up to 48 hours). Take Tamiflu twice a day for 5 days.

One capsule in the morning and one in the evening.

The dosage given to children for treatment of influenza depends

upon their body weight as detailed in the following table.

Body weight

Recommended

dosage for

5 days of

treatment

Which capsule should

be taken?

Less or equal

to 15 kg

30 mg

twice daily

1 capsule of 30 mg

twice daily

More than 15 kg

up to 23 kg

45 mg

twice daily

1 capsule of 45 mg

twice daily

More than 23 kg

up to 40 kg

60 mg

twice daily

2 capsules of 30 mg

twice daily

More than 40 kg

75 mg

twice daily

1 capsule of 75 mg or

1 capsule of 30 mg

+ 1 capsule of 45 mg

twice daily

∙ Prevention

Start preventive treatment immediately after exposure to the

disease and/or as soon as you suspect you have been infected.

Tamiflu should be taken once a day for 10 days.

The dosage given to children for prevention of influenza depends

upon their body weight as detailed in the following table

טמרופ

ןולע

הז

עבקנ

ע

"

י

דרשמ

תואירבה

ונכותו

קדבנ

רשואו

לע

ודי

ב

טסוגוא

2015

Tamiflu

®

Oseltamivir

CAPSULES

1

INDICATIONS AND USAGE

Treatment of Influenza

The treatment of uncomplicated acute illness due to influenza infection in adults and children 1 year of age or

older (30mg and 45 mg) who have been symptomatic for no more than 2 days.

Prophylaxis of Influenza

Post exposure prevention in adults and children 1 year of age or older following contact with a clinically

diagnosed influenza case when influenza virus is circulating in the community.

The appropriate use of Tamiflu for prevention of influenza should be determined on a case by case basis by

the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a

mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention

could be considered in adults and children 1 year of age or older.

TAMIFLU CAPSULES 75 mg is indicated for patients who weight > 40 k body weight.

Limitations of Use

The following points should be considered before initiating treatment or prophylaxis with TAMIFLU:

Efficacy of TAMIFLU in patients who begin treatment after 48 hours of symptoms has not been established.

TAMIFLU is not a substitute for early influenza vaccination on an annual basis as recommended by the

MOH (Ministry of Health).

There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza viruses

types A and B.

Influenza viruses change over time. Emergence of resistance mutations 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.

2

DOSAGE AND ADMINISTRATION

2.1

Dosing for Treatment and Prophylaxis of Influenza

Treatment should begin within 2 days of onset of symptoms of influenza or following close contact with an

infected individual.

TAMIFLU may be taken with or without food [see Clinical Pharmacology (12.3)]. However, when taken with

food, tolerability may be enhanced in some patients.

For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation. If the

oral suspension product is not available, 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). If the appropriate strengths of TAMIFLU capsules are not available to mix with sweetened liquids and

the oral suspension product is not available, then a pharmacist may compound an emergency supply of oral

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

suspension from TAMIFLU 75 mg capsules.

2.2

Treatment of Influenza

Adults and Adolescents (13 years of age and older)

The recommended oral dose of TAMIFLU for treatment of influenza in adults and adolescents 13 years and

older is 75 mg twice daily for 5 days.

Pediatric Patients (1 to 12 years of age)

TAMIFLU is not indicated for treatment of influenza in pediatric patients younger than 1 year.

The recommended oral dose of TAMIFLU for treatment of influenza in pediatric patients 1 year and older is

shown in the table below (Table 1).

2.3

Prophylaxis of Influenza

Adults and Adolescents (13 years of age and older)

The recommended oral dose of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and

older following close contact with an infected individual is 75 mg once daily for at least 10 days. The

recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and

efficacy have been demonstrated for up to 6 weeks in immunocompetent patients. The duration of protection

lasts

long

dosing

continued.

Safety

been

demonstrated

weeks

immunocompromised patients.

Pediatric Patients (1 to 12 years of age)

The recommended oral dose of Tamiflu for prophylaxis of influenza in pediatric patients 1 to 12 years of age is

shown in Table 1. Prophylaxis in pediatric patients following close contact with an infected individual is

recommended for 10 days. For prophylaxis in pediatric patients during a community outbreak of oseltamivir

susceptible influenza, dosing may be continued for up to 6 weeks.

The safety and efficacy of TAMIFLU for prophylaxis of influenza in pediatric patients younger than 1 year of

age have not been established.

Table 1

Treatment (twice daily dosing for 5 days) and Prophylaxis (once daily dosing for 10 days)

Dosing of Oral TAMIFLU for Influenza in Pediatric Patients

Weight

(kg)

Treatment Dosing

for 5 days

Prophylaxis Dosing

for 10 days

Number of Capsules and

Strength to Dispense

Patients 1 to 12 Years of Age Based on Body Weight

15 kg or less

30 mg twice daily

30 mg once daily

10 Capsules

30 mg

15.1 kg thru 23 kg

45 mg twice daily

45 mg once daily

10 Capsules

45 mg

23.1 kg thru 40 kg

60 mg twice daily

60 mg once daily

20 Capsules

30 mg

40.1 kg or more

75 mg twice daily

75 mg once daily

10 Capsules

75 mg

* An oral dosing dispensing device that measures the appropriate volume in mL should be utilized with the oral suspension.

† Oral Suspension is the preferred formulation for patients who cannot swallow capsules.

2.4

Renal Impairment

Data are available on plasma concentrations of oseltamivir carboxylate following various dosing schedules in

patients with renal impairment [see Clinical Pharmacology (12.3)].

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

Treatment of Influenza

Dose adjustment is recommended for adult patients with creatinine clearance between 10 and 60 mL/min and

patients with end-stage renal disease (ESRD) undergoing hemodialysis or continuous peritoneal dialysis

receiving TAMIFLU for the treatment of influenza [see Clinical Pharmacology (12.3)]. TAMIFLU is not

recommended for patients with ESRD not undergoing dialysis. The recommended doses are detailed in Table 2

below.

Table 2

Recommended Dose Adjustments for Treatment of Influenza in Adult Patients with Renal

Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment/Creatinine Clearance

Recommended Treatment Regimen

*

Mild

Creatinine Clearance >60-90 mL/min

75 mg twice daily for 5 days

Moderate

Creatinine Clearance >30-60 mL/min

30 mg twice daily for 5 days

Severe

Creatinine Clearance >10-30 mL/min

30 mg once daily for 5 days

ESRD Patients on Hemodialysis

Creatinine Clearance ≤10 mL/min

30 mg after every hemodialysis cycle.

Treatment duration not to exceed 5 days

ESRD Patients on Continuous Ambulatory Peritoneal

Dialysis

Creatinine Clearance ≤10 mL/min

A single 30 mg dose administered immediately after a

dialysis exchange

* Capsules or suspension can be used for 30 mg dosing.

† Assuming three hemodialysis sessions are performed in the 5-day period. Treatment can be initiated immediately if influenza

symptoms develop during the 48 hours between hemodialysis sessions; however, the post-hemodialysis dose should still be

administered independently of time of administration of the initial dose.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Prophylaxis of Influenza

For the prophylaxis of influenza, dose adjustment is recommended for adult patients with creatinine clearance

between 10 and 60 mL/min and patients with end-stage renal disease (ESRD) undergoing hemodialysis or

continuous peritoneal dialysis receiving TAMIFLU [see Clinical Pharmacology (12.3)]. The duration of

prophylaxis

same

recommended

patients

with

normal

renal

function.

TAMIFLU

recommended for patients with ESRD not undergoing dialysis. The recommended doses are detailed in Table 3

below.

Table 3

Recommended Dose Adjustments for Prophylaxis of Influenza in Adult Patients with Renal

Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment/Creatinine Clearance

Recommended Prophylaxis Regimen

*

Mild

Creatinine Clearance >60-90 mL/min

75 mg once daily

Moderate

Creatinine Clearance >30-60 mL/min

30 mg once daily

Severe

Creatinine Clearance >10-30 mL/min

30 mg every other day

ESRD Patients on Hemodialysis

Creatinine Clearance ≤10 mL/min

30 mg after alternate hemodialysis cycles

ESRD Patients on Continuous Ambulatory Peritoneal

Dialysis

Creatinine Clearance ≤10 mL/min

30 mg once weekly immediately after dialysis exchange

* Capsules or suspension can be used for 30 mg dosing.

† An initial dose can be administered prior to the start of dialysis.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

2.5

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh

score

9) [see Clinical Pharmacology: 12.3 ].

2.6

Geriatric Patients

No dose adjustment is required for geriatric patients [see use in Specific Populations (8.4) and Clinical

Pharmacology (12.3)].

3

DOSAGE FORMS AND STRENGTHS

Capsules: 30 mg, 45 mg, 75 mg

30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules.

“ROCHE” is printed in blue ink on the light yellow body and “30 mg” is printed in blue ink on the light

yellow cap.

45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules. “ROCHE” is

printed in blue ink on the grey body and “45 mg” is printed in blue ink on the grey cap.

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.

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

anaphylaxis

serious

skin

reactions

including

toxic

epidermal

necrolysis,

Stevens-Johnson

Syndrome,

erythema

multiforme

have

been

reported

postmarketing

experience

with

TAMIFLU.

TAMIFLU should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is

suspected.

5.2

Neuropsychiatric Events

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.

There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to

injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU.

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.

Closely monitor patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur,

evaluate the risks and benefits of continuing treatment for each patient.

5.3

Bacterial Infections

Serious

bacterial

infections

begin

with

influenza-like

symptoms

coexist

with

occur

complications during the course of influenza. TAMIFLU has not been shown to prevent such complications.

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

5.4

Limitations of Populations Studied

Efficacy of TAMIFLU in the treatment of influenza in patients 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.

Efficacy

TAMIFLU

treatment

prophylaxis

influenza

been

established

immunocompromised patients.

Safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have

not been established. Safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established

for pediatric patients less than 1 year of age.

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)]

The most common adverse reactions are nausea and vomiting.

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

Treatment Studies in Adult and adolescent Subjects (13 years of age and older)

A total of 1171 subjects who participated in adult controlled clinical trials for the treatment of influenza were

treated with TAMIFLU. The most frequently reported adverse events in these studies were nausea and

vomiting. These events were generally of mild to moderate severity and usually occurred on the first 2 days of

administration. Less than 1% of subjects discontinued prematurely from clinical trials due to nausea and

vomiting.

Adverse events that occurred with an incidence of

1% in 1440 subjects taking placebo or TAMIFLU 75 mg

twice daily in adult treatment studies are shown in Table 4. This summary includes 945 healthy young adults

and 495 “at risk” subjects (elderly patients and patients with chronic cardiac or respiratory disease). Those

events reported numerically more frequently in subjects taking TAMIFLU compared with placebo were nausea,

vomiting, bronchitis, insomnia, and vertigo.

Prophylaxis Studies in Adult and adolescent Subjects (13 years of age and older)

A total of 4187 subjects (adolescents, healthy adults, and elderly) participated in prophylaxis studies, of whom

1790 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively

very similar to those seen in the treatment studies, despite a longer duration of dosing (see Table 4). Events

reported

more

frequently

subjects

receiving

TAMIFLU

compared

subjects

receiving

placebo

prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhea, dyspepsia

and upper respiratory tract infections. However, the difference in incidence between TAMIFLU and placebo for

these events was less than 1%. There were no clinically relevant differences in the safety profile of the 942

elderly subjects who received TAMIFLU or placebo, compared with the younger population.

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

Table 4

Most Frequent Adverse Events in Studies in Naturally Acquired Influenza in Subjects 13 Years

of Age and Older

Treatment

Prophylaxis

Adverse Event

Placebo

N=716

TAMIFLU

75 mg twice

daily

N=724

Placebo/

No

Prophylaxis

b

N=1688

TAMIFLU

75 mg once

daily

N=1790

Nausea (without vomiting)

(6%)

(10%)

(3%)

(7%)

Vomiting

(3%)

(9%)

(1%)

(2%)

Diarrhea

(10%)

(7%)

(2%)

(3%)

Bronchitis

(2%)

(2%)

(1%)

(1%)

Abdominal pain

(2%)

(2%)

(1%)

(2%)

Dizziness

(3%)

(2%)

(1%)

(1%)

Headache

(2%)

(2%)

(18%)

(18%)

Cough

(2%)

(1%)

(7%)

(5%)

Insomnia

(1%)

(1%)

(1%)

(1%)

Vertigo

(1%)

(1%)

(<1%)

(<1%)

Fatigue

(1%)

(1%)

(10%)

(8%)

Adverse events included are all events reported in the treatment studies with frequency

1% in the TAMIFLU 75 mg twice daily

group.

The majority of subjects received placebo; 254 subjects from a randomized, open-label postexposure prophylaxis study in

households did not receive placebo or prophylaxis therapy.

Additional adverse events occurring in <1% of patients receiving TAMIFLU for treatment included unstable

angina, anemia, pseudomembranous colitis, humerus fracture, pneumonia, pyrexia, and peritonsillar abscess.

Treatment Studies in Pediatric Subjects (1 to 12 years of age)

A total of 1032 pediatric subjects aged 1 to 12 years (including 698 otherwise healthy pediatric subjects aged 1

to 12 years and 334 asthmatic pediatric subjects aged 6 to 12 years) participated in controlled clinical trials of

TAMIFLU given for the treatment of influenza. A total of 515 pediatric subjects received treatment with

TAMIFLU for oral suspension.

Adverse events occurring in

1% of pediatric subjects receiving TAMIFLU treatment are listed in Table 5. The

most frequently reported adverse event was vomiting. Other events reported more frequently by pediatric

subjects treated with TAMIFLU included abdominal pain, epistaxis, ear disorder, and conjunctivitis. These

events generally occurred once and resolved despite continued dosing resulting in discontinuation of drug in 8

out of 515 (2%) cases.

The adverse event profile in adolescents is similar to that described for adult subjects and pediatric subjects

aged 1 to 12 years.

Prophylaxis Studies in Pediatric Subjects (1 to 12 years of age)

Pediatric subjects aged 1 to 12 years participated in a postexposure prophylaxis study in households, both as

index cases (n=134) and as contacts (n=222). Gastrointestinal events were the most frequent, particularly

vomiting. In a separate 6-week, uncontrolled, pediatric seasonal prophylaxis study (n=49), the adverse events

noted were consistent with those previously observed (see Table 5).

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

Table 5

Most Frequent Adverse Events Occurring in Children Aged

1 to 12 Years in Studies in Naturally Acquired Influenza

Treatment Trials

b

Household Prophylaxis Trial

c

Adverse Event

Placebo

N=517

TAMIFLU

2 mg/kg twice

daily

N=515

No

Prophylaxis

d

N=87

Prophylaxis

with

TAMIFLU

once daily

d

N=99

Vomiting

(9%)

(15%)

(2%)

(10%)

Diarrhea

(11%)

(10%)

(1%)

Otitis media

(11%)

(9%)

(2%)

(2%)

Abdominal pain

(4%)

(5%)

(3%)

Asthma (including

aggravated)

(4%)

(3%)

(1%)

(1%)

Nausea

(4%)

(3%)

(1%)

(4%)

Epistaxis

(3%)

(3%)

(1%)

Pneumonia

(3%)

(2%)

(2%)

Ear disorder

(1%)

(2%)

Sinusitis

(3%)

(2%)

Bronchitis

(2%)

(2%)

(2%)

Conjunctivitis

(<1%)

(1%)

Dermatitis

(2%)

(1%)

Lymphadenopathy

(2%)

(1%)

Tympanic membrane

disorder

(1%)

(1%)

Adverse events included in Table 5 are all events reported in the treatment studies with frequency

1% in the TAMIFLU 75 mg

twice daily group.

Pooled data from trials of TAMIFLU treatment of naturally acquired influenza.

A randomized, open-label study of household transmission in which household contacts received either prophylaxis or no

prophylaxis but treatment if they became ill. Only contacts who received prophylaxis or who remained on no prophylaxis are included

in this table.

Unit dose = age-based dosing of 30 mg, 45 mg, or 60 mg

Prophylaxis Study in Immunocompromised Subjects

In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects

1 to 12 years of age, the safety profile in the 238 subjects receiving TAMIFLU was consistent with that

previously observed in other TAMIFLU prophylaxis clinical trials.

6.2

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TAMIFLU. Because these

reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their

frequency or establish a causal relationship to TAMIFLU exposure.

Body as a Whole: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia

Dermatologic: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome,

erythema multiforme [see Warnings and Precautions (5.1)]

Digestive: Hepatitis, liver function tests abnormal

Cardiac: Arrhythmia

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

Gastrointestinal disorders: Gastrointestinal bleeding, hemorrhagic colitis

Neurologic: Seizure

Metabolic: Aggravation of diabetes

Psychiatric: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered

level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation

by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.health.gov.

il ) or by email (adr@MOH.HEALTH.GOV.IL ).

7

DRUG INTERACTIONS

Influenza Vaccines

The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been

evaluated. However, because of the potential for interference between these products, LAIV should not be

administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated.

The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live

vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of

TAMIFLU.

Overall Drug Interaction Profile for Oseltamivir

Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically

significant drug interactions are unlikely.

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver.

Drug interactions involving competition for esterases have not been extensively reported in literature. Low

protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement

interactions is low.

In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450

mixed-function oxidases or for glucuronyl transferases.

Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the

known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate

(glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways.

Coadministration

probenecid

results

approximate

two-fold

increase

exposure

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 pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin,

acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), or

warfarin.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Category C

There are insufficient human data upon which to base an evaluation of risk of TAMIFLU to the pregnant

woman or developing fetus. Studies for effects on embryo-fetal development were conducted in rats (50, 250,

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route. Relative exposures at these

doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure

in the rabbit. Pharmacokinetic studies indicated that fetal exposure was seen in both species. In the rat study,

minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked

maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. There was a dose-

dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in the

exposed offspring in these studies. However, the individual incidence rate of each skeletal abnormality or

variant remained within the background rates of occurrence in the species studied.

Because animal reproductive studies may not be predictive of human response and there are no adequate and

well-controlled studies in pregnant women, TAMIFLU should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus.

8.2

NURSING MOTHERS

In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether

oseltamivir or oseltamivir carboxylate is excreted in human milk. TAMIFLU should, therefore, be used only if

the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant.

8.3

PEDIATRIC USE

The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been studied.

TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than

1 year of age because of the unknown clinical significance of nonclinical animal toxicology data for human

infants [see Nonclinical Toxicology (13.2)].

8.4

GERIATRIC USE

Of the total number of subjects in clinical studies of TAMIFLU for the treatment of influenza, 19% were 65 and

over, while 7% were 75 and over. Of the total number of patients in clinical studies of TAMIFLU for the

prophylaxis of influenza, 25% were 65 and over, while 18% were 75 and over. 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.

The safety of TAMIFLU in geriatric subjects has been established in clinical studies that enrolled 741 subjects

(374 received placebo and 362 received TAMIFLU). Some seasonal variability was noted in the clinical

efficacy outcomes) [see Clinical Studies (14.1)].

Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU for up

to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and

most had received vaccine that season [see Clinical Studies (14.2)].

8.5

Renal Impairment

Dose adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/min and

for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal

dialysis treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.6

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 Dosage and

Administration (2.5) and Clinical Pharmacology (12.3)].

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 events were reported. Adverse events

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

reported following overdose were similar in nature to those observed with therapeutic doses of TAMIFLU [see

Adverse Reactions (6)].

11

DESCRIPTION

TAMIFLU (oseltamivir) 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 pregelatinized

starch, talc, povidone K 30, croscarmellose sodium, and sodium stearyl fumarate. The 30 mg capsule shell

contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains

gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide,

yellow iron oxide, black iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes

FD&C Blue No. 2 as the colorant.

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

(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:

COOC

.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Oseltamivir is an antiviral drug [see Clinical Pharmacology (12.4)].

12.3

Pharmacokinetics

Absorption and Bioavailability

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate

and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. At least 75% of an

oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of

the total exposure after oral dosing (see Table 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

(ng/mL)

65 (26)

348 (18)

0-12h

(ng·h/mL)

112 (25)

2719 (20)

Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily

Coadministration with food has no significant effect on the peak plasma concentration (551 ng/mL under fasted

conditions and 441 ng/mL under fed conditions) and the area under the plasma concentration time curve

(6218 ng·h/mL under fasted conditions and 6069 ng·h/mL under fed conditions) of oseltamivir carboxylate.

Distribution

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

The volume of distribution (V

) of oseltamivir carboxylate, following intravenous administration in 24 subjects,

ranged between 23 and 26 liters.

The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of oseltamivir to

human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Metabolism

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver.

Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.

Elimination

Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma

concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration.

Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of

oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.

Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds

glomerular filtration rate (7.5 L/h), indicating that tubular secretion occurs in addition to glomerular filtration.

Less than 20% of an oral radiolabeled dose is eliminated in feces.

Specific Populations

Renal Impairment

Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various degrees of

renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal

function.

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

prophylaxis

regimens

provided

Table

pharmacokinetics

oseltamivir

have

been

studied

ESRD

patients

undergoing

dialysis

[see

Dosage

and

Administration (2.4)].

Table 7

Simulated Median Treatment Metrics of Oseltamivir Carboxylate Exposures in Normal

Renally Impaired and ESRD Patients on Hemodialysis

Renal Function/

Impairment

Normal

Creatinine

Clearance 90-

140 mL/min

(n=57)

Mild

Creatinine

Clearance 60-

90 mL/min

(n=45)

Moderate

Creatinine

Clearance 30-

60 mL/min

(n=13)

Severe Creatinine

Clearance

10-

30 mL/min (n=11)

ESRD

Creatinine Clearance on

Hemodialysis

(n=24)

Recommended Treatment Regimens

PK exposure

parameter

75 mg twice

daily

75 mg twice

daily

30 mg twice

daily

30 mg once daily

30 mg every HD cycle

(ng/mL)

(ng/mL)

1170

(ng h/mL)*

11224

18476

12008

16818

23200

Recommended Prophylaxis Regimens

PK exposure

parameter

75 mg once daily

75 mg once

daily

30 mg once

daily

30 mg every other

day

30 mg alternate HD cycle

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

Renal Function/

Impairment

Normal

Creatinine

Clearance 90-

140 mL/min

(n=57)

Mild

Creatinine

Clearance 60-

90 mL/min

(n=45)

Moderate

Creatinine

Clearance 30-

60 mL/min

(n=13)

Severe Creatinine

Clearance

10-

30 mL/min (n=11)

ESRD

Creatinine Clearance on

Hemodialysis

(n=24)

(ng/mL)

(ng/mL)

(ng hr/mL)*

5294

8336

6262

9317

11200

*AUC normalized to 48 hours.

Hepatic Impairment

In clinical studies oseltamivir carboxylate exposure was not altered in patients with mild or moderate hepatic

impairment [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].

Pediatric Patients (1 to 12 years of age)

pharmacokinetics

oseltamivir

oseltamivir

carboxylate

have

been

evaluated

single-dose

pharmacokinetic study in pediatric patients aged 5 to 16 years (n=18) and in a small number of pediatric

patients aged 3 to 12 years (n=5) enrolled in a clinical trial. Younger pediatric patients cleared both the prodrug

and the active metabolite faster than adult patients resulting in a lower exposure for a given mg/kg dose. For

oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). The

pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are similar to those in adult patients.

Geriatric Patients

Exposure to oseltamivir carboxylate at steady-state was 25% to 35% higher in geriatric patients (age range 65 to

78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric

patients were similar to those seen in young adults. Based on drug exposure and tolerability, dose adjustments

are not required for geriatric patients for either treatment or prophylaxis [see Dosage and Administration (2.6)].

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.

Antiviral Activity

The antiviral activity and neuraminidase inhibitory activity of oseltamivir carboxylate against laboratory strains

and clinical isolates of influenza virus was determined in cell culture and biochemical assays. 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

and EC

) were in the range of 0.0008

M to >35

M and 0.004

M to >100

M, respectively

M=0.284

g/mL). The median IC

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. 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

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

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, from

clinical isolates collected during treatment with oseltamivir, and from viral isolates sampled during community

surveillance studies. 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. 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

substitutions associated with oseltamivir resistance include A28T and R124M in influenza A H3N2 and H154Q

in H1N9, a reassortant human/avian virus.

Table 8

Neuraminidase Amino Acid Substitutions Observed in Oseltamivir Treatment

Studies or Community Surveillance

Amino Acid Substitution

Influenza Type/

Sub-type

Source

Catalytic Residues

R292K

A N2

Roche clinical trials, publication,

surveillance

Framework Residues

H275Y

A N1

Roche clinical trials, publication,

surveillance

N294S

A N1, N2

Publications

E119V

A N2

Roche clinical trials, publication,

surveillance

SASG245-248 deletion

A N2

Roche clinical trial

I222V

A N2

Publication

I222T

Publication

D198N

Publication, surveillance

D198E

Surveillance

R371K

Surveillance

G402S

Publication

Substitutions identified by surveillance data only; population and use of TAMIFLU are unknown

Selection of influenza A viruses resistant to oseltamivir can occur at higher frequencies in children. The

incidence of oseltamivir treatment-associated resistance in pediatric treatment studies has been detected at rates

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 and influenza A/H3N2, respectively. 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 >99% of US circulating 2008 H1N1 influenza isolates. The 2009 H1N1

influenza (“swine flu”) was almost uniformly susceptible to oseltamivir. Prescribers should consider available

information from the CDC on influenza 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,

S250G

zanamivir

resistance-associated

substitutions

observed

influenza

confer

reduced

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

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 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 proposed

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.

fertility

early

embryonic

development

study

rats,

doses

oseltamivir

250,

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 was approximately 100 times the human systemic exposure (AUC

0-24h

) of oseltamivir carboxylate.

13.2

Animal Toxicology and/or Pharmacology

Single, oral administration of

657 mg/kg oseltamivir resulted in toxicity, including death, in juvenile 7 day old

rats, but had no effect on adult rats. No toxicity was observed after repeated administration of up to 500 mg/kg

oseltamivir to developing juvenile rats 7 to 21 days old. This 500 mg/kg dose was approximately 280 and 14

times the human systemic exposure (AUC

0-24h

) of oseltamivir and oseltamivir carboxylate, respectively. Clinical

relevance of the juvenile rat study finding for young infants is unknown.

14

CLINICAL STUDIES

14.1

Treatment of Influenza

Adult and Adolescent Subjects (13 years of age and older)

Two placebo-controlled double-blind clinical trials were conducted: one in the U.S. and one outside the U.S.

Subjects were eligible for these trials if they had fever > 100

F (37.8ºC), accompanied by at least one

respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia,

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community.

In addition, all subjects enrolled in the trials were allowed to take fever-reducing medications.

Of 1355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (age range 18 to

65 years; 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.

TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were required

self-assess

influenza-associated

symptoms

“none,”

“mild,”

“moderate,”

“severe.”

Time

improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal

congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as “none” or “mild.”

In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day

reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to

subjects receiving placebo. Subgroup analyses of these studies by gender showed no differences in the treatment

effect of TAMIFLU in men and women.

In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg

TAMIFLU twice daily for 5 days.

Geriatric Subjects

Three double-blind placebo-controlled treatment trials were conducted in subjects

65 years of age in three

consecutive seasons. The enrollment criteria were similar to that of adult trials with the exception of fever being

defined as >97.5

F (36.9

C). Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected. Of the 476

influenza-infected subjects, 95% were infected with influenza type A and 5% with influenza type B.

In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1-day

reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to

those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies.

Pediatric Subjects (1 to 12 years of age)

One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 to 12 years

(median age 5 years), who had fever (>100ºF/37.8

C) 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.

The primary endpoint in this study was the time to freedom from illness, a composite endpoint that required 4

individual conditions to be met. These were: alleviation of cough, alleviation of coryza, resolution of fever, and

parental opinion of a return to normal health and activity. TAMIFLU treatment of 2 mg/kg twice daily, started

within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by

1.5 days compared to placebo. Subgroup analyses of this study by gender showed no differences in the

treatment effect of TAMIFLU in male and female pediatric subjects.

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 studies and a postexposure prophylaxis study in households. The primary efficacy

parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. Laboratory-

confirmed clinical influenza was defined as oral temperature

99.0ºF/37.2ºC plus at least one respiratory

symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain,

fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a four-

fold increase in virus antibody titers from baseline.

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years),

TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of

laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the

TAMIFLU group.

In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily

taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4% (12/272) for the

placebo group to <1% (1/276) for the TAMIFLU group. About 80% of this elderly population were vaccinated,

14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.

In a study of postexposure prophylaxis in household contacts (aged

13 years) of an index case, TAMIFLU

75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days

reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1%

(2/205) for the TAMIFLU group. Index cases did not receive TAMIFLU in the study.

Pediatric Subjects (1 to 12 years of age)

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a

randomized, open-label, postexposure prophylaxis study in households that included children aged 1 to

12 years, both as index cases and as family contacts. All index cases in this study received treatment. The

primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the

household. Laboratory-confirmed clinical influenza was defined as oral temperature

F/37.8

C plus cough

and/or coryza recorded within 48 hours, plus 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 to 12 years of age not

already shedding virus at baseline, TAMIFLU for oral suspension 30 mg to 60 mg taken once daily for 10 days

reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving

prophylaxis to 3% (3/95) in the group receiving prophylaxis.

Immunocompromised Subjects

double-blind,

placebo-controlled

study

conducted

seasonal

prophylaxis

influenza

immunocompromised subjects (including 18 pediatric subjects 1 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 1105 days for the placebo group and 1379 days for the

oseltamivir group. Median time since transplant for hematopoietic stem cell transplant recipients was 424 days

for the placebo group and 367 days for the oseltamivir group. Approximately 40% of subjects received

influenza vaccine prior to entering the study. The primary efficacy endpoint for this study was the incidence of

confirmed, clinical influenza, defined as oral temperature >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. The incidence of confirmed clinical influenza was 3% (7/238) in the group not receiving TAMIFLU

compared with 2% (5/237) in the group receiving TAMIFLU; this difference was not statistically significant. A

secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation

of influenza. Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-

confirmed clinical influenza was 3% (7/231) in the group not receiving TAMIFLU and <1% (1/232) in the

group receiving TAMIFLU.

16

HOW SUPPLIED/STORAGE

30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules.

“ROCHE” is printed in blue ink on the light yellow body and “30 mg” is printed in blue ink on the light yellow

cap. Available in blister packages of 10.

45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules. “ROCHE” is

printed in blue ink on the grey body and “45 mg” is printed in blue ink on the grey cap. Available in blister

packages of 10.

Ref: US PI 7.0 CDS 13

Tamiflu PI Ver1.0

75-mg capsules

(75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules.

“ROCHE” is printed in blue ink on the grey body and “75 mg” is printed in blue ink on the light yellow cap.

Available in blister packages of 10.

STORAGE

Do not store above 25

17

PATIENT COUNSELING INFORMATION

17.1

Information for Patients

Patients and/or caregivers should be advised of the risk of severe allergic reactions (including anaphylaxis) or

serious skin reactions and should stop TAMIFLU and seek immediate medical attention if an allergic-like

reaction occurs or is suspected.

Patients and/or caregivers should be advised of the risk of neuropsychiatric events in patients with influenza and

should contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU. Their

physician will determine if TAMIFLU treatment should be continued.

Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu

symptoms. Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a

physician.

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.

TAMIFLU is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination

according to guidelines on immunization practices.

18

LICENSE HOLDER

Roche Pharmaceuticals (Israel) Ltd., P.O.B. 6391, Hod Hasharon 4524079.

19

LICENSE NUMBER

Tamiflu Capsules 30 mg: 138 02 31733

Tamiflu Capsules 45 mg: 138 03 31734

Tamiflu Capsules 75 mg: 118 79 29952

20

MANUFACTURER

F. Hoffmann-La Roche Ltd., Basel, Switzerland

Medicine: keep out of reach of children