Consumer medicine information

Tamiflu Capsules

Oseltamivir

BRAND INFORMATION

Brand name

Tamiflu

Active ingredient

Oseltamivir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tamiflu Capsules.

SUMMARY CMI

Tamiflu® Capsules

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Tamiflu?

Tamiflu contains the active ingredient oseltamivir. Tamiflu is used to treat and prevent influenza (an infection caused by influenza virus). For more information, see Section 1. Why am I using Tamiflu? in the full CMI.

2. What should I know before I use Tamiflu?

Do not use if you have ever had an allergic reaction to Tamiflu or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.
For more information, see Section 2. What should I know before I use Tamiflu? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tamiflu and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Tamiflu?

  • Taking Tamiflu with food may reduce the potential for some or all of side effects.
  • Do not break or chew the capsules before swallowing.
  • If you are unable to swallow capsules, your doctor may prescribe Tamiflu 6 mg/mL oral suspension.

More instructions can be found in Section 4. How do I use Tamiflu? in the full CMI.

5. What should I know while using Tamiflu?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Tamiflu.
  • If symptoms do not improve and you still feel unwell after taking Tamiflu, talk to your doctor.
  • Tell your doctor if you have kidney failure, impairment, or any other problems with your kidneys.
  • Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.
  • Be sure to keep all of your appointments with your doctor so that your progress can be checked.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not give Tamiflu capsules to anyone else even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how Tamiflu affects you.
Looking after your medicine
  • Keep your capsules in the blister pack until it is time to take them.
  • Keep Tamiflu capsules in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using Tamiflu? in the full CMI.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are taking Tamiflu capsules. Common side effects include nausea, vomiting, headache and pain. Tell your doctor immediately or go to your nearest Emergency Department if you notice signs or symptoms of a serious allergic reaction such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Tamiflu® Capsules

Active ingredient: oseltamivir


Consumer Medicine Information (CMI)

This leaflet provides important information about using Tamiflu.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Tamiflu.

Where to find information in this leaflet:

1. Why am I using Tamiflu?
2. What should I know before I use Tamiflu?
3. What if I am taking other medicines?
4. How do I use Tamiflu?
5. What should I know while using Tamiflu?
6. Are there any side effects?
7. Product details

1. Why am I using Tamiflu?

Tamiflu contains the active ingredient oseltamivir. Tamiflu is an antiviral medicine.

Tamiflu is used for treatment and prevention of influenza (an infection caused by influenza virus). It has no effect on the common cold or other respiratory virus infections.

Tamiflu attacks the influenza virus and prevents it from spreading inside your body. Give Tamiflu capsules as directed by your doctor or pharmacist.

Tamiflu is absorbed to the key sites of influenza infection and treats the cause. Tamiflu will help reduce the chances of you passing the flu onto someone else. Taking Tamiflu can prevent you from catching the flu, or if you have already caught the flu, taking Tamiflu may help you feel better faster.

You will also be less likely to develop complications of influenza, such as bronchitis, pneumonia and sinusitis. Typical symptoms of influenza include fever, headache, muscle aches, sore throat, cough and generally feeling unwell.

Ask your doctor or pharmacist if you have any questions about why Tamiflu has been prescribed for you.

Tamiflu is not addictive.

Ask your doctor about having the influenza vaccination.

Vaccination every year is the best way to prevent influenza.

2. What should I know before I use Tamiflu?

Warnings

Do not use Tamiflu if:

  • you are allergic to oseltamivir, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
    Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body rash, itching or hives on the skin.
  • the package is torn or shows signs of tampering
  • the expiry date (EXP) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking Tamiflu, talk to your doctor.

Check with your doctor if you:

  • have any other medical conditions, especially kidney failure, kidney impairment or kidney disease
  • weakened immune system, caused by medical condition or medication you are taking
  • take any medicines for any other condition
  • you are allergic to any other medicines, foods, dyes or preservatives
  • if you have a suppressed immune system

If you have not told your doctor about any of the above, tell them before you start taking Tamiflu capsules.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

It is not known whether Tamiflu is harmful to an unborn baby when taken by a pregnant woman. If there is a need to take Tamiflu when you are pregnant, your doctor will discuss the risks and benefits to you and the unborn baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Tamiflu may pass into breast milk. Your doctor will discuss the risks and benefits of using Tamiflu if you are breast-feeding.

Use in the elderly

Although there is limited experience with use of Tamiflu in patients 65 years and older, the dose recommended for use in elderly patients is the same as that recommended for adults.

Use in children

Do not give Tamiflu to children under 1 year of age for the prevention of influenza.

Safety and effectiveness of Tamiflu in children under 1 year of age have not been established when used for the prevention of influenza.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Tamiflu and affect how it works.

You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Tamiflu including:

  • immunosuppressants, medicines used to suppress the immune system
  • probenecid, a medicine used to treat gout

It is safe to take aspirin, paracetamol and cough medicines with Tamiflu capsules. However, medical advice should be sought before giving aspirin to children with viral illness.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Tamiflu.

4. How do I use Tamiflu?

How much to use

  • Take Tamiflu exactly as your doctor has prescribed.
  • Follow the instructions provided and use Tamiflu until your doctor tells you to stop.
  • If you have kidney disease, your doctor may prescribe you a lower dose of Tamiflu.

When to use Tamiflu

  • Tamiflu should be used to treat and prevent influenza.

Treatment of Influenza

Adults and adolescents 13 years of age and older

The recommended oral dose of Tamiflu for adults and adolescents 13 years of age and older is 75 mg twice a day for 5 days.

Children under 1 year of age

Tamiflu 6mg/mL oral suspension is the preferred product (see separate Tamiflu 6mg/mL oral suspension Consumer Medicine Information).

Children 1 year of age and older and less than 13 years of age

Give Tamiflu as directed by your child's doctor or pharmacist.

The usual dose of Tamiflu is one dose taken TWICE a day for 5 days. The dose depends on your child's weight.

Prevention of Influenza

For prevention of influenza, Tamiflu capsules are taken once a day at the recommended dose while protection is required. Safety and effectiveness have been shown in patients taking Tamiflu for up to 6 weeks.

Adults and adolescents 13 years of age and older

The recommended prevention dose of Tamiflu for adults and adolescents 13 years and older is 75 mg once a day for 10 days. Children 1 year of age and older and less than 13 years of age

Give Tamiflu as directed by your child's doctor or pharmacist.

The usual dose of Tamiflu is one dose taken ONCE a day for 10 days. The dose may vary depending on your child's weight.

Do not give Tamiflu to children under 1 year of age for the prevention of influenza.

Safety and effectiveness in children under 1 year of age have not been established.

How to take it

Swallow capsules whole with a glass of water with or without food.

It does not matter whether you take Tamiflu with food or not. However, if Tamiflu upsets your stomach, it is better to take Tamiflu with food.

Do not break or chew the capsules before swallowing.

If you cannot swallow the capsule whole:

For adults, adolescents or children 1 year of age or older who are unable to swallow capsules please follow these instructions to ensure proper dosing:

  1. hold the required dosage capsule over a small bowl, carefully pull the capsule open and pour the powder into the bowl
  2. add a suitable, small amount (1 teaspoon maximum) of sweetened food product such as regular or sugar-free chocolate syrup, honey (only for children two years or older), light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yogurt to mask the bitter taste of the medicine
  3. stir the mixture well and give the entire contents of the bowl to the patient. The mixture must be swallowed immediately after its preparation. If there is some mixture left inside the bowl, rinse the bowl with a small amount of water and have the patient drink this remaining mixture. It is not necessary to take an undissolved white powder, as this is inactive.

For children 1 year of age or older requiring doses different to that available in capsule form, please follow these instructions to ensure proper dosing:

  1. hold one Tamiflu 75 mg capsule over a small bowl, carefully pull the capsule open and pour the powder into the bowl
  2. add 5 mL water to the powder using a syringe with markings (called a "graduated syringe") to show how much fluid has been drawn up. Stir for about two minutes
  3. draw up into the syringe the correct amount of mixture from the bowl based on the recommended dose required (see table below), which is body weight dependent (below).
It is not necessary to draw up any undissolved white powder.
  • Recommended dose 30mg: Amount of Tamiflu mixture for one dose - 2mL
  • Recommended dose 45mg: Amount of Tamiflu mixture for one dose - 3mL
  • Recommended dose 60mg: Amount of Tamiflu mixture for one dose - 4mL
    Push down on the plunger of the syringe, to empty its entire contents into a second bowl.
    Discard any unused mixture.
  1. in the second bowl, add a suitable, small amount (1 teaspoon maximum) of sweetened food product to the mixture to mask the bitter taste of the medicine.

The appropriate dose must be mixed by the caregiver with an equal quantity of sweetened food product such as regular or sugar-free chocolate syrup, light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yoghurt to mask the bitter taste of the medicine.

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

Patients who are unable to swallow capsules may receive Tamiflu 6 mg/mL oral suspension.

When to take it

Treatment with Tamiflu capsules should be started as soon as possible, but no later than 48 hours after the first symptoms of influenza.

For influenza treatment, Tamiflu capsules should be taken in the morning and in the evening.

For influenza prevention, Tamiflu capsules should be taken once a day.

If you have kidney problems, you doctor may tell you to take Tamiflu less often.

Taking your medicine at the same time each day will help you remember when to take your Tamiflu capsules.

How long to take it

Continue taking Tamiflu capsules until your doctor tells you to stop or your course of treatment is complete.

If you have a weakened immune system, your doctor may tell you to take a longer course.

If you forget to use Tamiflu

Tamiflu should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

  • Otherwise, take it as soon as you remember and then go back to taking it as you would normally.
  • If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering your dose, ask your pharmacist for some hints.
  • Do not take a double dose to make up for the dose you missed.

If you use too much Tamiflu

If you think that you have used too much Tamiflu, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning. If you are not sure what to do, contact your doctor or pharmacist.

The following are some symptoms of overdose which may or may not occur:

  • nausea (feeling like vomiting)
  • vomiting

5. What should I know while using Tamiflu?

Things you should do

Tell your doctor if:

  • you have kidney failure or impairment or any other problems with your kidneys.
  • you become pregnant while taking Tamiflu.
  • if for any reason, you have not taken your medicine exactly as prescribed.

Otherwise, your doctor may think that it was not effective and may change your treatment unnecessarily.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Call your doctor straightaway if you:

  • feel your symptoms have worsened after starting Tamiflu.

Remind any doctor, dentist or pharmacist you visit that you are using Tamiflu.

Things you should not do

  • Do not stop using this medicine suddenly or change the dose without first checking with your doctor.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not give Tamiflu to anyone else even if they have the same condition as you.
  • Do not use Tamiflu to treat other complaints unless your doctor says to.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tamiflu affects you.

However, Tamiflu is not expected to affect your ability to drive a car or operate machinery.

Looking after your medicine

  • Keep your capsules in the blister pack until it is time to take them. If you take the capsules out of the blister pack they may not keep well.
  • Keep Tamiflu capsules in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

This is not a complete list of all possible side effects.

Less serious side effects

Less serious side effectsWhat to do

Stomach

  • nausea (feeling like vomiting)
  • vomiting
  • stomach ache, indigestion
  • diarrhoea

Nervous system

  • dizziness/spinning sensation (vertigo)
  • headache
  • insomnia (difficulty sleeping)

Nose

  • sinusitis (stuffy nose and/or feeling of tension or fullness in the nose, cheeks and behind the eyes, sometimes with a throbbing ache)
  • runny nose or nose bleeds

Throat

  • cough
  • bronchitis
  • asthma (breathlessness, wheezing, a cough sometimes brought on by exercise and a feeling of tightness in the chest)

Ear

  • ear problems or ear infection

Eyes

  • conjunctivitis (discharge from the eyes with itching and crusty eyelids)
  • visual disturbances

Body

  • fatigue
  • aches and pains

Skin

  • mild skin rash
Speak to your doctor if you have any of these less serious side effects and they worry you.
Taking Tamiflu with food may reduce the potential for some or all of these side effects.

Serious side effects

Serious side effectsWhat to do

Stomach

  • diarrhoea with blood, along with fever and severe stomach pain

Skin and other allergies

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
  • yellowing of the skin and/or eyes, itching and dark coloured urine.

Infection

  • chest infection with fever, chills, shortness of breath, cough, phlegm and occasional blood.

Psychological

  • convulsions, confusion, drowsiness, abnormal behaviour, delusions, hallucinations, agitation, anxiety and nightmares.

These symptoms may also occur in influenza patients not treated with Tamiflu.

Patients (especially children and adolescents) should be closely monitored and their healthcare professional should be contacted immediately if the patient shows any signs of unusual behaviour.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side affects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Tamiflu contains

Active ingredient
(main ingredient)

Oseltamivir

  • 30 mg capsules contain 30 mg oseltamivir (present as 39.4 mg oseltamivir phosphate)
  • 45 mg capsules contain 45 mg oseltamivir (present as 59.1 mg oseltamivir phosphate)
  • 75 mg capsules contain 75 mg oseltamivir (present as 98.5 mg oseltamivir phosphate)
Other ingredients
(inactive ingredients)
  • Capsule contents:

pregelatinised maize starch
povidone
croscarmellose sodium
purified talc
sodium stearylfumarate

  • Capsule shell:

gelatin
titanium dioxide
iron oxide black
iron oxide red
iron oxide yellow
shellac
indigo carmine
Tamiflu capsules are gluten free and lactose free.

Do not take this medicine if you are allergic to any of these ingredients.

What Tamiflu looks like

Tamiflu capsules are available in the following strengths: 30 mg, 45 mg and 75 mg.

Tamiflu 30 mg hard gelatin capsules have a light yellow/opaque cap and a light yellow/opaque body. "ROCHE" is printed in blue ink on the light yellow body and "30 mg" is printed in blue ink on the light yellow cap (AUST R 145953).

Tamiflu 45 mg hard gelatin capsules have a grey/opaque cap and a grey/opaque body. "ROCHE" is printed in blue ink on the grey body and "45 mg" is printed in blue ink on the grey cap (AUST R 145957).

Tamiflu 75 mg hard gelatin capsules have a light yellow/opaque cap and a grey/opaque body. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the light yellow cap (AUST R 76017).

Tamiflu comes in blister packs containing 10 capsules.

Tamiflu is also available as 6mg/mL oral suspension.

Who distributes Tamiflu

Tamiflu is distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950

This leaflet was prepared in May 2023.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Tamiflu

Active ingredient

Oseltamivir

Schedule

S4

 

1 Name of Medicine

Oseltamivir phosphate.

2 Qualitative and Quantitative Composition

Tamiflu capsules.

Tamiflu 75 mg capsule contains of 98.5 mg of oseltamivir phosphate equivalent to 75 mg oseltamivir.
Tamiflu 45 mg capsule contains 59.1 mg oseltamivir phosphate, equivalent to 45 mg of oseltamivir.
Tamiflu 30 mg capsule contains 39.4 mg of oseltamivir phosphate, equivalent to 30 mg of oseltamivir.

Tamiflu 6 mg/mL powder for oral suspension.

Each bottle, with 13 g powder for oral suspension, contains 0.5122 g of oseltamivir phosphate and when constituted with 55 mL water results in a concentration of 6 mg/mL of oseltamivir.

Excipients with known effect.

Tamiflu 6 mg/mL powder for oral suspension.

5 mL oseltamivir suspension delivers 0.9 g of sorbitol.
7.5 mL oseltamivir suspension delivers 1.3 g of sorbitol.
10 mL oseltamivir suspension delivers 1.7 g of sorbitol.
12.5 mL oseltamivir suspension delivers 2.1 g of sorbitol*.
Also contains benzoates, saccharin and sorbitol.
*Maximum recommended daily dose of Tamiflu (150 mg) exceeds 2 g of sorbitol. Products containing sorbitol may have a laxative effect or cause diarrhoea.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tamiflu capsules.

Hard capsules.
Tamiflu 75 mg capsules has a light yellow/opaque cap and a grey/opaque body. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the light yellow cap.
Tamiflu 45 mg capsules has a grey/opaque cap and a grey/opaque body. "ROCHE" is printed in blue ink on the grey body and "45 mg" is printed in blue ink on the grey cap.
Tamiflu 30 mg capsules has a light yellow/opaque cap and a light yellow/opaque body. "ROCHE" is printed in blue ink on the yellow body and "30 mg" is printed in blue ink on the light yellow cap.

Tamiflu 6 mg/mL powder for oral suspension.

Powder for oral suspension.
The powder is a granulate or clumped granulate with a white to light yellow colour.

4 Clinical Particulars

4.1 Therapeutic Indications

Tamiflu is indicated for the treatment of infections due to influenza A and B viruses in adults and children including full term neonates. Treatment should commence as soon as possible, but no later than 48 hours after the onset of the initial symptoms of infection.
Tamiflu is indicated for the prevention of influenza in adults and children aged 1 year and older. Vaccination is the preferred method of routine prophylaxis against infection with influenza virus.

4.2 Dose and Method of Administration

Dosage.

Tamiflu may be taken with or without food (see Section 5.2 Pharmacokinetic Properties). However, taking with food may enhance tolerability in some patients.
Treatment of influenza. Treatment should begin within the first or second day of onset of symptoms of influenza.

Adults and adolescents.

The recommended oral dose of Tamiflu capsules in adults and adolescents ≥ 13 years of age is 75 mg twice daily, for 5 days. Adults and adolescents 13 years of age and older who are unable to swallow capsules may receive the appropriate dose of Tamiflu 6 mg/mL oral suspension (12.5 mL delivers a 75 mg dose) or home prepared or pharmacy compounded Tamiflu capsules (see instructions below).

Children ≥ 1 to < 13 years of age.

The recommended weight adjusted dosing regimens of Tamiflu for children ≥ 1 year old are shown in Table 1.
Children ≥ 1 year old who are able to swallow capsules may receive treatment with 30 mg, 45 mg or 75 mg capsules (one 30 mg capsule plus one 45 mg capsule may be used in place of a 75 mg capsule) twice daily.
Children ≥ 1 year old who are unable to swallow capsules may receive the appropriate dose of Tamiflu oral suspension or home prepared or pharmacy compounded Tamiflu capsules (see instructions below).

Children < 1 year of age.

The recommended oral dose of Tamiflu for children 0 to 12 months is 3 mg/kg twice daily for 5 days. These dosing recommendations are not intended for children who have a postconceptual age of less than 36 weeks.
The recommended oral dose of Tamiflu for children < 1 year of age is shown in Table 2.
For the oral suspension 3 mL and 10 mL oral dosing dispensers are provided.
It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient.
Prophylaxis of influenza.

Adults and adolescents.

The recommended oral dose of Tamiflu for prevention of influenza following close contact with an infected individual is 75 mg once daily for 10 days. Therapy should begin within two days of exposure. The recommended dose for prevention during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to six weeks. The duration of protection lasts for as long as dosing is continued.
Adults and adolescents 13 years of age and older who are unable to swallow capsules may receive the appropriate dose of Tamiflu 6 mg/mL oral suspension (12.5 mL delivers a 75 mg dose) or home prepared or pharmacy compounded Tamiflu capsules (see instructions below).

Children ≥ 1 to < 13 years of age.

The recommended weight adjusted prophylactic oral dosing regimens of Tamiflu for children ≥ 1 year old are shown in Table 3.
Children ≥ 1 year old who are able to swallow capsules may receive treatment with 30 mg, 45 mg or 75 mg capsules. A 75 mg dose may be achieved with a 75 mg capsule once daily or one 30 mg capsule plus one 45 mg capsule once daily.
Children ≥ 1 year old who are unable to swallow capsules may receive the appropriate dose of Tamiflu oral suspension or home prepared or pharmacy compounded Tamiflu capsules (see instructions below).
For the oral suspension 3 mL and 10 mL oral dosing dispensers are provided.
It is recommended that Tamiflu powder for oral suspension be constituted by a pharmacist prior to dispensing to the patient.

Dosage adjustment.

Hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic dysfunction in the treatment or prevention of influenza (see Section 5.2 Pharmacokinetic Properties). The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied.
No studies have been carried out in children with hepatic impairment.
Renal impairment.

Treatment of influenza.

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

Prophylaxis of influenza.

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

Children with renal impairment.

There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.
Immunocompromised patients.

Treatment of influenza.

The recommended duration for immunocompromised patients (adults and children aged 1 year and older) is 10 days. No dose adjustment is necessary unless there is evidence of moderate or severe renal impairment (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Treatment should be initiated as soon as possible after the onset of symptoms of influenza (see Section 5.2 Pharmacokinetic Properties, Immunocompromised patients).
Treatment of adult immunocompromised patients, 18 years of age and older, with standard and double doses of oseltamivir for a duration of 10 days has been evaluated. No efficacy benefit was seen with 150 mg BID compared to 75 mg BID for 10 days however, significantly higher oseltamivir exposure (up to twice the exposure) were found with both standard and double dosing of oseltamivir in immunocompromised patients (see Section 5.2 Pharmacokinetic Properties). Dosing adjustments may be required based on clinical and co-morbidities. For adult immunocompromised patients with renal impairment, doses should be adjusted as outlined, see Section 4.2 Dose and Method of Administration.

Prophylaxis of influenza.

Seasonal prophylaxis in immunocompromised patients ≥ 1 year of age is recommended for 12 weeks. No dose adjustment is necessary.
Children < 1 year of age. The efficacy of Tamiflu has not been established in children < 1 year of age. Pharmacokinetic data indicates that a dosage of 3 mg/kg twice daily in children 0 to 12 months of age provided plasma concentrations of the prodrug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (see Section 5.2 Pharmacokinetic Properties).
Elderly. No dose adjustment is required for elderly patients (aged ≥ 65 years) in the treatment or prevention of influenza unless there is coexistent renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).
Fructose intolerance. A bottle of 13 g Tamiflu powder for oral suspension contains 11.142 g of sorbitol. For subjects with hereditary fructose intolerance, Tamiflu powder for oral suspension is not recommended.
Patients unable to swallow capsules. When commercially manufactured Tamiflu powder for oral suspension is not readily available, adults, adolescents and children who are unable to swallow capsules may receive appropriate doses of Tamiflu prepared at home by parents or caregivers or prepared by a pharmacist.

Method of administration.

Home prepared Tamiflu for adults, adolescents and children ≥ 1 year of age.

Adults, adolescents and children who are unable to swallow capsules may receive their required dose of Tamiflu by following the instructions below.
1. Hold the Tamiflu capsule(s), corresponding to the required dose, over a small bowl. Carefully pull the capsule(s) open and pour the powder into the bowl.
2. Add a suitable, small amount (1 teaspoon maximum) of sweetened food product such as regular or sugar free chocolate syrup, honey, light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yogurt to mask the bitter taste of the medication.
3. Stir the mixture well and give the entire contents to the patient. The mixture must be swallowed immediately after its preparation. If there is some mixture left inside the bowl, rinse the bowl with a small amount of water and have the patient drink this remaining mixture. It is not necessary to administer any undissolved white powder as this is inert material.
This procedure describes the preparation of a 15 mg/mL solution.
If the patient requires a dose of Tamiflu, which is different to that available in capsule form, they may receive their appropriate dose of Tamiflu by following the instructions below.
1. Hold one Tamiflu 75 mg capsule over a small bowl. Carefully pull the capsule open and pour the powder into the bowl.
2. Using a graduated syringe, add 5 mL water to the powder. Stir for about two minutes.
3. Draw up into the syringe the correct amount of mixture from the bowl (see Table 4). The recommended dose is bodyweight dependent (see Tables 2 and 3).
Push down on the plunger of the syringe, to empty its entire contents into a second bowl. Discard any unused mixture.
4. In the second bowl, add a suitable, small amount (1 teaspoon maximum) of sweetened food product such as regular or sugar free chocolate syrup, honey (only for children two years or older), light brown or table sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yogurt to the mixture to mask the bitter taste of the medication.
5. Stir this mixture well and give the entire contents of the second bowl to the patient. This mixture must be swallowed immediately after its preparation. If there is some mixture left inside the bowl, rinse the bowl with a small amount of water and have the patient drink this remaining mixture.

Pharmacy compounded Tamiflu for adults, adolescents, children and infants ≥ 1 year of age.

Commercially manufactured Tamiflu for oral suspension 6 mg/mL is the preferred product for paediatric and adult patients who have difficulty in swallowing capsules or where lower doses are needed. In the event that Tamiflu for oral suspension is not available, the pharmacy may compound a suspension (6 mg/mL) from Tamiflu capsules.
This procedure describes the preparation of a 6 mg/mL suspension, which will provide one patient with enough medication for a 5 day course of treatment or a 10 day course of prophylaxis.
The pharmacist may compound a suspension (6 mg/mL) from Tamiflu 30 mg, 45 mg or 75 mg capsules using water containing 0.05% w/v sodium benzoate added as a preservative.
First, calculate the total volume needed to be compounded and dispensed to provide a 5 day course of treatment or a 10 day course of prophylaxis for the patient. The total volume of compounded Tamiflu 6 mg/mL suspension required is determined by the weight of the patient according to the recommendation in Table 5.
Second, determine the number of capsules and the amount of vehicle (water containing 0.05% w/v sodium benzoate added as a preservative) that is needed to prepare the total volume (calculated from Table 5: 25 mL, 30 mL, 50 mL, 75 mL, 100 mL or 125 mL) of compounded Tamiflu 6 mg/mL suspension as shown in Table 6.
Third, follow the procedure below for compounding the suspension (6 mg/mL) from Tamiflu capsules.
1. Transfer the contents of the stated amount of Tamiflu capsules into the bottle and add the stated amount of sodium benzoate solution (see Table 6).
2. Close the bottle with the child-resistant cap and shake for two minutes.
3. Put an ancillary label on the bottle indicating 'Shake gently before use'.
4. Instruct the parent or caregiver to discard any remaining solution after the patient has completed the full course of therapy.
5. Place an appropriate expiration date label according to storage condition (see Section 6.4 Special Precautions for Storage).
Place a pharmacy label on the bottle that includes the patient's name, dosing instructions (see Section 4.2 Dose and Method of Administration for dosing instructions), use by date, medicine name and any other required information to be in compliance with local pharmacy regulations.
Dispense 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 (1 mL, 2 mL, 3 mL, 4 mL or 5 mL) on the oral syringe for each patient.
The appropriate dose must be mixed by the caregiver with an equal quantity of sweet liquid food, such as sugar water, chocolate syrup, cherry syrup, dessert toppings (like caramel or fudge sauce) to mask the bitter taste.

Preparation of oral suspension.

It is recommended that Tamiflu 6 mg/mL oral suspension be constituted by the pharmacist prior to dispensing to the patient.
1. Tap the closed bottle several times to loosen the powder.
2. Measure 55 mL of purified water by filling the measuring cup to the indicated level (measuring cup included in the carton).
3. Add the total amount of purified water to the bottle and shake the closed bottle well for 15 seconds.
4. Remove the cap and push bottle adapter into neck of the bottle.
5. Close bottle with cap tightly. This will make sure that the bottle adapter fits in the bottle in the right position.
6. Write the date of expiry of the constituted oral suspension on the bottle label. The shelf life of the constituted oral suspension is 10 days if stored at room temperature (below 25°C) or 17 days if stored in a refrigerator (between 2-8°C).

Note.

Shake Tamiflu oral suspension well before each use.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Tamiflu is a specific treatment for infections due to influenza A or B viruses. Use should be limited to patients who have characteristic symptoms of influenza when influenza A or B virus infections have been documented locally. Data on the treatment of influenza B are limited.
There is no current evidence for the safety or efficacy of oseltamivir in persons with complications of an acute influenza episode such as viral or bacterial pneumonia. Such patients may require extensive supportive and adjunctive care. Antiviral therapy has not been shown to reduce the need for such care and monitoring.
Efficacy of oseltamivir in the treatment of subjects with chronic cardiac diseases/ or respiratory diseases has not been established.
Safety and efficacy of repeated treatment or prophylaxis courses have not been studied.

Sorbitol.

Tamiflu powder for oral suspension contains sorbitol. For subjects with hereditary fructose intolerance, Tamiflu powder for oral suspension is not recommended.
Sorbitol may have a laxative effect or cause diarrhoea.
A bottle of 13 g Tamiflu powder for oral suspension contains 11.142 g of sorbitol.
30 mg oseltamivir suspension delivers 0.9 g of sorbitol.
45 mg oseltamivir suspension delivers 1.3 g of sorbitol.
60 mg oseltamivir suspension delivers 1.7 g of sorbitol.
75 mg oseltamivir suspension delivers 2.1 g of sorbitol.

Immunocompromised patients.

The efficacy of oseltamivir in either treatment or prophylaxis of influenza in immunocompromised patients has not been firmly established. Limited data are available (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Pharmaceutical precautions.

Direct contact of oseltamivir phosphate with the skin and eyes should be avoided as it is a potential skin sensitiser and eye irritant.

Use in renal impairment.

For dose adjustments in patients with renal impairment, see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration.

Paediatric use.

Data are not available for infants aged 0 to 2 weeks. It is reasonable to propose that term neonates can receive the same 3 mg/kg dose given the risk posed by influenza to the very young and the likelihood that exposures in the term neonate will not be markedly different to those seen in infants 2 to 8 weeks old.
No studies have been carried out in children with hepatic impairment.
There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.

Use in the elderly.

Limited numbers of subjects aged ≥ 65 years old have been included in the clinical trials. However, on the basis of drug exposure and tolerability, dose adjustments are not required for elderly patients unless there is coexistent renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

Elevated liver enzymes have been reported in patients with influenza-like illness receiving oseltamivir.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Information derived from pharmacology and pharmacokinetic studies of oseltamivir phosphate suggest that clinically significant drug interactions are unlikely.
Oseltamivir phosphate is rapidly converted to the active metabolite by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in the literature. These esterases have been shown not to be saturable at concentrations of oseltamivir 100 times those which occur during treatment. Therefore, drug interactions caused by competition for these enzymes are highly unlikely.
In vitro studies demonstrated that neither oseltamivir phosphate nor the active metabolite is a good substrate for P450 mixed function oxidases or for glucuronyl transferases. As a result, drug interactions involving P450 isozymes are unlikely.
Oseltamivir is a weak substrate in vitro for the P-glycoprotein transport system; however, no adverse event for oseltamivir or the concomitant administrated drug, which could be due to an interaction at the P-glycoprotein level, has been detected.
Cimetidine 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.
No pharmacokinetic interactions between oseltamivir or its major metabolite have been observed when coadministering oseltamivir with paracetamol, acetylsalicylic acid (aspirin), cimetidine, antacids (magnesium and aluminium hydroxides and calcium carbonates), warfarin, rimantadine or amantadine.
There is no mechanistic basis for an interaction with oral contraceptives.
Drug interaction studies have not been undertaken with oseltamivir and a number of drugs and drug classes, including erythromycin and macrolide antibiotics, theophylline derivatives and antihistamines.
Coadministration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic pathway is weak.
Coadministration of probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion, results in an approximate 2-fold increase in exposure to the active metabolite of oseltamivir, although no dose adjustment is required when coadministering with probenecid in patients with normal renal function.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on male or female fertility was observed in rats exposed to oseltamivir phosphate. The highest dose has approximately 180 times the human systemic exposure (AUC) to the active metabolite.
(Category B1)
Studies for effects on embryofoetal development were conducted in rats (at doses up to 1500 mg/kg/day) and rabbits (at doses up to 500 mg/kg/day) by the oral route. Relative exposures in these studies were 180 times human exposure (AUC0-24h of the active metabolite) in the rat and 50 times human exposure in the rabbit. Foetal exposure in both species was approximately 15-20% of that of the mother. 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. The duration of parturition was increased in rats at oral doses of 1500 mg/kg/day of oseltamivir phosphate, 180 times human exposure (AUC0-24h), but it was not affected at 500 mg/kg/day (approximately 40 times human exposure). Oseltamivir phosphate was not teratogenic in these studies.
Animal reproductive studies may not be predictive of human response, and there are no adequate and well controlled studies in pregnant women. A large amount of data from pregnant women exposed to oseltamivir (more than 1000 exposed outcomes during the first semester) from post-marketing reports and observational studies in conjunction with animal studies (see Section 5.3 Preclinical Safety Data) indicate that there are unlikely to be direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development. Tamiflu should be used during pregnancy only if the potential benefit justifies the potential risk to the pregnant woman and/or foetus.
The safe use of oseltamivir during labour and delivery has not been established.
In lactating rats, oseltamivir and the active metabolite are excreted in milk. Very limited information is available on children breastfed by mothers taking Tamiflu and on excretion of oseltamivir in breast milk. Limited data demonstrated that oseltamivir and the active metabolite were detected in breast milk at very low levels. Tamiflu should be used in lactating mothers only if the potential benefit for the lactating mother justifies the potential risk of exposure of the medicine to the nursing infant.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed. The pharmacological activity and adverse events reported to date do not indicate such an effect is likely.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The overall safety profile of Tamiflu is based on data from more than 2646 adults/ adolescents and 859 paediatric patients with influenza, and on data from more than 1943 adult/ adolescent and 148 paediatric patients receiving Tamiflu for the prophylaxis of influenza in clinical trials. In adult/ adolescent treatment studies, the most frequently reported adverse drug reactions (ADRs) were nausea, vomiting and headache. The majority of these ADRs were reported on a single occasion, occurred on either the first or second treatment day and resolved spontaneously within 1-2 days. In adult/ adolescent prophylaxis studies, the most frequently reported ADRs were nausea, vomiting, headache and pain. In children, the most commonly reported ADR was vomiting. In the majority of patients, these events did not lead to discontinuation of Tamiflu.
Treatment and prophylaxis of influenza in adults and adolescents. In adult/ adolescent treatment and prophylaxis studies, ADRs that occurred the most frequently (≥ 1%) at the recommended dose (75 mg twice daily for 5 days for treatment and 75 mg once daily for up to 6 weeks for prophylaxis), and whose incidence is at least 1% higher on Tamiflu compared to placebo, are shown in Table 7.
The population included in the influenza treatment studies comprised of otherwise healthy adults/ adolescents and patients "at risk" (patients at higher risk of developing complications associated with influenza, e.g. elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients "at risk" was qualitatively similar to that in otherwise healthy adults/ adolescents.
The safety profile reported in the subjects that received the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies (see Table 7), despite a longer duration of dosing in the prophylaxis studies.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions from clinical trials are listed according to the MedDRA system organ class. The corresponding frequency category for each adverse drug reaction (Table 7) is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Treatment and prophylaxis of influenza in elderly. There were no clinically relevant differences in the safety profile of the 942 subjects 65 years of age and older, who received Tamiflu or placebo, compared with the younger population (aged up to 65 years).
Treatment and prophylaxis of influenza in immunocompromised patients. The treatment of influenza in immunocompromised patients was evaluated in two studies receiving standard dose or high dose regimens (double dose or triple dose) of Tamiflu (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The safety profile of Tamiflu observed in these studies, was consistent with that observed in previous clinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromised patients across all age groups (otherwise healthy patients or "at risk" patients [i.e. those with respiratory and/or cardiac co-morbidities]). The most frequent ADR reported in immunocompromised children was vomiting (28%).
A 12 week prophylaxis study in 475 immunocompromised patients, including 18 children 1-12 years old, showed that the safety profile in the 238 subjects receiving Tamiflu was consistent with that previously observed in Tamiflu prophylaxis clinical trials.
Treatment and prophylaxis of influenza in children > 1 year of age. A total of 1481 paediatric patients (including otherwise healthy children aged 1-12 years old and asthmatic children aged 6-12 years old) participated in clinical studies investigating the use of Tamiflu in the treatment of influenza. A total of 859 paediatric patients received treatment with Tamiflu suspension.
The ADRs that occurred in ≥ 1% of children aged 1-12 years receiving Tamiflu in the clinical trials for treatment of naturally acquired influenza (n = 859), and whose incidence is at least 1% higher on Tamiflu compared to placebo (n = 622), is vomiting (16% on oseltamivir vs. 8% on placebo). Amongst the 148 children who received the recommended dose of Tamiflu once daily in a postexposure prophylaxis study in households (n = 99), and in a separate 6 week paediatric prophylaxis study (n = 49), vomiting was the most frequent ADR (8% on Tamiflu vs. 2% in the no prophylaxis group). Tamiflu was well tolerated in these studies and the adverse events noted were consistent with those previously observed in paediatric treatment studies.
Children < 1 year of age. In two studies to characterise the pharmacokinetics, pharmacodynamics and safety profile of oseltamivir therapy in 124 influenza infected children less than one year of age, the safety profile was similar among age cohorts with vomiting, diarrhoea and nappy rash being the most frequently reported AEs (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). Insufficient data are unavailable for children who have a postconceptual age of less than 36 weeks.
Safety information available on Tamiflu administered for treatment of influenza in children less than 1 year of age from prospective and retrospective observational trials (comprising together more than 2400 children of that age class), epidemiological database research and postmarketing reports suggest that the safety profile in children less than 1 year of age is similar to the established safety profile of children aged 1 year and above.

Postmarketing experience.

The following adverse events have been identified during postmarketing use of Tamiflu.
Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency and/or establish a causal relationship to Tamiflu exposure.

Skin and subcutaneous tissue disorders.

Hypersensitivity reactions such as allergic skin reactions including dermatitis, rash, eczema and urticaria, erythema multiforme, allergy, anaphylactic/ anaphylactoid reactions, face oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Hepatobiliary disorders.

Hepatitis and elevated liver enzymes have been reported in patients with influenza-like illness receiving oseltamivir.

Psychiatric disorders/ nervous system disorders.

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

Gastrointestinal disorders.

Gastrointestinal bleeding was observed after the use of Tamiflu. In particular, haemorrhagic colitis was reported and subsided when the course of influenza abated or treatment with Tamiflu was interrupted.

Blood and lymphatic system disorders.

Thrombocytopenia.

Eye disorders.

Visual disturbances.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Treatment of overdose should consist of general supportive measures.
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 reported following overdose were similar in nature and distribution to those observed with therapeutic doses of Tamiflu, see Section 4.8 Adverse Effects (Undesirable Effects).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antivirals for systemic use, neuraminidase inhibitors. ATC code: J05AH02.

Mechanism of action.

Oseltamivir phosphate is a prodrug of the active metabolite oseltamivir carboxylate. The active metabolite is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase is essential for the release of recently formed virus particles from infected cells and the further spread of infectious virus in the body. A study in cultured tracheobronchial epithelial cells and primary nasal epithelial cells has shown that oseltamivir may also suppress virus entry to cells.

In vitro susceptibility tests.

Antiviral susceptibility and development of resistance to oseltamivir is usually discussed in the context of cell culture experiments involving Madin-Darby Canine Kidney (MDCK) virus reduction assay and/or neuraminidase inhibition assay (NA IC50). The concentrations of oseltamivir carboxylate required for inhibition of influenza virus were highly variable depending on the assay method used and the virus tested. Oseltamivir carboxylate showed antiviral activity in the low nanomolar range in all these cell assays.
In vitro neuraminidase enzyme IC50 (NA IC50) values for oseltamivir susceptible clinical isolates of influenza A ranged from 0.1-1.3 nanomolar and for influenza B from 2.6-8.7 nanomolar.
Reduced susceptibility to oseltamivir carboxylate has been recovered in vitro by passage of virus in the presence of increasing concentrations of oseltamivir carboxylate. In vitro NA IC50 assays showed that the degree of reduced sensitivity (IC50) differs markedly for different mutations from 2-fold for resistant variant with the I222V mutation in influenza A N1 to 30,000-fold for resistant variant with the R292K mutation in influenza A N2.
The relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established.

Viral resistance.

Reduced sensitivity of viral neuraminidase.

Clinical studies.

The risk of emergence of influenza viruses with reduced susceptibility or resistance to oseltamivir has been examined in clinical studies (see Table 8). In children, a higher proportion of resistance was observed compared to adults and adolescents. In some paediatric patients, oseltamivir resistant virus was detected for a longer period than in with patients with an oseltamivir sensitive virus. Patients (paediatrics and adults) with an oseltamivir resistant virus generally experienced longer viral shedding than patients with a susceptible virus. However, treatment-emergent resistance showed no apparent effect on treatment response.
An overall higher incidence of oseltamivir-resistance was observed in adult and adolescent immunocompromised patients, treated with standard dose or double dose of oseltamivir for a duration of 10 days [14.5% (10/69) in standard dose group and 2.7% (2/74) in double dose group], compared to data from studies with oseltamivir-treated otherwise healthy adult and adolescent patients. The majority of adult patients that developed resistance were transplant recipients (8/10 patients in the standard dose group and 2/2 patients in the double dose group). Most of the patients with oseltamivir-resistant virus were infected with influenza type A and had prolonged viral shedding.
The incidence of oseltamivir-resistance observed in immunocompromised children, treated with Tamiflu across the two studies evaluated for resistance was 20.7% (6/29). Of the six immunocompromised children with treatment-emergent resistance to oseltamivir, three patients had received a standard dose and three patients a high dose (double or triple dose). The majority had acute lymphoid leukaemia and were ≤ 5 years of age.

Prophylaxis of influenza.

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

Clinical and surveillance data.

Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. For example, in 2008 the oseltamivir resistance associated substitution H275Y was found in > 99% of circulating 2008 H1N1 influenza isolates in Europe, while the 2009 H1N1 influenza ("swine flu") was almost uniformly susceptible to oseltamivir. Resistant strains have also been isolated from both immunocompetent and immunocompromised patients treated with oseltamivir. The susceptibility to oseltamivir and the prevalence of such viruses appears to vary seasonally and geographically. Oseltamivir resistance has also been reported in patients with pandemic H1N1 influenza in connection with both therapeutic and prophylactic regimens.
The rate of emergence of resistance may be higher in the youngest age groups, and in immunocompromised patients. Oseltamivir resistant viruses isolated from oseltamivir treated patients and oseltamivir resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral subtype specific.
Prescribers should consider available information on influenza virus drug susceptibility patterns for each season when deciding whether to use Tamiflu (for the latest information, please refer to WHO and/or local government websites).

Cross resistance.

Cross resistance between zanamivir resistant influenza mutants and oseltamivir resistant influenza mutants has been observed in vitro. Due to limitations in the assays available to detect drug induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possible cross resistance to zanamivir in clinical isolates cannot be made. However, two of the three oseltamivir induced mutations (E119V, H274Y and R292K) in the viral neuraminidase from clinical isolates occur at the same amino acid residues as two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir resistant virus.

Clinical trials.

Treatment of influenza in adults. A total of 1355 patients were included in two phase III multicentre, placebo controlled trials in naturally acquired influenza which were conducted in the Northern Hemisphere influenza season of 1997-1998 (studies WV15670 and WV15671). An identical trial (study WV15730) followed in the Southern Hemisphere winter of 1998 where 60 patients were recruited. 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 had laboratory confirmed influenza. The 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 the two pivotal studies are shown in Tables 9 and 10.

Studies WV15670 and WV15671.

Studies WV15670 and WV15671 were multicentre, double blind, randomised, parallel group studies with the objective of assessing the safety and antiviral efficacy of Tamiflu. Subjects who enrolled in these studies presented with symptoms of influenza defined as:
fever (defined as body temperature ≥ 38°C);
plus one respiratory symptom [cough, sore throat, nasal symptoms (rhinorrhoea/ congestion)];
plus one constitutional symptom [headache, malaise (feeling unwell), myalgia (aches and pains), sweats/ chills (feeling feverish), prostration (fatigue)].
Subjects were randomised to receive either 75 mg Tamiflu twice daily, 150 mg Tamiflu twice daily or placebo twice daily for a period of 5 days, commencing up to 36 hours, later amended to 48 hours after the reported onset of symptoms.

Primary efficacy parameter.

Time to alleviation of all symptoms was significantly reduced by up to 30 hours in both the 75 mg and 150 mg active treatment groups compared with placebo, demonstrating a more rapid recovery for subjects on Tamiflu. Treatment with Tamiflu resulted in a reduced median time to alleviation of all of the seven defined influenza symptoms. No increase in efficacy was demonstrated in subjects who received Tamiflu 150 mg twice daily compared to 75 mg twice daily.

Secondary efficacy parameters.

Both doses of Tamiflu significantly reduced the median total symptom score AUC (measure of extent and severity of illness) by up to 40% compared to placebo. The duration of virus shedding was also reduced in subjects treated with Tamiflu.
Temperature AUC was reduced in Tamiflu treated subjects compared with placebo. Fewer subjects reported fever following dosing with Tamiflu, despite a lower consumption of symptom relief medication (paracetamol) by the Tamiflu groups compared to the placebo group. This was in addition to a marked reduction in the time taken for subjects on Tamiflu to return to an afebrile state during the treatment interval compared with placebo.
Based on studies WV15670, WV15671 and WV15730, the overall incidence of secondary illnesses (bronchitis, otitis media, sinusitis and pneumonia at least 48 hours after the start of treatment in confirmed cases of influenza) requiring antibiotic medication was 11/301 (3.7%) in Tamiflu treated (75 mg twice daily) patients compared to 23/309 (7.4%) in placebo group. The treatment difference was 3.8% (95% CI 0.2%, 7.4%; p = 0.052) in favour of Tamiflu. Subjects treated with Tamiflu rated their health, activity and quality of sleep to be better than patients on placebo during the dosing period. Moreover, treatment with Tamiflu was associated with a reduction in time taken to return to normal (preinfluenza) health status and ability to perform daily activity.
Treatment of influenza in adolescents, adults and elderly.

Study M76001.

In a recent study which included adolescents, adults and elderly patients (13-80 years), time to alleviation of all symptoms was significantly reduced by up to 24.2 hours in patients treated with Tamiflu. There was a significant reduction of the median total symptom score AUC in the treatment group compared to placebo. Consistent with other studies, temperature AUC, number of patients with fever and the time to afebrile state were reduced in Tamiflu treated subjects compared with placebo. There was also a reduced need for patients receiving Tamiflu to take symptom relief medication (paracetamol).
Treatment of influenza in high risk populations.

Study WV15758/872.

In a separate study, patients aged > 13 years with influenza and coexisting chronic cardiac and/or respiratory disease received Tamiflu 75 mg or placebo twice daily. No difference in the median time to alleviation of all symptoms was seen between patients taking Tamiflu or placebo. However, the duration of febrile illness was reduced by approximately one day in the Tamiflu treatment group. The number of patients shedding virus on days 2 and 4 was also markedly reduced in those treated with Tamiflu. There was no difference in the safety profile of Tamiflu in the at risk populations compared to the general adult population.
Prevention of influenza in adults and adolescents. The efficacy of Tamiflu in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and 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 ≥ 37.2°C/ 99.0°F 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 4-fold increase in virus antibody titres from baseline.
In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 18-65 years), Tamiflu 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2% (6/520) for the Tamiflu group.
In a seasonal prophylaxis study in elderly residents of nursing homes, Tamiflu 75 mg once daily taken for 42 days reduced the incidence of laboratory confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the Tamiflu group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.
In a postexposure prophylaxis study, household contacts (aged ≥ 13 years) who had no laboratory evidence of influenza at baseline, and who were living with an index case who was subsequently shown to have had influenza infection, were randomised to treatment (the intent to treat index infected, not infected at baseline (ITTIINAB) population). In this population Tamiflu 75 mg administered once daily within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory confirmed clinical influenza in the contacts from 12% (24/200) in the placebo group to 1% (2/205) for the Tamiflu group (risk reduction 91.9%, p < 0.001). For the study population as a whole (the ITT population), including contacts of index cases in whom influenza infection was not confirmed, the incidence of laboratory confirmed clinical influenza was reduced from 7.4% (34/462) in the placebo group to 0.8% (4/493) for the Tamiflu group (risk reduction 89%, p < 0.001). Index cases did not receive Tamiflu in the study. In the ITT population 13.9% of contacts in the placebo group and 11.4% of contacts in the Tamiflu group had been vaccinated.
Treatment of influenza in children. One double blind placebo controlled treatment trial was conducted in children, aged 1-12 years old (mean age 5.3 years old), who had fever (≥ 37.8°C) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. Of 698 patients enrolled in this trial, 452 (65%) were influenza infected (50% male; 68% Caucasian). Of the 452 influenza infected patients, 67% were infected with influenza A and 33% with influenza B.
The primary endpoint in this study was the time to freedom from illness, a composite endpoint which required 4 individual conditions to be met. These were alleviation of cough, alleviation of coryza, resolution of fever and parental opinion of a return to normal health and activity. Tamiflu treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. The median time to freedom from illness in the intent to treat infected (ITTI) population was 5.7 days in the placebo group and 4.2 days in patients treated with Tamiflu. In the intent to treat population (ITT), the median time to freedom from illness was 5.2 days in the placebo group and 4.4 days in patients treated with Tamiflu. The median time to freedom from illness was significantly reduced in the subgroup of patients infected with influenza A and treated with Tamiflu, compared to patients infected with influenza B and treated with Tamiflu (not statistically significant). The proportion of patients developing acute otitis media was reduced by 40% in children receiving Tamiflu compared to placebo. Subgroup analyses of this study by gender showed no differences in the treatment effect of Tamiflu in males and females.
A second study was conducted in 334 asthmatic children aged 6-12 years of age, 53.6% of whom were influenza positive. The median time to freedom from illness was reduced by 8% in patients treated with Tamiflu compared to placebo (not statistically significant). By day 6 (the last day of treatment) FEV1 had increased by 10.8% in the Tamiflu treated group compared to 4.7% in the placebo group (p = 0.0148) although there was no difference in the use of asthma medication between groups.
Prevention of influenza in children.

Study WV16193.

The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in a postexposure prevention study in households that included adults, adolescents, children aged 1-12 years old, both as index cases and as family contacts. The primary efficacy parameter for this study was the incidence of laboratory confirmed clinical influenza in the households. Oseltamivir prophylaxis lasted for 10 days (prophylactic efficacy in adults and adolescents ≥ 13 years old has previously been demonstrated with a 7 day dosing regimen (see above)).
In the total population, there was a reduction in the incidence of laboratory confirmed clinical influenza in households from 20% (27/136) in the group not receiving prevention to 7% (10/135) in the group receiving prevention (62.7% reduction, (95% CI 26.0-81.2); p = 0.0042). In households of influenza infected index cases, there was a reduction in the incidence of influenza from 26% (23/89) in the group not receiving prevention to 11% (9/84) in the group receiving prevention (58.5% reduction, (95% CI 15.6-79.6); p = 0.0114).
According to subgroup analysis in children 1-12 years of age, the incidence of laboratory confirmed clinical influenza among children was significantly reduced from 19% (21/111) in the group not receiving prevention to 7% (7/104) in the group receiving (64.4% reduction, (95% CI 15.8-85.0); p = 0.01; ITT). Among children who were not already shedding virus at baseline, the incidence of laboratory confirmed clinical influenza was reduced from 21% (15/70) in the group not receiving prevention to 4% (2/47) in the group receiving prevention (80.1% reduction, (95% CI 22.0-94.9); p = 0.0206; ITTIINAB) (see Table 11).
Prophylaxis of influenza in immunocompromised patients. A double blind, placebo controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects, including 18 children 1-12 years old. Laboratory confirmed clinical influenza, as defined by RT-PCR plus oral temperature ≥ 37.2°C/ 99.0°F plus cough and/or coryza, all recorded within 24 hours, was evaluated. Among subjects who were not already shedding virus at baseline, Tamiflu reduced the incidence of laboratory confirmed clinical influenza from 3.0% (7/231) in the group not receiving prophylaxis to 0.4% (1/232) in the group receiving prophylaxis (see Table 12).
Treatment of influenza in immunocompromised patients (children, adolescents, and adults). A randomized, double blind study, to evaluate safety and characterise the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected immunocompromised patients, included 151 adult patients, 7 adolescents and 9 children evaluable for efficacy of oseltamivir (secondary analysis, not powered). The study included solid organ transplant [SOT] patients, haematopoietic stem cell transplant [HSCT] patients, HIV positive patients with a CD4+ cell count < 500 cells/mm3, patients on systemic immunosuppressive therapy, and those with haematological malignancy. These patients were randomized to be treated, within 96 hours of symptoms onset for a duration of 10 days. The treatment regimens were: standard dose 75 mg twice daily (73 adult patients, 4 adolescent patients and 4 children) or double dose, 150 mg twice daily (78 adult patients, 3 adolescent patients and 5 children) of oseltamivir, weight adjusted for children.
The median time to resolution of symptoms (TTRS) for adults and adolescents was similar between the standard dose group (103.4 hours [95% CI 75.4-122.7]) and double dose group (107.2 hours [95% CI 63.90-140.0]). The TTRS for children was highly variable and the interpretation is limited by the small sample size.
The proportion of adult patients with secondary infections in the standard dose group and double dose group was comparable (8.2% vs 5.1%).
For adolescents and children, only one patient (an adolescent) in the standard dose group experienced a secondary infection (bacterial sinusitis). The TTRS in all oseltamivir-treated adult immunocompromised patients (combined from both dose groups) was shorter when compared to matched placebo-treated otherwise healthy (reduced by 14 hours) and "at risk" patients (reduced by 60 hours), from previous studies.
A pharmacokinetics and pharmacodynamics study was conducted in severely immunocompromised children (≤ 12 years of age, n=30) receiving weight adjusted standard (75 mg twice daily) vs. triple dose (225 mg twice daily) oseltamivir for an adaptive dosing period of 5-20 days dependant on the duration of viral shedding (mean treatment duration: 9 days). No patients in the standard dose group and 2 patients in the triple dose group reported secondary bacterial infections (bronchitis and sinusitis).

5.2 Pharmacokinetic Properties

Absorption.

Oseltamivir is absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is converted predominantly by hepatic esterases to the active metabolite. In multiple dose studies the peak concentration of the active metabolite occurs 2-3 hours after dosing. Following an oral dose of 75 mg twice daily the peak concentration (Cmax) of the active metabolite is approximately 350-400 nanogram/mL. 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 the active metabolite are unaffected by coadministration with food (see Section 4.2 Dose and Method of Administration).

Distribution.

The active metabolite reaches all key sites of influenza infection as shown by studies in the ferret, rat and rabbit. In these studies, antiviral concentrations of the active metabolite were seen in the lung, bronchoalveolar lavage, nasal mucosa, middle ear and trachea, following oral administration of oseltamivir phosphate.
The mean volume of distribution (Vss) of the active metabolite is approximately 23 L in humans. The binding of the active metabolite to human plasma protein 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 is a substrate for, or an inhibitor of, the major cytochrome P450 isoforms. Thus interactions mediated by competition for these enzymes are unlikely.

Excretion.

Absorbed oseltamivir is primarily (> 90%) eliminated by conversion to the active metabolite. Peak plasma concentrations of the active metabolite decline with a half-life of 6-10 hours in most subjects. The active metabolite is not further metabolised and is eliminated entirely (> 99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion (via the anionic pathway) in addition to glomerular filtration occurs. Less than 20% of an oral radiolabelled dose is eliminated in faeces.

Pharmacokinetics in special populations.

Renal impairment.

Administration of 100 mg of Tamiflu twice daily, for 5 days, to patients with various degrees of renal impairment showed that exposure to the active metabolite is inversely proportional to renal function.
A population pharmacokinetic model describing the impact of creatinine clearance (CrCL) on oseltamivir and oseltamivir carboxylate pharmacokinetics was developed and qualified for simulation using 80 subjects with varying degrees of renal function. Subjects had dense pharmacokinetic profiles and were identified from three clinical studies; a study in subjects with either normal renal function or mild, moderate or severe renal impairment (WP15648) and two studies in healthy subjects receiving a range of single (WP15517) or multiple doses of oseltamivir (WP15525). Simulations were performed and suitable regimens using available capsule formulations were selected on the basis to provide oseltamivir carboxylate exposures considered safe and efficacious in clinical trials.
See Section 4.2 Dose and Method of Administration for recommended dosing for patients with severe, moderate and mild renal impairment.
Two clinical studies were performed to evaluate the pharmacokinetic, safety and tolerability of oseltamivir and oseltamivir carboxylate in endstage renal disease patients undergoing haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In study PP15974 patients undergoing either CAPD or HD received a single 75 mg capsule of oseltamivir, whereas in study NP16472 patients received 30 mg oseltamivir oral suspension for 6.5 weeks, with CAPD patients receiving a single dose per week and HD patients a dose after alternate dialysis sessions. In order to assist in determining appropriate dosing recommendations in HD, a population pharmacokinetic model for HD was constructed and qualified for simulation. Suitable regimens using available capsule formulations were selected on their basis to achieve oseltamivir carboxylate plasma trough levels in subjects with normal renal function dosed at 75 mg twice daily for treatment, or 75 mg oseltamivir given orally once daily for prophylaxis.
See Section 4.2 Dose and Method of Administration for recommended dosing for patients with endstage renal disease undergoing haemodialysis and continuous ambulatory peritoneal dialysis.

Hepatic impairment.

Based on in vitro and animal studies, significant increases in exposure to oseltamivir or its metabolite are not expected and this has been confirmed in clinical studies in patients with mild or moderate hepatic impairment. The pharmacokinetics of a single oral dose of oseltamivir 75 mg have been established in moderately hepatic impaired (Child-Pugh score 7-9) patients. Results of the study showed that Cmax and AUC of active metabolite of oseltamivir in the 12 hepatic impaired patients fell within the therapeutic margin of safety and efficacy. The safety and pharmacokinetics in patients with severe hepatic impairment have not been studied (see Section 4.2 Dose and Method of Administration).

Elderly.

Exposure to the active metabolite at steady state was approximately 25% higher in elderly patients (age range 65-78 years old) compared to young adults given comparable doses of Tamiflu. Half-lives observed in 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 prophylaxis of influenza unless there is coexistent renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Pregnant women.

A pooled population pharmacokinetic analysis predicted that pregnancy has a significant effect on apparent clearance (CL) of oseltamivir carboxylate. In pregnant patients treated with Tamiflu 75 mg twice daily, CL was 63%, 47% and 14% higher in trimester 1, 2 and 3 respectively compared to nonpregnant subjects. The systemic exposure (AUC24) was predicted to be 36%, 34% and 15% lower in trimester 1, 2 and 3 respectively compared to nonpregnant subjects. However, this predicted exposure is expected to have activity against susceptible influenza virus strains and there are insufficient pharmacokinetic and safety data to recommend a dose adjustment for pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation).

Immunocompromised patients.

Population pharmacokinetic analyses indicate that treatment of adult and paediatric (< 18 years old) immunocompromised patients with oseltamivir results in an increased exposure (of up to 50%) to the active metabolite when compared to non-immunocompromised patients with comparable creatinine clearance. However, due to the wide safety margin of the active metabolite, no dose adjustments are required in immunocompromised patients. However, for immunocompromised patients with renal impairment, doses should be adjusted as outlined, see Section 4.2 Dose and Method of Administration. The population pharmacodynamic analyses indicated that treatment initiation one day after the onset of symptoms was associated with a more rapid decline in virus load than treatment initiation 2, 4, 7 or 10 days after the onset of symptoms.
Pharmacokinetic and pharmacodynamic analyses from two studies in immunocompromised patients indicated that there was no meaningful additional benefit in exposures higher than those achieved after the administration of the standard dose (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Children ≥ 1 year of age.

The pharmacokinetics of Tamiflu have been evaluated in pharmacokinetic studies in children aged 1-16 years old. Multiple dose pharmacokinetics were studied in a small number of children aged 3-12 years old enrolled in a clinical trial. The rate of clearance of the active metabolite, corrected for bodyweight, was faster in younger children than in adults, resulting in lower exposure in these children for a given mg/kg dose. Doses of 2 mg/kg and unit doses of 30 and 45 mg, administered to children in the appropriate categories according to the recommendation (see Section 4.2 Dose and Method of Administration), yield oseltamivir carboxylate exposures comparable to those achieved in adults receiving a single 75 mg capsule dose (approximately 1 mg/kg). With advancing age, the difference in exposure between children and adults (per mg/kg dose) lessened to the extent that the exposure in children over 12 years of age was similar to that in adults (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Children < 1 year of age.

The pharmacokinetics, pharmacodynamics and safety of Tamiflu have been evaluated in two open label studies including influenza infected children less than one year of age (n = 124). The rate of clearance of the active metabolite, corrected for bodyweight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3 mg/kg dose in children 0-12 months of age provides prodrug and metabolite exposures anticipated to be efficacious with a safety profile comparable to that seen in older children and adults using the approved dose. The reported adverse events were consistent with the established safety profile in older children.

5.3 Preclinical Safety Data

Genotoxicity.

Oseltamivir phosphate was found to be nongenotoxic in the Ames test and the human lymphocyte chromosome assay, with or without metabolic activation, and negative in the mouse micronucleus test. It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. The active metabolite of oseltamivir phosphate was nonmutagenic in the Ames test and the L5178Y mouse lymphoma assay and negative in the SHE cell transformation test.

Carcinogenicity.

A two year carcinogenicity study with oseltamivir phosphate in rats was negative at oral doses up to 500 mg/kg/day, resulting in respective relative systemic exposures (based on AUC0-24h, maximum clinical dose of 75 mg twice daily) to oseltamivir phosphate and its active metabolite of 352 times and 52 times, respectively.
A two year carcinogenicity study with oseltamivir phosphate in mice was negative at oral doses up to 400 mg/kg/day, resulting in respective relative systematic exposures (based on AUC0-24h, maximum clinical dose of 75 mg twice daily) to oseltamivir phosphate and its active metabolite of 130 times and 15 times, respectively.
A 26 week dermal carcinogenicity study of oseltamivir carboxylate in FVB/Tg.AC transgenic mice was negative when tested at doses up to 780 mg/kg/day.

Toxicology.

In unweaned rats a single oral dose of oseltamivir phosphate 500 mg/kg (free base equivalent) to 7 day old pups resulted in deaths associated with high exposure to the prodrug. However, at 1520 mg/kg in 14 day old unweaned pups, there were no deaths or other significant effects. No adverse effects occurred at 300 mg/kg administered to 7 day old rats. This dose level resulted in maximum plasma concentrations of 42.4 microgram/mL for the prodrug and 9.4 microgram/mL for the active metabolite, and maximum brain concentrations of 10.7 microgram/g for the prodrug and 0.54 microgram/g for the active metabolite. Based on the correlation between mortality and plasma exposure across the dose range, the prodrug, but not the active metabolite, appears to underlie the toxicity in 7 day old juvenile rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tamiflu capsules.

Pregelatinised maize starch, purified talc, povidone, croscarmellose sodium and sodium stearylfumarate.

Capsule shell.

Gelatin, titanium dioxide, iron oxide red, iron oxide yellow, iron oxide black, shellac and indigo carmine.

Tamiflu 6 mg/mL powder for oral suspension.

Xanthan gum, sodium dihydrogen citrate, sodium benzoate, sorbitol, saccharin sodium, titanium dioxide and tutti-frutti flavouring.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tamiflu capsules.

Store below 25°C.

Tamiflu 6 mg/mL powder for oral suspension.

Store below 25°C.
After constitution, the suspension can be stored at room temperature (below 25°C) for up to 10 days or in a refrigerator (2 to 8°C) for up to 17 days. Tamiflu oral suspension should not be frozen.
After pharmacy compounding of Tamiflu capsules the 6 mg/mL suspension can be stored at room temperature (below 25°C) for up to 3 weeks (21 days) or in a refrigerator (2 to 8°C) for up 6 weeks. Pharmacy-compounded Tamiflu suspension should not be frozen.
Home-prepared Tamiflu mixture must be swallowed immediately after preparation.

6.5 Nature and Contents of Container

Tamiflu capsules.

Tamiflu 30 mg, 45 mg and 75 mg capsules are available in blister packages of 10 capsules.

Tamiflu 6 mg/mL powder for oral suspension.

100 mL bottle with 13 g of white to light yellow powder for constitution.
Tamiflu suspension is supplied with a plastic adapter, a plastic oral dispenser and a measuring plastic cup.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


The chemical name (3R,4R,5S)-4-acetylamino-5- amino-3-(1-ethylpropoxy)- 1-cyclohexene- 1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt.
Oseltamivir phosphate is a white crystalline solid, highly soluble in water (> 500 mg/mL).

CAS number.

204255-11-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes