Consumer medicine information

Oseltamivir Lupin

Oseltamivir

BRAND INFORMATION

Brand name

Oseltamivir Lupin

Active ingredient

Oseltamivir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Oseltamivir Lupin.

SUMMARY CMI

Oseltamivir Lupin

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 Oseltamivir Lupin?

Oseltamivir Lupin contains the active ingredient oseltamivir phosphate. Oseltamivir Lupin is used to treat and prevent influenza (an infection caused by influenza virus).

For more information, see Section 1. Why am I using Oseltamivir Lupin? in the full CMI.

2. What should I know before I use Oseltamivir Lupin?

Do not use if you have ever had an allergic reaction to oseltamivir phosphate 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 Oseltamivir Lupin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Oseltamivir Lupin 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 Oseltamivir Lupin?

  • Your doctor will tell you how much Oseltamivir Lupin to take.
  • Taking Oseltamivir Lupin 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 Oseltamivir Lupin 6 mg/mL oral suspension.

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

5. What should I know while using Oseltamivir Lupin?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Oseltamivir Lupin.
  • If symptoms do not improve and you still feel unwell after taking Oseltamivir Lupin, 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 Oseltamivir Lupin 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 Oseltamivir Lupin affects you.
Looking after your medicine
  • Keep your capsules in the blister pack until it is time to take them.
  • Keep Oseltamivir Lupin 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 Oseltamivir Lupin? 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 Oseltamivir Lupin 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

Oseltamivir Lupin

Active ingredient(s): oseltamivir phosphate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Oseltamivir Lupin. 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 Oseltamivir Lupin.

Where to find information in this leaflet:

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

1. Why am I using Oseltamivir Lupin?

Oseltamivir Lupin contains the active ingredient oseltamivir phosphate. Oseltamivir Lupin is an antiviral medicine.

Oseltamivir Lupin 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.

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

Oseltamivir Lupin is absorbed to the key sites of influenza infection and treats the cause. Oseltamivir Lupin will help reduce the chances of you passing the flu onto someone else. Taking Oseltamivir Lupin can prevent you from catching the flu, or if you have already caught the flu, taking Oseltamivir Lupin 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 Oseltamivir Lupin has been prescribed for you.

Oseltamivir Lupin 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 Oseltamivir Lupin?

Warnings

Do not use Oseltamivir Lupin 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 expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering.

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

Check with your doctor if you:

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

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

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 Oseltamivir Lupin is harmful to an unborn baby when taken by a pregnant woman. If there is a need to take Oseltamivir Lupin 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.

Oseltamivir Lupin may pass into breast milk. Your doctor will discuss the risks and benefits of using Oseltamivir Lupin if you are breastfeeding.

Use in the elderly

Although there is limited experience with use of Oseltamivir Lupin 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 Oseltamivir Lupin to children under 1 year of age for the prevention of influenza.

Safety and effectiveness of Oseltamivir Lupin 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 Oseltamivir Lupin and affect how it works.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Oseltamivir Lupin 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 Oseltamivir Lupin capsules. However, medical advice should be sought before giving aspirin to children with viral illnesses.

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

4. How do I use Oseltamivir Lupin?

How much to use

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

Treatment of influenza

Adults and adolescents 13 years of age and older

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

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

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

The usual dose of Oseltamivir Lupin 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, Oseltamivir Lupin capsules are taken once a day at the recommended dose while protection is required. Safety and effectiveness have been shown in patients taking Oseltamivir Lupin for up to 6 weeks.

Adults and adolescents 13 years of age and older

The recommended prevention dose of Oseltamivir Lupin 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 Oseltamivir Lupin as directed by your child's doctor or pharmacist.

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

Do not give Oseltamivir Lupin 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 Oseltamivir Lupin

  • Swallow capsules whole with a glass of water with or without food.
  • It does not matter whether you take Oseltamivir Lupin with food or not. However, if Oseltamivir Lupin upsets your stomach, it is better to take Oseltamivir Lupin with food.
  • Do not break or chew the capsules before swallowing.
  • If you cannot swallow the capsule whole note the following:
    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 (one 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 white sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yoghurt 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 Oseltamivir Lupin 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 added. Stir for about two minutes.
  3. Draw up the correct amount of mixture from the bowl into the syringe based on the recommended dose required which is body weight dependent (see table below). It is not necessary to draw up any undissolved white powder:
Recommended DoseAmount of Oseltamivir Lupin Mixture for One Dose
30 mg2 mL
45 mg3 mL
60 mg4 mL
  1. In the second bowl, add a suitable, small amount (one teaspoon maximum) of sweetened food product (see below) 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 white sugar dissolved in water, dessert toppings, sweetened condensed milk, apple sauce or yoghurt to mask the bitter taste of the medicine.
  2. 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 an oseltamivir 6 mg/mL oral suspension.

When to take it

  • Treatment with Oseltamivir Lupin capsules should be started as soon as possible, but no later than 48 hours after the first symptoms of influenza.
  • For influenza treatment, Oseltamivir Lupin capsules should be taken in the morning and in the evening.
  • For influenza prevention, Oseltamivir Lupin capsules should be taken once a day.
  • If you have kidney problems, you doctor may tell you to take Oseltamivir Lupin less often.
  • Taking your medicine at the same time each day will help you remember when to take your Oseltamivir Lupin capsules.

How long to take it

  • Continue taking Oseltamivir Lupin 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 Oseltamivir Lupin

Oseltamivir Lupin 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.

Do not take a double dose to make up for the dose you missed.

If you use too much Oseltamivir Lupin

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

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

  • nausea (feeling like vomiting);
  • vomiting.

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.

5. What should I know while using Oseltamivir Lupin?

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 Oseltamivir Lupin;
    - 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 straight away if you:

  • feel your symptoms have worsened after startingOseltamivir Lupin.

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

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 Oseltamivir Lupin to anyone else even if they have the same condition as you.
  • Do not use Oseltamivir Lupin 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 Oseltamivir Lupin affects you.

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

Looking after your medicine

  • Keep Oseltamivir Lupin capsules in a cool dry place where the temperature stays below 25°C.
  • 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.

Follow the instructions on 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 window sills.

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.

Less serious side effects

Less serious side effectsWhat to do
Stomach:
  • Nausea (feeling like vomiting).
  • Vomiting.
  • Stomach ache, indigestion.
  • Diarrhoea.
Nervous system:
  • Dizziness/spinning sensations (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.

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 Oseltamivir Lupin.
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.

Reporting side effects

After you have received medical advice for any side effects 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 Oseltamivir Lupin contains

Active ingredient
(main ingredient)		Oseltamivir phosphate
Other ingredients
(inactive ingredients)		Capsule contents:
Pregelatinised maize starch
Povidone
Croscarmellose sodium
Purified talc
Sodium stearylfumarate
Ethanol absolute
Capsule shell:
Gelatin
Titanium dioxide
Iron oxide black
Iron oxide yellow
TekPrint SB-6003 Blue Ink (PI 12154)
Potential allergensContains sulfites (as gelatin)

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

Oseltamivir Lupin capsules are gluten free and lactose free.

What Oseltamivir Lupin looks like

Oseltamivir Lupin 30 mg is a size “4” hard gelatin capsule with light yellow cap imprinted with “30 mg” in blue ink and light yellow body imprinted with “LU” in blue ink containing white to off-white granular powder (AUST R 328422).

Oseltamivir Lupin 45 mg is a size “4” hard gelatin capsule with grey opaque cap imprinted with “45 mg” in blue ink and grey opaque body imprinted with “LU” in blue ink containing white to off-white granular powder (AUST R 328424).

Oseltamivir Lupin 75 mg is a size “2” hard gelatin capsule with light yellow cap imprinted with “75 mg” in blue ink and grey opaque body imprinted with “LU” in blue ink containing white to off white granular powder (AUST R 328428).

Who distributes Oseltamivir Lupin

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

ii1316301  [email protected]

ii1316302  +61 3 9809 7900

ii1316303  www.generichealth.com.au

This leaflet was prepared in October 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Oseltamivir Lupin

Active ingredient

Oseltamivir

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Oseltamivir phosphate.

2 Qualitative and Quantitative Composition

Oseltamivir Lupin 75 mg capsules contain 98.5 mg of oseltamivir phosphate equivalent to 75 mg of oseltamivir.
Oseltamivir Lupin 45 mg capsules contain 59.1 mg oseltamivir phosphate, equivalent to 45 mg of oseltamivir.
Oseltamivir Lupin 30 mg capsules contain 39.4 mg of oseltamivir phosphate, equivalent to 30 mg of oseltamivir.

List of excipients with known effect.

Contains sulfites (as gelatin).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Oseltamivir Lupin capsules.

Oseltamivir Lupin 75 mg capsules.

Size "2" hard gelatin capsule with light yellow cap imprinted with "75 mg" in blue ink and grey opaque body imprinted with "LU" in blue ink containing white to off white granular powder.

Oseltamivir Lupin 45 mg capsules.

Size "4" hard gelatin capsule with grey opaque cap imprinted with "45 mg" in blue ink and grey opaque body imprinted with "LU" in blue ink containing white to off white granular powder.

Oseltamivir Lupin 30 mg capsules.

Size "4" hard gelatin capsule with light yellow cap imprinted with "30 mg" in blue ink and light yellow body imprinted with "LU" in blue ink containing white to off white granular powder.

Oseltamivir powder for oral suspension.

Available in other brands.

4 Clinical Particulars

4.1 Therapeutic Indications

Oseltamivir Lupin 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.
Oseltamivir Lupin 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

Oseltamivir oral suspension is unavailable in this brand but it is available in other brands. Where correct dosing requires oseltamivir oral suspension, or if patient is unable to swallow capsules, refer to the specific product information for this formulation for its complete dosage and administration instructions.

Dosage.

Oseltamivir Lupin 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 oseltamivir 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 commercially manufactured oseltamivir powder for oral suspension (available in other brands).

Children ≥ 1 to < 13 years of age.

The recommended weight-adjusted dosing regimens of oseltamivir 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 oseltamivir oral suspension (available in other brands).

Children < 1 year of age.

Oseltamivir Lupin is unavailable as an oral suspension and therefore only appropriate for use in peadiatric patients aged 1 years and older, weighing ≥ 10 kg. For paediatric patients requiring treatment with the oral suspension formulation, other brands are available.
Prophylaxis of influenza.

Adults and adolescents.

The recommended oral dose of oseltamivir 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 commercially manufactured oseltamivir powder for oral suspension (available in other brands).

Children ≥ 1 to < 13 years of age.

The recommended weight-adjusted prophylactic oral dosing regimens of oseltamivir for children ≥ 1 year old are shown in Table 2.
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 commercially manufactured oseltamivir powder for oral suspension (available in other brands).

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 oseltamivir 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 oseltamivir once daily, for 5 days. In patients undergoing routine haemodialysis, an initial dose of 30 mg of oseltamivir 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 oseltamivir 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 end stage renal disease (i.e. creatinine clearance of < 10 mL/min) not undergoing dialysis. Hence, dosing recommendation cannot be provided for this group.

Prophylaxis of influenza.

In adults, no dose adjustment is necessary for patients with creatinine clearance above 60 mL/min. In patients with a creatinine clearance of > 30-60 mL/min, it is recommended that the dose be reduced to 30 mg of oseltamivir once daily. In patients with creatinine clearance between 10-30 mL/min receiving oseltamivir it is recommended that the dose be reduced to 30 mg of oseltamivir every other day. In patients undergoing routine haemodialysis, an initial dose of 30 mg of oseltamivir 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 oseltamivir 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 end stage renal disease (i.e. creatinine clearance of < 10 mL/min) not undergoing dialysis. Hence, dosing recommendation cannot be provided for this group.
Children with renal impairment. There is insufficient clinical data available in children with renal impairment to be able to make any dosing recommendation.
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 Pharmacodynamics Properties, Clinical trials). Treatment should be initiated as soon as possible after the onset of symptoms of influenza (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 oseltamivir 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 pro-drug and active metabolite that are anticipated to be clinically efficacious with a safety profile comparable to that seen in older children and adults (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 co-existent renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Oseltamivir Lupin 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

Oseltamivir oral suspension is unavailable in this brand but it is available in other brands. Clinical trial and pharmacokinetic information obtained using oseltamivir oral suspension formulation are also included in the following sub-sections for prescriber information.
Oseltamivir 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.

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.

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 co-existent 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.

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 co-administering 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.
Co-administration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic pathway is weak.
Co-administration 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 co-administering 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 embryo-fetal 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. Fetal 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/fetal development. Oseltamivir 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 breast-fed by mothers taking oseltamivir 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. Oseltamivir 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 oseltamivir is based on data from more than 2,646 adults/adolescents and 859 paediatric patients with influenza, and on data from more than 1,943 adult/adolescent and 148 paediatric patients receiving oseltamivir 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 oseltamivir.
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 oseltamivir compared to placebo, are shown in Table 3.
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 oseltamivir for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies (see Table 3), 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 3) 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 oseltamivir 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 oseltamivir (see Section 5.1 Pharmacodynamics Properties, Clinical trials). The safety profile of oseltamivir observed in these studies was consistent with that observed in previous clinical trials where oseltamivir 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 oseltamivir was consistent with that previously observed in oseltamivir prophylaxis clinical trials.
Treatment and prophylaxis of influenza in children > 1 year of age. A total of 1,481 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 oseltamivir in the treatment of influenza. A total of 859 paediatric patients received treatment with oseltamivir suspension.
The ADRs that occurred in ≥ 1% of children aged 1-12 years receiving oseltamivir in the clinical trials for treatment of naturally acquired influenza (n = 859), and whose incidence is at least 1% higher on oseltamivir compared to placebo (n = 622), is vomiting (16% on oseltamivir vs 8% on placebo). Amongst the 148 children who received the recommended dose of oseltamivir once daily in a post-exposure prophylaxis study in households (n = 99), and in a separate 6-week paediatric prophylaxis study (n = 49), vomiting was the most frequent ADR (8% on oseltamivir vs 2% in the no prophylaxis group). Oseltamivir 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, Special populations). Insufficient data are unavailable for children who have a post-conceptual age of less than 36 weeks.
Safety information available on oseltamivir administered for treatment of influenza in children less than 1 year of age from prospective and retrospective observational trials (comprising together more than 2,400 children of that age class), epidemiological database research and post-marketing reports suggest that the safety profile in children less than 1 year of age is similar to the established safety profile of children aged 1 year and above.

Post-marketing experience.

The following adverse events have been identified during post-marketing use of oseltamivir.
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 oseltamivir 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 oseltamivir 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 oseltamivir to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking oseltamivir. Three separate large epidemiological studies confirmed that influenza-infected patients receiving oseltamivir 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 oseltamivir. In particular, haemorrhagic colitis was reported and subsided when the course of influenza abated or treatment with oseltamivir was interrupted.

Blood and lymphatic system disorders.

Thrombocytopenia.

Eye disorders.

Visual disturbances.

Reporting 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 oseltamivir have been received from clinical trials and during post-marketing experience. In the majority of cases reporting overdose, no adverse events were reported.
Adverse events reported following overdose were similar in nature and distribution to those observed with therapeutic doses of oseltamivir, 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 pro-drug 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.

Anti-viral 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 nano-molar 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 nanoM and for influenza B from 2.6-8.7 nanoM.
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 anti-viral 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 4). 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 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 oseltamivir 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 post-exposure (7 days), post-exposure within household groups (10 days) and seasonal (42 days) prophylaxis of influenza in immunocompetent persons, there was no evidence for emergence of drug resistance associated with the use of oseltamivir. There was no resistance observed during a 12-week seasonal prophylaxis study in immunocompromised subjects.

Clinical and surveillance data.

Natural mutations associated with reduced susceptibility to oseltamivir in vitro have been detected in influenza A and B viruses isolated from patients without exposure to oseltamivir. For example, in 2008 the oseltamivir resistance-associated substitution H275Y was found in > 99% of circulating 2008 H1N1 influenza isolates in Europe, while the 2009 H1N1 influenza ("swine flu") was almost uniformly susceptible to oseltamivir. Resistant strains have also been isolated from both immunocompetent and immunocompromised patients treated with oseltamivir. The susceptibility to oseltamivir and the prevalence of such viruses appears to vary seasonally and geographically. Oseltamivir resistance has also been reported in patients with pandemic H1N1 influenza in connection with both therapeutic and prophylactic regimens.
The rate of emergence of resistance may be higher in the youngest age groups, and in immunocompromised patients. Oseltamivir-resistant viruses isolated from oseltamivir-treated patients and oseltamivir-resistant laboratory strains of influenza viruses have been found to contain mutations in N1 and N2 neuraminidases. Resistance mutations tend to be viral sub-type specific.
Prescribers should consider available information on influenza virus drug susceptibility patterns for each season when deciding whether to use oseltamivir (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 1,355 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 Table 5 and Table 6.

Studies WV15670 and WV15671.

Studies WV15670 and WV15671 were multicentre, double-blind, randomised, parallel group studies with the objective of assessing the safety and anti-viral efficacy of oseltamivir. 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 oseltamivir twice daily, 150 mg oseltamivir 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 oseltamivir. Treatment with oseltamivir 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 oseltamivir 150 mg twice daily compared to 75 mg twice daily.

Secondary efficacy parameters.

Both doses of oseltamivir 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 oseltamivir.
Temperature AUC was reduced in oseltamivir-treated subjects compared with placebo. Fewer subjects reported fever following dosing with oseltamivir, despite a lower consumption of symptom relief medication (paracetamol) by the oseltamivir groups compared to the placebo group. This was in addition to a marked reduction in the time taken for subjects on oseltamivir 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 oseltamivir-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 oseltamivir. Subjects treated with oseltamivir rated their health, activity and quality of sleep to be better than patients on placebo during the dosing period. Moreover, treatment with oseltamivir was associated with a reduction in time taken to return to normal (pre-influenza) 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 oseltamivir. 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 oseltamivir treated subjects compared with placebo. There was also a reduced need for patients receiving oseltamivir 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 co-existing chronic cardiac and/or respiratory disease received oseltamivir 75 mg or placebo twice daily. No difference in the median time to alleviation of all symptoms was seen between patients taking oseltamivir or placebo. However, the duration of febrile illness was reduced by approximately one day in the oseltamivir treatment group. The number of patients shedding virus on days 2 and 4 was also markedly reduced in those treated with oseltamivir. There was no difference in the safety profile of oseltamivir in the at-risk populations compared to the general adult population.
Prevention of influenza in adults and adolescents. The efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a post-exposure prophylaxis study in households. The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. Laboratory-confirmed clinical influenza was defined as oral temperature ≥ 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), oseltamivir 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 oseltamivir group.
In a seasonal prophylaxis study in elderly residents of nursing homes, oseltamivir 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 oseltamivir group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders and 43% had cardiac disorders.
In a post-exposure prophylaxis study, household contacts (aged ≥ 13 years) who had no laboratory evidence of influenza at baseline, and who were living with an index case 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, oseltamivir 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 oseltamivir 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 oseltamivir group (risk reduction 89%, p < 0.001). Index cases did not receive oseltamivir in the study. In the ITT population, 13.9% of contacts in the placebo group and 11.4% of contacts in the oseltamivir 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. Oseltamivir 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 oseltamivir. 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 oseltamivir. The median time to freedom from illness was significantly reduced in the subgroup of patients infected with influenza A and treated with oseltamivir, compared to patients infected with influenza B and treated with oseltamivir (not statistically significant). The proportion of patients developing acute otitis media was reduced by 40% in children receiving oseltamivir compared to placebo. Subgroup analyses of this study by gender showed no differences in the treatment effect of oseltamivir 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 oseltamivir compared to placebo (not statistically significant). By day 6 (the last day of treatment) FEV1 had increased by 10.8% in the oseltamivir-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 post-exposure 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 7).
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, oseltamivir 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 8).
Treatment of influenza in immunocompromised patients (children, adolescents and adults). A randomised, double blind study, to evaluate safety and characterise the effects of oseltamivir on the development of resistant influenza virus (primary analysis) in influenza-infected adult 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 randomised 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 63.9-140.0]). 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 pro-drug is less than 5% relative to the active metabolite. Plasma concentrations of the active metabolite are unaffected by co-administration 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, anti-viral 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 oseltamivir 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 end stage renal disease patients undergoing haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In study PP15974 patients undergoing either CAPD or HD received a single 75 mg capsule of oseltamivir, whereas in study NP16472 patients received 30 mg oseltamivir oral suspension for 6.5 weeks, with CAPD patients receiving a single dose per week and HD patients a dose after alternate dialysis sessions. In order to assist in determining appropriate dosing recommendations in HD, a population pharmacokinetic model for HD was constructed and qualified for simulation. Suitable regimens using available capsule formulations were selected on their basis to achieve oseltamivir carboxylate plasma trough levels in subjects 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 end stage 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 oseltamivir. 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 co-existent 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 oseltamivir 75 mg twice daily, CL was 63%, 47% and 14% higher in trimester 1, 2 and 3, respectively compared to non-pregnant subjects. The systemic exposure (AUC24) was predicted to be 36%, 34% and 15% lower in trimester 1, 2 and 3, respectively compared to non-pregnant 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 in 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 Pharmacodynamics Properties, Clinical trials).

Children ≥ 1 year of age.

The pharmacokinetics of oseltamivir 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 mg 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 oseltamivir 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 body-weight, decreases with ages below one year. Metabolite exposures are also more variable in the youngest infants. The available data indicates that the exposure following a 3 mg/kg dose in children 0-12 months of age provides pro-drug 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 non-genotoxic 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 non-mutagenic 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

Oseltamivir Lupin capsules.

Pregelatinised maize starch, purified talc, povidone, croscarmellose sodium, sodium stearylfumarate, ethanol absolute.

Capsule shell.

Gelatin, titanium dioxide, iron oxide yellow, iron oxide black, TekPrint SB-6003 Blue Ink (PI 12154).

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

Store below 25°C.

6.5 Nature and Contents of Container

Oseltamivir Lupin 30 mg, 45 mg and 75 mg capsules are available in PVC/PE/PVDC blister pack of 10 capsules.

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

Oseltamivir phosphate is a white crystalline solid, highly soluble in water (> 500 mg/mL).

Chemical structure.


Chemical Name: (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1).
Molecular Formula: C16H28N2O4 (free base).
Molecular Weight: 312.4 for oseltamivir free base; 410.4 for oseltamivir phosphate salt.

CAS number.

204255-11-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes