Consumer medicine information

Pegasys Pre-Filled Syringes

Peginterferon alfa-2a

BRAND INFORMATION

Brand name

Pegasys

Active ingredient

Peginterferon alfa-2a

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pegasys Pre-Filled Syringes.

What is in this leaflet

This leaflet answers some common questions about Pegasys pre-filled syringes.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Pegasys against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Pegasys is used for

Pegasys contains the active ingredient peginterferon alfa-2a.

Pegasys belongs to a group of medicines called interferons. Pegasys is a long-acting interferon.

Interferons are proteins that modify the response of the body's immune system to help fight infections and severe diseases.

Pegasys is used to treat chronic hepatitis B or C, which are viral infections of the liver.

If these viral infections are not managed, in some people, the liver becomes badly damaged and scarred.

This is called cirrhosis. Cirrhosis can cause the liver to stop working.

Cirrhosis can also be caused by things other than viral infections such as long-term alcoholism.

It is not known if Pegasys can prevent liver failure or liver cancer that is caused by hepatitis infection.

Most people who get hepatitis B or C carry the virus in their blood for the rest of their lives, unless successfully treated. Most of these people will have some liver damage, but not all feel sick from the disease.

For chronic hepatitis B, Pegasys is usually used alone.

For chronic hepatitis C, Pegasys is best used in combination with ribavirin tablets.

If you are given Pegasys in combination therapy, you should also read the ribavirin Consumer Medicine Information leaflet before use.

Pegasys is used alone for chronic hepatitis C only if you cannot take ribavirin tablets for any reason.

Pegasys treatment will not prevent a hepatitis B or C infected person from giving another person hepatitis B or C.

There are many different types of medicines used to treat chronic hepatitis B or C.

Your doctor, however, may have prescribed Pegasys for another purpose.

Ask your doctor if you have any questions why Pegasys has been prescribed for you.

Pegasys is not addictive.

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

Before you use Pegasys

When you must not use it

Do not use Pegasys if:

  1. you have had an allergic reaction to alfa interferons, E.coli-derived products, polyethylene glycol or any of the ingredients listed at the end of this leaflet
Some symptoms of an allergic reaction include:
  • hives or skin rash
  • swelling of the face, lips or tongue
  • wheezing or troubled breathing
  • faintness
  1. you have autoimmune hepatitis
  2. you have decompensated cirrhosis (severe liver disease)
  3. you have severe heart problems or any previous heart conditions
  4. you are breast-feeding or plan to breast-feed
It is not known whether Pegasys or ribavirin passes into breast milk. Your doctor will advise you.
  1. you are HIV co-infected with cirrhosis (Child-Pugh score of 6 or more)
  2. the package is torn or shows signs of tampering
  3. the expiry date (EXP) printed on the pack has passed
If you use this medicine after the expiry date has passed it may not work as well.

Do not use Pegasys with ribavirin if:

  1. you have blood disorders including anaemia (low number of red blood cells), thalassaemia (mediterranean anaemia)
  2. you are pregnant or your female partner is pregnant (if you are male).
Ribavirin may cause birth defects and/or death of an unborn baby. Extreme care must be taken to avoid pregnancy during treatment and for 6 months after completion of treatment. Effective contraception must be used during this time.

Before starting Pegasys, you should talk to your doctor about the possible benefits and possible side effects of treatment, to decide if Pegasys is right for you. While taking Pegasys you will need to see your doctor regularly for medical examinations and blood tests to make sure your treatment is working and to check for side effects.

Use in children

Do not give Pegasys to children under 18 years of age. Safety and effectiveness in children have not been established.

Delayed growth and development has been reported in children under 18 years of age.

This product contains benzyl alcohol and should not be given to babies from birth up to the age of 3 years.

Before you start to use it

Your doctor must know all about the following before you start to use Pegasys.

Tell your doctor if:

  1. you are pregnant or plan to become pregnant
It is not known whether Pegasys is harmful to an unborn baby when used by a pregnant woman. If there is a need to use Pegasys when you are pregnant, your doctor will discuss the risks and benefits to you and the unborn baby.
  1. you are breast-feeding or plan to breast-feed
It is not known whether Pegasys passes into the breast milk. Your doctor will discuss the risks and benefits of using Pegasys if you are breast-feeding.
  1. you have ever had any of the following medical conditions, tell your doctor before you start taking Pegasys:
  • current, or a history of, depression (feeling low)
  • history of injecting drug use or excessive alcohol use
  • history of heart disease or previous heart attack
  • autoimmune disease (where the body's immune system attacks the body's own cells), such as psoriasis (a skin disease)
  • kidney problems
  • blood disorders
  • diabetes (high blood sugar)
  • problems with the thyroid gland
  • liver problems, other than hepatitis B or C
  • vision problems
  1. you have HIV infection and are being treated with anti-HIV medicines
  2. if you are under 18 years of age
Delayed growth and development has been reported in children under 18 years of age.
  1. if you are under 18 years of age and have current, or a history of, depression (feeling low)
  2. if you are allergic to any other medicines, foods, dyes or preservatives

Taking other medicines

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

You must tell your doctor if you are taking:

  • theophylline, a medicine used to treat asthma, bronchitis and emphysema
  • Sho-saiko-to, a Chinese herbal medicine, also known as Xiao-Chai-Hu-Tang
  • methadone, used to treat opioid dependence
  • didanosine, stavudine, or zidovudine, medicines used to treat HIV/AIDS
  • telbivudine, a medicine used to treat hepatitis B infection
  • azathioprine, a medicine used to suppress the immune system.

Some medicines may interfere with Pegasys or may affect how well 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 using Pegasys.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to use Pegasys

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

How much to inject

Your doctor will tell you how much Pegasys to inject according to your individual needs.

Pegasys, whether given alone or in combination with ribavirin tablets, is usually administered as a 180 mcg per 0.5 mL injection once a week for 24 to 72 weeks depending on the type of virus you are infected with and any previous treatment you have had.

If necessary, your dose may be changed by your doctor during therapy according to your response.

Your doctor will keep track of your response to Pegasys by asking questions and performing occasional laboratory tests.

Do not exceed or change the dose recommended by your doctor.

How to inject it

Pegasys is administered by subcutaneous injection. This means that Pegasys is injected with a short needle into the fatty tissue just under the skin in the stomach or thigh.

Your doctor may discuss whether it would be more convenient for you to receive your injection at home, in which case, you or a family member would be instructed on how to give the injection. This is a simple procedure and many patients prefer it.

If your doctor has directed you to use Pegasys by subcutaneous injection at home, please follow the instructions below. Your doctor or nurse will usually show you how to inject Pegasys.

Directions for self-injection

You should read these directions from beginning to end before starting so that each step of the procedure becomes familiar. These instructions must be carefully followed. Consult your doctor or nurse if you require further instructions.

Remember that cleanliness is vital.

  1. Preparing to self-inject
Before you begin:
  • Wash your hands thoroughly
  • Find a clean, comfortable area
  • Gather all the medicinal supplies you will need:
    - An alcohol swab
    - One Pegasys pre-filled syringe and unused injection needle
    - Some cotton wool
    - A sharps disposal bin
  • Check the expiry date. Do not use Pegasys after the expiry date shown on the pre-filled syringe label
  • Check the liquid has no discolouration, cloudiness or particles. The liquid should look clear and colourless to slightly yellow
  • Remove the Pegasys pre-filled syringe from the fridge. Leave the syringe out of the fridge for 30 minutes before use; or gently warm the syringe in the palms of your hands for about 1 minute. Be careful not to shake the medication.
  1. Preparing the syringe and needle
  • Remove the protective cap from the end of the needle
  • Remove the rubber cap from the end of the syringe
  • Place the needle firmly on the end of the syringe
  • If you notice any air bubbles in the syringe, hold the syringe with the needle facing upwards, lightly tap the syringe to bring the air bubbles to the top. You may need to gently push the plunger in slightly to push air out of the syringe
  • Check the dose of medication your doctor has prescribed. You may need to gently push the plunger to push out some medication to get to the dose your doctor has prescribed
  • If you need to put the syringe (with the needle attached) down, make sure the plastic guard covers the needle and place on a clean flat surface
  • The syringe is now ready for use.
  1. Choosing the injection site
  • Choose an injection site in your stomach area or the top of your thigh
  • Avoid your navel and waistline
  • Change injection sites each time to prevent soreness in one spot
  • Never inject into a red or swollen area
  • Never inject Pegasys into a vein or muscle.
  1. Preparing the injection site
  • Clean the injection site with an alcohol swab and let the skin dry (10 seconds)
  • Remove the protective needle guard from the end of the syringe and hold the syringe with the needle facing upwards
  • Grab your skin at the injection site firmly between your thumb and forefinger to elevate your skin.
  1. Injecting the medication
  • Hold the syringe at a 45 degree angle to your skin
  • Insert the needle in one quick motion with the bevel (flat edge) facing upwards
  • Slowly push the plunger all the way down
  • Once all the liquid has left the syringe, pull out the needle at the same angle at which you put it in
  • Do not recap the needle
  • If you notice slight bleeding gently press over the injection site with some cotton wool
  1. Cleaning up after your injection
  • Place the syringe and needle (as one) into the sharps container immediately after injection
  • When the sharps container is full, take it to your clinic for correct disposal
  • Never throw used needles and syringes in with your household rubbish
  • Never re-use the syringe or needle. The needle and syringe are to be used once only.

Remember: Most people can learn to give themselves a subcutaneous injection, but if you experience difficulty, please do not be afraid to ask for help and advice from your doctor, nurse or pharmacist.

Please note that the needle supplied with the Pegasys pre-filled syringe is for subcutaneous injection only and is not suitable for any other type of injection (e.g. intramuscular injection).

When to inject Pegasys

Your doctor will tell you how often to use this medicine. Pegasys is usually given as a single injection once a week.

If you are injecting this medicine yourself, use it at bedtime, as Pegasys may cause unusual tiredness or flu-like symptoms.

If you are working, you should inject Pegasys at the beginning of your weekend. This will help to reduce the impact of side effects of Pegasys on your ability to work.

How long to use Pegasys

Continue using Pegasys until your doctor tells you to stop. Your doctor will determine when your treatment should be stopped.

If you forget to use Pegasys

If you realise you missed your injection within 2 days after the scheduled dose, you should inject your recommended dose as soon as you remember. Take your next injection on the following regularly scheduled day.

If you realise you missed your injection 3 to 5 days after your scheduled dose, you should inject your recommended dose as soon as you remember. Take your next doses at 5-day intervals until you return to your regularly scheduled day of the week.

If you realise you missed your injection 6 days after the scheduled dose, you should wait and inject your dose on the next day.

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

If you are not sure what to do, ask your doctor, nurse or pharmacist.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you use too much Pegasys (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26 in Australia or 0800 764 766 [0800 POISON] in New Zealand) for advice or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have used too much Pegasys, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

While you are using Pegasys

Things you must do

Use Pegasys exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are using Pegasys.

Tell your doctor if you become pregnant while using Pegasys.

Tell your doctor if, for any reason, you have not used Pegasys exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

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

Things you must not do

Do not stop using Pegasys 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 Pegasys to anyone else even if they have the same condition as you.

Do not use Pegasys to treat other complaints unless your doctor says to.

Do not switch to any other brand of interferon without consulting your doctor because a change in dose may be required.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Pegasys affects you.

Pegasys may cause dizziness, drowsiness or light-headedness in some people. If you drink alcohol, dizziness, drowsiness or light-headedness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Pegasys.

Pegasys helps most people with chronic hepatitis B or C.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • flu-like symptoms such as fever, tiredness/fatigue, chills, muscle or joint pain and headache (these symptoms can usually be relieved by paracetamol)
  • injection site reaction
  • nausea (feeling sick)
  • insomnia (difficulty sleeping)
  • temporary hair loss (reversible after finishing treatment)
  • loss of appetite
  • weight loss
  • diarrhoea
  • itchiness or rash
  • irritability (getting easily upset)
  • depression (feeling low, feeling bad about yourself or feeling hopeless)
  • anxiety
  • aggressive behaviour
  • colouring of the tongue

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of anaemia, such as tiredness, shortness of breath when exercising, headaches, dizziness and looking pale
  • severe chest pain
  • feeling very depressed or suicidal
  • thoughts of causing serious harm to others
  • persistent cough
  • trouble breathing
  • irregular heartbeat
  • problems with your eyesight, such as blurred or loss of vision
  • severe stomach pain
  • unusual bleeding or bruising
  • swelling of the face or tongue, hives, skin pain
  • a red or purple skin rash that spreads
  • blisters, particularly on your mouth nose, or eyes
  • fever or chills beginning a few weeks after treatment has started

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Ask your doctor or pharmacist if you don't understand anything in this list.

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

After using Pegasys

Storage

Always keep this medicine in the carton until it is time to take it. If you take the pre-filled syringes out of the pack they may not keep well.

Store Pegasys pre-filled syringes in the fridge at 2 to 8°C. Do not freeze.

Do not shake Pegasys. Shaking can destroy Pegasys so that it will not work.

Protect Pegasys pre-filled syringes from light.

Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep Pegasys where young children cannot reach it. The top shelf of the refrigerator is a good place to store this medicine.

Pegasys pre-filled syringes are for single use only. The pre-filled syringe should be used once only and any remaining contents should be discarded with the needle.

Disposal

If your doctor tells you to stop using Pegasys, or the pre-filled syringe has passed its expiry date, ask your pharmacist what to do with any pre-filled syringes that are left over.

If you use Pegasys at home, you must throw away the syringes and needles in a sharps container. This will help protect you and other people from accidental needle stick injuries. Being struck by a needle can pass diseases onto other people. Sharps containers are available from your pharmacist.

Product description

Availability

Pegasys pre-filled syringes are available in packs of four, in the following strengths:

  • 135 mcg per 0.5 mL solution*
  • 180 mcg per 0.5 mL solution

Not available in New Zealand

What Pegasys pre-filled syringes look like

Pegasys solution for injection is contained in a disposable glass syringe. The solution is clear and colourless to light yellow.

A stainless steel needle is also supplied with the syringe to allow for subcutaneous injection.

Ingredients

Active ingredient

  • peginterferon alfa-2a

Inactive ingredients

Each pre-filled syringe also contains:

  • sodium chloride
  • benzyl alcohol
  • sodium acetate
  • acetic acid
  • polysorbate 80
  • water for injections

Distributor

Pegasys pre-filled syringes are distributed by:

Echo Therapeutics Pty Limited
ABN 628 298 699
Suite 1, 2 Kochia Lane
Lindfield NSW 2070
AUSTRALIA
Medical enquiries: 1300 848 328

Please check with your pharmacist for the latest Consumer Medicine Information

Australian Registration Numbers:

180 mcg/0.5 mL AUST R 91837

135 mcg/0.5 mL AUST R 91836

This leaflet was prepared on 15 September 2022

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Pegasys

Active ingredient

Peginterferon alfa-2a

Schedule

S4

 

1 Name of Medicine

Peginterferon alfa-2a.

2 Qualitative and Quantitative Composition

Pegasys 135 micrograms solution for injection in pre-filled syringe. Each syringe of 0.5 mL solution contains 135 micrograms of peginterferon alfa-2a.
Pegasys 180 micrograms solution for injection in pre-filled syringe. Each syringe of 0.5 mL solution contains 180 micrograms of peginterferon alfa-2a.

Excipient with known effect.

Benzyl alcohol (10 mg/1 mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
The solution is clear and colourless to light yellow.

4 Clinical Particulars

4.1 Therapeutic Indications

Chronic hepatitis C (CHC).

The combination of Pegasys and ribavirin is indicated for the treatment of chronic hepatitis C in patients who have received no prior interferon therapy (treatment-naïve patients) and patients who have failed previous treatment with interferon alfa (pegylated or non-pegylated) alone or in combination therapy with ribavirin.
The combination of Pegasys and ribavirin is also indicated for the treatment of chronic hepatitis C patients with clinically stable human immunodeficiency virus (HIV) co-infection who have previously not received interferon therapy.
Pegasys monotherapy is indicated for the treatment of chronic hepatitis C in treatment-naïve patients (see Section 4.2 Dose and Method of Administration).
Patients must be 18 years of age or older and have compensated liver disease.

Chronic hepatitis B (CHB).

Pegasys is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and liver inflammation and compensated liver disease.

4.2 Dose and Method of Administration

Dose.

Before beginning Pegasys, standard haematological and biochemical laboratory tests are recommended for all patients (see Section 4.4 Special Warnings and Precautions for Use).
When used in combination with ribavirin, please refer to the ribavirin prescribing information.

Chronic hepatitis C: treatment-naïve patients.

Pegasys and ribavirin combination treatment is recommended unless intolerance or contraindication to ribavirin.
The recommended dose of Pegasys, alone or in combination with oral ribavirin is 180 microgram once a week by subcutaneous administration in the abdomen or thigh. Ribavirin should be administered in divided doses (morning and evening) with food. The recommended duration of Pegasys monotherapy is 48 weeks. The duration of combination therapy and the daily dose of ribavirin should be individualised based on the patient's viral genotype (see Table 1).
Consideration should be given to discontinuing therapy after 12 weeks of treatment if the patient has failed to demonstrate an early virologic response (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Chronic hepatitis C: prior treatment non-responder and relapser patients.

The recommended dosage of Pegasys and ribavirin combination therapy is Pegasys 180 microgram once a week by subcutaneous administration in the abdomen or thigh. For patients < 75 kg and ≥ 75 kg, 1000 mg and 1200 mg of ribavirin, respectively, should be administered daily. Ribavirin should be administered in divided doses (morning and evening) with food. Please refer to the full prescribing information for ribavirin.
The recommended duration of therapy is up to 72 weeks in genotype 1 or 4 patients and 48 weeks in genotype 2 or 3 patients.

HIV-HCV co-infection.

The recommended dose of Pegasys, alone or in combination with oral ribavirin 800 mg daily, is 180 microgram once a week by subcutaneous administration in the abdomen or thigh. The recommended duration of therapy is 48 weeks. Efficacy of a treatment period shorter than 48 weeks has not been studied in Hepatitis C virus (HCV) genotype 2 and 3 infected patients co-infected with HIV.

Chronic hepatitis B.

The recommended dose of Pegasys is 180 microgram once a week by subcutaneous administration in the abdomen or thigh. The recommended duration of therapy is 48 weeks.

Dose modification.

When dose modification is required for moderate to severe adverse reactions (clinical and/or laboratory), initial dose reduction to 135 microgram is generally adequate. However, in some cases, dose reduction to 90 microgram or 45 microgram is necessary. Dose increases to, or toward, the original dose may be considered when the adverse reactions abate (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Haematological.

See Tables 2 and 3.
If the laboratory abnormality is reversed, ribavirin may be restarted at 600 mg daily and further increased to 800 mg daily at the discretion of the treating physician. However, a return to original dosing is not recommended. In cases of intolerance to ribavirin, Pegasys monotherapy may be continued.

Hepatic function.

Fluctuations in abnormalities of hepatic function tests are common in patients with chronic hepatitis. As with other alfa interferons, increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a virological response. For HCV patients, the dose should be reduced initially to 135 microgram in the presence of progressive ALT increases above baseline values. When increase in ALT levels is progressive despite dose reduction, or is accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be discontinued.
For use of ribavirin in combination with Pegasys, please refer also to the ribavirin Product Information.
For HBV patients, transient flares of ALT levels sometimes exceeding 10 times the ULN are not uncommon, and may reflect immune clearance. Consideration should be given to continuing treatment with more frequent monitoring of hepatic function during ALT flares (> 5 x ULN). If ALT increases are severe (> 10 x ULN) and persistent then consideration should be given to discontinuation of treatment. If ALT increases are severe and progressive despite reduction of Pegasys dose or are accompanied by increase in bilirubin or evidence of hepatic decompensation, Pegasys should be immediately discontinued (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
After Pegasys dose reduction or withholding, therapy can be restored once the flare subsides.

Special populations.

Renal impairment.

No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduced dose of 135 microgram once weekly Pegasys is recommended in adult patients with severe renal impairment. In adult patients with end stage renal disease, a starting dose of Pegasys 135 microgram once weekly should be used (see Section 5.2 Pharmacokinetic Properties).
Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions.
No data is available for paediatric patients with renal impairment.
In renally impaired patients receiving chronic haemodialysis, ribavirin may be administered at a dose of 200 mg daily (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).
For use of ribavirin in combination with Pegasys, please refer also to the ribavirin Product Information.

Hepatic impairment.

In patients with compensated cirrhosis Pegasys has been shown to be effective and safe. Pegasys has not been studied in patients with decompensated cirrhosis (see Section 4.3 Contraindications).
The Child-Pugh classification divides patients into groups A, B, and C, or Mild, Moderate and Severe corresponding to scores of 5-6, 7-9 and 10-15, respectively (see Table 4).

Children.

Safety and effectiveness have not been established in patients below the age of 18. In addition, Pegasys injection solutions contain benzyl alcohol, therefore Pegasys should not be used in neonates or infants up to the age of 3 years (see Section 4.3 Contraindications).

Elderly.

No special dosage modification is required for elderly patients based upon pharmacokinetic, pharmacodynamic, tolerability, and safety data from clinical trials.

Method of administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.
Pegasys is for single use in one patient only. Discard any residue.

4.3 Contraindications

Pegasys is contraindicated in patients with:
known hypersensitivity to alfa interferons, to E. coli-derived products, to polyethylene glycol or to any component of the product;
autoimmune hepatitis;
decompensated cirrhosis;
HIV-HCV co-infection with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by medicines such as atazanavir and indinavir;
neonates and infants up to the age of 3 years, because of the excipient benzyl alcohol.
Pegasys in combination with ribavirin is contraindicated in:
patients with a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous 6 months (see Section 4.4 Special Warnings and Precautions for Use);
patients with haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia);
women who are pregnant or breast-feeding;
men whose female partners are pregnant or are not using adequate contraception.
For full product information on Pegasys in combination with ribavirin, please refer to the ribavirin Product Information.

4.4 Special Warnings and Precautions for Use

General.

In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded in the patient medical record. Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Treatment with Pegasys should be administered under guidance of a qualified physician and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of therapy (see Section 4.2 Dose and Method of Administration).
The optimal treatment for CHC is considered to be the administration of combination interferon alfa based therapies with ribavirin. For Pegasys in combination with ribavirin therapy, please refer to the ribavirin Product Information.
The use of Pegasys and ribavirin combination therapy in CHC patients who discontinued hepatitis C therapy for haematological adverse events has not been adequately studied. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.

Neuropsychiatric.

Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferons, including Pegasys. Depression, suicidal ideation, suicide, relapse of drug dependence and drug overdose may occur in patients with or without previous psychiatric illness. Pegasys should be used with caution in patients who report a history of depression, and physicians should monitor all patients for evidence of depression. Physicians should inform patients of the possible development of depression prior to initiation of Pegasys therapy, and patients should report any sign or symptom of depression immediately. In severe cases therapy should be stopped and psychiatric intervention sought.
Exercise caution and monitor for evidence of depression when administering Pegasys to paediatric patients with a prior history of or concurrent psychiatric disorders.

Use in hepatic impairment.

Patients who develop evidence of hepatic decompensation during treatment should discontinue Pegasys.

HCV.

As with other alfa interferons, increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a virological response. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, therapy should be discontinued (see Section 4.2 Dose and Method of Administration).

HIV-HCV.

HIV-HCV co-infected patients with advanced cirrhosis receiving concomitant highly active anti-retroviral therapies (HAART) may be at an increased risk of hepatic decompensation and possibly death when treated with alfa interferons, including Pegasys, with or without ribavirin. In Study NR15961, among 123 HIV-HCV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 (5%) deaths. Of the 14 patients, 13 were on NRTIs at the onset of hepatic decompensation.
During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g. Child-Pugh score ≥ 7). Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include increased serum bilirubin, decreased haemoglobin, decreased platelet count, increased alkaline phosphatase, and treatment with didanosine.

HBV.

Disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, marked transaminase flares have been accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. ALT elevation > 10-fold higher than the upper limit of normal (ULN) were reported in 12% and 18% during Pegasys treatment and 7% and 12% post-treatment in HBeAg-negative and HBeAg-positive patients, respectively. In approximately half the cases of flares exceeding 10 x ULN, Pegasys dosing was reduced or withheld until the transaminase elevations subsided, while in the rest, therapy was continued unchanged. More frequent monitoring of hepatic function was recommended in all instances. If ALT increases are severe and progressive despite reduction of Pegasys dose or are accompanied by increase in bilirubin or evidence of hepatic decompensation, Pegasys should be immediately discontinued (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

Growth and development (paediatric patients).

During the course of Pegasys plus ribavirin therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common.
At 2 years post-treatment, 16% of paediatric patients were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
At 5 to 6 years post-treatment, pediatric patients who were more than 15 percentiles below their baseline at 2 years post-treatment, either returned to baseline comparable height percentiles or a non-treatment related causative factor has been identified. The long term follow up data suggests that Pegasys treatment is unlikely to be associated with a sustained growth inhibition in children. The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials on a case by case basis.
It is important to consider that the combination therapy induced a growth inhibition during treatment.
This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression, as well as prognostic factors of response (HCV genotype and viral load).

Pulmonary.

As with other alfa interferons, pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis, including fatality, have been reported during therapy with Pegasys. If there is evidence of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.

Endocrine.

As with other interferons, Pegasys may cause or aggravate hypothyroidism and hyperthyroidism. Discontinuation should be considered in patients whose thyroid abnormalities cannot be adequately treated. Hyperglycaemia, hypoglycaemia and diabetes mellitus have been observed in patients treated with alfa interferons. Patients with these conditions who cannot be effectively controlled by medication should not begin Pegasys therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys therapy.

Autoimmune.

Exacerbation of autoimmune disease has been reported in patients receiving alfa interferon therapy. Pegasys should be used with caution in patients with autoimmune disorders. Use of alfa interferons has been associated with exacerbation or provocation of psoriasis. Pegasys must be used with caution in patients with psoriasis, and in case of appearance or worsening of psoriatic lesions, discontinuation of therapy should be considered.

Hypersensitivity.

Serious, acute hypersensitivity reactions (e.g. urticara, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alfa interferon therapy. If such a reaction develops during treatment with Pegasys, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Cardiovascular.

As cardiac disease may be worsened by ribavirin-induced anaemia, HCV patients with a history of significant or unstable cardiac disease in the previous 6 months should not use ribavirin. Cardiovascular events, such as hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with interferon therapy, including Pegasys. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to and during the course of treatment. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued.

Bone marrow suppression.

It is advised that complete blood counts be obtained pre-treatment and monitored routinely during therapy. Pegasys should be used with caution in patients with baseline neutrophil counts < 1500 cells/mm3, with baseline platelet count < 90,000 cells/mm3 or baseline haemoglobin < 120 g/L (see Section 4.2 Dose and Method of Administration). As with other interferons, caution should be exercised when administering Pegasys with other potentially myelosuppressive agents.
Pancytopenia (marked decreases in red blood cells, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3-7 weeks after the concomitant administration of ribavirin and azathioprine. This myelotoxicity was reversible within 4-6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Ophthalmologic.

As with other interferons, retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction, which may result in loss of vision, have been reported after treatment with Pegasys. All patients should have a baseline eye examination. Patients with pre-existing ophthalmological disorders (e.g. diabetic or hypertension retinopathy) should receive periodic eye examinations during alfa interferon therapy. Any patient complaining of decreased or loss of vision must have a prompt and complete eye examination. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Infections.

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, fungal) have been reported during treatment with alfa interferons, including Pegasys. Appropriate anti-infective therapy should be started immediately, and discontinuation of therapy should be considered.

Organ transplant recipients.

The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alfa interferons, liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.

Use in renal impairment.

No dose adjustment is required for patients with mild to moderate renal impairment. A reduced dose of Pegasys 135 microgram once weekly is recommended in patients with severe renal impairment. In patients with end stage renal disease, a starting dose of Pegasys 135 microgram once weekly should be used (see Section 5.2 Pharmacokinetic Properties). Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions (see Section 4.2 Dose and Method of Administration). Caution should be exercised in prescribing Pegasys to patients with severe renal impairment.

Paediatric use.

Safety and effectiveness have not been established in patients below the age of 18. Therefore, Pegasys is not recommended for use in children under 18 years of age (see Section 4.4 Special Warnings and Precautions for Use).
This product contains benzyl alcohol and should not be used in neonates and infants up to the age of 3 years. There have been rare reports of death in neonates and infants associated with excessive exposure to benzyl alcohol. The amount of benzyl alcohol at which toxicity or adverse effects may occur in neonates or infants is not known (see Section 4.3 Contraindications).

Use in the elderly.

No special dosage modification is required for elderly patients based on pharmacokinetic, pharmacodynamic, tolerability, and safety data from clinical trials (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

Before beginning Pegasys, standard haematological and biochemical laboratory tests are recommended for all patients. After initiation of therapy, haematological tests should be performed at week 2 and 4 and biochemical tests should be performed at week 4. Additional testing should be performed periodically during therapy.
The entrance criteria used for the clinical trials of Pegasys may be considered as a guideline to acceptable baseline values for initiation of treatment:
platelet count ≥ 90,000 cells/mm3;
absolute neutrophil count (ANC) ≥ 1500 cells/mm3;
thyroid stimulating hormone (TSH) and T4 within normal limits or adequately controlled thyroid function;
HIV-HCV co-infection: CD4+ ≥ 200/microL or CD4+ ≥ 100/microL to < 200/microL and HIV-1 RNA < 5000 copies/mL using Amplicor HIV-1 monitor test, version 1.5.
For Pegasys in combination with ribavirin, please refer also to the ribavirin Product Information for the effects on laboratory parameters.
Pegasys treatment was associated with decreases in both total white blood cell (WBC) count and absolute neutrophil count (ANC), usually starting within the first 2 weeks of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). In clinical trials, progressive decreases after 4-8 weeks were infrequent. Dose reduction is recommended when ANC decreases to levels below 750 cells/mm3 (see Section 4.2 Dose and Method of Administration). For patients with ANC values below 500 cells/mm3 treatment should be suspended until ANC values return to more than 1000 cells/mm3. In clinical trials with Pegasys, the decrease in ANC was reversible upon dose reduction or cessation of therapy. While fever may be associated with flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia.
Pegasys treatment was associated with decreases in platelet count, which returned to pre-treatment (baseline) levels during the post-treatment observation period (see Section 4.8 Adverse Effects (Undesirable Effects)). Dose reduction is recommended when platelet count decreases to below 50,000 cells/mm3, and cessation of therapy is recommended when platelet count decreases to below 25,000 cells/mm3 (see Section 4.2 Dose and Method of Administration).
Anaemia (haemoglobin ≤ 100 g/L) was observed in 13% and 3% of patients in clinical trials treated with Pegasys with ribavirin for 48 weeks and 24 weeks, respectively (see Section 4.8 Adverse Effects (Undesirable Effects)). The risk of developing anaemia is higher in the female population. The maximum drop in haemoglobin occurred within 4 weeks of initiation of ribavirin therapy. Complete blood counts should be obtained pre-treatment, at week 2 and week 4 of therapy and periodically thereafter. If there is any deterioration of cardiovascular status, ribavirin therapy should be suspended or discontinued (see Section 4.2 Dose and Method of Administration).
The occurrence of thyroid function abnormalities or the worsening of pre-existing thyroid disorders has been reported with the use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, evaluate thyroid stimulating hormone (TSH) levels. Pegasys treatment may be initiated if TSH levels can be maintained in the normal range by medication. If the patient develops clinical symptoms consistent with possible thyroid dysfunction, determine TSH levels during the course of therapy. In the presence of thyroid dysfunction, discontinuation of therapy should be considered in patients whose thyroid abnormalities cannot be adequately treated.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No pharmacokinetic interactions between Pegasys and ribavirin have been observed during HCV clinical trials. Similarly, lamivudine had no effect on Pegasys pharmacokinetics during HBV clinical trials.
Treatment with Pegasys 180 microgram once a week for 4 weeks had no effect on the pharmacokinetic profiles of tolbutamide (CYP 2C9), mephenytoin (CYP 2C19), debrisoquine (CYP 2D6), and dapsone (CYP 3A4) in healthy male subjects. Pegasys is a modest inhibitor of cytochrome P450 1A2 as a 25% increase in AUC of theophylline was observed in the same study. Comparable effects on the pharmacokinetics of theophylline have been seen after treatment with standard alfa interferons. Alfa interferons have been shown to affect the oxidative metabolism of some drugs by reducing the activity of hepatic microsomal cytochrome P450 enzymes. Theophylline serum concentrations should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys therapy concomitantly.

Chinese medicine.

Pulmonary symptoms have been reported more frequently when sho-saiko-to, a Chinese herbal medicine also known as Xiao-Chai-Hu-Tang, was given with interferon alfa-2a. This herb should not be taken by patients receiving interferon.

Methadone.

In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg-150 mg), treatment with Pegasys 180 microgram SC once a week for 4 weeks was associated with mean methadone levels that were 10%-15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity.

Azathioprine.

Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methyl-thioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine.
Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3-7 weeks after the concomitant administration of ribavirin and azathioprine. This myelotoxicity was reversible within 4-6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see Bone marrow suppression).
In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicines should be stopped.

Nucleoside analogues.

In Study NR15961, cases of hepatic decompensation (some fatal) were observed among HIV-HCV co-infected cirrhotic patients receiving HAART (see Section 4.4 Special Warnings and Precautions for Use).
No evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12-week pharmacokinetic sub-study to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (NRTIs, i.e. lamivudine, zidovudine, or stavudine). Plasma exposure of ribavirin did not appear to be affected by concomitant administration of NRTIs.

Didanosine.

Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis and symptomatic hyperlactacidaemia/lactic acidosis have been reported in clinical trials. This potential interaction may also apply to other purine analogues and the co-administration of ribavirin with these agents is not recommended.

Telbivudine.

A clinical trial investigating the combination of telbivudine 600 mg daily, with Pegasys 180 microgram SC once a week, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known. Such an increased risk cannot be excluded for other interferons (pegylated or standard). Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.

Zidovudine.

In Study NR 15961, patients who were administered zidovudine in combination with Pegasys and ribavirin developed severe neutropenia (ANC < 500) and severe anaemia (haemoglobin < 80 g/L) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anaemia 5% vs. 1%).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Pegasys has not been studied for its effect on fertility. As with other alfa interferons, prolongation of the menstrual cycle accompanied by both a decrease and delay in the peak of 17β-estradiol and progesterone levels have been observed following administration of peginterferon alfa-2a to female monkeys. A return to normal menstrual rhythm followed discontinuation of treatment. Peginterferon alfa-2a has not been studied for its effect on male fertility.
(Category B3)
Safe use in human pregnancy has not been established. Therefore, Pegasys should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Pegasys has not been studied for its teratogenic effect in humans. Treatment with interferon alfa-2a resulted in a statistically significant increase in abortifacient activity in rhesus monkeys. Abortion was observed in all dose groups (1, 5 and 25 million IU/kg/day). No teratogenic effects were seen in delivered offspring. However, as with other alfa interferons, women of childbearing potential receiving Pegasys therapy should be advised to use effective contraception during therapy.
For Pegasys in combination with ribavirin, please refer also to the ribavirin Product Information.
 It is not known whether peginterferon alfa-2a or its metabolites are excreted in human breast milk. No studies have been conducted to assess the impact of Pegasys or ribavirin on milk production or its presence in breast milk. Due to the potential for adverse reactions from the drug in nursing infants, a decision must be made either to discontinue breast-feeding or discontinue treatment, based on the importance of the therapy to the mother.

4.7 Effects on Ability to Drive and Use Machines

Patients who develop dizziness, confusion, somnolence, or fatigue should be cautioned to avoid driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions observed with other alfa interferons, alone or in combination with ribavirin, may also be expected with Pegasys alone or in combination with ribavirin.

Experience from clinical trials.

The frequency and severity of the most commonly reported adverse reactions are similar in patients treated with Pegasys and interferon alfa-2a as well as in patients treated with Pegasys or interferon alfa in combination with ribavirin.
The most frequently reported adverse reactions with Pegasys alone and in combination with ribavirin were mostly mild to moderate in severity and were manageable without the need for discontinuation of therapy.

Chronic hepatitis C (CHC).

Treatment-naïve patients.

Patients with elevated ALT levels.

In clinical trials, the incidence of withdrawal from treatment for all patients due to adverse reactions and laboratory abnormalities was 9% for Pegasys and 13% for Pegasys in combination with ribavirin 1000/1200 mg given for 48 weeks. Discontinuation of treatment due to laboratory abnormalities occurred in only 1% and 3% of patients on Pegasys alone or in combination, respectively. The withdrawal rates for patients with cirrhosis were similar to those of the overall population.
In comparison to 48 weeks of treatment with Pegasys and ribavirin 1000/1200 mg, reducing treatment exposure to 24 weeks and daily dose of ribavirin to 800 mg resulted in a reduction in the serious adverse reactions (11% vs. 3%), premature withdrawals for safety reasons (13% vs. 5%) and the need for ribavirin dose modification (39% vs. 19%).

Patients with normal ALT levels.

The safety profile of Pegasys in HCV patients with normal ALT was consistent with that previously observed in HCV patients with elevated ALT. Similarly, 24 week treatment was better tolerated than 48 weeks (see Table 5).

Prior treatment non-responder patients.

In study MV17150, which included 72 and 48 weeks treatment of prior pegylated interferon alfa-2b/ribavirin non-responder patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the frequency of withdrawal due to adverse events or laboratory abnormalities from Pegasys treatment was 12% and ribavirin treatment was 13%. In comparison, in the 48 week treatment arms, 6% withdrew from Pegasys and 7% withdrew from ribavirin treatment. Similarly, for patients with cirrhosis, withdrawal rates from Pegasys and ribavirin treatment were higher in the 72 week treatment arms (13% and 15%) compared with the 48 week arms (6% and 6%). Patients who withdrew from previous therapy due to haematological toxicity were excluded from enrolling in this trial.
In the HALT-C study, patients with advanced fibrosis or cirrhosis (Ishak score of 3-6) were enrolled with baseline platelet counts as low as 50,000/mm3 and treated for 48 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Due to a high prevalence of the advanced cirrhosis/fibrosis state and the low baseline platelet counts among patients in this study, the frequency of haematologic lab abnormalities in the first 20 weeks of the trial were as follows: haemoglobin < 100 g/L, 26.3%; absolute neutrophil counts (ANC) < 750/mm3, 30%; and platelet < 50,000/mm3, 13% (see Section 4.4 Special Warnings and Precautions for Use).

HIV-HCV co-infection.

In study NR15961, 180 microgram Pegasys with and without 800 mg ribavirin in HIV-HCV co-infected patients, the adverse reactions reported with Pegasys, alone or in combination with ribavirin, were similar to those observed in HCV infected patients. The incidence of withdrawal from treatment for adverse reactions, laboratory abnormalities or AIDS-defining events was 16% for Pegasys alone and 15% for Pegasys in combination with ribavirin 800 mg, given for 48 weeks. Respectively, 4% and 3% of patients required discontinuation of Pegasys alone or in combination with ribavirin, due to blood and lymphatic system disorder adverse events. Serious adverse reactions were reported in 21% and 17% of those receiving Pegasys alone or in combination with ribavirin, respectively.
Pegasys-containing treatment was associated with an on-treatment reduction in absolute CD4+ cell count without a reduction in CD4+ cell percentage. CD4+ cell count indices returned to baseline values during the follow-up period of the study. Pegasys-containing treatment had no apparent negative impact on the control of HIV viraemia during therapy or follow-up.
Study NV18209 compared 48 weeks of treatment with either Pegasys 180 microgram plus ribavirin 1000 or 1200 mg or Pegasys 180 microgram plus ribavirin 800 mg in interferon naïve patients with HIV-HCV co-infected patients (HCV genotype 1 virus). 275 patients received the ribavirin 1000/1200 mg regime and 135 patients received the 800 mg regime. 80% of patients were male, median age 46 years, 64% Caucasian and 30% non-Hispanic African Americans. Over half of the patients in both treatment groups prematurely withdrew from either treatment and from either treatment group for safety (12-13%) or non-safety reasons (40-45%). The primary non-safety reason for premature withdrawal was insufficient therapeutic response (25-26%). The incidence of withdrawal for safety reasons was 12% (abnormal laboratory tests 4%, adverse events 8-9%). The incidence of adverse reactions of ≥ 10% of patients in study NV18209 were similar to those within Table 5 for HIV-HCV co-infected patients, with no increased frequency for Pegasys plus ribavirin 1000/1200 mg compared with Pegasys plus ribavirin 800 mg except for anaemia (see below Laboratory test values).

Chronic hepatitis B (CHB).

In CHB patients, adverse reactions reported with Pegasys were similar to that seen in CHC, although the frequency of reported adverse reactions was notably less in hepatitis B (see Table 6). Serious adverse reactions were reported in 6% of patients receiving Pegasys and 4% of patients receiving lamivudine. The incidence of withdrawal due to adverse reactions or laboratory abnormalities was 5% for Pegasys. The withdrawal rates for patients with cirrhosis were similar to those of the overall population. The addition of lamivudine did not adversely affect the safety profile of Pegasys.
Table 6 shows those adverse reactions occurring in ≥ 10% of HCV patients receiving Pegasys alone or combination with ribavirin, HIV-HCV patients receiving Pegasys in combination with ribavirin, HBV patients receiving Pegasys alone and HCV patients who did not respond to previous peginterferon alfa-2b treatment receiving Pegasys in combination with ribavirin.

Patients with normal ALT levels.

The safety profile of Pegasys and ribavirin combination therapy in HCV patients with normal ALT was consistent with that previously observed in HCV patients with elevated ALT. Similarly, 24 week treatment was better tolerated than 48 weeks (see Table 6).
Commonly reported adverse reactions (1-10%) in patients treated with Pegasys in combination with ribavirin or Pegasys monotherapy during clinical trials were:

General disorders and administration site conditions.

Lethargy, influenza-like illness, malaise, shivering, hot flushes, chest pain, thirst.

Infections and infestations.

Herpes simplex, upper respiratory tract infection, bronchitis, oral candidiasis.

Ear and labyrinth disorders.

Vertigo, earache.

Vascular disorders.

Flushing.

Blood and lymphatic system disorders.

Lymphadenopathy, anaemia, thrombocytopenia.

Cardiac disorders.

Palpitations, peripheral oedema, tachycardia.

Gastrointestinal disorders.

Vomiting, dyspepsia, gingival bleeding, mouth ulceration, flatulence, gastritis, dry mouth, gingivitis, cheilitis, constipation, stomatitis, dysphagia, glossitis.

Endocrine disorders.

Hypothyroidism, hyperthyroidism.

Musculoskeletal and connective tissue disorders.

Muscle cramps, neck pain, bone pain, back pain, muscle weakness, musculoskeletal pain, arthritis.

Neuropsychiatric.

Memory impairment, taste disturbance, paraesthesia, hypoesthesia, tremor, weakness, emotional disorders, mood alteration, nervousness, aggression, decreased libido, impotence, migraine, somnolence, hyperesthesia, nightmares, syncope, anxiety.

Respiratory, thoracic and mediastinal disorders.

Exertional dyspnoea, sore throat, nasopharyngitis, sinus congestion, rhinitis, pulmonary congestion, chest tightness, upper respiratory tract infection, epistaxis, pneumonia.

Skin and subcutaneous tissue disorders.

Rash, photosensitivity reaction, eczema, skin disorder, psoriasis, urticaria, increased sweating, night sweats.

Eye disorders.

Blurred vision, eye inflammation, eye pain, xerophthalmia.
Other adverse reactions reported in 1-2% of HIV-HCV patients receiving Pegasys in combination with ribavirin included: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.
As with other interferons, uncommon to rare cases of the following serious adverse reactions have been reported in patients receiving Pegasys in combination with ribavirin or Pegasys monotherapy during clinical trials:

General disorders and administration site conditions.

Substance overdose.

Cardiac disorders.

Arrhythmia, endocarditis, cerebral haemorrhage, atrial fibrillation, pericarditis.

Gastrointestinal disorders.

Peptic ulcer, gastrointestinal bleeding, reversible pancreatic reaction (i.e. amylase/lipase increase with or without abdominal pain).

Hepatobiliary disorders.

Hepatic dysfunction, fatty liver, cholangitis, malignant hepatic neoplasm, pancreatitis.

Metabolism and nutrition disorders.

Autoimmune phenomena [e.g. immune thrombocytopenic purpura (ITP), thyroiditis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE)].

Musculoskeletal and connective tissue disorders.

Myositis.

Neuropsychiatric.

Peripheral neuropathy, coma, depression, suicide, psychotic disorder, hallucination.

Respiratory, thoracic and mediastinal disorders.

Interstitial pneumonitis with fatal outcome, pulmonary embolism, lower respiratory tract infection, sarcoidosis.

Eye disorders.

Corneal ulcer.

Ear and labyrinth disorders.

Otitis externa.

Skin and subcutaneous tissue disorders.

Skin infection, thrombotic thrombocytopenic purpura (TTP).

Post-marketing experience.

During the post-marketing period, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, pure red cell aplasia (PRCA) and homicidal ideation have been reported very rarely with combination therapy of Pegasys and ribavirin.
Dehydration has been reported rarely with combination therapy of Pegasys and ribavirin.
As with other alfa interferons, serous retinal detachment has been reported with Pegasys and ribavirin combination therapy.
As with other alfa interferons, liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.
Rarely, alfa interferon including Pegasys, used in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anaemia has been reported.
Tongue pigmentation has been reported in a post marketing setting.
Facial palsy has been reported with Pegasys.

Laboratory test values.

Haematology.

As with other interferons, treatment with Pegasys alone or in combination therapy were associated with decreases in haematological values, which generally improved with dosage modification and returned to pre-treatment levels within 4 to 8 weeks upon cessation of therapy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration). Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment.

Haemoglobin and haematocrit.

Although treatment with Pegasys alone was associated with small gradual decreases in haemoglobin and haematocrit, less than 1% of all patients, including those with cirrhosis, required dose modification for anaemia (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration). Anaemia (haemoglobin < 100 g/L) was reported in 7%, 14% and 28% of HIV-HCV co-infected patients treated with Pegasys, alone or in combination with ribavirin 800 mg and 1000/1200 mg respectively in studies NR15961 and NV18209.
In study NV18209, patients with anaemia were clinically managed with the use of growth factors and transfusions 26% and 37% of patients in the Pegasys plus ribavirin 800 mg group and in the Pegasys plus ribavirin 1000/1200 mg groups respectively, and with dose modification of either treatment in 13% and 21% of patients, respectively.

White blood cells.

Pegasys treatment was associated with decreases in values for both total WBC count and ANC. Approximately 4% of HCV/HBV patients on Pegasys monotherapy and 5% of HCV patients receiving Pegasys combination therapy had transient decreases in ANC to levels below 500 cells/mm3 at some time during therapy. In HIV-HCV co-infected patients, 13% and 11% of those receiving Pegasys, alone or in combination with ribavirin, respectively, had decreases in ANC < 500 cells/mm3.

Platelet count.

Pegasys treatment was associated with decreases in values for platelet counts. In clinical trials, approximately 5% of patients had decreases in platelet counts to levels below 50,000 cells/mm3 mostly in patients with cirrhosis and who entered the trial with baseline platelet counts as low as 75,000 cells/mm3. In clinical trials for HBV, 14% of patients had decreases in platelet counts to below 50,000 cells/mm3, mostly in patients who entered the study with low baseline platelet counts. In HIV-HCV co-infected patients, 10% and 8% of those receiving Pegasys, alone or in combination with ribavirin, respectively, had decreases in platelets below 50,000 cells/mm3.

Thyroid function.

Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see Section 4.4 Special Warnings and Precautions for Use). The frequencies observed with Pegasys were similar to those observed with other interferons.

Triglycerides.

Triglyceride levels were found to be elevated in patients receiving alfa interferon therapy, including Pegasys therapy.

ALT elevations.

HBV: Transient ALT elevations were observed with hepatitis B therapy with Pegasys. ALT elevation > 10-fold higher than the ULN were reported in 12% and 18% during Pegasys treatment and 7% and 12% post-treatment in HBeAg-negative and HBeAg-positive patients, respectively (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Anti-interferon antibodies.

Two percent of HCV patients receiving Pegasys monotherapy or in combination with ribavirin developed low titre neutralising anti-interferon antibodies. The clinical and pathological significance of the appearance of serum neutralising antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse reactions was observed.

Reporting of suspected adverse reactions.

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

Overdoses with Pegasys involving at least 2 injections on consecutive days (instead of weekly intervals) up to daily injections for one week (i.e. 1260 microgram/week) have been reported. None of these patients experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and 630 microgram have been administered in renal cell carcinoma and chronic myelogenous leukaemia clinical trials, respectively. Dose-limiting toxicities were fatigue, elevated liver enzymes, neutropenia and thrombocytopenia consistent with interferon therapy.
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poison Information Centre call 13 11 26 (Australia) and 0800 764 766 (0800 POISON) in New Zealand.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB11.

Mechanism of action.

The conjugation of a PEG reagent to interferon alfa-2a forms peginterferon alfa-2a (Pegasys). Interferon alfa-2a is produced biosynthetically using recombinant DNA technology, and is the product of a cloned human leukocyte interferon gene inserted into and expressed in E.coli. The structure of the PEG moiety directly affects the clinical pharmacology of peginterferon alfa-2a. Specifically, the size and branching of the 40 kD PEG reagent define the absorption, distribution, and elimination characteristics of peginterferon alfa-2a.
Peginterferon alfa-2a possesses the in vitro anti-viral and anti-proliferative activities of interferon alfa-2a. Interferons bind to specific receptors on the cell surface initiating a complex intracellular signalling pathway and rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation, and immunomodulation.
HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received peginterferon alfa-2a. The first phase of decline occurs within 24-36 h after the first dose of peginterferon alfa-2a and the second phase of decline occurs over the next 4-16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4-6 weeks in patients treated with peginterferon alfa-2a or interferon alfa in combination with ribavirin.
Peginterferon alfa-2a stimulates the production of effector proteins such as serum neopterin and 2',5'-oligoadenylate synthetase (2',5'-OAS) in a dose dependent manner. The stimulation of 2',5'-OAS is maximal after single doses of peginterferon alfa-2a 135 to 180 microgram and stays maximal throughout the 1 week dosing interval. The magnitude and duration of peginterferon alfa-2a induced 2',5'-OAS activity were reduced in subjects older than 62 and in subjects with significant renal impairment (creatinine clearance 20-40 mL/min).

Clinical trials.

Clinical trials have demonstrated that Pegasys alone or in combination with ribavirin is effective in the treatment of patients with CHC or CHB, including cirrhotic patients with compensated liver disease and in patients with HIV-HCV co-infection.

Chronic hepatitis C (CHC).

Monotherapy in treatment naïve patients. The safety and effectiveness of Pegasys for the treatment of hepatitis C were assessed in randomised, open-label, active-controlled clinical trials (NV15495 and NV15497). All patients were adults with compensated CHC, detectable HCV RNA, persistently abnormal ALT levels, a histological diagnosis consistent with CHC, and previously untreated with interferon therapy.

Patients with cirrhosis.

In NV15495, patients received either interferon alfa-2a (Roferon-A) 3 MIU subcutaneous (SC) three times a week, Pegasys 90 microgram SC once a week, or Pegasys 180 microgram SC once a week for 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. The study enrolled 271 patients whose baseline characteristics were 72% male, 88% Caucasian, 78% with cirrhosis and 21% with bridging fibrosis, and 56% genotype 1.

Patients with or without cirrhosis.

In NV15497, patients received either Roferon-A 6 MIU SC three times a week for 12 weeks followed by 3 MIU SC three times a week for 36 weeks or Pegasys 180 microgram SC once a week for 48 weeks, both arms were followed by 24 weeks of treatment-free follow-up. The study enrolled 531 patients whose baseline characteristics were 67% male, 85% Caucasian, 13% with cirrhosis or bridging fibrosis, a mean Knodell HAI score of 9, and 62% genotype 1.
Sustained virological response (SVR) was defined as a single undetectable HCV RNA measurement at the end of treatment-free follow-up period, measured by the qualitative Cobas Amplicor HCV test, version 2.0 (limit of detection 100 copies/mL equivalent to 50 IU/mL) (see Table 7). Histological improvement was measured as ≥ 2 point decrease in total Knodell HAI score at end of follow-up as compared to pre-treatment values (see Table 8).
Patients treated with Pegasys 180 microgram had overall SVRs of 30% in patients with cirrhosis and 39% in patients without cirrhosis. In the dose finding study, NV15489, a SVR was achieved in 6/20 (30%) patients given Pegasys 90 microgram for 48 weeks.
In all trials, most patients treated with Pegasys have normalisation or improvement of serum ALT during therapy. However, ALT may not normalise, even in patients in whom HCV RNA has become undetectable, until after Pegasys treatment has been completed. Whether or not ALT normalises, virological determination provides a more reliable means of determining the effectiveness of Pegasys treatment.
Quality of life assessment. During treatment with Roferon-A, patients commonly experience shaking chills, body aches, headache, loss of concentration, fatigue, anxiety, and insomnia. Such complaints reflect the significant quality of life reductions associated with standard interferon alfa-2a therapy.
In NV15497, patients treated with Pegasys experienced superior quality of life during the first 12 weeks of therapy than those receiving standard interferon alfa-2a. Most of these differences were statistically and clinically significant in terms of physical health, mental health and fatigue severity.
Combination therapy in treatment naïve patients.

Patients with elevated alanine transferase (ALT) levels.

The safety and effectiveness of Pegasys in combination with ribavirin for the treatment of hepatitis C were assessed in two prospective, randomised controlled, multinational clinical trials (NV15942 and NV15801). All patients were adults with compensated CHC, detectable HCV RNA, persistently elevated ALT levels, a histological diagnosis consistent with CHC, and previously untreated with interferon and/or ribavirin. Approximately 20% of patients in both studies had compensated cirrhosis.
In NV15942, a prospective, randomised controlled, multinational clinical trial, 1284 patients received Pegasys 180 microgram SC once a week and randomised to treatment for either 24 or 48 weeks and to a ribavirin daily dose of 800 mg or 1000/1200 mg (for bodyweight < 75 kg/≥ 75 kg). Assignment to the 4 treatment arms was stratified by viral genotype and baseline HCV viral titer.
In NV15801, a prospective, randomised controlled, multinational clinical trial, 1121 patients received either Pegasys 180 microgram SC once a week with placebo, Pegasys 180 microgram SC once a week with ribavirin 1000 mg (body weight < 75 kg) or 1200 mg (body weight ≥ 75 kg), or Intron A 3 MIU SC three times a week with Rebetol 1000 mg or 1200 mg daily (Revetron) for 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded.
SVR was defined as a single undetectable HCV RNA measurement at the end of the treatment-free follow-up period, measured by the qualitative Cobas Amplicor HCV test, version 2.0 (lower limit of detection 100 copies/mL equivalent to 50 IU/mL).
In NV15942 the SVR for patients infected with genotype 1 was significantly higher after 48 weeks of treatment than after 24 weeks (p = 0.001) and with the higher dose of ribavirin (p = 0.005). For patients infected with genotype 2 and 3 there was no statistically significant difference between 48 and 24 weeks of treatment and between the low and high dose of ribavirin (see Table 9). For genotype 4 patients (n = 36), the SVR was highest in patients treated for 48 weeks with ribavirin 1000/1200 mg (n = 9/11, 82%). The SVR in cirrhotic patients followed the same pattern as that of the overall population.
In NV15801, the SVR rate was 43% in cirrhotic patients treated with Pegasys in combination with ribavirin therapy compared to 33% in the Intron A in combination with Rebetol treatment group. At the end of follow-up, 80% of patients who had a paired biopsy and were treated with Pegasys in combination with ribavirin therapy had a histological response, compared to 72% and 76% in the Pegasys alone and interferon alfa-2b and ribavirin groups, respectively. Histological response was defined as ≥ 2 point decrease in total Knodell HAI score at end of follow-up as compared to pre-treatment. Paired biopsies were obtained in 17% of patients.

Patients with normal ALT levels.

The safety and effectiveness of Pegasys in combination with ribavirin for the treatment of hepatitis C were assessed in a phase III, prospective, randomised, open-label, multinational clinical trial (NR16071). All patients were non-cirrhotic adults with compensated CHC, detectable HCV RNA, persistently normal ALT levels, defined as serum ALT levels equal to or below the upper limit of normal, documented on at least 3 occasions, a minimum of 4 weeks apart. The patient population across the 3 study groups was 60% female, 85% Caucasian with a median age of 43 years. Median pre-treatment HCV RNA titres were 520 to 600 IU/mL and approximately 26% had no evidence of fibrotic liver disease.
In NR16071, 514 patients were randomised to receive Pegasys 180 microgram SC once a week with ribavirin 800 mg daily for either 24 weeks followed by a 48 week treatment-free period; 48 weeks followed by a 24 week treatment-free period; or no treatment for 72 weeks. The SVR rates reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942. No patients in the control arm achieved a SVR.
Patients infected with HCV genotype 1 had significantly higher SVR rates when treated for 48 weeks (40%) than when treated for 24 weeks (13%) [odds ratio = 4.47, 95% CI (2.47, 8.08), p < 0.001]. In patients infected with genotype non-1, SVR was not statistically different between patients treated for 48 weeks (75%) than when treated for 24 weeks (65%) [odds ratio = 1.69, 95% CI (0.79, 3.61), p = 0.177]. Of note, SVR was similar in patients with HCV genotype 2 or 3 infection whether these patients were treated for 48 weeks (78%) or 24 weeks (72%) [odds ratio = 1.40, 95% CI (0.59, 3.30), p = 0.452] (see Table 10).
A further analysis was conducted for HCV genotype 1 patients with normal ALT activity to predict the SVR that may have been achieved when treated with a higher dose of ribavirin. According to the predictive model, this group of patients has the potential to achieve a higher SVR when treated for 48 weeks with Pegasys 180 microgram SC once a week and ribavirin 1000/1200 mg daily than when treated with ribavirin 800 mg for 48 weeks. Based on this analysis, it is recommended that HCV genotype 1 patients with normal ALT receive ribavirin 1000/1200 mg.

Predictability of response in treatment-naïve patients.

In combination trials, an early virological response was defined as undetectable levels of HCV RNA or a 99% reduction (2 log drop) in viral titre from baseline by week 12 of therapy. Of patients experiencing an early virological response, 66% went on to achieve a SVR. In monotherapy trials, 98% of total patients treated with Pegasys 180 microgram once a week and who achieved a SVR had an early virological response by week 12. In HIV-HCV co-infected patients treated with Pegasys in combination with ribavirin and who achieved a SVR, 98% achieved an early virological response.
In NV15801 trial, patients who had an early virological response by week 12 and adhered to at least 80% (A ≥ 80%) of the planned Pegasys in combination with ribavirin treatment achieved a higher SVR regardless of genotype.

Chronic hepatitis C.

Prior treatment non-responder patients.

Study MV17150.

In this open-label, randomised, Phase III study, a total of 950 patients, who were previous non-responders to peginterferon alfa-2b in combination with ribavirin therapy (at least 12 weeks of prior treatment), were randomised to 4 different treatments: Pegasys 360 microgram once a week for 12 weeks, followed by 180 microgram once a week for a further 60 weeks; Pegasys 360 microgram once a week for 12 weeks, followed by 180 microgram once a week for a further 36 weeks; Pegasys 180 microgram once a week for 72 weeks; or Pegasys 180 microgram once a week for 48 weeks. All patients received ribavirin (1000 or 1200 mg daily) in combination with Pegasys. The end-of-treatment (EOT) virological response and SVR following the 24 week treatment-free period comparing duration of therapy or Pegasys induction dosing are summarised in Table 11. The SVRs following the 24 week treatment-free period from a pooled analysis comparing duration of therapy or Pegasys induction dosing are summarised in Table 12.
The SVR rate after 72 weeks treatment was superior to that after 48 weeks.
Differences in SVR based on treatment duration and demographics found in study MV17150 are displayed in Table 13.

HALT-C study.

In the HALT-C study, patients with CHC and advanced fibrosis or cirrhosis who had not responded to previous treatment with interferon alfa or peginterferon alfa monotherapy or combination ribavirin therapy were treated with Pegasys 180 microgram once a week and ribavirin 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 weeks after the EOT. The SVR rates varied depending upon the previous treatment regimen. Treatment outcome was poorest among patients who were non-responders to peginterferon in combination with ribavirin, identifying the most difficult to treat subpopulation of non-responder patients. The SVR in this treatment arm of the HALT-C study was comparable with the rate observed in the 48 week treatment arms of study MV17150. Despite higher SVR rates in non-responders to interferon or peginterferon monotherapy, efficacy in these less difficult to treat non-responders remains substantially lower than what is achievable in treatment-naïve patients (see Table 14). There was no difference in disease progression/cirrhosis with or without treatment (33% versus 34%).

Predictability of response and non-response in prior non-responder patients.

In non-responder patients treated for 72 weeks, the best on-treatment predictor of response was viral suppression at week 12 (undetectable HCV RNA, defined as HCV RNA < 50 IU/mL). The negative predictive value of viral suppression at week 12 was 96% (324/339) and the positive predictive value was 57% (57/100).

Chronic hepatitis C.

Prior treatment relapser patients. In an open-label study (Study WV16143) conducted in patients who relapsed after 24 weeks of treatment with peginterferon alfa and ribavirin, 64 patients (45 patients with genotype 1, 14 with genotype 2/3 and 5 with other genotypes) were re-treated with 48 weeks of Pegasys 180 microgram once a week and weight-based ribavirin daily. SVR was achieved in 51% of patients infected with genotype 1 and 64% of patients with genotype 2 or 3.

HIV-HCV co-infection.

In NR15961, 860 patients with HIV-HCV were randomised to a partially-blinded, controlled clinical trial. All patients were adults with compensated liver disease, detectable HCV, elevated ALT, serologically and histologically proven CHC, serological evidence of HIV-1 infection, CD4 cell count > 100 cells/microL and stable HIV-1 disease with or without anti-retroviral therapy. Patients received either Pegasys 180 microgram SC once a week with placebo, Pegasys 180 microgram SC once a week with ribavirin 800 mg daily or Roferon-A 3 MIU three times a week with ribavirin 800 mg daily for 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. The SVRs for the 3 treatment groups are summarised for all patients and by genotype in Table 15.
Patients treated with Pegasys in combination with ribavirin achieved higher SVRs irrespective of HCV genotype or baseline viral titre than patients treated with conventional Roferon-A with ribavirin or with Pegasys alone.
A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared Pegasys 180 microgram/week and either ribavirin 800 mg or 1000 mg (< 75 kg)/1200 mg (≥ 75 kg) daily for 48 weeks. The results are reported in Table 16 and showed that the study was not powered for efficacy considerations.
The safety profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus ribavirin combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose ribavirin arm.

Chronic hepatitis B (CHB).

Clinical trials have demonstrated that Pegasys is effective in the treatment of patients with CHB, in both HBeAg-positive patients and HBeAg-negative/anti-HBe positive patients.
The safety and effectiveness of Pegasys for the treatment of CHB were assessed in two randomised, partially double blinded clinical trials in HBeAg-positive patients (WV16240) and HBeAg-negative patients (WV16241). Both trials recruited patients with CHB who had active viral replication measured by HBV DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. No HBV-HIV co-infected patients were included in these clinical trials.
In both trials, patients received either Pegasys 180 microgram SC once a week with placebo, Pegasys 180 microgram SC once a week with lamivudine 100 mg daily or lamivudine 100 mg daily for 48 weeks of therapy followed by 24 weeks of treatment-free follow-up.
In WV16240, the primary measures were HBeAg seroconversion and suppression of HBV DNA to < 105 copies/mL. HBV DNA was measured by the Cobas Amplicor HBV Monitor Assay (limit of detection 200 copies/mL). Response rates at the end of follow-up are presented in Table 17.
In WV16241, the primary measures were normalised ALT and suppression of HBV DNA to < 2 x 104 copies/mL. Response rates at the end of follow-up are presented in Table 18.

5.2 Pharmacokinetic Properties

The pharmacokinetics of peginterferon alfa-2a were studied in healthy subjects and patients infected with hepatitis C. The results for patients with chronic hepatitis B (CHB) were similar to those for patients with chronic hepatitis C (CHC).

Absorption.

The absorption of peginterferon alfa-2a is sustained with peak serum concentrations reached 72-96 h after dosing. Serum concentrations are measurable within 3-6 h of a single subcutaneous injection of Pegasys 180 microgram. Within 24 h, about 80% of the peak serum concentration is reached. The absolute bioavailability of peginterferon alfa-2a is 84% and is similar to that seen with interferon alfa-2a.

Distribution.

Peginterferon alfa-2a is found predominately in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (Vss) of 6-14 L after intravenous (IV) dosing in humans. Based on studies in rats, peginterferon alfa-2a is distributed to the liver, kidney, and bone marrow in addition to being highly concentrated in the blood.

Metabolism.

The metabolic profile of peginterferon alfa-2a is not fully characterised.

Excretion.

After IV administration, the terminal half-life of peginterferon alfa-2a in healthy subjects is approximately 60 h compared to 3-4 h for standard interferon. A mean elimination half-life of 160 h (84-353 h) at primary elimination phase was observed in patients after subcutaneous (SC) administration of Pegasys. The elimination half-life determined after SC administration may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of peginterferon alfa-2a.

Pharmacokinetic overview.

In patients with CHC, steady-state serum concentrations increase 2-3-fold compared with single dose values and reach steady-state within 5-8 weeks of once a week dosing. Once steady-state has been achieved there is no accumulation of peginterferon alfa-2a. The peak to trough ratio after 48 weeks of treatment is about 1.5-2. Peginterferon alfa-2a serum concentrations are sustained throughout 1 full week (168 h) (see Table 19 and Figure 1).

Pharmacokinetics in special populations.

Renal impairment.

A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease (ESRD) requiring chronic haemodialysis (HD). Patients with moderate renal impairment receiving Pegasys 180 microgram once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to patients with normal renal function. Patients with severe renal impairment receiving Pegasys 180 microgram once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal function, therefore a reduced dose of Pegasys 135 microgram once weekly is recommended in patients with severe renal impairment. In 18 patients with ESRD requiring chronic HD, administration of Pegasys 135 microgram once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with normal renal function. Despite the lower plasma peginterferon alfa-2a exposure, patients with ESRD experienced the highest frequency of serious adverse events among the other groups in the study, likely owing to the severity and complexity of comorbidities in this patient population.

Gender.

The pharmacokinetics of peginterferon alfa-2a were comparable between male and female healthy subjects.

Elderly.

The AUC was modestly increased in subjects older than 62 years taking Pegasys 180 microgram, but peak concentrations were similar in those older and younger than 62 years. Based on drug exposure, pharmacodynamic response, and tolerability, a dose modification is not needed in the elderly (see Section 4.2 Dose and Method of Administration).

Children.

The pharmacokinetics of peginterferon alfa-2a has not been established in patients below the age of 18.

Non-cirrhotic and cirrhotic patients.

The pharmacokinetics of peginterferon alfa-2a were similar between healthy subjects and patients with CHC or CHB. Comparable exposure and pharmacokinetic profiles were seen in patients with cirrhosis with compensated liver disease and patients without cirrhosis.

5.3 Preclinical Safety Data

Genotoxicity.

Pegasys was neither mutagenic nor clastogenic when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.

Carcinogenicity.

Pegasys has not been tested for its carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, benzyl alcohol, sodium acetate, acetic acid, polysorbate 80, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 in the refrigerator at 2 to 8°C.
Do not freeze or shake.
Protect from light.

6.5 Nature and Contents of Container

0.5 mL of solution for injection in pre-filled syringe (Type I glass).

Pegasys 135 microgram/0.5 mL solution for injection in pre-filled syringe*.

Available in packs of 4 with corresponding number of injection needles.

Pegasys 180 microgram/0.5 mL solution for injection in pre-filled syringe.

Available in packs of 4 with corresponding number of injection needles.
*Presentation not available in New Zealand.

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. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

198153-51-4.
Pegasys (peginterferon alfa-2a) is made by conjugating a single branched polyethylene glycol chain (PEG) of approximate molecular weight of 40 kilodaltons (kD) to interferon alfa-2a (20 kD) via a stable amide bond. The combination of PEG and interferon alfa-2a forms an intact active molecule known as peginterferon alfa-2a, having an approximate molecular weight of 60 kD. Chemically, it is a bis-(N-monomethoxypolyethylene-glycol-urethanyl) lysyl interferon alfa-2a.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine - S4.

Summary Table of Changes