Consumer medicine information

IBAVYR

Ribavirin

BRAND INFORMATION

Brand name

Ibavyr

Active ingredient

Ribavirin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using IBAVYR.

SUMMARY CMI

IBAVYR®

Consumer Medicine Information (CMI) summary

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

1. Why am I using IBAVYR?

IBAVYR contains the active ingredient ribavirin. IBAVYR is used in combination with other oral agents for the treatment of chronic hepatitis C (CHC). CHC is a viral infection of the liver. For more information, see Section 1. Why am I using IBAVYR? in the full CMI.

2. What should I know before I use IBAVYR?

Do not use if you have ever had an allergic reaction to ribavirin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use IBAVYR? in the full CMI.

3. What if I am taking other medicines?

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

4. How do I use IBAVYR?

  • Take IBAVYR exactly as your doctor has directed.

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

5. What should I know while using IBAVYR?

Things you should do
  • Use IBAVYR Tablets exactly as your doctor has prescribed.
  • Use contraception in order to avoid pregnancy.
  • Stop using IBAVYR Tablets if you become pregnant and immediately tell your doctor.
  • If you are male and your partner becomes pregnant while you are using IBAVYR, ask your partner to tell her doctor immediately.
Things you should not do
  • Do not stop taking IBAVYR or change the dose without first checking with your doctor.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or pharmacist.
Driving or using machines
  • Be careful driving or operating machinery until you know how IBAVYR affects you.
  • If you become drowsy from the combination therapy, do not drive or use machinery.
Looking after your medicine
  • Keep your medicine in a cool dry place where the temperature stays below 25°C.

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

6. Are there any side effects?

Mild side effects include headache, fatigue, fever and chills, weakness, sleeplessness, stomach pain, discomfort or constipation, muscular ache and pain or joint pain, agitation, irritability, mood swings, or disturbance in attention, hair loss/change in hair texture, itching, rash or dry or redness of the skin, sore throat, cough, shortness of breath back pain. Serious side effects include signs of anaemia such as tiredness, being short of breath and looking pale, signs of liver decompensation such as a swollen abdomen lower back or side pain, severe stomach pain, fever or chills beginning after a few weeks of treatment, persistent cough or shortness of breath, depression, confusion, trouble sleeping, thinking or concentrating and allergic reactions.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

IBAVYR®

Active ingredient: Ribavirin

Consumer Medicine Information (CMI)

This leaflet provides important information about using IBAVYR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using IBAVYR.

Where to find information in this leaflet:

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

1. Why am I using IBAVYR?

IBAVYR contains the active ingredient ribavirin. Ribavirin belongs to a group of medicines called antivirals.

IBAVYR is used in combination with other oral agents for the treatment of chronic hepatitis C (CHC).

CHC is a viral infection of the liver. There are different types of the hepatitis C virus, referred to as genotypes. If this viral infection is not managed in some people, the liver becomes badly damaged and scarred. This is called cirrhosis. Cirrhosis can cause the liver to stop working. CHC may also be associated with the development of hepatocellular carcinoma.

IBAVYR is not effective when used alone and must only be used in combination with other oral agents. For more information please refer to the respective Consumer Medicine Information of the other oral agent used during the treatment.

2. What should I know before I use IBAVYR?

Warnings

Do not use IBAVYR if:

  • you are allergic to ribavirin, or any of the ingredients listed at the end of this leaflet, or any other similar medicines
Some of the symptoms of an allergic reaction may include:
- shortness of breath
- wheezing or difficulty breathing
- swelling of the face, lips, tongue or other parts of the body
- rash, itching or hives on the skin
  • you are taking didanosine (a medicine used to treat patients with human immunodeficiency virus (HIV).
  • you have blood disorders including anaemia (low number of red blood cells), thalassaemia (Mediterranean anaemia) or sickle-cell anaemia

If you are not sure whether you should start taking IBAVYR, talk to your doctor or pharmacist.

Check with your doctor if you:

  • have any other medical conditions
  • have, or have ever had any of the following medical conditions before you start taking IBAVYR:
  • heart problems such as congestive heart failure, irregular or very fast heartbeat, heart disease, or you have ever had a heart attack
  • anaemia (a low number of red blood cells)
  • kidney problems
  • liver problems other than hepatitis C
  • organ transplant
  • HIV
  • Also refer to the respective Consumer Medicines Information of the other oral agent used during the treatment, for other things to be careful of when IBAVYR is taken in combination with other oral agents.
  • take any medicines for any other condition

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

Pregnancy and breastfeeding

Do not use IBAVYR if you or your partner is pregnant or planning to become pregnant.

IBAVYR may cause birth defects and/or death of an unborn baby. It is very important that you or your partner avoid becoming pregnant during treatment and for 6 months after treatment. This is because IBAVYR Tablets can affect the sperm as well as the unborn child.

If you are or your partner is a woman of childbearing age, you or your partner must have a negative pregnancy test before treatment with IBAVYR Tablets starts.

You or your partner must also have a negative pregnancy test each month during treatment and for the 6 months after treatment is stopped. Two effective forms of contraception must be used, one by each partner, male and female, during treatment with IBAVYR Tablets and for the 6 months after treatment is completed. IBAVYR Tablets can cause harm to the unborn child if a pregnant woman takes IBAVYR Tablets herself during pregnancy or has unprotected sex (sex without using a condom) with a man who is taking IBAVYR Tablets. IBAVYR Tablets can damage the sperm and the embryo (unborn child).

Do not use IBAVYR Tablets if you are breastfeeding.

It is not known if IBAVYR passes into breast milk. Therefore to avoid any potential side effects in the nursing infant, nursing mothers should stop breast feeding when taking IBAVYR.

Use in children and adolescents

Do not give IBAVYR to children under 18 years of age

Safety and effectiveness in children has not been established.

3. What if I am taking other medicines?

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

You must not take IBAVYR if you are taking didanosine (a medicine used to treat HIV).

You must tell your doctor if you are taking:

  • stavudine, zidovudine or lamivudine (medicines used to treat HIV),
  • azathioprine (a medicine used to treat organ transplant patients),
  • severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis/polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune haemolytic anaemia, chronic refractory idiopathic thrombocytopenic purpura

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

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

Your doctor or pharmacist has more information on medicines to be careful of or avoid using while taking IBAVYR.

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

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

4. How do I use IBAVYR?

How much to take

  • The usual dose of IBAVYR depends on your weight and genotype. This can range from 600 mg to 1200 mg daily, to be taken in two divided doses (morning and evening).
  • Routine blood tests will help your doctor to monitor your response to treatment.
  • Your doctor may adjust your dose during therapy according to your response.
  • Follow the instructions provided and use IBAVYR until your doctor tells you to stop. Take IBAVYR exactly as your doctor has directed.
  • Your doctor will tell you how many tablets to take each day.
  • Do not exceed the recommended dosage.
  • IBAVYR has a child resistant cap. To open cap, push cap downward and twist counter clockwise.
  • To close cap, place cap on bottle and turn clockwise
  • IBAVYR should be taken with food.
  • Do not crush or chew the tablets.
  • IBAVYR 200mg tablets should be swallowed whole with water.

When to take IBAVYR

  • Take IBAVYR during or immediately after a meal, at about the same times each day.
  • Taking IBAVYR at the same times every day will have the best effect and help you to remember to take your tablets.
  • Do not stop taking IBAVYR unless your doctor tells you to stop.
  • Treatment is usually for at least 12 weeks and can go up to 24 weeks depending on your response.
  • If you become pregnant while using IBAVYR Tablets, you should immediately stop taking IBAVYR and tell your doctor. If you are male and your partner becomes pregnant while you are taking IBAVYR, ask your partner to tell her doctor immediately.

If you forget to use IBAVYR

IBAVYR should be used regularly at the same time each day. If you miss your dose at the usual time, take the missed dose as soon as possible during the same day.

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

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

  • If you are not sure what to do, ask your doctor or pharmacist.
  • If you have trouble remembering when to use your medicine, ask your pharmacist for some helpful hints.

If you use too much IBAVYR

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

You should immediately:

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

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using IBAVYR?

Things you should do

Use IBAVYR Tablets exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are taking IBAVYR.

Use contraception in order to avoid pregnancy.

Stop using IBAVYR Tablets if you become pregnant and immediately tell your doctor.

If you are male and your partner becomes pregnant while you are using IBAVYR, ask your partner to tell her doctor immediately.

Keep all your doctor's appointments so that your progress can be checked. Your doctor will carry out blood tests to monitor your response to treatment.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking IBAVYR

Things you should not do

  • Do not stop taking IBAVYR or change the dose without first checking with your doctor.
  • Do not use it to treat any other complaints unless your doctor says to.
  • Do not give IBAVYR to anyone else, even if their symptoms seem similar to yours.
  • Do not let yourself run out of medicine over weekends or holiday periods.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or pharmacist.

Driving or using machines

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

If you become drowsy from the combination therapy, do not drive or use machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Always keep this medicine in the bottle until it is time to take it.
  • Keep your medicine in a cool dry place where the temperature stays below 25°C.
  • Keep bottle tightly closed.
  • Heat and dampness can destroy some medicines.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking IBAVYR in combination with other oral agents.

The side effects listed below are possible side effects.

For more information please refer to the respective Consumer Medicine Information of the other oral agent used during the treatment.

Do not be alarmed by the following lists of side effects. You may not experience any of them

Less serious side effects

Less serious side effectsWhat to do
  • headache, fatigue, fever and chills
  • weakness
  • sleeplessness
  • stomach pain, discomfort or constipation
  • muscular ache and pain or joint pain
  • agitation, irritability, mood swings, or disturbance in attention
  • hair loss/change in hair texture, itching, rash or dry or redness of the skin
  • sore throat, cough, shortness of breath
  • back pain.
Speak to your doctor if you have any of these less serious side effects and they worry you.
These are mild side effects of the medicine and are usually short-lived. If they continue or are severe, tell your doctor.

Serious side effects

Serious side effectsWhat to do

signs of anaemia such as tiredness, being short of breath and looking pale

  • signs of liver decompensation such as a swollen abdomen lower back or side pain
  • severe stomach pain
  • fever or chills beginning after a few weeks of treatment
  • persistent cough or shortness of breath
  • depression
  • confusion, trouble sleeping, thinking or concentrating.

These could be signs of a serious allergic reaction.

  • itchy rash,
  • swelling of the face, lips or tongue,
  • wheezing or troubled breathing or faintness.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may occur in some people. Check with your doctor as soon as possible if you have any problems while using the combination therapy, even if you do not think the problems are connected with the medicines.

Reporting side effects

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

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

7. Product details

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

What IBAVYR contains

Active ingredient
(main ingredient)		Ribavirin
Other ingredients
(inactive ingredients)		Povidone
Croscarmellose sodium
Microcrystalline cellulose
Crospovidone
Silicon dioxide
Magnesium stearate
Opadry White 03F180000 (PI 109444)
Potential allergens-

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

What IBAVYR looks like

IBAVYR 200 mg tablets are white, capsule-shaped, coated tablet, debossed with "200" on one side and nothing on the other side.

The 200 mg tablets are packaged in HDPE bottles of 100 tablets.

AUST R 243632 - 200 mg tablets

Who distributes IBAVYR

In Australia and New Zealand:
Clinect Pty Ltd
120 - 132 Atlantic Drive
Keysborough VIC 3173
Australia
Free Call Australia:
1800 899 005
Free Call New Zealand:
0800 138 803

This leaflet was prepared on 14 December 2021.

® Registered trademark of PHARMASCIENCE Inc.

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Ibavyr

Active ingredient

Ribavirin

Schedule

S4

 

1 Name of Medicine

Ribavirin.

2 Qualitative and Quantitative Composition

Each Ibavyr (ribavirin) 200 mg tablet contains 200 mg ribavirin.
Ribavirin is a nucleoside analogue with antiviral activity.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.
Ibavyr (ribavirin) 200 mg tablet is a white, capsule-shaped, coated tablet, debossed with "200" on one side and nothing on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ibavyr (ribavirin tablets) is indicated in combination with other oral agents for the treatment of chronic hepatitis C (CHC) in adults.

4.2 Dose and Method of Administration

Dose.

Ribavirin monotherapy is not effective and Ibavyr must only be used in combination with other oral agents for the treatment of CHC.
Treatment with Ibavyr should be initiated and monitored by a physician experienced in the management of CHC.
The recommended dose and treatment duration should be individualised to the patient depending on body weight, baseline disease characteristics (e.g. genotype), response to therapy, and underlying conditions.
The recommended dose and treatment duration for combination therapy with sofosbuvir are shown in Table 1. When Ibavyr is used in combination treatment with any other oral agent, refer to the appropriate product information for dosage information.

Dose modifications.

If a patient has a serious adverse effect or develops laboratory abnormalities potentially related to ribavirin, the dose should be modified or discontinued, as appropriate, until the adverse effects abate or decrease in severity.
Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
When Ibavyr is used in combination treatment with any other oral agent, refer to the appropriate product information for dose reduction information.

Discontinuation of dosing.

If the other oral agents used in combination with Ibavyr are permanently discontinued, Ibavyr should not be continued as monotherapy.

Missed dose.

The missed doses should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to call their healthcare provider if they have questions.

Renal impairment.

Ibavyr should not be used in patients with creatinine clearance < 50 mL/min.

Method of administration.

Ibavyr is administered orally in two daily divided doses with food.

4.3 Contraindications

Ibavyr is used in combination with other therapeutic agents; the contraindications applicable to those agents are therefore applicable to the combination therapy. Refer to their respective product information for a list of their contraindications.
Ibavyr is also contraindicated in:
Women who are pregnant [see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy].
Men whose partners are pregnant [see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy].
Patients with hemoglobinopathies (e.g. thalassemia major or sickle cell anaemia).
In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions].
Patients with hypersensitivity to ribavirin or to any of the excipients listed in List of Excipients.
A history of severe pre-existing cardiac, including unstable or uncontrolled cardiac disease, in the previous six months.

4.4 Special Warnings and Precautions for Use

The product information of other oral agent(s) used in combination should be consulted before starting treatment with Ibavyr.

Cardiovascular.

Fatal and nonfatal myocardial infarctions have been reported in patients with anaemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. Because cardiac disease may be worsened by drug induced anaemia, patients with a history of significant or unstable cardiac disease should not use ribavirin.

Hematologic.

Anaemia.

The primary toxicity of ribavirin is haemolytic anaemia, which was commonly observed in clinical trials with other therapies and is the most common reason for dose modification of ribavirin in CHC patients [see Section 4.2 Dose and Method of Administration]. Anaemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in haemoglobin may be significant, it is advised that haemoglobin or haematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anaemia (e.g. spherocytosis, history of gastrointestinal bleeding).

Bone marrow suppression.

Concomitant administration of ribavirin and azathioprine has been reported to produce myelotoxicity (pancytopenia and bone marrow suppression) within 3 to 7 weeks of concomitant therapy. This was reversible within 4 to 6 weeks after withdrawal of either drug and did not recur after the reintroduction of either drug alone [see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions].

Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection.

The safety and efficacy of Ibavyr combination therapy has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established.
The clinical data to support the use of Ibavyr combination therapy in patients with genotype 5 and 6 HCV infection is very limited.

Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection.

Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not been fully investigated in Phase 3 studies. The optimal regimen and treatment duration have not been established. Such regimens should only be used for patients that are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.

HCV/HBV (hepatitis B virus) coinfected patients.

The safety and efficacy of Ibavyr combination therapy have not been established in patients co-infected with Hepatitis B Virus (HBV).

HCV/HIV coinfected patients.

There is limited data on the safety and efficacy of Ibavyr combination therapy in HCV/HIV co-infected patients with untreated HIV.

Post-liver transplant patients.

The safety and efficacy of Ibavyr combination therapy has not been established in post-liver transplant patients.

Acute hypersensitivity.

If an acute hypersensitivity reaction (e.g. urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ibavyr tablets should be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.

Race.

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n = 14), Hispanic (n = 13) and Caucasian (n = 15) subjects.

Gender.

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects. Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

Use in hepatic impairment.

Safety and efficacy of ribavirin have not been established in patients with decompensated cirrhosis.
The effect of hepatic impairment on the pharmacokinetics of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.

Use in renal impairment.

The pharmacokinetics of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on the administration of ribavirin in patients with creatinine clearance < 50 mL/min. Therefore, patients with creatinine clearance < 50 mL/min should not be treated with ribavirin.

Effects on laboratory tests.

It is recommended that standard haematological and biochemical laboratory tests be performed in all patients prior to initiating combination therapy with Ibavyr and periodically during therapy. Haematological tests should be performed at least at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks after initiation of therapy. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including haemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks.
Pregnancy screening in women of childbearing potential must be performed. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuation of therapy in female patients and the female partners of male patients.
Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Ibavyr and should be monitored during therapy.

Use in the elderly.

Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ibavyr should not be administered to patients with creatinine clearance < 50 mL/min.

Paediatric use.

Safety and effectiveness in paediatric patients have not been established. Therefore, use in children under the age of 18 is not recommended.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The drug interactions applicable to agents used in combination with ribavirin also apply to Ibavyr combination therapy. Refer to the appropriate product information for a detailed list of their drug interactions.
Ribavirin does not inhibit cytochrome P450 enzymes. There is no evidence from toxicology studies that ribavirin induces liver enzymes. Therefore, ribavirin has a minimal potential for P450 enzyme based interactions.
Due to the long half-life of ribavirin (approximately 120-170 h) any potential drug interactions may persist for up to 2 months (5 half-lives for ribavirin) following the end of treatment.
There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors.

Nucleoside reverse transcriptase inhibitors (NRTIs).

Lamivudine, stavudine, and zidovudine.

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g. plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g. loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multidrug regimen to HCV/HIV coinfected patients.

Didanosine.

Coadministration of Ibavyr and didanosine is contraindicated. Ribavirin potentiates the phosphorylation of didanosine via inhibition of inosine 5-monophosphate dehydrogenase (IMPD) enzyme. As a result, the concentrations of didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) are increased when didanosine is coadministered with ribavirin. There have been reports of fatal hepatic failure, pancreatitis, peripheral neuropathy, and symptomatic hyperlactatemia/lactic acidosis in clinical trials.

Azathioprine.

The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine related myelotoxicity. IMDH is involved in one of the metabolic pathways of azathioprine. Coadministration of this drug with ribavirin may possibly lead to an accumulation of the 6-methylthioinosine monophosphate (6-MTITP) metabolite. This metabolite has been associated with myelotoxicity (neutropenia, thrombocytopenia, and anaemia) in patients treated with azathioprine anaemia.
Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Section 4.4 Special Warnings and Precautions for Use].

Drug-food interactions.

The presence of food in the gastrointestinal tract appears to increase the bioavailability of ribavirin. Ibavyr tablets should be taken with food [see Section 5.2 Pharmacokinetic Properties].

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.
Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Ibavyr unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilised for 6 months post-therapy (i.e. 15 half-lives of clearance for ribavirin).
(Category X)
Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose.
Survival of foetuses and offspring was reduced.
In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended daily human dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin).
Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Ibavyr should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Ibavyr unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post-therapy [see Section 4.3 Contraindications].
 It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with Ibavyr, based on the importance of the therapy to the mother.

4.7 Effects on Ability to Drive and Use Machines

Patients should be informed that fatigue, disturbance in attention, dizziness and blurred vision have been reported during treatment with ribavirin in combination with other agents. Patients who develop these symptoms should be cautioned to avoid driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

When ribavirin is used in combination with other oral agents, please refer to the appropriate product information for a complete list of adverse drug effects.

Adverse events from clinical trials.

Assessment of adverse reactions associated with ribavirin and sofosbuvir combination therapy is based on pooled data from 650 patients who received sofosbuvir and ribavirin combination therapy for 12 weeks, 98 patients who received sofosbuvir and ribavirin combination therapy for 16 weeks, 250 patients who received sofosbuvir and ribavirin for 24 weeks, and 71 patients who received placebo for 12 weeks.
The proportion of patients who permanently discontinued treatment due to adverse events was 4% for patients receiving placebo, 1% for patients receiving sofosbuvir + ribavirin for 12 weeks, and < 1% for patients receiving sofosbuvir + ribavirin for 24 weeks.
The following adverse reactions listed below by body system organ class have been identified with sofosbuvir and ribavirin therapy (Table 3). Frequencies are defined as follows: very common ≥ 10%, common ≥ 1% and < 10%, or uncommon > 0.1% and ≤ 1%.
The most common adverse events (≥ 20%) for sofosbuvir + ribavirin combination therapy were fatigue and headache.
With the exception of anaemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir containing regimens.
Less common adverse reactions reported in clinical trials (< 1%). The following ADRs occurred in < 1% of patients receiving ribavirin in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Psychiatric disorders.

Severe depression (particularly in patients with pre-existing history of psychiatric illness), including suicidal ideation and suicide.
Other special population(s).

HIV/HCV coinfection.

The safety profile of ribavirin and sofosbuvir in HCV/HIV coinfected patients was similar to that observed in monoinfected HCV patients treated with of ribavirin and sofosbuvir in phase 3 clinical studies.

Patients awaiting liver transplantation.

The safety profile of ribavirin and sofosbuvir in HCV infected patients prior to liver transplantation was similar to that observed in patients treated with ribavirin and sofosbuvir in phase 3 clinical studies.

Postmarket adverse drug effects.

For complete safety information of ribavirin in combination with other oral agents, please refer to the appropriate product information.

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

No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcaemia and hypomagnesaemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.
For information on the management of overdose, contact the Poison Information Centre at 131126 (Australia) or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for treatment of HCV infections, ATC code: J05AP01.

Mechanism of action.

Ribavirin is an antiviral drug. The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. It has shown direct antiviral activity in tissue culture against numerous viruses. Ribavirin increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits hepatitis C virus (HCV) polymerase in a biochemical reaction.

Antiviral activity in vitro.

The antiviral activity of ribavirin was investigated in the stable HCV cell culture model system (HCV replicon). Ribavirin inhibited autonomous HCV RNA replication with a 50% effective concentration (EC50) value of 11-21 microM. Evaluation of sofosbuvir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Clinical trials.

Ribavirin monotherapy is not effective and Ibavyr must only be used in combination with other oral agents for the treatment of CHC.
The clinical trials which evaluated the efficacy of ribavirin in combination therapy with sofosbuvir are summarised below. For more information on the clinical trials conducted on ribavirin in combination with sofosbuvir and/or other agents, please consult the respective product information.
Clinical trials of ribavirin in combination with sofosbuvir. The efficacy of ribavirin in combination with sofosbuvir was evaluated in five phase 3 trials in patients with genotypes 1 to 6 chronic hepatitis C (CHC). One study was conducted in treatment naïve patients with genotype 1, 4, 5 or 6 CHC and the other four trials were conducted in patients with genotype 2 or 3 CHC including one trial in treatment naïve patients, one in interferon intolerant, ineligible or unwilling patients and one in patients previously treated with an interferon based regimen and one in all patients irrespective of prior treatment history or ability to take interferon. Patients in these trials had compensated liver disease including cirrhosis. The ribavirin dose was weight based 1000-1200 mg daily administered in two divided doses. Sofosbuvir was administered at a dose of 400 mg once daily. Treatment duration was fixed in each trial and was not guided by patients' HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all trials which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12).

Treatment naïve adults - FISSION (study 1231).

FISSION was a randomised, open label, active controlled trial that evaluated 12 weeks of treatment with ribavirin and sofosbuvir compared to 24 weeks of treatment with ribavirin and peginterferon alfa-2a in treatment naïve patients with genotype 2 and 3 HCV. The ribavirin doses used in the sofosbuvir + ribavirin and peginterferon alfa-2a + ribavirin arms were weight based 1000-1200 mg per day and 800 mg per day regardless of weight, respectively. Patients were randomised in a 1:1 ratio and stratified by cirrhosis (presence vs absence), HCV genotype (2 vs 3) and baseline HCV RNA level (< 6 log10 IU/mL vs ≥ 6 log10 IU/mL). Patients with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio.
Treated patients (N = 499) had a median age of 50 years (range: 19 to 77); 66% of the patients were male; 87% were White, 3% were Black; 14% were Hispanic or Latino, 29% were Asian; mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype 3.9% were on opiate replacement therapy. Table 4 presents the response rates from this study.
The difference in the overall SVR rates between sofosbuvir + ribavirin and peginterferon alfa + ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met the predefined noninferiority criterion. Among the small number of Black/African Americans enrolled in the trial, 75% (9/12) of patients achieved SVR in the sofosbuvir + ribavirin treatment group compared to 40% (2/5) in the peginterferon alfa + ribavirin treatment group.
Response rates for patients with cirrhosis at baseline are presented in Table 5 by genotype.

Interferon intolerant, ineligible or unwilling adults - POSITRON (study 107).

POSITRON was a randomised, double blinded, placebo controlled trial that evaluated 12 weeks of treatment with ribavirin and sofosbuvir (N = 207) compared to placebo (N = 71) in patients who are interferon intolerant, ineligible or unwilling. Patients were randomised in 3:1 ratio and stratified by cirrhosis (presence vs absence).
Treated patients (N = 278) had a median age of 54 years (range: 21 to 75); 54% of the patients were male; 91% were White, 5% were Black; 11% were Hispanic or Latino, 8% were Asian; mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype 3. 8% were on opiate replacement therapy. The proportions of patients who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47%, respectively. Most patients had no prior HCV treatment (81.3%). Table 6 presents the response rates for the treatment groups of sofosbuvir + ribavirin and placebo.
The SVR12 rate in the sofosbuvir + ribavirin treatment group was statistically significant when compared to placebo (p < 0.001).
Table 7 presents the subgroup analysis by genotype for cirrhosis and interferon classification.

Previously treated adults - FUSION (study 108).

FUSION was a randomised, double blinded trial that evaluated 12 or 16 weeks of treatment with ribavirin and sofosbuvir in patients who did not achieve SVR with prior interferon based treatment (relapsers and nonresponders). Patients were randomised in a 1:1 ratio and stratified by cirrhosis (presence vs absence) and HCV genotype (2 vs 3).
Treated patients (N = 201) had a median age of 56 years (range: 24 to 70); 70% of the patients were male; 87% were White; 3% were Black; 9% were Hispanic or Latino, 12% were Asian; mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV RNA levels greater than 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% were prior relapsers. 3% were on opiate replacement therapy. Table 8 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 16 weeks.
Table 9 presents the subgroup analysis by genotype for cirrhosis and response to prior HCV treatment.

Treatment naïve and previously treated adults - VALENCE (study 133).

The VALENCE trial evaluated sofosbuvir in combination with weight based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment naïve patients or patients who did not achieve SVR with prior interferon based treatment, including patients with compensated cirrhosis. The study was designed as a direct comparison of sofosbuvir and ribavirin versus placebo for 12 weeks. However, based on emerging data, the study was unblinded and all HCV genotype 2 patients continued to receive sofosbuvir and ribavirin for 12 weeks, whilst treatment for HCV genotype 3 patients was extended to 24 weeks. Eleven HCV genotype 3 patients had already completed treatment with sofosbuvir and ribavirin for 12 weeks at the time of the amendment.
Treated patients (n = 419) had a median age of 51 years (range: 19 to 74); 60% of the patients were male; median body mass index was 25 kg/m2 (range: 17 to 44 kg/m2); the mean baseline HCV RNA level was 6.4 log10 IU/mL; 21% had cirrhosis; 78% had HCV genotype 3; 65% were prior relapsers. Table 10 presents the response rates for the treatment groups of sofosbuvir + ribavirin for 12 weeks and 24 weeks.
Placebo recipients are not included in the tables since none achieved SVR12.
Table 11 presents the subgroup analysis by genotype for cirrhosis and exposure prior to HCV treatment.

SVR12 to SVR24 concordance.

The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of the treatment) following treatment with sofosbuvir in combination with ribavirin or ribavirin and pegylated interferon demonstrates a positive predictive value of 99% and a negative predictive value of 99%.
Clinical efficacy and safety in special populations.

HCV/HIV coinfected patients - PHOTON-1 (study 123).

Sofosbuvir was studied in an open label clinical study evaluating the safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir and ribavirin in patients with genotype 1, 2 or 3 chronic hepatitis C coinfected with HIV-1. Genotype 2 and 3 patients were either treatment naïve or experienced, whereas genotype 1 patients were naïve to prior treatment. Patients received 400 mg sofosbuvir and weight based ribavirin (1,000 mg for patients weighing < 75 kg or 1,200 mg for patients weighing ≥ 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment history. Patients were either not on antiretroviral therapy with a CD4+ cell count > 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count > 200 cells/mm3. Efficacy data 12 weeks post-treatment are available for 210 patients (Table 12).
There is limited data on the safety and efficacy of sofosbuvir in HCV/HIV coinfected patients with untreated HIV.
Table 13 presents the subgroup analysis by genotype for cirrhosis.

Patients awaiting liver transplantation.

Sofosbuvir was studied in HCV infected patients prior to undergoing liver transplantation in an open label clinical trial evaluating the safety and efficacy of sofosbuvir and ribavirin administered pretransplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) (HCV RNA < lower limit of quantification [LLOQ] at 12 weeks post-transplant). HCV infected patients, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria received 400 mg sofosbuvir and 1000-1200 mg ribavirin daily for a maximum of 24 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 patients who received sofosbuvir and ribavirin; 45 had genotype 1; 44 patients had a baseline CPT score less than 7. Of these 61 patients, 44 patients underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 41 had HCV RNA < LLOQ at the time of transplantation, one of whom received an HCV infected liver. The viral response rates of the 41 patients transplanted with HCV RNA < LLOQ are described in Table 14.

5.2 Pharmacokinetic Properties

Absorption.

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean ± SD (n = 39; body weight > 75 kg) AUC0-12hr was 25,361 ± 7110 nanogram.hr/mL and Cmax was 2748 ± 818 nanogram/mL.
The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662 ± 545 nanogram/mL in HCV infected patients who received 800 mg/day (n = 89), and 2112 ± 810 nanogram/mL in patients who received 1200 mg/day (n = 75; body weight > 75 kg).

Distribution.

Ribavirin partitions into all cells rapidly and extensively. It has a very large steady-state volume of distribution after intravenous dosing. This distribution is facilitated by the sodium independent equilibrative sensitive (es) nucleoside transporter that is present on virtually all cell types and may account for the extensive distribution. Ribavirin sequesters in erythrocytes extensively with a ratio of 60:1 between whole blood and plasma concentrations. Ribavirin does not bind to plasma proteins.

Metabolism.

Ribavirin has two pathways of metabolism: (1) a reversible phosphorylation pathway (to mono-, di-, and triphosphate metabolites); and (2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxamide. Ribavirin is not a substrate and does not inhibit any cytochrome P450 (CYP) enzymes. There is minimal potential for P450 enzyme based drug interactions.

Excretion.

The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known; however, it is thought that the principal route of elimination for both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites is renal (accounting for about 5-15% of single dose elimination), with the majority of the dose eliminated as metabolites rather than as parent compound.
Due to extensive distribution, the terminal half-life of a single oral dose is around 120 to 170 hours and the total apparent clearance is around 26 L/h. There was extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose. The terminal elimination phase was elongated following multiple dosing with a mean t1/2 in the range 274-298 h. Ribavirin was detectable until 4 weeks following cessation of dose administration. These results reflect the slow elimination of ribavirin from tissue compartments.

Effect of food.

Bioavailability of a single oral dose of ribavirin was increased by coadministration with a high fat meal. Patients are advised to take ribavirin with food [see Section 4.2 Dose and Method of Administration].

Age, gender and ethnicity.

Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ribavirin should not be administered to patients with creatinine clearance < 50 mL/min [see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration].
No clinically significant differences in ribavirin pharmacokinetics were observed between male and females subjects when corrected for weight. In a pharmacokinetic study in 42 subjects there were no clinically significant differences observed in ribavirin pharmacokinetics between black, Hispanic or Caucasian subjects.

Patients with impaired renal function.

The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance < 50 mL/min. Therefore, patients with creatinine clearance < 50 mL/min should not be treated with ribavirin [see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration].

Patients with hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated.

5.3 Preclinical Safety Data

Carcinogenicity.

In a p53 (±) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2 year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively. Potential carcinogenic risk to humans cannot be excluded.

Genotoxicity.

Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Ibavyr (ribavirin) 200 mg tablet contains povidone, croscarmellose sodium, microcrystalline cellulose, crospovidone, silicon dioxide, magnesium stearate, Opadry White 03F180000 PI (109444).

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 below 25°C. Keep bottle tightly closed. Protect from light.

6.5 Nature and Contents of Container

200 mg.

HDPE bottles with child resistant closure of 28 tablets or HDPE bottles of 100 tablets.
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Ribavirin is a white to off-white crystalline powder which is freely soluble in water and slightly soluble in anhydrous ethanol.
Chemical name: 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
Molecular formula: C8H12N4O5.
Molecular mass: 244.21 g/mol.

Chemical structure.


CAS number.

36791-04-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes