RIBAVIRIN

Treatment should be initiated and monitored by a physician experienced in the management of chronic hepatitis C. Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin for the treatment of hepatitis C.

Method of Administration Ribavirin film-coated tablets are administered orally in two divided doses with food (morning and evening). Due to the teratogenic potential of ribavirin, the tablets should not be broken or crushed. Posology Dose to be administered The dose of Ribavirin is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1).

Ribavirin tablets are to be administered orally each day in two divided doses (morning and evening) with food. Table 1. Ribavirin dosing recommendation according to the medicinal product used in combination Medicinal product used in combination Daily Ribavirin Dose Number of 200/400mg tablets Direct acting antivirals (DAA) <75kg=1000mg =>75 kg = 1200 mg 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) PegIFN alfa-2a without DAA <75kg=1000mg =>75 kg = 1200 mg 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) Genotype 2/3 treatment- naïve Genotype 2/3/4 with HIV-coinfection 800mg 4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening) PegIFN alfa-2a without DAA Genotype 1/4 Genotype 2/3 treatment- experienced Genotype 1 HIV- coinfection <75kg=1000mg =>75 kg = 1200 mg 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) IFN alfa-2a without DAA <75kg=1000mg =>75 kg = 1200 mg 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) <65kg= 800 mg 4x 200mg (2 morning, 2 evening) or 2 x 400 (1 morning, 1 evening) 65-80kg= 1,000 mg 5 (2 morning, 3 evening) 81-105kg= 1,200 mg 6 (3 morning, 3 evening) PegIFN alfa-2b with or without DAA >105kg= 1,400 mg 7 (3 morning, 4 evening) Duration of treatment Duration of treatment depends on medicinal products that it is being combined with and may depend on several patients or virus characteristics including genotype, co-infection status, previous history of treatment, on-treatment response.

Refer to the SPC of the medicinal product that is used in combination with Ribavirin. Dosage modification for adverse reactions Dose modification of Ribavirin depends on medicinal products that it is being combined with. If a patient has a severe adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status. 5 g/dl Haemoglobin: Patients with History of Stable Cardiac Disease > 2 g/dl decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction) <12 g/dl despite 4 weeks at reduced dose [1] For patients receiving a 1000mg (<75kg) or 1200mg (>75kg) dose, Ribavirin dose should be reduced to 600mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening).

If the 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 higher doses is not recommended. [2] For patients receiving a 800mg (<65kg)-1000mg (65-80kg)-1200mg (81-105kg) or 1400mg (>105kg) dose, 1st dose reduction of Ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day).

If needed, 2nd dose reduction of Ribavirin is by an additional 200 mg/day. Patients whose dose of Ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. ” Special populations Use in renal impairment: The recommended dose regimens (adjusted by the body weight cut-off of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment.

2). 4). If severe adverse reactions or laboratory abnormalities develop, ribavirin should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin, ribavirin therapy should be discontinued.

No data are available for pediatric subjects with renal impairment. 2). Therefore, no dose adjustment of Ribavirin is required in patients with hepatic impairment.

Use in elderly patients over the age of 65:

There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of ribavirin.

Use in patients under the age of 18 years:

Treatment with […]

The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy. The hemolytic anemia associated with ribavirin therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease.

4). Use of Ribavirin in combination with direct antiviral agents (DAA) Based on the review of safety data derived from clinical studies in adults with DAA in combination with ribavirin, the most frequent adverse reactions identified as associated with ribavirin were anaemia, nausea, vomiting, asthenia, fatigue, insomnia, cough, dyspnoea, pruritus and rash.

Except anaemia, the majority of these adverse reactions were not serious and resolved without treatment discontinuation. Use of Ribavirin in combination with interferon alfa-2a or peginterferon alfa-2a The adverse events listed in this section are reported in clinical trials and/or as adverse drug reactions from spontaneous reports primarily when ribavirin was used in combination with interferon alfa-2a or peginterferon alfa-2a.

Adverse events reported in patients receiving ribavirin in combination with interferon alfa-2a are essentially the same as for those reported for ribavirin in combination with peginterferon alfa-2a. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Refer also to the SmPC of the medicinal products that are used in combination with ribavirin for additional undesirable effects reported with these products. Chronic Hepatitis C The most frequently reported adverse events with ribavirin in combination with peginterferon alfa-2a 180 μg were mostly mild to moderate in severity, Most of them were manageable without the need for discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients Overall, the safety profile for ribavirin in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and ribavirin treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms.

Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and ribavirin treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%).

Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial. In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks.

4). Chronic Hepatitis C and Human Immunodeficiency Virus Co-infection In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients.

For HIV-HCV patients receiving Ribavirin and peginterferon alfa-2a combination therapy other undesirable effects have been reported in ≥1% to ≤2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.

Peginterferon alfa-2a treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy.

The use of peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts ≤ 200/μl. (see peginterferon alfa-2a SmPC).

Table 4 shows the undesirable effects reported in patients who have received ribavirin primarily in combination with peginterferon alfa-2a or interferon alfa-2a. Table 4 Undesirable Effects Reported with Ribavirin primarily in combination with Peginterferon alfa-2a for HCV Patients Body system Very Common ≥1 /10 Common ≥1 /100 to < 1 /10 Uncommo n ≥1 /1000 to < 1 /100 Rare ≥1 /10,000 to < 1 /1000 Very rare <1/10,000 Frequenc y not known* Infections and infestations Upper respiratory infection, bronchitis, oral candidiasis, Lower respiratory tract infection, pneumonia, urinary Endocarditis , Otitis externa herpes simplex tract infection, skin infection Blood and lymphatic system disorders Anaemia, neutropenia Thrombocyto penia, lymphadenop athy Pancytopeni a Aplastic anaemia Pure red cell aplasia Immune system disorders Sarcoidosis, thyroiditis Anaphylaxis , systemic lupus erythematos us, rheumatoid arthritis idiopathic or thromboti c thromboc ytopenic purpura Liver and renal graft rejection, Vogt- Koyanagi- Harada disease Endocrine disorders Hypothyroidi sm, hyperthyroidi sm Diabetes Metabolism and Nutrition Disorders Anorexia Dehydratio n Psychiatric disorders Depression , insomnia Mood alteration, emotional disorders, anxiety, aggression, nervousness, libido decreased Suicidal ideation, hallucinatio ns, anger Suicide, psychotic disorder Mania, bipolar disorders, homicidal ideation Nervous system disorders Headache, dizziness, concentrati on impaired Memory impairment, […]

Ribavirin monotherapy must not be used Combination therapy of ribavirin with (peg) interferon alfa. There are several severe adverse reactions associated with the combination therapy of ribavirin with (peg) interferon alfa. ) - Severe ocular disorders - Dental and periodontal disorders - Growth inhibition in children and adolescents that may be irreversible in some patients Please refer to the SmPC of (peg) interferon alfa-2a for details on the recommendations of monitoring and management regarding these adverse reactions before initiating therapy.

Teratogenic risk:

See section

1. 4). Ribavirin must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. 6). - a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

g. thalassaemia, sickle-cell anaemia). Refer also to the SmPC of the medicinal products that are used in combination with ribavirin for contraindications related to those products.