Ribavirin Teva Pharma B.V.

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C. V. 1. V. V. V. tablets are to be administered orally each day in two divided doses (morning and evening) with food. V. depends on patient’s weight and on the medicinal product that is used in combination.

V. In the cases in which no specific dose recommendation is made, the following dose should be used: Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg.

Medicinal product no longer authorised 3 Note:

For patients who weigh < 47 kg, or are unable to swallow tablets, ribavirin oral solution is available and should be used if appropriate. Dosing of ribavirin for children and adolescent patients is determined by the patient body weight.

For example, the body weight dosing used in conjunction with interferon alfa-2b or peginterferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin as some combination regimens do not adhere to the ribavirin dosing guidance provided in Table 1.

Table 1 Ribavirin dose based on body weight when used in combination with interferon alfa- 2b or peginterferon alfa-2b in paediatric patients Patient weight (kg) Daily ribavirin dose Number of 200 mg tablets 47-49 600 mg 3 x 200 mg tabletsa 50-65 800 mg 4 x 200 mg tabletsb > 65 Refer to adult dose recommendations a: 1 morning, 2 evening b: 2 morning, 2 evening Dose modification for adverse reactions Dose modification for adults Dose reduction of ribavirin depends on the initial ribavirin posology which depends on the medicinal product that is used in combination with ribavirin.

If a patient has a serious 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, cardiac status and indirect bilirubin concentration.

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 Bilirubin – Indirect > 5 mg/dL > 4 mg/dL (adults) * For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, ribavirin dose should be reduced to 600 mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets in the evening).

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

An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients. The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when ribavirin was used in combination with interferon alfa-2b or peginterferon alfa-2b.

Please refer to the corresponding SmPC of medicinal products that are used in combination with ribavirin for additional undesirable effects reported with these products. Adults Bitherapy with peginterferon alfa-2b or interferon alfa-2b The safety of ribavirin is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied ribavirin in combination with interferon alfa-2b, two trials studied ribavirin in combination with peginterferon alfa-2b.

Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below. Tabulated list of adverse reactions for adults The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use.

A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table

1). Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa.

There are several serious adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. ) - Growth inhibition in children and adolescents that may be irreversible in some patients - Increased thyroid stimulating hormone (TSH) in children and adolescents - Severe ocular disorders - Dental and periodontal disorders.

Paediatric population When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients.

The decision to treat should be made on a case by case. Haemolysis A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and 7 % of children and adolescents treated with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials.

Although ribavirin has no direct cardiovascular effects, anaemia associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. 3). 2). Cardiovascular Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders must be closely monitored.

It is recommended that those patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of therapy.

There are no data in children or adolescents with a history of cardiac disease. 6). For laboratory monitoring of pregnancy, please refer to Laboratory tests. , urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, ribavirin must be discontinued immediately and appropriate medical therapy instituted.

1. 3). In females of childbearing potential, ribavirin must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. 4). , thalassemia, sickle-cell anaemia). V. for contraindications specific to these products.