Rebetol - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Rebetol 200 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of ribavirin.

Excipient with known effect

Each hard capsule contains 40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule)

White, opaque and imprinted with blue ink.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Rebetol is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults (see sections 4.2, 4.4, and 5.1).

Rebetol is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) for paediatric patients (children 3 years of age and older and adolescents) not previously treated and without liver decompensation (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.

Posology

Rebetol must be used in combination therapy as described in section 4.1.

Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products used in combination with Rebetol for additional prescribing information particular to that product and for further dosage recommendations on co-administration with Rebetol.

Rebetol capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adults

The recommended dose and duration of Rebetol depends on patient’s weight and on the medicinal product that is used in combination. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol.

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.

Paediatric population

No data are available in children below 3 years of age.

Note: For patients who weigh < 47 kg, or are unable to swallow capsules, please refer to the SmPC for Rebetol 40 mg/mL oral solution.

Dosing of Rebetol 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 Rebetol as some combination regimens do not adhere to the Rebetol dosing guidance provided in Table 1.

Table 1 Rebetol dose based on body weight when used in combination with interferon alfa-2b or peginterferon alfa-2b in paediatric patients
Patient weight (kg)	Daily Rebetol dose	Number of 200 mg capsules
47 – 49	600 mg	3 capsules a
50 – 65	800 mg	4 capsules b
> 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 Rebetol depends on the initial Rebetol posology which depends on the medicinal product that is used in combination with Rebetol.

If a patient has a serious adverse reaction potentially related to Rebetol, the Rebetol 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.

Table 2 Management of Adverse Reactions
Laboratory values	Reduce Rebetol dose if:	Discontinue Rebetol if:
Haemoglobin in patients with No Cardiac Disease	< 10 g/dL	< 8.5 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)

In case of serious adverse reaction potentially related to medicinal products used in combination with Rebetol, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the Rebetol dose modification and/or discontinuation guidelines as described in Table 2.

Dose modification for paediatric patients

Dose reduction in paediatric patients without cardiac disease follows the same guidelines as adult patients without cardiac disease regarding haemoglobin levels (Table 2 ).

There are no data for paediatric patients with cardiac disease (see section 4.4).

Table 3 provides guidelines for discontinuation based on the patient’s indirect bilirubin concentration.

Table 3 Management of Adverse Reactions
Laboratory values	Discontinue Rebetol if:
Bilirubin – Indirect	> 5 mg/dL (for > 4 weeks) (children and adolescents treated with interferon alfa-2b), or > 4 mg/dL (for > 4 weeks) (children and adolescents treated with peginterferon alfa-2b)

Special populations

Elderly ( > 65 years of age)

There does not appear to be a significant age-related effect on the pharmacokinetics of Rebetol. However, as in younger patients, renal function must be determined prior to administration of Rebetol (see section 5.2).

Paediatric patients (children 3 years of age and older and adolescents)

Rebetol may be used in combination with peginterferon alfa-2b or interferon alfa-2b (see section 4.4). The selection of Rebetol formulation is based on individual characteristics of the patient.

The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has not been established. No data are available.

Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for further dosage recommendations on co-administration.

Renal impairment

The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Adult patients with moderate renal impairment (creatinine clearance of 30–50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Rebetol 200 mg/day. Table 4 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Table 4 Dosage Modification for Renal Impairment in Adult Patients
Creatinine Clearance	Rebetol Dose (daily)
30 to 50 mL/min	Alternating doses, 200 mg and 400 mg every other day
Less than 30 mL/min	200 mg daily
Haemodialysis (ESRD)	200 mg daily

Hepatic impairment

No pharmacokinetic interaction appears between Rebetol and hepatic function (see section 5.2). For use in patients with decompensated cirrhosis, see the corresponding SmPC of the medicinal products used in combination with Rebetol.

Method of administration

Rebetol should be administered orally with food.

4.3 Contraindications

• – Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• – Pregnancy (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Rebetol must not

be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

• – Breast-feeding.

• – History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease,

in the previous six months (see section 4.4).

• – Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).

Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for contraindications specific to these products.

4.4 Special warnings and precautions for use

Rebetol must be used in combination with other medicinal products (see section 5.1).

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 Rebetol with (peg)interferon alfa. These include:

• – Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behaviour, etc.)

• – 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 Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Rebetol has no direct cardiovascular effects, anaemia associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Rebetol must be administered with caution to patients with pre-existing cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).

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.

Teratogenic risk

Prior to initiation of treatment with Rebetol the physician must comprehensively inform both male and female patients of the teratogenic risk of Rebetol, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with Rebetol (see section 4.6). For laboratory monitoring of pregnancy, please refer to Laboratory tests.

Acute hypersensitivity

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

Liver function

Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for discontinuation or dose modification recommendations.

Renal impairment

The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Rebetol dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment (see sections 4.2 and 5.2). Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary (see section 4.2).

Potential to exacerbate immunosuppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and Rebetol concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 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).

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis:

Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when Rebetol is administered. For additional details see section 4.5.

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentrations.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for discontinuation or dose modification recommendations. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and cART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with Rebetol and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Rebetol with zidovudine is not recommended (see section 4.5).

Patients with low CD4 counts

In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/gL. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the corresponding SmPC of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Rebetol.

Laboratory tests

Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Rebetol therapy:

• • Haemoglobin           Adult: > 12 g/dL (females); > 13 g/dL (males)

Children and adolescents: > 11 g/dL (females); > 12 g/dL (males)

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).

Uric acid may increase with Rebetol due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.

Lactose

Each Rebetol capsule contains 40 mg of lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome P450 enzyme mediated metabolism of Rebetol. Rebetol does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that Rebetol induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions.

Rebetol, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of pegylated alpha interferons and Rebetol concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering Rebetol concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicines should be stopped (see section 4.4).

No interaction studies have been conducted with Rebetol and other medicinal products, except for peginterferon alfa-2b, interferon alfa-2b and antacids.

No pharmacokinetic interactions were noted between Rebetol and peginterferon alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic stu­dy.

Antacid

The bioavailability of Rebetol 600 mg was decreased by co-administration with an antacid containing magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of Rebetol or modified pH. This interaction is not considered to be clinically relevant.

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, Rebetol increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of Rebetol and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see section 4.4).

The exacerbation of anaemia due to Rebetol has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of Rebetol with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Any potential for interactions may persist for up to two months (five half-lives for Rebetol) after cessation of Rebetol therapy due to the long half-life (see section 5.2).

There is no evidence that Rebetol interacts with non-nucleoside reverse transcriptase inhibitors or protease inhibitors.

Conflicting findings are reported in literature on co-administration between abacavir and Rebetol. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/Rebetol therapy. Caution should be exercised when both medicines are co-administered.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/con­traception in males and females

Female patients

Rebetol must not be used by females who are pregnant (see sections 4.3 and 5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential must use an effective contraceptive during treatment and for nine months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within nine months from stopping treatment, the patient must be advised of the significant teratogenic risk of Rebetol to the foetus (see section 4.4).

Male patients and their female partners

Extreme care must be taken to avoid pregnancy in partners of male patients taking Rebetol (see sections 4.3, 4.4 and 5.3). Rebetol accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the Rebetol that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectively followed pregnancies with paternal exposure to Rebetol have not shown an increased risk of malformation compared to the general population, nor any specific pattern of malformation, either male patients or their female partners of childbearing age must be advised to use an effective contraceptive during treatment with Rebetol and for six months after treatment. Routine monthly pregnancy tests must be performed during this time. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of Rebetol to the partner.

Pregnancy

The use of Rebetol is contraindicated during pregnancy. Rebetol has been shown in preclinical studies to be teratogenic and genotoxic (see section 4.4 and 5.3).

Breast-feeding

It is not known whether Rebetol is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.

Fertility

Preclinical data

• – Fertility: In animal studies, Rebetol produced reversible effects on spermatogenesis (see section 5.3).

• – Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for Rebetol in all animal species in which adequate studies have been conducted, occurring at doses as low as one twentieth of the recommended human dose (see section 5.3).

• – Genotoxicity: Rebetol induces genotoxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Rebetol has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile

The salient safety issue of Rebetol is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Rebetol 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 Rebetol was used in combination with interferon alfa-2b or peginterferon alfa-2b.

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.

Please refer to the corresponding SmPC of medicinal products that are used in combination with Rebetol for additional undesirable effects reported with these products.

Adults

Bitherapy with peginterferon alfa-2b or interferon alfa-2b

The safety of Rebetol capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combination with interferon alfa-2b, two trials studied Rebetol in combination with peginterferon alfa-2b.

Patients who are treated with interferon alfa-2b and Rebetol 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 Rebetol) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class	Adverse Reactions
Infections and infestations
Very common:	Viral infection, pharyngitis
Common:	Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection
Uncommon:	Lower respiratory tract infection
Rare:	Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:	Neoplasm unspecified
Blood and lymphatic system disorders
Very common:	Anaemia, neutropenia
Common:	Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia
Very rare:	Aplastic anaemia*
Not known:	Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:	Drug hypersensitivity
Rare:	Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known:	Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstric­tion, anaphylaxis
Endocrine disorders
Common:	Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite
Uncommon:	Diabetes mellitus, hypertriglyce­ridemia*
Psychiatric disorders
Very common:	Depression, anxiety, emotional lability, insomnia
Common:	Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, decreased libido apathy, abnormal dreams, crying
Uncommon:	Suicide attempts, panic attack, hallucination
Rare:	Bipolar disorder*
Very rare:	Suicide*
Not known:	Homicidal ideation*, mania*, mental status change
Nervous system disorders
Very common:	Headache, dizziness, dry mouth, concentration impaired
Common:	Amnesia, memory impairment, syncope, migraine, ataxia, paraesthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia
Uncommon:	Neuropathy, peripheral neuropathy
Rare:	Seizure (convulsion)
Very rare:	Cerebrovascular haemorrhage, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class	Adverse Reactions
Not known:	Facial palsy, mononeuropathies
Eye disorders
Common:	Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye
Rare:	Retinal haemorrhages*, retinopathies (including macular oedema), retinal artery occlusion, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates
Ear and labyrinth disorders
Common:	Vertigo, hearing impaired/loss, tinnitus, ear pain
Cardiac disorders
Common:	Palpitation, tachycardia
Uncommon:	Myocardial infarction
Rare:	Cardiomyopathy, arrhythmia*
Very rare:	Cardiac ischaemia*
Not known:	Pericardial effusion*, pericarditis*
Vascular disorders
Common:	Hypotension, hypertension, flushing
Rare:	Vasculitis
Very rare:	Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:	Dyspnoea, coughing
Common:	Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough
Very rare:	Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*
Gastro-intestinal disorders
Very common:	Diarrhoea, vomiting, nausea, abdominal pain
Common:	Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophoageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence
Uncommon:	Pancreatitis, oral pain
Rare:	Ischaemic colitis
Very rare:	Ulcerative colitis*
Not known:	Periodontal disorder, dental disorder, tongue pigmentation
Hepatobiliary disorders
Common:	Hepatomegaly, jaundice, hyperbilirubinemia*
Very rare:	Hepatotoxicity (including fatalities)
Skin and subcutaneous tissue disorders
Very common:	Alopecia, pruritus, skin dry, rash
Common:	Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder
Rare:	Cutaneous sarcoidosis

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b
System Organ Class	Adverse Reactions
Very rare:	Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*
Musculoskeletal and connective tissue disorders
Very common:	Arthralgia, myalgia, musculoskeletal pain
Common:	Arthritis, back pain, muscle spasms, pain in extremity
Uncommon:	Bone pain, muscle weakness
Rare:	Rhabdomyolysis*, myositis*
Renal and urinary disorders
Common:	Micturition frequency, polyuria, urine abnormality
Rare:	Renal failure, renal insufficiency*
Very rare:	Nephrotic syndrome*
Reproductive system and breast disorders
Common:	Female : amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction. Sexual dysfunction (not specified)
General disorders and administration site conditions
Very common:	Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability
Common:	Chest pain, chest discomfort, peripheral oedema, malaise, feeling abnormal, thirst
Uncommon:	Face oedema
Investigations
Very common:	Weight decrease
Common:	Cardiac murmur

Since Rebetol has always been prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using Rebetol in combination with interferon alfa-2b (pegylated or non-pegylated).

Description of selected adverse reactions

A reduction in haemoglobin concentrations by > 4 g/dL was observed in 30 % of patients treated with Rebetol and peginterferon alfa-2b and 37 % of patients treated with Rebetol and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dL in up to 14 % of adult patients and 7 % of children and adolescents treated with Rebetol in combination with either peginterferon alfa-2b or interferon alfa-2b.

Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Rebetol in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group.

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials.

HCV/HIV co-infected patients

For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-Rebetol for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving Rebetol in combination with peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving Rebetol in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dL) was reported in 12 % (23/194) of patients treated with Rebetol in combination with peginterferon alfa-2b.

CD4 lymphocytes decrease

Treatment with Rebetol in combination with peginterferon alfa-2b 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 Rebetol in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected patients with CD4+ cell counts < 200/^L (see section 4.4).

Please refer to the corresponding SmPC of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Rebetol in combination with other medicinal products.

Paediatric population

In combination with peginterferon alfa-2b

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and Rebetol, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with pegylated interferon alfa-2b and Rebetol, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively.

Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %).

Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/de­pressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidis­m/elevated TSH.

In combination with interferon alfa-2b

In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Rebetol, 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with interferon alfa-2b and Rebetol, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs. 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse reactions (e.g., depression, emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, anorexia, vomiting and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropenia.

Tabulated list of adverse reactions in paediatric population

Reported adverse reactions listed in Table 6 are based on experience from the two multicentre children and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (> 1/10); common (> 1/100 to < 1/10), and uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Rebetol in combination with interferon alfa-2b or peginterferon alfa-2b
System Organ Class	Adverse Reactions
Infections and infestations
Very common:	Viral infection, pharyngitis
Common:	Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis
Uncommon:	Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis
Neoplasms benign, malignant and uns|	3ecified (including cysts and polyps)
Common:	Neoplasm unspecified
Blood and lymphatic system disorders
Very common:	Anaemia, neutropenia
Common:	Thrombocytopenia, lymphadenopathy
Endocrine disorders
Very common:	Hypothyroidism
Common:	Hyperthyroidism, virilism
Metabolism and nutrition disorders
Very common:	Anorexia, increased appetite, decreased appetite
Common:	Hypertriglyce­ridemia, hyperuricemia
Psychiatric disorders
Very common:	Depression, insomnia, emotional lability
Common:	Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy
Uncommon:	Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
Nervous system disorders
Very common:	Headache, dizziness
Common:	Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep
Uncommon:	Neuralgia, lethargy, psychomotor hyperactivity
Eye disorders
Common:	Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Uncommon:	Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Ear and labyrinth disorders
Common:	Vertigo
Cardiac disorders
Common:	Tachycardia, palpitations
Vascular disorders
Common:	Pallor, flushing
Uncommon:	Hypotension

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Rebetol in combination with interferon alfa-2b or peginterferon alfa-2b
System Organ Class	Adverse Reactions
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryn­geal pain
Uncommon:	Wheezing, nasal discomfort
Gastro-intestinal disorders
Very common:	Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea
Common:	Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain
Uncommon:	Gingivitis
Hepatobiliary disorders
Common:	Hepatic function abnormal
Uncommon:	Hepatomegaly
Skin and subcutaneous tissue disorders
Very common:	Alopecia, rash
Common:	Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise
Uncommon:	Pigmentation disorder, dermatitis atopic, skin exfoliation
Musculoskeletal and connective tissue disorders
Very common:	Arthralgia, myalgia, musculoskeletal pain
Common:	Pain in extremity, back pain, muscle contracture
Renal and urinary disorders
Common:	Enuresis, micturition disorder, urinary incontinence, proteinuria
Reproductive system and breast disord	lers
Common:	Female : amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain
Uncommon:	Female: dysmenorrhoea
General disorders and administration site conditions
Very common:	Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability
Common:	Chest pain, oedema, pain, feeling cold
Uncommon:	Chest discomfort, facial pain
Investigations
Very common:	Growth rate decrease (height and/or weight decrease for age)
Common:	Blood thyroid stimulating hormone increased, thyroglobulin increased
Uncommon:	Anti-thyroid antibody positive
Injury, poisoning and procedural com	plications
Common:	Skin laceration
Uncommon:	Contusion

Most of the changes in laboratory values in the Rebetol/pegin­terferon alfa-2b clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with Rebetol used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in

4.9 Overdose

In clinical trials with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Rebetol (50 × 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, ATC code: J05AP01.

Mechanism of action

Ribavirin (Rebetol) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Rebetol in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Rebetol monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Rebetol monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical efficacy and safety

Rebetol in combination with Direct Antiviral Agent (DAA):

Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with such combination.

Only the description of the use of Rebetol from the original development with (peg)interferon alfa-2b is detailed in the current SmPC:

Bitherapy with peginterferon alfa-2b or interferon alfa-2b:

The use of Rebetol in combination treatment with peginterferon alfa-2b or interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/mL), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

Naïve patients

Three trials examined the use of interferon in naïve patients, two with Rebetol + interferon alfa-2b (C95–132 and I95–143) and one with Rebetol + peginterferon alfa-2b (C/I98–580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of Rebetol to interferon alfa-2b (41 % vs 16 %, p < 0.001).

In clinical trials C95–132 and I95–143, Rebetol + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes, particularly Genotype 1, in which the relapse rate was reduced by 30 % compared with interferon alfa-2b monotherapy.

In clinical trial C/I98–580, 1,530 naïve patients were treated for one year with one of the following combination regimens:

• • Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 microgram­s/kg/week) (n = 511).
• • Rebetol (1,000/1,200 m­g/day) + peginterferon alfa-2b (1.5 microgram­s/kg/week for one month followed by 0.5 microgram/kg/we­ek for 11 months) (n = 514).
• • Rebetol (1,000/1,200 m­g/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

In this trial, the combination of Rebetol and peginterferon alfa-2b (1.5 microgram­s/kg/week) was significantly more effective than the combination of Rebetol and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of Rebetol administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg Rebetol (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received < 10.6 mg/kg Rebetol (Table 7 ), while response rates in patients that received > 13.2 mg/kg Rebetol were even higher.

Table 7 Sustained response rates with Rebetol + peginterferon alfa-2b (by Rebetol dose [mg/kg], genotype and viral load)
HCV Genotype	Rebetol dose (mg/kg)	P 1.5/R	P 0.5/R	I/R
All Genotypes	All < 10.6 > 10.6	54 % 50 % 61 %	47 % 41 % 48 %	47 % 27 % 47 %
Genotype 1	All < 10.6 > 10.6	42 % 38 % 48 %	34 % 25 % 34 %	33 % 20 % 34 %
Genotype 1 < 600,000 lU/mL	All < 10.6 > 10.6	73 % 74 % 71 %	51 % 25 % 52 %	45 % 33 % 45 %
Genotype 1 > 600,000 lU/mL	All < 10.6 > 10.6	30 % 27 % 37 %	27 % 25 % 27 %	29 % 17 % 29 %
Genotype 2/3	All < 10.6 > 10.6	82 % 79 % 88 %	80 % 73 % 80 %	79 % 50 % 80 %

P1.5/R        Rebetol (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)

P0.5/R        Rebetol (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)

I/R           Rebetol (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months

(based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 8 ).

Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 8 Virologic Response at End of Treatment, Sustained Virologic Response and Relapse by HCV Genotype and Viral Load*
	Rebetol 800–1,400 mg/day plus peginterferon alfa-2b 1.5 pg/kg once weekly
	End of Treatment Response	Sustained Virologic Response	Relapse
All Subjects	94 % (211/224)	81 % (182/224)	12 % (27/224)
HCV 2	100 % (42/42)	93 % (39/42)	7 % (3/42)
< 600,000 lU/mL	100 % (20/20)	95 % (19/20)	5 % (1/20)
> 600,000 lU/mL	100 % (22/22)	91 % (20/22)	9 % (2/22)
HCV 3	93 % (169/182)	79 % (143/182)	14 % (24/166)
< 600,000 lU/mL	93 % (92/99)	86 % (85/99)	8 % (7/91)
> 600,000 lU/mL	93 % (77/83)	70 % (58/83)	23 % (17/75)

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/mL) received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two peginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 pg/kg and 1 pg/kg subcutaneously once weekly both in combination with Rebetol 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 pg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naive adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 9 ).

Table 9 Virologic response at treatment week 12, end of treatment response, relapse rate* and

Sustained Virologic Response (SVR)

Treatment group	% (number) of patients
	peginterferon alfa-2b 1.5 pg/kg + Rebetol	peginterferon alfa-2b 1 pg/kg + Rebetol	peginterferon alfa-2a 180 pg + ribavirin
Undetectable HCV-RNA at treatment week 12	40 (407/1,019)	36 (366/1,016)	45 (466/1,035)
End of treatment response	53 (542/1,019)	49 (500/1,016)	64 (667/1,035)

Treatment group	% (number) of patients
Relapse	24 (123/523)	20 (95/475)	32 (193/612)
SVR	40 (406/1,019)	38 (386/1,016)	41 (423/1,035)
SVR in patients with undetectable HCV-RNA at treatment week 12	81 (328/407)	83 (303/366)	74 (344/466)

HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/mL

Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with peginterferon alfa-2b (1.5 pg/kg)/Rebetol combination therapy resulted in a higher sustained virologic response rate compared to peginterferon alfa-2b 1 pg/kg dose. At the peginterferon alfa-2b 1.5 pg/kg plus Rebetol dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/mL and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response in naïve patients

Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA. Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 10 ).

Table 10 Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b
1.5 pg/kg/Re	betol 800–1,400 mg Combination Therapy
	Negative			Positive
	No response at Treatment Week	No sustained Response	Predictive Value	Response at Treatment Week	Sustained Response	Predictive Value
Genotype 1*
By Week 4 *** (n= 950)
HCV-RNA negative	834	539	65 % (539/834)	116	107	92 % (107/116)
HCV-RNA negative or > 1 log decrease in viral load	220	210	95 % (210/220)	730	392	54 % (392/730)
By Week 12 *** (n= 915)
HCV-RNA negative	508	433	85 % (433/508)	407	328	81 % (328/407)
HCV-RNA negative or > 2 log decrease in viral load	206	205	N/A':'	709	402	57 % (402/709)

Genotype 2, 3

By Week 12

(n=215)

HCV-RNA negative     2         1       50 % 213       177       83 %

or                                          (­1/2)                               ­(177/213)

> 2 log decrease in

viral load

Genotype 1 receive 48 weeks treatment

Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or

week 12.

t These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 logio decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased > 2 logio from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 11. Study 1 (RIBAVIC; Po1o17) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol (8oo mg/day) plus peginterferon alfa-2b (1.5 gg/kg/week) or Rebetol (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (Po2o8o) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol (800–1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 gg/week based on weight) or Rebetol (800–1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.

Table 11 Sustained virological response based on genotype after Rebetol in combination with peginterferon alfa-2b in HCV/HIV co-infected patients
	Study 1 1			Study 2 2
	Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 pg kg week)	Rebetol (800 mg/day) + interferon alfa-2b (3 MIU TIW)	P valuea	Rebetol (8001,200 mg/day)d + peginterferon alfa-2b (100 or 150c pg/week)	Rebetol (8001,200 mg/day)d + interferon alfa-2b (3 MIU TIW)	p valueb
All	27 % (56/205)	20 % (41/205)	0.047	44 % (23/52)	21 % (9/43)	0.017
Genotype 1, 4	17 % (21/125)	6 % (8/129)	0.006	38 % (12/32)	7 % (2/27)	0.007
Genotype 2, 3	44 % (35/80)	43 % (33/76)	0.88	53 % (10/19)	47 % (7/15)	0.730

MIU = million international units; TIW = three times a week.

a: p value based on Cochran-Mantel Haenszel Chi square test.

b: p value based on chi-square test.

c: subjects < 75 kg received 100 gg/week peginterferon alfa-2b and subjects > 75 kg received 150 gg/week peginterferon alfa-2b.

d: Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60–75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839–2848.

2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response

Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Rebetol in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and –1.2 for Ishak) and stable (-0.1 for Metavir and –0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

Previously treated patients

• – Retreatment of prior treatment failures (relapse and non-responder patients) with peginterferon alfa-2b in combination with Rebetol:

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ri­bavirin were retreated with peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 12 ).

Table 12 Rates of Response to retreatment in prior treatment failures
	Patients with undetectable HCV-RNA at treatment week 12 and SVR upon retreatement
	interferon alpha/ribavirin		peginterferon alpha/ribavirin		Overall Population
	Response week 12 % (n/N)	SVR % (n/N) 99% CI	Response week 12 % (n/N)	SVR % (n/N) 99% CI	SVR % (n/N) 99 % CI
Overall	38.6 (549/1,423)	59.4 (326/549) 54.0,64.8	31.5 (272/863)	50.4 (137/272) 42.6, 58.2	21.7 (497/2,293) 19.5, 23.9
Prior Response
Relapse	67.7 (203/300)	59.6 (121/203) 50.7, 68.5	58.1 (200/344)	52.5 (105/200) 43.4, 61.6	37.7 (243/645) 32.8, 42.6
Genotype 1/4	59.7 (129/216)	51.2 (66/129) 39.8, 62.5	48.6 (122/251)	44.3 (54/122) 32.7, 55.8	28.6 (134/468) 23.3, 34.0
Genotype 2/3	88.9 (72/81)	73.6 (53/72) (60.2, 87.0)	83.7 (77/92)	64.9 (50/77) 50.9, 78.9	61.3 (106/173) 51.7, 70.8
NR	28.6 (258/903)	57.0 (147/258) 49.0, 64.9	12.4 (59/476)	44.1 (26/59) 27.4, 60.7	13.6 (188/1,385) 11.2, 15.9
Genotype 1/4	23.0 (182/790)	51.6 (94/182) 42.1, 61.2	9.9 (44/446)	38.6 (17/44) 19.7, 57.5	9.9 (123/1,242) 7.7, 12.1
Genotype 2/3	67.9 (74/109)	70.3 (52/74) 56.6, 84.0	53.6 (15/28)	60.0 (9/15) 27.4, 92.6	46.0 (63/137) 35.0, 57.0
Genotype
1	30.2 (343/1,135)	51.3 (176/343) 44.4, 58.3	23.0 (162/704)	42.6 (69/162) 32.6, 52.6	14.6 (270/1,846) 12.5, 16.7
2/3	77.1 (185/240)	73.0 (135/185) 64.6, 81.4	75.6 (96/127)	63.5 (61/96) 50.9, 76.2	55.3 (203/367) 48.6, 62.0
4	42.5 (17/40)	70.6 (12/17) 42.1, 99.1	44.4 (12/27)	50.0 (6/12) 12.8, 87.2	28.4 (19/67) 14.2, 42.5

Table 12 Rates of Response to retreatment in prior treatment failures
	Patients with undetectable HCV-RNA at treatment week 12 and SVR upon retreatement
	interferon alpha/ribavirin		peginterferon alpha/ribavirin		Overall Population*
	Response week 12 % (n/N)	SVR % (n/N) 99% CI	Response week 12 % (n/N)	SVR % (n/N) 99% CI	SVR % (n/N) 99 % CI
METAVIR Fibrosis score
F2	46.0 (193/420)	66.8 (129/193) 58.1, 75.6	33.6 (78/232)	57.7 (45/78) 43.3, 72.1	29.2 (191/653) 24.7, 33.8
F3	38.0 (163/429)	62.6 (102/163) 52.8, 72.3	32.4 (78/241)	51.3 (40/78) 36.7, 65.9	21.9 (147/672) 17.8, 26.0
F4	33.6 (192/572)	49.5 (95/192) 40.2, 58.8	29.7 (116/390)	44.8 (52/116) 32.9, 56.7	16.5 (159/966) 13.4, 19.5
Baseline Viral Load
HVL (>600,000 lU/mL)	32.4 (280/864)	56.1 (157/280) 48.4, 63.7	26.5 (152/573)	41.4 (63/152) 31.2, 51.7	16.6 (239/1,441) 14.1, 19.1
LVL_(<600,000 IU/mL)	48.3 (269/557)	62.8 (169/269) 55.2, 70.4	41.0 (118/288)	61.0 (72/118) 49.5, 72.6	30.2 (256/848) 26.1, 34.2

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment. Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory

intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/mL). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to non-pegylated interferon alpha/ribavirin (12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response.

• – Retreatment of relapse patients with Rebetol and interferon alfa-2b combination treatment Two trials examined the use of Rebetol and interferon alfa-2b combination treatment in relapse patients (C95–144 and I95–145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging.

Long-term efficacy data - Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon alfa-2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.

The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95–99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Rebetol), and is 99 % (95 % CI: 98–100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).

SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated, with or without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical ‚cure‘ from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Paediatric population

Clinical efficacy and safety

Rebetol in combination with peginterferon alfa-2b

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with Rebetol 15 mg/kg per day plus pegylated interferon alfa-2b 60 gg/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Rebetol and pegylated interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 13.

Table 13 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n = 107
	24 weeks	48 weeks
All Genotypes	26/27 (96 %)	44/80 (55 %)
Genotype 1		38/72 (53 %)
Genotype 2	14/15 (93 %)
Genotype 3c	12/12 (100 %)	2/3 (67 %)
Genotype 4		4/5 (80 %)

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of

detection = 125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (> 600,000 lU/mL) were to receive 48 weeks of treatment.

Rebetol in combination with interferon alfa-2b

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m2 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % < 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Rebetol and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).The study results are summarized in Table 14.

Table 14 Sustained virological response in previously untreated children and adolescents
	Rebetol 15 mg/kg/day + interferon alfa-2b 3 MIU/m2 3 times a week
Overall Responsea (n = 118)	54 (46 %)
Genotype 1 (n = 92)	33 (36 %)
Genotype 2/3/4 (n = 26)	21 (81 %)

* Number (%) of patients

a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

Long-term efficacy data

Rebetol in combination with peginterferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up.

Rebetol in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Rebetol results in long-term clearance of the virus providing resolution of the hepatic infection and clinical ‚cure‘ from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

5.2 Pharmacokinetic properties

In a single dose, crossover study of ribavirin in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUCtffollowing single doses of 200–1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Biotransformation

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/mL. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

Food effect

The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin.

Renal function

Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUCtf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.

Hepatic function

Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) is similar to those of normal controls.

Elderly patients ( > 65 years of age)

Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model.

Paediatric population

Rebetol in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 60 pg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141–177 %) higher than observed in adults receiving 1.5 pg/kg/week. The pharmacokinetics of Rebetol (dose-normalized) in this trial was similar to those reported in a prior study of Rebetol in combination with interferon alfa-2b in children and adolescent patients and in adult patients.

Rebetol in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 15. The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

Table 15 Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Rebetol capsules when administered to paediatric patients with chronic hepatitis C
Parameter	Rebetol 15 mg/kg/day as 2 divided doses (n = 17)	Interferon alfa-2b 3 MIU/m2 3 times a week (n = 54)
Tmax (hr)	1.9 (83)	5.9 (36)
Cmax (ng/mL)	3,275 (25)	51 (48)
AUC*	29,774 (26)	622 (48)
Apparent clearance L/hr/kg	0.27 (27)	Not done

*AUC12 (ng.hr/mL) for Rebetol; AUC0–24 (IU.hr/mL) for interferon alfa-2b

5.3 Preclinical safety data

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which 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 dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3– and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles (see section 4.6).

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20–200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely.

Ribavirin plus interferon

When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule contents

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Capsule shell

Gelatine

Titanium dioxide (E 171)

Capsule imprint

Shellac

Propylene glycol (E 1520)

Ammonium hydroxide

Colouring agent (E 132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Rebetol capsules are packaged in blisters consisting of polyvinyl chloride (PVC)/polyethylene (PE)/polyvinylidene chloride (PVdC).

Packs of 84, 112, 140 and 168 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/107/001     84 hard capsules

EU/1/99/107/005     112 hard capsules

EU/1/99/107/002    140 hard capsules

EU/1/99/107/003     168 hard capsules

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 07 May 1999

Date of latest renewal: 23 April 2009