REBETOL 200mg capsules medication leaflet

Rebetol 200 mg hard capsules

Each hard capsule contains 200 mg of ribavirin.

Each hard capsule contains 40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

White, opaque and imprinted with blue ink.

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

Rebetol is indicated in combination with other medicinal products for the treatment of chronichepatitis C (CHC) for paediatric patients (children 3 years of age and older and adolescents) notpreviously treated and without liver decompensation (see sections 4.2, pct. 4.4 and 5.1).

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

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 productsused in combination with Rebetol for additional prescribing information particular to that product andfor 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.

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

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. Forexample, the body weight dosing used in conjunction with interferon alfa-2b or peginterferon alfa-2bis shown in Table 1. Please refer to the corresponding SmPC of medicinal products used incombination with Rebetol as some combination regimens do not adhere to the Rebetol dosingguidance provided in Table 1.

Table 1 Rebetol dose based on body weight when used in combination with interferon alfa-2b orpeginterferon alfa-2b in paediatric patients

Patient weight (kg) Daily Rebetol dose Number of 200 mg capsules47 - 49 600 mg 3 capsules a50 - 65 800 mg 4 capsules b> 65 Refer to adult dose recommendationsa1 morning, 2 eveningb2 morning, 2 evening

Dose modification for adults

Dose reduction of Rebetol depends on the initial Rebetol posology which depends on the medicinalproduct that is used in combination with Rebetol.

If a patient has a serious adverse reaction potentially related to Rebetol, the Rebetol dose should bemodified 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’shaemoglobin concentration, cardiac status and indirect bilirubin concentration.

Table 2 Management of Adverse Reactions

Laboratory values Reduce Rebetol dose* Discontinueif: Rebetol if:

Haemoglobin in patients with < 10 g/dL < 8.5 g/dL

No Cardiac Disease

Haemoglobin: Patients with  2 g/dL decrease in haemoglobin < 12 g/dL despite 4 weeks at

History of Stable Cardiac during any reduced dose

Disease 4 week period during treatment(permanent dose reduction)

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, Rebetol dose should bereduced to 600 mg/day (administered as one 200 mg capsule in the morning and two 200 mg capsulesin the evening). If the abnormality is reversed, Rebetol may be restarted at 600 mg daily, and furtherincreased to 800 mg daily at the discretion of the treating physician. However, a return to higher dosesis not recommended.

For patients receiving a 800 mg (< 65 kg)-1,000 mg (65-80 kg)-1,200 mg (81-105 kg) or 1,400 mg(> 105 kg) dose, 1st dose reduction of Rebetol is by 200 mg/day (except in patients receiving the1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Rebetol is by anadditional 200 mg/day. Patients whose dose of Rebetol is reduced to 600 mg daily receive one 200 mgcapsule in the morning and two 200 mg capsules in the evening.

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 regimensdo 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 adultpatients 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 bilirubinconcentration.

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)

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 hasnot been established. No data are available.

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

The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction ofapparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended thatrenal function be evaluated in all patients prior to initiation of Rebetol. Adult patients with moderaterenal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating dailydoses 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 beadministered Rebetol 200 mg/day. Table 4 provides guidelines for dose modification for patients withrenal dysfunction. Patients with impaired renal function should be more carefully monitored withrespect to the development of anaemia. No data are available regarding dose modification forpaediatric 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

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

Rebetol should be administered orally with food.

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

- Pregnancy (see sections 4.4, pct. 4.6 and 5.3). In females of childbearing potential, Rebetol must notbe initiated until a report of a negative pregnancy test has been obtained immediately prior toinitiation 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 forcontraindications specific to these products.

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 andmanagement regarding the adverse reactions listed below before initiating therapy and otherprecautions 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.

When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2buntil adulthood, it is important to consider that this combination therapy induced a growth inhibitionthat 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 % ofchildren and adolescents treated with Rebetol in combination with peginterferon alfa-2b or interferonalfa-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 coronarydisease, or both. Thus, Rebetol must be administered with caution to patients with pre-existing cardiacdisease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinicallyduring therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).

Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or currentarrhythmic disorders must be closely monitored. It is recommended that those patients who havepre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course oftreatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy butmay require discontinuation of therapy. There are no data in children or adolescents with a history ofcardiac disease.

Teratogenic risk

Prior to initiation of treatment with Rebetol the physician must comprehensively inform both maleand female patients of the teratogenic risk of Rebetol, the necessity of effective and continuouscontraception, the possibility that contraceptive methods may fail and the possible consequences ofpregnancy should it occur during or following treatment with Rebetol (see section 4.6). For laboratorymonitoring 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.

Any patient developing significant liver function abnormalities during treatment must be monitoredclosely. Please refer to the corresponding SmPC of medicinal products used in combination with

Rebetol for discontinuation or dose modification recommendations.

The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction ofapparent clearance in these patients. Therefore, it is recommended that renal function be evaluated inall patients prior to initiation of Rebetol. Due to substantial increases in ribavirin plasmaconcentrations in patients with moderate and severe renal impairment, Rebetol dose adjustments arerecommended in adult patients with creatinine clearance < 50 mL/minute. No data are availableregarding 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 takenas necessary (see section 4.2).

Potential to exacerbate immunosuppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to7 weeks after the administration of a peginterferon and Rebetol concomitantly with azathioprine. Thismyelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy andconcomitant azathioprine and did not recur upon reintroduction of either treatment alone (seesection 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 nucleosidereverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferonalfa/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians shouldcarefully 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) maybe at increased risk of hepatic decompensation and death. Other baseline factors in co-infectedpatients that may be associated with a higher risk of hepatic decompensation include treatment withdidanosine and elevated bilirubin serum concentrations.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closelymonitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPCof medicinal products used in combination with Rebetol for discontinuation or dose modificationrecommendations. Patients progressing to hepatic decompensation should have their anti-hepatitistreatment 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 beat increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia andanaemia) compared to HCV mono-infected patients. Although, the majority of them could bemanaged by dose reduction, close monitoring of haematological parameters should be undertaken inthis 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 insubjects with CD4 counts less than 200 cells/µL. Caution is therefore warranted in the treatment ofpatients with low CD4 counts.

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

Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, plateletcount, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must beconducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered asa 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 asclinically 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 goutmust be carefully monitored in pre-disposed patients.

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

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

Interaction studies have only been performed in adults.

Results of in vitro studies using both human and rat liver microsome preparations indicated nocytochrome 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 withazathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate(6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. Theuse of pegylated alpha interferons and Rebetol concomitantly with azathioprine should be avoided. Inindividual cases where the benefit of administering Rebetol concomitantly with azathioprine warrantsthe potential risk, it is recommended that close hematologic monitoring be done during concomitantazathioprine use to identify signs of myelotoxicity, at which time treatment with these medicinesshould be stopped (see section 4.4).

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

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

Antacid

The bioavailability of Rebetol 600 mg was decreased by co-administration with an antacid containingmagnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreasedbioavailability in this study was due to delayed transit of Rebetol or modified pH. This interaction is notconsidered to be clinically relevant.

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lacticacidosis. Pharmacologically, Rebetol increases phosphorylated metabolites of purine nucleosides invitro. 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 regimenused 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 aknown history of zidovudine induced anaemia.

Any potential for interactions may persist for up to two months (five half-lives for Rebetol) aftercessation 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 orprotease 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 atrisk of a lower response rate to pegylated interferon/Rebetol therapy. Caution should be exercisedwhen both medicines are co-administered.

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 betaken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must not be initiated untila 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 fornine months after treatment has been concluded; routine monthly pregnancy tests must be performedduring this time. If pregnancy does occur during treatment or within nine months from stoppingtreatment, the patient must be advised of the significant teratogenic risk of Rebetol to the foetus (seesection 4.4).

Male patients and their female partners

Extreme care must be taken to avoid pregnancy in partners of male patients taking Rebetol (seesections pct. 4.3, pct. 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 orgenotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectivelyfollowed pregnancies with paternal exposure to Rebetol have not shown an increased risk ofmalformation compared to the general population, nor any specific pattern of malformation, eithermale patients or their female partners of childbearing age must be advised to use an effectivecontraceptive during treatment with Rebetol and for six months after treatment. Routine monthlypregnancy tests must be performed during this time. Men whose partners are pregnant must beinstructed to use a condom to minimise delivery of Rebetol to the partner.

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

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

Preclinical data

- Fertility: In animal studies, Rebetol produced reversible effects on spermatogenesis (seesection 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 dosesas low as one twentieth of the recommended human dose (see section 5.3).

- Genotoxicity: Rebetol induces genotoxicity (see section 5.3).

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

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 cardiacfunction and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirectbilirubin 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 adversedrug reactions from spontaneous reports when Rebetol was used in combination with interferonalfa-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 combinationwith ribavirin, the most frequent adverse reactions identified as associated with ribavirin wereanaemia, nausea, vomiting, asthenia, fatigue, insomnia, cough, dyspnoea, pruritus and rash. Exceptanaemia, the majority of these adverse reactions were not serious and resolved without treatmentdiscontinuation.

Please refer to the corresponding SmPC of medicinal products that are used in combination with

Rebetol for additional undesirable effects reported with these products.

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 noprevious exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combinationwith 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 interferontherapy or who are treated for a shorter period are likely to have an improved safety profile than thatdescribed below.

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïvepatients treated for 1 year and post-marketing use. A certain number of adverse reactions, generallyattributed to interferon therapy but that have been reported in the context of hepatitis C therapy (incombination with Rebetol) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2band interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferonsmonotherapy. Within the organ system classes, adverse reactions are listed under headings offrequency 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 Rebetolwith pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class Adverse Reactions

Very common: Viral infection, pharyngitis

Common: Bacterial infection (including sepsis), fungal infection,influenza, respiratory tract infection, bronchitis, herpessimplex, sinusitis, otitis media, rhinitis, urinary tractinfection

Uncommon: Lower respiratory tract infection

Rare: Pneumonia*

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: Neoplasm unspecified

Very common: Anaemia, neutropenia

Common: Haemolitic anaemia, leukopenia, thrombocytopenia,lymphadenopathy, lymphopenia

Very rare: Aplastic anaemia*

Not known: Pure red cell aplasia, idiopathic thrombocytopenicpurpura, thrombotic thrombocytopenic purpura

Uncommon: Drug hypersensitivity

Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated)

Not known: Vogt-Koyanagi-Harada syndrome, systemic lupuserythematosus, vasculitis, acute hypersensitivity reactionsincluding urticaria, angioedema, bronchoconstriction,anaphylaxis

Common: Hypothyroidism, hyperthyroidism

Very common: Anorexia

Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia,dehydration, increased appetite

Uncommon: Diabetes mellitus, hypertriglyceridemia*

Very common: Depression, anxiety, emotional lability, insomnia

Common: Suicidal ideation, psychosis, aggressive behaviour,confusion, agitation, anger, mood altered, abnormalbehaviour, nervousness, sleep disorder, decreased libidoapathy, abnormal dreams, crying

Uncommon: Suicide attempts, panic attack, hallucination

Rare: Bipolar disorder*

Very rare: Suicide*

Not known: Homicidal ideation*, mania*, mental status change

Very common: Headache, dizziness, dry mouth, concentration impaired

Common: Amnesia, memory impairment, syncope, migraine, ataxia,paraesthaesia, dysphonia, taste loss, hypoaesthesia,hyperaesthesia, hypertonia, somnolence, disturbance inattention, tremor, dysgeusia

Uncommon: Neuropathy, peripheral neuropathy

Rare: Seizure (convulsion)*

Very rare: Cerebrovascular haemorrhage*, cerebrovascularischaemia*, encephalopathy*, polyneuropathy*

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Rebetolwith pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class Adverse Reactions

Not known: Facial palsy, mononeuropathies

Common: Visual disturbance, blurred vision, conjunctivitis, eyeirritation, eye pain, abnormal vision, lacrimal glanddisorder, dry eye

Rare: Retinal haemorrhages*, retinopathies (including macularoedema)*, retinal artery occlusion*, retinal veinocclusion*, optic neuritis*, papilloedema*, loss of visualacuity or visual field*, retinal exudates

Ear and labyrinth disorders

Common: Vertigo, hearing impaired/loss, tinnitus, ear pain

Common: Palpitation, tachycardia

Uncommon: Myocardial infarction

Rare: Cardiomyopathy, arrhythmia*

Very rare: Cardiac ischaemia*

Not known: Pericardial effusion*, pericarditis*

Common: Hypotension, hypertension, flushing

Rare: Vasculitis

Very rare: Peripheral ischaemia*

Very common: Dyspnoea, coughing

Common: Epistaxis, respiratory disorder, respiratory tractcongestion, sinus congestion, nasal congestion, rhinorrhea,increased upper airway secretion, pharyngolaryngeal pain,nonproductive cough

Very rare: Pulmonary infiltrates*, pneumonitis*, interstitialpneumonitis*

Gastro-intestinal disorders

Very common: Diarrhoea, vomiting, nausea, abdominal pain

Common: Ulcerative stomatitis, stomatitis, mouth ulceration, colitis,upper right quadrant pain, dyspepsia, gastroesophoagealreflux*, glossitis, cheilitis, abdominal distension, gingivalbleeding, 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

Common: Hepatomegaly, jaundice, hyperbilirubinemia*

Very rare: Hepatotoxicity (including fatalities)*

Very common: Alopecia, pruritus, skin dry, rash

Common: Psoriasis, aggravated psoriasis, eczema, photosensitivityreaction, maculopapular rash, erythematous rash, nightsweats, hyperhidrosis, dermatitis, acne, furuncule,erythema, urticaria, skin disorder, bruise, sweatingincreased, abnormal hair texture, nail disorder*

Rare: Cutaneous sarcoidosis

Table 5 Adverse reactions reported during clinical trials or following the marketing use of Rebetolwith pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class Adverse Reactions

Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*,erythema multiforme*

Very common: Arthralgia, myalgia, musculoskeletal pain

Common: Arthritis, back pain, muscle spasms, pain in extremity

Uncommon: Bone pain, muscle weakness

Rare: Rhabdomyolysis*, myositis*

Common: Micturition frequency, polyuria, urine abnormality

Rare: Renal failure, renal insufficiency*

Very rare: Nephrotic syndrome*

Common: Female: amenorrhea, menorrhagia, menstrual disorder,dysmenorrhea, breast pain, ovarian disorder, vaginaldisorder. Male: impotence, prostatitis, erectiledysfunction.

Sexual dysfunction (not specified)*

Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia,irritability

Common: Chest pain, chest discomfort, peripheral oedema, malaise,feeling abnormal, thirst

Uncommon: Face oedema

Very common: Weight decrease

Common: Cardiac murmur

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

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 andadolescents treated with Rebetol in combination with either peginterferon alfa-2b or interferonalfa-2b.

Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). Therewere some cases of more severe neutropenia in patients treated with Rebetol in combination withpeginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHOgrade 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 insome patients treated with Rebetol used in combination with peginterferon alfa-2b or interferonalfa-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 combinationdeveloped clinical gout, none of which required treatment modification or discontinuation from theclinical trials.

HCV/HIV co-infected patients

For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, otheradverse reactions (that were not reported in mono-infected patients) which have been reported in thestudies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4lymphocytes 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 NRTIregimen 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 morefrequently in HCV/HIV co-infected patients, the majority could be managed by dose modification andrarely required premature discontinuation of treatment (see section 4.4). Haematologicalabnormalities were more frequently reported in patients receiving Rebetol in combination withpeginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferonalfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in4 % (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 incombination with peginterferon alfa-2b.

CD4 lymphocytes decrease

Treatment with Rebetol in combination with peginterferon alfa-2b was associated with decreases inabsolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. Thedecrease 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 controlof HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infectedpatients with CD4+ cell counts < 200/µL (see section 4.4).

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

In combination with peginterferon alfa-2b

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated withcombination 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 adversereactions profile in children and adolescents was similar to that observed in adults, although there is apaediatric-specific concern regarding growth inhibition. During combination therapy for up to48 weeks with pegylated interferon alfa-2b and Rebetol, growth inhibition was observed that resultedin reduced height in some patients (see section 4.4). Weight loss and growth inhibition were verycommon during the treatment (at the end of treatment, mean decrease from baseline in weight and inheight percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity wasinhibited (< 3rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and heightpercentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continuedto have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 children enrolled in the5 year long-term follow-up trial. The effects on growth were less in those children treated for24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up amongchildren 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 theend of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent ofchildren (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observedto have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 yearlong-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-agepercentiles 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 percentilesdecreased 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 inprepubertal age children. The decline of height, weight and BMI Z scores observed during thetreatment phase in comparison to a normative population did not fully recover at the end of long-termfollow-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-siteerythema (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 inseverity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injectionsite pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %).

Important treatment-emergent adverse reactions that occurred in this patient population werenervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) andhypothyroidism (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 therapyof interferon alfa-2b and Rebetol, 6 % discontinued therapy due to adverse reactions. In general, theadverse reaction profile in the limited children and adolescent population studied was similar to thatobserved in adults, although there is a paediatric-specific concern regarding growth inhibition, asdecrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (meanpercentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-uppost-treatment period, the children had a mean height of 44th percentile, which was below the medianof 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-termfollow-up (up to 5 years). Final adult height was available for 14 of those children and demonstratedthat 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 inhibitionwas observed that resulted in reduced final adult height in some patients. In particular, decrease inmean height percentile from baseline to the end of the long-term follow-up was most prominent inprepubertal 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 adultpatients, 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 andadolescents compared to adult patients. Dose modifications were required in 30 % of patients, mostcommonly 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 multicentrechildren 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 thefollowing categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinicaltrials in children and adolescents with Rebetol in combination with interferon alfa-2b orpeginterferon alfa-2b

System Organ Class Adverse Reactions

Very common: Viral infection, pharyngitis

Common: Fungal infection, bacterial infection, pulmonary infection,nasopharyngitis, pharyngitis streptococcal, otitis media,sinusitis, tooth abscess, influenza, oral herpes, herpessimplex, urinary tract infection, vaginitis, gastroenteritis

Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common: Neoplasm unspecified

Very common: Anaemia, neutropenia

Common: Thrombocytopenia, lymphadenopathy

Very common: Hypothyroidism

Common: Hyperthyroidism, virilism

Very common: Anorexia, increased appetite, decreased appetite

Common: Hypertriglyceridemia, hyperuricemia

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

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

Common: Conjunctivitis, eye pain, abnormal vision, lacrimal glanddisorder

Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, visionblurred, photophobia

Ear and labyrinth disorders

Common: Vertigo

Common: Tachycardia, palpitations

Common: Pallor, flushing

Uncommon: Hypotension

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinicaltrials in children and adolescents with Rebetol in combination with interferon alfa-2b orpeginterferon alfa-2b

System Organ Class Adverse Reactions

Common: Dyspnoea, tachypnea, epistaxis, coughing, nasalcongestion, 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, aphthousstomatitis, dyspepsia, cheilosis, glossitis, gastroesophoagealreflux, rectal disorder, gastrointestinal disorder,constipation, loose stools, toothache, tooth disorder,stomach discomfort, oral pain

Uncommon: Gingivitis

Common: Hepatic function abnormal

Uncommon: Hepatomegaly

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

Very common: Arthralgia, myalgia, musculoskeletal pain

Common: Pain in extremity, back pain, muscle contracture

Common: Enuresis, micturition disorder, urinary incontinence,proteinuria

Common: Female: amenorrhea, menorrhagia, menstrual disorder,vaginal disorder, Male: testicular pain

Uncommon: Female: dysmenorrhoea

Very common: Fatigue, rigors, pyrexia, influenza-like illness, asthenia,malaise, irritability

Common: Chest pain, oedema, pain, feeling cold

Uncommon: Chest discomfort, facial pain

Very common: Growth rate decrease (height and/or weight decrease forage)

Common: Blood thyroid stimulating hormone increased, thyroglobulinincreased

Uncommon: Anti-thyroid antibody positive

Common: Skin laceration

Uncommon: Contusion

Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b clinical trial were mildor moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase inbilirubin 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 incombination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within afew weeks after the end of therapy.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

Pharmacotherapeutic group: antivirals for systemic use, antivirals for treatment of HCV infections,

ATC code: J05AP01.

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 productsexerts its effects against HCV is unknown. Oral formulations of Rebetol monotherapy have beeninvestigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigationsshowed that Rebetol monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improvinghepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

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 withsuch combination.

Only the description of the use of Rebetol from the original development with (peg)interferon alfa-2bis 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 wasevaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis Cconfirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/mL), a liverbiopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronichepatitis, 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 thetreatment was for one year with a follow-up of six months. The sustained response at the end offollow-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 besignificantly 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 interferonalfa-2b monotherapy.

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the followingcombination 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 monthfollowed 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) wassignificantly more effective than the combination of Rebetol and interferon alfa-2b, particularly inpatients infected with Genotype 1. Sustained response was assessed by the response rate six monthsafter the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect responserates. However, response rates in this trial were shown to be dependent also on the dose of Rebetoladministered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients thatreceived > 10.6 mg/kg Rebetol (800 mg dose in typical 75 kg patient), regardless of genotype or viralload, 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 evenhigher.

Table 7 Sustained response rates with Rebetol + peginterferon alfa-2b(by Rebetol dose [mg/kg], genotype and viral load)

HCV Genotype Rebetol dose P 1.5/R P 0.5/R I/R(mg/kg)

All Genotypes All 54 % 47 % 47 % 10.6 50 % 41 % 27 %> 10.6 61 % 48 % 47 %

Genotype 1 All 42 % 34 % 33 % 10.6 38 % 25 % 20 %> 10.6 48 % 34 % 34 %

Genotype 1 All 73 % 51 % 45 % 600,000 IU/mL  10.6 74 % 25 % 33 %> 10.6 71 % 52 % 45 %

Genotype 1 All 30 % 27 % 29 %> 600,000 IU/mL  10.6 27 % 25 % 17 %> 10.6 37 % 27 % 29 %

Genotype 2/3 All 82 % 80 % 79 % 10.6 79 % 73 % 50 %> 10.6 88 % 80 % 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/kgsubcutaneously, 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 g/kg once weekly

End of Treatment Sustained Virologic Response Relapse

Response

All Subjects 94 % (211/224) 81 % (182/224) 12 % (27/224)

HCV 2 100 % (42/42) 93 % (39/42) 7 % (3/42) 600,000 100 % (20/20) 95 % (19/20) 5 % (1/20)

IU/mL> 600,000 100 % (22/22) 91 % (20/22) 9 % (2/22)

IU/mL

HCV 3 93 % (169/182) 79 % (143/182) 14 % (24/166) 600,000 93 % (92/99) 86 % (85/99) 8 % (7/91)

IU/mL> 600,000 93 % (77/83) 70 % (58/83) 23 % (17/75)

IU/mL

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-upweek 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-upweek 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 thepivotal 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 withweight adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration was50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological responserate. 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 highersustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with twopeginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 µg/kg and 1 µg/kg subcutaneouslyonce weekly both in combination with Rebetol 800 to 1,400 mg p.o. daily (in two divided doses)] andpeginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily(in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Responseto the treatment was measured by Sustained Virologic Response (SVR) which is defined asundetectable 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 patientspeginterferon alfa-2b peginterferon alfa-2b peginterferon alfa-2a1.5 µg/kg 1 µg/kg 180 µg+ Rebetol + Rebetol + ribavirin

Undetectable HCV-RNA40 (407/1,019) 36 (366/1,016) 45 (466/1,035)at treatment week 12

End of treatment53 (542/1,019) 49 (500/1,016) 64 (667/1,035)response*

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 withundetectable HCV-RNA 81 (328/407) 83 (303/366) 74 (344/466)at treatment week 12

*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 frombaseline) 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 withpeginterferon alfa-2b (1.5 µg/kg)/Rebetol combination therapy resulted in a higher sustained virologicresponse rate compared to peginterferon alfa-2b 1 µg/kg dose. At the peginterferon alfa-2b 1.5 µg/kgplus Rebetol dose, sustained virologic response rates were lower in patients with cirrhosis, in patientswith 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 relapserate 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 levelsof HCV-RNA. Virological response by week 4 is defined as at least 1-log viral load decrease orundetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) havebeen shown to be predictive for sustained response (Table 10).

Table 10 Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b1.5 µg/kg/Rebetol 800-1,400 mg Combination Therapy

Negative Positive

Noresponse Responseat No at

Treatment sustained Predictive Treatment Sustained Predictive

Week Response Value Week Response Value

Genotype 1*

By Week 4***(n= 950)

HCV-RNA negative 834 539 65 % 116 107 92 %(539/834) (107/116)

HCV-RNA negative 220 210 95 % 730 392 54 %or (210/220) (392/730)≥ 1 log decrease inviral load

By Week 12***(n= 915)

HCV-RNA negative 508 433 85 % 407 328 81 %(433/508) (328/407)

HCV-RNA negative 206 205 N/A† 709 402 57 %or (402/709)≥ 2 log decrease inviral load

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 inviral 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 orweek 12.† These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 log10 decrease from baseline, patients tostop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2 log10 from baseline, then retest HCV-RNA at week 24and 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 treatmentin both of these trials is presented in Table 11. Study 1 (RIBAVIC; P01017) was a randomized,multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C whowere co-infected with HIV. Patients were randomized to receive either Rebetol (800 mg/day) pluspeginterferon alfa-2b (1.5 µg/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 (P02080) was a randomized, single centrestudy that enrolled 95 previously untreated adult patients with chronic hepatitis C who wereco-infected with HIV. Patients were randomized to receive either Rebetol (800-1,200 mg/day basedon weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Rebetol(800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapywas 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6 month follow-upperiod.

Table 11 Sustained virological response based on genotype after Rebetol in combination withpeginterferon alfa-2b in HCV/HIV co-infected patients

Study 11 Study 22

Rebetol(800 mg/day) Rebetol (800- Rebetol (800-+ Rebetol 1,200 mg/day)d 1,200 mg/day)dpeginterferon (800 mg/day) + + +alfa-2b interferon peginterferon interferon(1.5 µg/kg/ alfa-2b (3 MIU p alfa-2b (100 or alfa-2b pweek) TIW) valuea 150c µg/week) (3 MIU TIW) 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 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferonalfa-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 the412 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) amongnon-responders. In terms of activity, about one-third of sustained responders showed improvementand 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 peginterferonalfa-2b in combination with Rebetol:

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

Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks andwere 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 asundetectable HCV-RNA at 24 weeks post-treatment (Table 12).

Table 12 Rates of Response to retreatment in prior treatment failures

Patients with undetectable HCV-RNAat treatment week 12 and SVR upon retreatement

Overallinterferon alpha/ribavirin peginterferon alpha/ribavirin Population*

Response SVR % (n/N) Response SVR % (n/N) SVR % (n/N)week 12 % 99% CI week 12 % 99% CI 99 % CI(n/N) (n/N)

Overall 38.6 59.4 31.5 50.4 21.7(549/1,423) (326/549) (272/863) (137/272) (497/2,293)54.0,64.8 42.6, 58.2 19.5, 23.9

Prior Response

Relapse 67.7 (203/300) 59.6 58.1 52.5 37.7 (243/645)(121/203) (200/344) (105/200) 32.8, 42.650.7, 68.5 43.4, 61.6

Genotype 1/4 59.7 (129/216) 51.2 (66/129) 48.6 44.3 (54/122) 28.6 (134/468)39.8, 62.5 (122/251) 32.7, 55.8 23.3, 34.0

Genotype 2/3 88.9 (72/81) 73.6 (53/72) 83.7 (77/92) 64.9 (50/77) 61.3 (106/173)(60.2, 87.0) 50.9, 78.9 51.7, 70.8

NR 28.6 (258/903) 57.0 12.4 (59/476) 44.1 (26/59) 13.6(147/258) 27.4, 60.7 (188/1,385)49.0, 64.9 11.2, 15.9

Genotype 1/4 23.0 (182/790) 51.6 (94/182) 9.9 (44/446) 38.6 (17/44) 9.9 (123/1,242)42.1, 61.2 19.7, 57.5 7.7, 12.1

Genotype 2/3 67.9 (74/109) 70.3 (52/74) 53.6 (15/28) 60.0 (9/15) 46.0 (63/137)56.6, 84.0 27.4, 92.6 35.0, 57.0

Genotype1 30.2 51.3 23.0 42.6 (69/162) 14.6(343/1,135) (176/343) (162/704) 32.6, 52.6 (270/1,846)44.4, 58.3 12.5, 16.72/3 77.1 (185/240) 73.0 75.6 (96/127) 63.5 (61/96) 55.3 (203/367)(135/185) 50.9, 76.2 48.6, 62.064.6, 81.44 42.5 (17/40) 70.6 (12/17) 44.4 (12/27) 50.0 (6/12) 28.4 (19/67)42.1, 99.1 12.8, 87.2 14.2, 42.5

Table 12 Rates of Response to retreatment in prior treatment failures

Patients with undetectable HCV-RNAat treatment week 12 and SVR upon retreatement

Overallinterferon alpha/ribavirin peginterferon alpha/ribavirin Population*

Response SVR % (n/N) Response SVR % (n/N) SVR % (n/N)week 12 % 99% CI week 12 % 99% CI 99 % CI(n/N) (n/N)

METAVIR

Fibrosis score

F2 46.0 (193/420) 66.8 33.6 (78/232) 57.7 (45/78) 29.2 (191/653)(129/193) 43.3, 72.1 24.7, 33.858.1, 75.6

F3 38.0 (163/429) 62.6 32.4 (78/241) 51.3 (40/78) 21.9 (147/672)(102/163) 36.7, 65.9 17.8, 26.052.8, 72.3

F4 33.6 (192/572) 49.5 (95/192) 29.7 44.8 (52/116) 16.5 (159/966)40.2, 58.8 (116/390) 32.9, 56.7 13.4, 19.5

Baseline Viral

Load

HVL (>600,000 32.4 (280/864) 56.1 26.5 41.4 (63/152) 16.6

IU/mL) (157/280) (152/573) 31.2, 51.7 (239/1,441)48.4, 63.7 14.1, 19.1

LVL (≤600,000 48.3 (269/557) 62.8 41.0 61.0 (72/118) 30.2 (256/848)

IU/mL) (169/269) (118/288) 49.5, 72.6 26.1, 34.255.2, 70.4

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 centrallaboratory

*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 atweek 12 of therapy measured using a research-based test (limit of detection 125 IU/mL). In thissubgroup, there was a 56 % (463/823) sustained virological response rate. For patients with priorfailure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12, thesustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viralreduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patientsthe SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve aweek 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 SVRregardless 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 relapsepatients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previousinterferon treatment were treated for six months with a six month follow-up. Combination therapywith Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-foldhigher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintainedirrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotypeand histological staging.

Long-term efficacy data - Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment inprior studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated interferonalfa-2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate thedurability of sustained virologic response (SVR) and assess the impact of continued viral negativityon clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of366 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 orwithout Rebetol) results in long-term clearance of the virus providing resolution of the hepaticinfection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence ofhepatic events in patients with cirrhosis (including hepatocarcinoma).

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 pluspegylated interferon alfa-2b 60 µg/m2 once weekly for 24 or 48 weeks, based on HCV genotype andbaseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of107 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 withmild to moderate hepatitis C. Due to the lack of data in children with severe progression of thedisease, and the potential for undesirable effects, the benefit/risk of the combination of Rebetol andpegylated interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, pct. 4.4and 4.8). The study results are summarized in Table 13.

Table 13 Sustained virological response rates (na,b (%)) in previously untreated children andadolescents by genotype and treatment duration - All subjectsn = 10724 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 ofdetection = 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 withgenotype 3 and high viral load (≥ 600,000 IU/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 intwo multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m23 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients wereenrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 %  12 years of age. The populationenrolled 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 tothe lack of data in these two multicentre trials for children with severe progression of the disease, andthe potential for undesirable effects, the benefit/risk of the combination of Rebetol and interferonalfa-2b needs to be carefully considered in this population (see sections 4.1, pct. 4.4 and 4.8).The studyresults 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 duringfollow-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 Cpatients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. Thepurpose 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 weresustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b andribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) ofsustained responders completed the study. No paediatric subjects with SVR relapsed during the5 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 Cpatients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of allenrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purposeof the study was to annually evaluate the durability of sustained virologic response (SVR) and assessthe impact of continued viral negativity on clinical outcomes for patients who were sustainedresponders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All butone of the paediatric subjects remained sustained virologic responders during long-term follow-upafter completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate forcontinued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patientstreated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels atfollow-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 inlong-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' fromchronic HCV. However, this does not preclude the occurrence of hepatic events in patients withcirrhosis (including hepatocarcinoma).

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

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 withapproximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability isapproximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linearrelationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume ofdistribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

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

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradativepathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Bothribavirin 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 followingsingle oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may bedue to extensive first pass metabolism and transfer within and beyond the blood compartment.

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-doseto single-dose AUC12hr. Following oral dosing with 600 mg BID, steady-state was reached byapproximately 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 slowelimination from non-plasma compartments.

Transfer into seminal fluid

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

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

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 and30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and50 mL/min, AUCtf was twofold greater compared with control subjects. This appears to be due toreduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged byhaemodialysis.

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 apopulation pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function isthe determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration valuesfrom 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 % higherthan for females. Clearance increased as a function of body weight and was reduced at ages greater than40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significancedue to the substantial residual variability not accounted for by the model.

Rebetol in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children andadolescent patients with chronic hepatitis C have been evaluated during a clinical study. In childrenand adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at60 µg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predictedto be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 µg/kg/week. Thepharmacokinetics of Rebetol (dose-normalized) in this trial was similar to those reported in a priorstudy of Rebetol in combination with interferon alfa-2b in children and adolescent patients and inadult patients.

Rebetol in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children andadolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 15. Thepharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) is similar in adults and childrenor 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 Interferon alfa-2b15 mg/kg/day as 2 divided doses 3 MIU/m2 3 times a week(n = 17) (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

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose inall 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 effectsincreased 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 ofribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifestedas slight decreases in body weight, crown-rump length and bone length. At the end of the recoveryperiod, tibial and femoral changes were minimal although generally statistically significant comparedto controls in males at all dose levels and in females dosed with the two highest doses compared tocontrols. No histopathological effects on bone were observed. No ribavirin effects were observedregarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pupswere below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly afterinitiation 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 producesystemic exposures well below those achieved in humans at therapeutic doses. Upon cessation oftreatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or twospermatogenic cycles (see section 4.6).

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

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

Ribavirin plus interferon

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

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Gelatine

Titanium dioxide (E 171)

Capsule imprint

Shellac

Propylene glycol (E 1520)

Ammonium hydroxide

Colouring agent (E 132)

Not applicable.

2 years

Do not store above 30°C.

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.

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

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

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

Date of first authorisation: 07 May 1999

Date of latest renewal: 23 April 2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.