Rebetol 40 mg/ml oral solution

Each ml of oral solution contains 40 mg of ribavirin.

Rebetol contains 142 mg of sorbitol and 300 mg of sucrose per ml.

For a full list of excipients, see section 6.1.

Oral solution

Clear, colourless to pale or light yellow oral solution

Rebetol is indicated, in a combination regimen with peginterferon alfa-2b or interferon alfa-2b, for the treatment of paediatric patients (children 3 years of age and older and adolescents), who have chronic hepatitis C virus (HCV) infection, not previously treated, without liver decompensation, and who are positive for hepatitis C viral ribonucleic acid (HCV-RNA).

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).

Rebetol monotherapy must not be used.

There is no safety or efficacy information in children or adolescents on the use of Rebetol with other forms of interferon (i.e., not alfa-2b).

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

Please refer also to the pegylated interferon alfa-2b or interferon alfa-2b Summary of Product Characteristics (SmPC) for prescribing information particular to that product.

Dose to be administered

Rebetol oral solution is supplied in a concentration of 40 mg/ml.

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

Rebetol oral solution is administered orally in two divided doses (morning and evening) with food

Dosing for children and adolescent patients is determined by body weight for Rebetol and by body surface area for peginterferon alfa-2b and interferon alfa-2b.

The recommended dose of peginterferon alfa-2b is 60 µg/m²/week subcutaneously in combination with Rebetol 15 mg/kg/day (Table 1).

In clinical studies performed in this population, ribavirin and interferon alfa-2b were used in doses of 15 mg/kg/day (Table 1) and 3 million international units (MIU)/m² three times a week, respectively.

Patients who weigh > 47 kg and are able to swallow capsules may take the equivalent dose of ribavirin 200 mg capsules in two divided doses (Please see SmPC for ribavirin capsules).

Duration of treatment

• Genotype 1. The recommended duration of treatment is one year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa-2b/Rebetol), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving interferon alfa-2b (pegylated and non-pegylated)/Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log₁₀ compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.

• Genotype 2 or 3: The recommended duration of treatment is 24 weeks.

• Genotype 4: Only 5 children and adolescents with Genotype 4 were treated in the peginterferon alfa-2b/Rebetol clinical trial. The recommended duration of treatment is 1 year. It is recommended that children and adolescent patients receiving peginterferon alfa-2b/Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log₁₀ compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.

Dose modification

If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol oral solution and interferon alfa-2b, modify the dosages of each product if appropriate, until the adverse reactions abate. Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines, Table 2). As adherence might be of importance for outcome of therapy, the dose should be kept as close as possible to the recommended standard dose. The potential negative impact of ribavirin dose reduction on efficacy results could not be ruled out.

^* Upper limit of normal

^** Refer to the SPC for pegylated interferon alfa-2b and interferon alfa-2b for dose modification and discontinuation.

Note 1: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1^st dose reduction of Rebetol is to 12 mg/kg/day, 2^nd dose reduction of Rebetol is to 8 mg/kg/day.

In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce Rebetol dose to 7.5 mg/kg/day.

Note 2: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1^st dose reduction of peginterferon alfa-2b is to 40 µg/m²/week, 2^nd dose reduction of peginterferon alfa-2b is to 20 µg/m²/week.

In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose.

Special populations

Use in renal impairment: The pharmacokinetics of ribavirin are 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. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol (see section 4.3). Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. If serum creatinine rises to > 2.0 mg/dl (see Table 2), Rebetol and interferon alfa-2b must be discontinued.

Use in hepatic impairment: No pharmacokinetic interaction appears between ribavirin and hepatic function (see section 5.2). Therefore, no dose adjustment of Rebetol is required in patients with hepatic impairment. The use of ribavirin is contraindicated in patients with severe hepatic impairment or decompensated cirrhosis (see section 4.3).

Use in paediatric patients: Rebetol may be used in combination with peginterferon alfa-2b or interferon alfa-2b in children 3 years of age and older and adolescents. The selection of formulation is based on individual characteristics of the patient. Safety and effectiveness of Rebetol with other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.

Patients co-infected with HCV/HIV: Patients taking nucleoside reverse transcriptase inhibitor (NRTI) treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section 4.4). Please refer also to the relevant product information for antiretroviral medicinal products.

Method of administration:

Rebetol should be administered orally. No special precautions for disposal or handling are required.

- Hypersensitivity to the active substance or to any of the excipients.

- Pregnant women (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.

- Lactation.

- A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months (see section 4.4).

- Patients with severe, debilitating medical conditions.

- Patients with chronic renal failure, patients with creatinine clearance < 50 ml/minute and/or on haemodialysis.

- Severe hepatic impairment (Child-Pugh Classification B or C) or decompensated cirrhosis of the liver.

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

Children and adolescents:

- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation, or suicide attempt.

Because of co-administration with peginterferon alfa-2b or interferon alfa-2b:

- Autoimmune hepatitis; or history of autoimmune disease.

Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Rebetol must not be used alone. The safety and efficacy of this combination have been established only using ribavirin together with peginterferon alfa-2b or with interferon alfa-2b solution for injection.

Haemolysis: A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14 % of adult patients and in 7 % of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although ribavirin 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 and adolescents with a history of cardiac disease.

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.

Ocular changes: Ribavirin is used in combination therapy with alpha interferons. Retinopathy including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery or vein occlusion which may result in loss of vision have been reported in rare instances with combination therapy with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferons. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Liver function: Any patient developing significant liver function abnormalities during treatment must be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation markers which might indicate liver decompensation.

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 ribavirin 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).

Thyroid supplemental monitoring for children and adolescents:

Approximately 12 to 21 % of children treated with Rebetol and interferon alfa-2b (pegylated and non-pegylated) developed increase in thyroid stimulating hormone (TSH). Another approximately 4 % had a transient decrease below the lower limit of normal. Prior to initiation of interferon alfa-2b therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Interferon alfa-2b (pegylated and non-pegylated) therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during treatment with Rebetol and interferon alfa-2b and during treatment with Rebetol and peginterferon alfa-2b has been observed. If thyroid abnormalities are detected, the patient's thyroid status should be evaluated and treated as clinically appropriate. Children and adolescents patients should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).

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-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is administered. In particular:

- co-administration of Rebetol and didanosine is not recommended due to the risk of mitochondrial toxicity (see section 4.5).

- co-administration of Rebetol and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.

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

Co-infected patients with advanced cirrhosis receiving highly active anti-retroviral therapy (HAART) may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset.

Haematological abnormalities in HCV/HIV co-infected patients:

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

Dental and periodontal disorders: Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Rebetol and peginterferon alfa-2b or interferon alfa-2b combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Rebetol and peginterferon alfa-2b or interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Laboratory tests: Standard haematological tests and blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) 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 in children and adolescents:

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).

For females of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for four months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for seven months thereafter (see section 4.6).

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

Use in patients with rare hereditary disorders: This product contains sucrose and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency should not take this medicine.

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

Ribavirin, 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 ribavirin concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering ribavirin 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 interferon alfa-2b and antacids.

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

Antacid: The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing magnesium, aluminium and simethicone; AUC_tf decreased 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of ribavirin 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, ribavirin 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 ribavirin 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 ribavirin 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 ribavirin) after cessation of Rebetol therapy due to the long half-life (see section 5.2).

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

Pregnancy

The use of Rebetol is contraindicated during pregnancy.

Fertility

Preclinical data:

- Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section 5.3).

- Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin 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: Ribavirin induces genotoxicity (see section 5.3).

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 four months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within four months from stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to the foetus.

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, and 5.3). Ribavirin accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the ribavirin 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 ribavirin 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 seven months after treatment. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the partner.

Breast-feeding

It is not known whether ribavirin 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.

Rebetol has no or negligible influence on the ability to drive or use machines; however, interferon alfa-2b 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.

Paediatric patients:

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 is observed, the reversibility of which is uncertain (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 (< 3^rd 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 of 3 percentiles and 7 percentiles, respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3^rd percentile). Based on interim data from the long-term follow-up portion of this study, 22 % (16/74) of children had a > 15 percentile decrease in height percentile, of whom 3 (4 %) children had a > 30 percentile decrease despite being off treatment for more than 1 year. In particular, decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children (see section 4.4).

In 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 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th 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). During combination therapy for up to 48 weeks with interferon alfa-2b and Rebetol, growth inhibition is observed, the reversibility of which is uncertain. 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.

Reported adverse reactions listed in Table 3 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.

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.

Adult patients:

Adverse reactions reported with a > 10 % incidence in adult patients treated with ribavirin capsules in combination with interferon alfa-2b or pegylated interferon alfa-2b for one year have also been reported in children and adolescents. The side effect profile was also similar at the lower incidences.

The adverse reactions listed in Table 4 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table 4. 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.

* Since ribavirin is always 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 ribavirin in combination with interferon alfa-2b (pegylated or non-pegylated).

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Rebetol used in combination with interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy.

In clinical trials with Rebetol used in combination with interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Rebetol (50 x 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.

Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

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 peginterferon alfa-2b or interferon alfa-2b 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 trials in paediatric subjects

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 µg/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 5.

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 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 in two multicentre trials and received Rebetol 15 mg/kg per day plus interferon alfa-2b 3 MIU/m² three 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. 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 (see Table 6). 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 6.

*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 - Children and adolescents

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).

Ribavirin is absorbed rapidly following oral administration of a single dose (mean T_max= 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 AUC_tf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

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 C_max), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-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.

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.

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr. 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 (AUC_tf and C_max 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: Single-dose ribavirin pharmacokinetics were altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). 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) are similar to those of normal controls.

Children and adolescents:

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 µg/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 µg/kg/week. The pharmacokinetics of Rebetol (dose-normalized) in this trial were 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 7. The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.

*AUC₁₂ (ng.hr/ml) for Rebetol; AUC_0-24 (IU.hr/ml) for interferon alfa-2b

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.

Oral solution contents:

Sodium citrate

Citric acid, anhydrous

Sodium benzoate

Glycerol

Sucrose

Sorbitol liquid (crystallising)

Propylene glycol

Purified Water

Natural and artificial bubble gum flavouring.

Not applicable.

3 years

In use: After first opening the medicinal product should be used within one month.

Do not store above 30°C.

Rebetol oral solution 100 ml is packaged in 118 ml amber glass bottles (coloured EP Type IV glass, Ph Eur.).

The child-resistant cap has inner and outer polypropylene shells.

The 10 ml oral dosing syringe consists of a natural polyethylene barrel, with a white polystyrene plunger rod. Calibrations are marked at 0.5 m1 increments from 1.5 ml to 10 ml.

No special requirements.

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

United Kingdom

EU/1/99/107/004

Date of first authorisation: 25 January 2005

Date of last renewal: 07 May 2009

4 April 2012

Prescription Only Medicine

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Rebetol OS/SPC/EU/05-12/11