1. Name Of The Medicinal Product
Rebetol 40 mg/ml oral solution
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
Oral solution
Clear, colourless to pale or light yellow oral solution
4. Clinical Particulars
4.1 Therapeutic Indications
Rebetol is indicated, in a combination regimen with peginterferon alfa-2b or interferon alfa-2b, for the treatment of 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).
4.2 Posology And Method Of Administration
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 (SPC) for prescribing information particular to that product.
Dose to be administered
Rebetol oral solution is supplied in a concentration of 40 mg/ml.
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.
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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 SPC 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.
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* 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, 1st dose reduction of Rebetol is to 12 mg/kg/day, 2nd dose reduction of Rebetol is to 8 mg/kg/day. |
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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). Subjects 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 patients under the age of 18 years: 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.
4.3 Contraindications
- 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.
4.4 Special Warnings And Precautions For Use
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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:
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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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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; AUCtf 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.
4.6 Pregnancy And Lactation
The use of Rebetol is contraindicated during pregnancy.
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).
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 and their partners must each 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, male patients and their female partners of childbearing age must be advised to each 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.
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
Children and adolescents:
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 (< 3rd percentile in 70 % of the patients).
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles, respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd 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 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a> 15 percentile decrease in height percentile, of whom 10 of the 20 children had a> 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). 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 (
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