This information is intended for use by health professionals

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.

Excipients with known effect

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

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

4.2 Posology and method of administration

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

Posology

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

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

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

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

Paediatric population

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

Dosing of Rebetol for children and adolescent patients is determined by the patient body weight. For example, the body weight dosing used in conjunction with interferon alfa-2b or peginterferon alfa-2b is shown in Table 1. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol as some combination regimens do not adhere to the Rebetol dosing guidance provided in Table 1.

In clinical studies performed in this population, Rebetol was used in doses of 15 mg/kg/day (Table 1).

Table 1 Rebetol oral solution - Children and adolescents dosage to be administered with interferon alfa-2b or peginterferon alfa-2b

Body Weight (kg)

Measured Dose

(Morning / Evening)

10-12

2 mL / 2 mL

13-14

3 mL / 2 mL

15-17

3 mL / 3 mL

18-20

4 mL / 3 mL

21-22

4 mL / 4 mL

23-25

5 mL / 4 mL

26-28

5 mL / 5 mL

29-31

6 mL / 5 mL

32-33

6 mL / 6 mL

34-36

7 mL / 6 mL

37-39

7 mL / 7 mL

40-41

8 mL / 7 mL

42-44

8 mL / 8 mL

45-47

9 mL / 8 mL

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 Rebetol capsules).

Dose modification for adverse reactions

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

If a patient has a serious adverse reaction potentially related to Rebetol, the Rebetol dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.

Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and indirect bilirubin concentration.

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

Table 2 Management of Adverse Reactions

Laboratory values

Reduce Rebetol dose*

if:

Discontinue

Rebetol if:

Haemoglobin in patients with No Cardiac Disease

< 10 g/dL

< 8.5 g/dL

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)

* 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.

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

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

Special populations

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

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

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

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

Renal impairment

The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Adult patients with moderate renal impairment (creatinine clearance 30- 50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered Rebetol 200 mg/day. Table 3 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Table 3 Dosage Modification for Renal Impairment in Adult Patients

Creatinine Clearance

Rebetol Dose (daily)

30 to 50 mL/min

Alternating doses, 200 mg and 400 mg every other day

Less than 30 mL/min

200 mg daily

Haemodialysis (ESRD)

200 mg daily

Hepatic impairment

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

Method of administration

Rebetol should be administered orally with food.

4.3 Contraindications

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

• Pregnancy (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Rebetol must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

• Breast-feeding.

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

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

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

4.4 Special warnings and precautions for use

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

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

There are several serious adverse reactions associated with the combination therapy of Rebetol with (peg)interferon alfa. These include:

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

Growth inhibition in children and adolescents that may be irreversible in some patients

Increased thyroid stimulating hormone (TSH) in children and adolescents

Severe ocular disorders

Dental and periodontal disorders.

Paediatric population

When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case.

Haemolysis

A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and in 7 % of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Rebetol has no direct cardiovascular effects, anaemia associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease or both. Thus, Rebetol must be administered with caution to patients with pre-existing cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).

Cardiovascular

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

Teratogenic risk

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

Acute hypersensitivity

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

Liver function

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

Renal impairment

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

Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary (see section 4.2).

Potential to exacerbate immunosuppression

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and Rebetol concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 4.5).

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis:

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

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

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

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

Haematological abnormalities in HCV/HIV co-infected patients

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

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

Patients with low CD4 counts

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

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

Laboratory tests

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

• Haemoglobin          ≥ 11 g/dL (females); ≥ 12 g/dL (males)

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

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

Information on excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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

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

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

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

Antacid

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

Nucleoside analogues

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

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

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

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Female patients

Rebetol must not be used by females who are pregnant (see sections 4.3 and 5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential must use an effective contraceptive during treatment and for 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 Rebetol to the foetus (see section 4.4).

Male patients and their female partners

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

Pregnancy

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

Breast-feeding

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

Fertility

Preclinical data

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

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

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

The salient safety issue of Rebetol is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Rebetol therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients.

The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when Rebetol was used in combination with interferon alfa-2b or peginterferon alfa-2b.

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

Paediatric population

In combination with peginterferon alfa-2b

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

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

In combination with interferon alfa-2b

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

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

Tabulated list of adverse reactions in paediatric population

Reported adverse reactions listed in Table 4 are based on experience from the two multicentre children and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4 Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Rebetol in combination with interferon alfa-2b or peginterferon alfa-2b

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

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

Uncommon:

Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis

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

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Thrombocytopenia, lymphadenopathy

Endocrine disorders

Very common:

Hypothyroidism

Common:

Hyperthyroidism, virilism

Metabolism and nutrition disorders

Very common:

Anorexia, increased appetite, decreased appetite

Common:

Hypertriglyceridemia, hyperuricemia

Psychiatric disorders

Very common:

Depression, insomnia, emotional lability

Common:

Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy

Uncommon:

Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

Nervous system disorders

Very common:

Headache, dizziness

Common:

Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep

Uncommon:

Neuralgia, lethargy, psychomotor hyperactivity

Eye disorders

Common:

Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder

Uncommon:

Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

Common:

Tachycardia, palpitations

Vascular disorders

Common:

Pallor, flushing

Uncommon:

Hypotension

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain

Uncommon:

Wheezing, nasal discomfort

Gastro-intestinal disorders

Very common:

Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea

Common:

Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain

Uncommon:

Gingivitis

Hepatobiliary disorders

Common:

Hepatic function abnormal

Uncommon:

Hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Alopecia, rash

Common:

Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise

Uncommon:

Pigmentation disorder, dermatitis atopic, skin exfoliation

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Pain in extremity, back pain, muscle contracture

Renal and urinary disorders

Common:

Enuresis, micturition disorder, urinary incontinence, proteinuria

Reproductive system and breast disorders

Common:

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

Uncommon:

Female: dysmenorrhoea

General disorders and administration site conditions

Very common:

Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability

Common:

Chest pain, oedema, pain, feeling cold

Uncommon:

Chest discomfort, facial pain

Investigations

Very common:

Growth rate decrease (height and/or weight decrease for age)

Common:

Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon:

Anti-thyroid antibody positive

Injury, poisoning and procedural complications

Common:

Skin laceration

Uncommon:

Contusion

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

Adults

Adverse reactions reported with a > 10 % incidence in adult patients treated with Rebetol 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.

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with Rebetol) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection

Uncommon:

Lower respiratory tract infection

Rare:

Pneumonia*

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

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia

Very rare:

Aplastic anaemia*

Not known:

Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura

Immune system disorders

Uncommon:

Drug hypersensitivity

Rare:

Sarcoidosis* rheumatoid arthritis (new or aggravated)

Not known:

Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis

Endocrine disorders

Common:

Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite

Uncommon:

Diabetes mellitus, hypertriglyceridemia*

Psychiatric disorders

Very common:

Depression, anxiety, emotional lability, insomnia

Common:

Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour,nervousness, sleep disorder, decreased libido, apathy, abnormal dreams, crying

Uncommon:

Suicide attempts, panic attack, hallucination

Rare:

Bipolar disporder*

Very rare:

Suicide*

Not known:

Homicidal ideation*, mania*, mental status change

Nervous system disorders

Very common:

Headache, dizziness, dry mouth, concentration impaired

Common:

Amnesia, memory impairment, syncope, migraine, ataxia, paresthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia

Uncommon:

Neuropathy, peripheral neuropathy

Rare:

Seizure (convulsion)

Very rare:

Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*

Not known:

Facial palsy, mononeuropathies

Eye disorders

Common:

Visual disturbance, blurred vision, conjunctivitis, eye irritiation, eye pain, abnormal vision, lacrimal gland disorder, dry eye

Rare:

Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery occlusion*, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates

Ear and labyrinth disorders

Common:

Vertigo, hearing impaired/loss, tinnitus, ear pain

Cardiac disorders

Common:

Palpitation, tachycardia

Uncommon:

Myocardial infarction

Rare:

Cardiomyopathy, arrhythmia*

Very rare:

Cardiac ischaemia*

Not known:

Pericardial effusion*, pericarditis*

Vascular disorders

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Very rare:

Peripheral ischaemia*

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea, coughing

Common:

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

Very rare:

Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*

Gastro-intestinal disorders

Very common:

Diarrhoea, vomiting, nausea, abdominal pain

Common:

Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophoageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence

Uncommon:

Pancreatitis, oral pain

Rare:

Ischaemic colitis

Very rare:

ulcerative colitis*

Not known:

Periodontal disorder, dental disorder, tongue pigmentation

Hepatobiliary disorders

Common:

Hepatomegaly, jaundice, hyperbilirubinemia*

Very rare:

Hepatotoxicity (including fatalities)*

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus, skin dry, rash

Common:

Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*

Rare:

Cutaneous sarcoidosis

Very rare:

Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis*, myositis*

Renal and urinary disorders

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure*, renal insufficiency*

Very rare:

Nephrotic syndrome*

Reproductive system and breast disorders

Common:

Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction.

Sexual dysfunction (not specified)*

General disorders and administration site conditions

Very common:

Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability

Common:

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

Uncommon:

Face oedema

Investigations

Very common:

Weight decrease

Common:

Cardiac murmur

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

Description of selected adverse reactions

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, antivirals for treatment of HCV infections, ATC code: J05AP01.

Mechanism of action

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

Clinical efficacy and safety

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

Paediatric population

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 6

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration –All subjects

n = 107

24 weeks

48 weeks

All Genotypes

26/27 (96 %)

44/80 (55 %)

Genotype 1

-

38/72 (53 %)

Genotype 2

14/15 (93 %)

-

Genotype 3c

12/12 (100 %)

2/3 (67 %)

Genotype 4

-

4/5 (80 %)

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of detection = 125 IU/mL.

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

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥ 600,000 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 7). 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 7.

Table 7 Sustained virological response: previously untreated children and adolescents

Rebetol 15 mg/kg/day

+

interferon alfa-2b 3 MIU/m2 3 times a week

Overall Responsea (n = 118)

54 (46 %)*

Genotype 1 (n = 92)

33 (36 %)*

Genotype 2/3/4 (n = 26)

21 (81 %)*

*Number (%) of patients

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

Long-term efficacy data

Rebetol in combination with peginterferon alfa-2b

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

Rebetol in combination with interferon alfa-2b

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

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

5.2 Pharmacokinetic properties

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

Absorption

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

Distribution

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

Biotransformation

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

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

Elimination

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

Transfer into seminal fluid

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

Food effect

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

Renal function

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

Hepatic function

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

Paediatric population

Rebetol in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 60 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 was similar to those reported in a prior study of Rebetol in combination with interferon alfa-2b in children and adolescent patients and in adult patients.

Rebetol in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 8. The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

Table 8 Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Rebetol capsules when administered to paediatric patients with chronic hepatitis C

PARAMETER

Rebetol

15 mg/kg/day as 2 divided doses

(n = 17)

Interferon alfa-2b

3 MIU/m2 3 times a week

(n = 54)

Tmax (hr)

1.9 (83)

5.9 (36)

Cmax (ng/mL)

3,275 (25)

51 (48)

AUC*

29,774 (26)

622 (48)

Apparent clearance L/hr/kg

0.27 (27)

Not done

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

5.3 Preclinical safety data

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

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

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

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

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

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

Ribavirin plus interferon

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

6. Pharmaceutical particulars
6.1 List of excipients

Sodium citrate

Citric acid, anhydrous

Sodium benzoate

Glycerol

Sucrose

Sorbitol liquid (crystallising)

Propylene glycol

Purified Water

Natural and artificial bubble gum flavouring

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

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

6.4 Special precautions for storage

Do not store above 30°C.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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 mL increments from 1.5 mL to 10 mL.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. Marketing authorisation number(s)

EU/1/99/107/004

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 25 January 2005

Date of latest renewal: 23 April 2009

10. Date of revision of the text

08 February 2019

11. LEGAL CATEGORY

Prescription Only Medicine

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

© Merck Sharp & Dohme Limited 2019. All rights reserved.

SPC.RBO.19.UK.6765.IA-085