Rebetol

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

Rebetol 200 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of ribavirin.

Excipient with known effect
Each hard capsule contains 40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule)

White, opaque and imprinted with blue ink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

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

4.2 Posology and method of administration

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

Posology

Rebetol must be used in combination therapy as described in section 4.1.
Please refer to the corresponding Summary of Product Characteristics (SmPC) of medicinal products 
used in combination with Rebetol for additional prescribing information particular to that product and 
for further dosage recommendations on co-administration with Rebetol.

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

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

In the cases in which no specific dose recommendation is made, the following dose should be used: 
Patient weight: < 75 kg =1,000 mg and > 75 kg = 1,200 mg.

 



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

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

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

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

Patient weight (kg) Daily Rebetol dose Number of 200 mg capsules
47 - 49 600 mg 3 capsules a

50 - 65 800 mg 4 capsules b

> 65 Refer to adult dose recommendations
a1 morning, 2 evening
b2 morning, 2 evening

Dose modification for adverse reactions

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

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

Table 2 provides guidelines for dose modifications and discontinuation based on the patient’s 
haemoglobin concentration, cardiac status and indirect bilirubin concentration.

Table 2 Management of Adverse Reactions
Laboratory values Reduce Rebetol dose*

if:
Discontinue
Rebetol if:

Haemoglobin in patients with 
No Cardiac Disease

< 10 g/dL < 8.5 g/dL

Haemoglobin: Patients with 
History of Stable Cardiac 
Disease

 2 g/dL decrease in haemoglobin 
during any

4 week period during treatment 
(permanent dose reduction)

< 12 g/dL despite 4 weeks at 
reduced dose

Bilirubin – Indirect > 5 mg/dL > 4 mg/dL (adults)

* For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, Rebetol dose should be 
reduced to 600 mg/day (administered as one 200 mg capsule in the morning and two 200 mg capsules
in the evening). If the abnormality is reversed, Rebetol may be restarted at 600 mg daily, and further 
increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses 
is not recommended.
For patients receiving a 800 mg (< 65 kg)-1,000 mg (65-80 kg)-1,200 mg (81-105 kg) or 1,400 mg 
(> 105 kg) dose, 1st dose reduction of Rebetol is by 200 mg/day (except in patients receiving the 
1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Rebetol is by an 
additional 200 mg/day. Patients whose dose of Rebetol is reduced to 600 mg daily receive one 200 mg 
capsule in the morning and two 200 mg capsules in the evening.

 



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

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

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

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

Table 3 Management of Adverse Reactions
Laboratory values Discontinue Rebetol if: 
Bilirubin – Indirect > 5 mg/dL (for > 4 weeks)

(children and adolescents treated with interferon alfa-2b),
or

> 4 mg/dL (for > 4 weeks)
(children and adolescents treated with peginterferon alfa-2b)

Special populations

Elderly ( 65 years of age)
There does not appear to be a significant age-related effect on the pharmacokinetics of Rebetol. 
However, as in younger patients, renal function must be determined prior to administration of Rebetol
(see section 5.2).

Paediatric patients (children 3 years of age and older and adolescents)
Rebetol may be used in combination with peginterferon alfa-2b or interferon alfa-2b (see section 4.4). 
The selection of Rebetol formulation is based on individual characteristics of the patient. 
The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has 
not been established. No data are available.
Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for 
further dosage recommendations on co-administration.

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

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

 



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

Method of administration

Rebetol should be administered orally with food. 

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Pregnancy (see sections 4.4, 4.6 and 5.3). In females of childbearing potential, Rebetol must not 

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

- Breast-feeding.
- History of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, 

in the previous six months (see section 4.4).
- Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).

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

4.4 Special warnings and precautions for use

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

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

There are several serious adverse reactions associated with the combination therapy of Rebetol with 
(peg)interferon alfa. These include:
- Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, 

attempted suicide and aggressive behaviour, etc.)
- Growth inhibition in children and adolescents that may be irreversible in some patients
- Increased thyroid stimulating hormone (TSH) in children and adolescents
- Severe ocular disorders
- Dental and periodontal disorders.

Paediatric population

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

Haemolysis

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

 



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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.

 



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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:

 Haemoglobin Adult:  12 g/dL (females);  13 g/dL (males)
Children and adolescents:  11 g/dL (females);  12 g/dL (males)

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

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

Information on excipients

Each Rebetol capsule contains 40 mg of lactose. Patients with rare hereditary problems of galactose 
intolerance, Lapp lactase deficiency or glucose-galactose malabsorption 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.

 



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

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

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

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

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

Nucleoside analogues
Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic 
acidosis. Pharmacologically, Rebetol increases phosphorylated metabolites of purine nucleosides in 
vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs 
(e.g. didanosine or abacavir). Co-administration of Rebetol and didanosine is not recommended. 
Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, 
have been reported (see section 4.4).
The exacerbation of anaemia due to Rebetol has been reported when zidovudine is part of the regimen 
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of 
Rebetol with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). 
Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment 
(ART) regimen if this is already established. This would be particularly important in patients with a 
known history of zidovudine induced anaemia. 

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

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

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

 



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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.

 



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4.8 Undesirable effects

Summary of the safety profile

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

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

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

Adults

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

Patients who are treated with interferon alfa-2b and Rebetol after previous relapse from interferon 
therapy or who are treated for a shorter period are likely to have an improved safety profile than that 
described below.

Tabulated list of adverse reactions for adults

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

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

System Organ Class Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Bacterial infection (including sepsis), fungal infection, 

influenza, respiratory tract infection, bronchitis, herpes 
simplex, sinusitis, otitis media, rhinitis, urinary tract 
infection

Uncommon: Lower respiratory tract infection
Rare: Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common: Neoplasm unspecified

 



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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
Blood and lymphatic system disorders
Very common: Anaemia, neutropenia
Common: Haemolitic anaemia, leukopenia, thrombocytopenia, 

lymphadenopathy, lymphopenia
Very rare: Aplastic anaemia*
Not known: Pure red cell aplasia, idiopathic thrombocytopenic 

purpura, thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon: Drug hypersensitivity
Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known: Vogt-Koyanagi-Harada syndrome, systemic lupus 

erythematosus, vasculitis, acute hypersensitivity reactions 
including urticaria, angioedema, bronchoconstriction, 
anaphylaxis

Endocrine disorders
Common: Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common: Anorexia
Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia, 

dehydration, increased appetite
Uncommon: Diabetes mellitus, hypertriglyceridemia*
Psychiatric disorders
Very common: Depression, anxiety, emotional lability, insomnia
Common: Suicidal ideation, psychosis, aggressive behaviour, 

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

Uncommon: Suicide attempts, panic attack, hallucination
Rare: Bipolar disorder*
Very rare: Suicide*
Not known: Homicidal ideation*, mania*, mental status change
Nervous system disorders
Very common: Headache, dizziness, dry mouth, concentration impaired
Common: Amnesia, memory impairment, syncope, migraine, ataxia,  

paraesthaesia, dysphonia, taste loss, hypoaesthesia, 
hyperaesthesia, hypertonia, somnolence, disturbance in 
attention, tremor, dysgeusia

Uncommon: Neuropathy, peripheral neuropathy
Rare: Seizure (convulsion)*
Very rare: Cerebrovascular haemorrhage*, cerebrovascular 

ischaemia*, encephalopathy*, polyneuropathy*
Not known: Facial palsy, mononeuropathies
Eye disorders
Common: Visual disturbance, blurred vision, conjunctivitis, eye 

irritation, eye pain, abnormal vision, lacrimal gland 
disorder, dry eye

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

 



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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
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*

 



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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
Renal and urinary disorders
Common: Micturition frequency, polyuria, urine abnormality
Rare: Renal failure, renal insufficiency*
Very rare: Nephrotic syndrome*
Reproductive system and breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, 

dysmenorrhea, breast pain, ovarian disorder, vaginal 
disorder. Male: impotence, prostatitis, erectile 
dysfunction.
Sexual dysfunction (not specified)*

General disorders and administration site conditions
Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia, 

irritability
Common: Chest pain, chest discomfort, peripheral oedema, malaise, 

feeling abnormal, thirst
Uncommon: Face oedema
Investigations
Very common: Weight decrease
Common: Cardiac murmur
* Since Rebetol has always been prescribed with an alpha interferon product, and the listed adverse drug reactions included 
reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from 
clinical trials using Rebetol in combination with interferon alfa-2b (pegylated or non-pegylated).

Description of selected adverse reactions

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

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

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

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

 



14

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

Laboratory values for HCV/HIV co-infected patients
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more 
frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and 
rarely required premature discontinuation of treatment (see section 4.4). Haematological 
abnormalities were more frequently reported in patients receiving Rebetol in combination with 
peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon 
alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3

was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 
4 % (8/194) of patients receiving Rebetol in combination with peginterferon alfa-2b. Anaemia
(haemoglobin < 9.4 g/dL) was reported in 12 % (23/194) of patients treated with Rebetol in 
combination with peginterferon alfa-2b.

CD4 lymphocytes decrease
Treatment with Rebetol in combination with peginterferon alfa-2b was associated with decreases in 
absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The 
decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of 
Rebetol in combination with peginterferon alfa-2b had no observable negative impact on the control 
of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-infected 
patients with CD4+ cell counts < 200/µL (see section 4.4).

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

Paediatric population

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

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

 



15

decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. 
Decrease in mean height percentile at year 1 of long term follow-up was most prominent in 
prepubertal age children. The decline of height, weight and BMI Z scores observed during the 
treatment phase in comparison to a normative population did not fully recover at the end of long-term 
follow-up period for children treated with 48 weeks of therapy (see section 4.4).

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

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

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

Tabulated list of adverse reactions in paediatric population

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

 



16

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical 
trials in children and adolescents with Rebetol in combination with interferon alfa-2b or 
peginterferon alfa-2b

System Organ Class Adverse Reactions
Infections and infestations
Very common: Viral infection, pharyngitis
Common: Fungal infection, bacterial infection, pulmonary infection, 

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

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

Neoplasms benign, malignant and 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

 



17

Table 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical 
trials in children and adolescents with Rebetol in combination with interferon alfa-2b or 
peginterferon alfa-2b

System Organ Class Adverse Reactions
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.

 



18

Reporting of suspected adverse reactions

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

4.9 Overdose

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

Rebetol in combination with Direct Antiviral Agent (DAA):
Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with 
such combination.
Only the description of the use of Rebetol from the original development with (peg)interferon alfa-2b 
is detailed in the current SmPC:

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

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

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

 

https://www.whocc.no/atc_ddd_index/?code=J05AP&showdescription=no
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


19

particularly Genotype 1, in which the relapse rate was reduced by 30 % compared with interferon 
alfa-2b monotherapy.

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following 
combination regimens:
 Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).
 Rebetol (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month 

followed by 0.5 microgram/kg/week for 11 months) (n = 514).
 Rebetol (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

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

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

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

HCV Genotype Rebetol dose
(mg/kg)

P 1.5/R P 0.5/R I/R

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

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

Genotype 1 
 600,000 IU/mL

All 73 % 51 % 45 %
 10.6 74 % 25 % 33 %
> 10.6 71 % 52 % 45 %

Genotype 1
> 600,000 IU/mL

All 30 % 27 % 29 %
 10.6 27 % 25 % 17 %
> 10.6 37 % 27 % 29 %

Genotype 2/3 All 82 % 80 % 79 %
 10.6 79 % 73 % 50 %
> 10.6 88 % 80 % 80 %

P1.5/R Rebetol (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg) 
P0.5/R Rebetol (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)
I/R Rebetol (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b, 1.5 microgram/kg 
subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months 
(based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 8). 
Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

 



20

Table 8 Virologic Response at End of Treatment, Sustained Virologic Response and Relapse by 
HCV Genotype and Viral Load*

Rebetol 800-1,400 mg/day plus peginterferon alfa-2b 1.5 g/kg once weekly 
End of Treatment 

Response
Sustained Virologic Response Relapse

All Subjects 94 % (211/224) 81 % (182/224) 12 % (27/224)
HCV 2 100 % (42/42) 93 % (39/42) 7 % (3/42)
 600,000 

IU/mL
100 % (20/20) 95 % (19/20) 5 % (1/20)

> 600,000 
IU/mL

100 % (22/22) 91 % (20/22) 9 % (2/22)

HCV 3 93 % (169/182) 79 % (143/182) 14 % (24/166)
 600,000 

IU/mL
93 % (92/99) 86 % (85/99) 8 % (7/91)

> 600,000 
IU/mL

93 % (77/83) 70 % (58/83) 23 % (17/75)

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

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

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/mL) 
received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with 
weight adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration was 
50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 
and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response 
rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis 
(n=49) and prospectively confirmed (n=48).
Limited historical data indicate that treatment for 48 weeks might be associated with a higher 
sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 
24 weeks of treatment).

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

Table 9 Virologic response at treatment week 12, end of treatment response, relapse rate* and 
Sustained Virologic Response (SVR)

Treatment group % (number) of patients

peginterferon alfa-2b 
1.5 µg/kg 
+ Rebetol

peginterferon alfa-2b 
1 µg/kg 

+ Rebetol

peginterferon alfa-2a
180 µg

+ ribavirin
Undetectable HCV-RNA 

at treatment week 12
40 (407/1,019) 36 (366/1,016) 45 (466/1,035)

End of treatment 
response*

53 (542/1,019) 49 (500/1,016) 64 (667/1,035)

Relapse* 24 (123/523) 20 (95/475) 32 (193/612)

SVR* 40 (406/1,019) 38 (386/1,016) 41 (423/1,035)

 



21

Treatment group % (number) of patients

SVR in patients with 
undetectable HCV-RNA 

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

*HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/mL
Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from 
baseline) was a criterion for discontinuation of treatment.

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

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

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

Negative Positive
No 

response 
at 

Treatment 
Week

No 
sustained 
Response

Predictive 
Value

Response 
at 

Treatment 
Week

Sustained 
Response

Predictive 
Value

Genotype 1*

By Week 4***
(n= 950)
HCV-RNA negative 834 539 65 %

(539/834)
116 107 92 %

(107/116)

HCV-RNA negative
or

≥ 1 log decrease in 
viral load

220 210 95 %
(210/220)

730 392 54 %
(392/730)

By Week 12***
(n= 915)
HCV-RNA negative 508 433 85 %

(433/508)
407 328 81 %

(328/407)
HCV-RNA negative

or
≥ 2 log decrease in 

viral load

206 205 N/A† 709 402 57 %
(402/709)

 



22

Genotype 2, 3**

By Week 12
(n=215)
HCV-RNA negative 

or 
≥ 2 log decrease in 

viral load 

2 1 50 %
(1/2)

213 177 83 %
(177/213)

*Genotype 1 receive 48 weeks treatment
**Genotype 2, 3 receive 24 weeks treatment
***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or 

week 12.
† These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 log10 decrease from baseline, patients to 

stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2 log10 from baseline, then retest HCV-RNA at week 24 
and if positive, patients to stop therapy.

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment 
in both of these trials is presented in Table 11. Study 1 (RIBAVIC; P01017) was a randomized, 
multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who 
were co-infected with HIV. Patients were randomized to receive either Rebetol (800 mg/day) plus 
peginterferon alfa-2b (1.5 µg/kg/week) or Rebetol (800 mg/day) plus interferon alfa-2b (3 MIU TIW) 
for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre 
study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were 
co-infected with HIV. Patients were randomized to receive either Rebetol (800-1,200 mg/day based 
on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Rebetol 
(800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy 
was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 
and viral load < 800,000 IU/mL (Amplicor) who were treated for 24 weeks with a 6 month follow-up 
period.

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

Study 11 Study 22

Rebetol 
(800 mg/day) 

+
peginterferon 

alfa-2b 
(1.5 µg/kg/

week)

Rebetol 
(800 mg/day) +

interferon 
alfa-2b (3 MIU 

TIW)
p 

valuea

Rebetol (800-
1,200 mg/day)d

+
peginterferon 

alfa-2b (100 or 
150c µg/week)

Rebetol (800-
1,200 mg/day)d

+
interferon 

alfa-2b 
(3 MIU TIW)

p 
valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017
Genotype 1, 4 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007
Genotype 2, 3 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a: p value based on Cochran-Mantel Haenszel Chi square test.
b: p value based on chi-square test.
c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferon 

alfa-2b .
d: Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response
Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 
412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with 
Rebetol in combination with peginterferon alfa-2b. This decline was significant among responders 

 



23

(-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among 
non-responders. In terms of activity, about one-third of sustained responders showed improvement 
and none showed worsening. There was no improvement in terms of fibrosis observed in this study. 
Steatosis was significantly improved in patients infected with HCV Genotype 3. 

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

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

Table 12 Rates of Response to retreatment in prior treatment failures 
Patients with undetectable HCV–RNA 

at treatment week 12 and SVR upon retreatement

interferon alpha/ribavirin peginterferon alpha/ribavirin
Overall 

Population*
Response 
week 12 % 
(n/N)

SVR % (n/N)
99% CI

Response 
week 12 % 
(n/N)

SVR % (n/N)
99% CI

SVR % (n/N)
99 % CI

Overall 38.6 
(549/1,423)

59.4
(326/549)
54.0,64.8

31.5 
(272/863)

50.4 
(137/272)
42.6, 58.2

21.7 
(497/2,293)
19.5, 23.9

Prior Response
  Relapse 67.7 (203/300) 59.6 

(121/203)
50.7, 68.5

58.1 
(200/344)

52.5 
(105/200)
43.4, 61.6

37.7 (243/645)
32.8, 42.6

     Genotype 1/4 59.7 (129/216) 51.2 (66/129)
39.8, 62.5

48.6 
(122/251)

44.3 (54/122)
32.7, 55.8

28.6 (134/468)
23.3, 34.0

     Genotype 2/3 88.9 (72/81) 73.6 (53/72)
(60.2, 87.0)

83.7 (77/92) 64.9 (50/77)
50.9, 78.9

61.3 (106/173)
51.7, 70.8

  NR 28.6 (258/903) 57.0 
(147/258)
49.0, 64.9

12.4 (59/476) 44.1 (26/59)
27.4, 60.7

13.6 
(188/1,385)
11.2, 15.9

     Genotype 1/4 23.0 (182/790) 51.6 (94/182)
42.1, 61.2

9.9 (44/446) 38.6 (17/44)
19.7, 57.5

9.9 (123/1,242)
7.7, 12.1

     Genotype 2/3 67.9 (74/109) 70.3 (52/74)
56.6, 84.0

53.6 (15/28) 60.0 (9/15)
27.4, 92.6

46.0 (63/137)
35.0, 57.0

Genotype
    1 30.2 

(343/1,135)
51.3 
(176/343)
44.4, 58.3

23.0 
(162/704)

42.6 (69/162)
32.6, 52.6

14.6 
(270/1,846)
12.5, 16.7

    2/3 77.1 (185/240) 73.0 
(135/185)
64.6, 81.4

75.6 (96/127) 63.5 (61/96)
50.9, 76.2

55.3 (203/367)
48.6, 62.0

     4 42.5 (17/40) 70.6 (12/17)
42.1, 99.1

44.4 (12/27) 50.0 (6/12)
12.8, 87.2

28.4 (19/67)
14.2, 42.5

 



24

Table 12 Rates of Response to retreatment in prior treatment failures 
Patients with undetectable HCV–RNA 

at treatment week 12 and SVR upon retreatement

interferon alpha/ribavirin peginterferon alpha/ribavirin
Overall 

Population*
Response 
week 12 % 
(n/N)

SVR % (n/N)
99% CI

Response 
week 12 % 
(n/N)

SVR % (n/N)
99% CI

SVR % (n/N)
99 % CI

METAVIR 
Fibrosis score
    F2 46.0 (193/420) 66.8 

(129/193)
58.1, 75.6

33.6 (78/232) 57.7 (45/78)
43.3, 72.1

29.2 (191/653)
24.7, 33.8

    F3 38.0 (163/429) 62.6 
(102/163)
52.8, 72.3

32.4 (78/241) 51.3 (40/78)
36.7, 65.9

21.9 (147/672)
17.8, 26.0

    F4 33.6 (192/572) 49.5 (95/192)
40.2, 58.8

29.7 
(116/390)

44.8 (52/116)
32.9, 56.7

16.5 (159/966)
13.4, 19.5

Baseline Viral 
Load
HVL (>600,000 
IU/mL)

32.4 (280/864) 56.1 
(157/280)
48.4, 63.7

26.5 
(152/573)

41.4 (63/152)
31.2, 51.7

16.6 
(239/1,441)
14.1, 19.1

LVL (≤600,000 
IU/mL)

48.3 (269/557) 62.8 
(169/269)
55.2, 70.4

41.0 
(118/288)

61.0 (72/118)
49.5, 72.6

30.2 (256/848)
26.1, 34.2

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

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

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

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

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

 



25

Long-term efficacy data – Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in 
prior studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon 
alfa-2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate the 
durability of sustained virologic response (SVR) and assess the impact of continued viral negativity 
on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 
462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 
366 sustained responders relapsed, respectively, in the studies.
The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) 
for patients receiving non-pegylated interferon alfa-2b (with or without Rebetol), and is 99 % (95 % 
CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated, with or 
without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic 
infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of 
hepatic events in patients with cirrhosis (including hepatocarcinoma).

Paediatric population

Clinical efficacy and safety

Rebetol in combination with peginterferon alfa-2b
Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA were enrolled in a multicentre trial and treated with Rebetol 15 mg/kg per day plus 
pegylated interferon alfa-2b 60 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 13.

Table 13 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107
24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)
Genotype 1 - 38/72 (53 %)
Genotype 2 14/15 (93 %) -
Genotype 3c 12/12 (100 %) 2/3 (67 %)
Genotype 4 - 4/5 (80 %)

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

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 

genotype 3 and high viral load (≥ 600,000 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

3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were 
enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 %  12 years of age. The population 
enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, 
sustained virological response rates in children and adolescents were similar to those in adults. Due to 

 



26

the lack of data in these two multicentre trials for children with severe progression of the disease, and 
the potential for undesirable effects, the benefit/risk of the combination of Rebetol and interferon 
alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).The study 
results are summarized in Table 14.

Table 14 Sustained virological response in previously untreated children and adolescents
Rebetol 15 mg/kg/day 

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

Overall Responsea (n = 118) 54 (46 %)*
Genotype 1 (n = 92) 33 (36 %)*
Genotype 2/3/4 (n = 26) 21 (81 %)*
* Number (%) of patients
a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during 
follow-up period.

Long-term efficacy data

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

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

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

5.2 Pharmacokinetic properties

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

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), 
followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, 
distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with 

 



27

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. 

 



28

Elderly patients ( 65 years of age)
Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a 
population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is 
the determining factor.

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

Paediatric population

Rebetol in combination with peginterferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b in children and 
adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children 
and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 
60 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 15. The 
pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) is similar in adults and children 
or adolescents.

Table 15 Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and 
Rebetol capsules when administered to paediatric patients with chronic hepatitis C
Parameter Rebetol

15 mg/kg/day as 2 divided doses
(n = 17)

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

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for Rebetol; AUC0-24 (IU.hr/mL) for interferon alfa-2b

5.3 Preclinical safety data

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

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of 
ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested 
as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery 
period, tibial and femoral changes were minimal although generally statistically significant compared 
to controls in males at all dose levels and in females dosed with the two highest doses compared to 

 



29

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

Capsule contents

Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Magnesium stearate

Capsule shell

Gelatine
Titanium dioxide

Capsule imprint

Shellac
Propylene glycol
Ammonium hydroxide
Colouring agent (E 132)

 



30

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30C.

6.5 Nature and contents of container

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

Packs of 84, 112, 140 and 168 capsules.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/107/001 84 hard capsules
EU/1/99/107/005 112 hard capsules
EU/1/99/107/002 140 hard capsules
EU/1/99/107/003 168 hard capsules

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 07 May 1999
Date of latest renewal: 23 April 2009

10. DATE OF REVISION OF THE TEXT

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

 



31

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).

 



32

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 

 



33

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.

 



34

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 adolscents
- 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.

 



35

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).

 



36

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.

 



37

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).

 



38

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 

 



39

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.

 



40

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

 



41

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
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

 



42

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
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)

 



43

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

System Organ Class Adverse Reactions
Not known: 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

 



44

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
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)*

 



45

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
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 national reporting system listed in Appendix V.

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.

 

https://www.whocc.no/atc_ddd_index/?code=J05AP&showdescription=no
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46

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.

 



47

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.

 



48

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.

 



49

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).

 



50

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.

 



51

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/99/107/004

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

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

 



52

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



53

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release for the hard capsules

SP Labo N.V.
Industriepark 30
2220 Heist op den Berg
Belgium

Name and address of the manufacturer responsible for batch release for the oral solution

Cenexi HSC
2, rue Louis Pasteur
14200 Hérouville-Saint-Clair
France

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.

 



54

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



55

A. LABELLING

 



56

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

REBETOL – 84, 112, 140, 168 hard capsules

1. NAME OF THE MEDICINAL PRODUCT

Rebetol 200 mg hard capsules
ribavirin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 200 mg of ribavirin.

3. LIST OF EXCIPIENTS

Contains lactose
See leaflet for further information

4. PHARMACEUTICAL FORM AND CONTENTS

84 hard capsules
112 hard capsules 
140 hard capsules 
168 hard capsules 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

 



57

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/107/001 (84 hard capsules)
EU/1/99/107/005 (112 hard capsules)
EU/1/99/107/002 (140 hard capsules)
EU/1/99/107/003 (168 hard capsules)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Rebetol 200 mg capsules

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

 



58

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



59

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Immediate packaging (blister foil)

1. NAME OF THE MEDICINAL PRODUCT

Rebetol 200 mg capsules
ribavirin 

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP 

4. BATCH NUMBER

Lot

5. OTHER

 



60

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Rebetol oral solution 40 mg/mL

1. NAME OF THE MEDICINAL PRODUCT

Rebetol 40 mg/mL oral solution 
ribavirin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of oral solution contains 40 mg of ribavirin.

3. LIST OF EXCIPIENTS

Contains Sorbitol liquid (crystallising), sucrose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

oral solution
1 bottle of 100 mL
10 mL oral dosing syringe

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

 



61

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/107/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Rebetol 40 mg/mL oral solution

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



62

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Rebetol oral solution 40 mg/mL

1. NAME OF THE MEDICINAL PRODUCT

Rebetol 40 mg/mL oral solution 
ribavirin

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of oral solution contains 40 mg of ribavirin.

3. LIST OF EXCIPIENTS

Contains Sorbitol liquid (crystallising), sucrose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

oral solution
100 mL

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

 



63

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/107/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

Not applicable.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

Not applicable.

 



64

B. PACKAGE LEAFLET

 



65

Package leaflet: Information for the user

Rebetol 200 mg hard capsules
ribavirin

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Rebetol is and what it is used for
2. What you need to know before you use Rebetol 
3. How to use Rebetol
4. Possible side effects
5. How to store Rebetol
6. Contents of the pack and other information

1. What Rebetol is and what it is used for

Rebetol contains the active substance ribavirin. This medicine stops the multiplication of hepatitis C 
virus. Rebetol must not be used alone.

Depending on the genotype of the hepatitis C virus that you have, your doctor may choose to treat you 
with a combination of this medicine with other medicines. There may be some further treatment 
limitations if you have or have not been previously treated for chronic hepatitis C infection. Your 
doctor will recommend the best course of therapy.

The combination of Rebetol and other medicines is used to treat adult patients who have chronic 
hepatitis C (HCV).
Rebetol may be used in paediatric patients (children 3 years of age and older and adolescents) who are 
not previously treated and without severe liver disease.

For paediatric patients (children and adolescents) weighing less than 47 kg a solution formulation is 
available.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

2. What you need to know before you use Rebetol

Do not take Rebetol
Do not take Rebetol if any of the following apply to you or the child you are caring for.

If you are not sure, talk to your doctor or pharmacist before taking Rebetol.
 are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6).
 are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”).
 are breast-feeding.
 had a serious heart problem during the past 6 months.

 



66

 have any blood disorders, such as anaemia (low blood count), thalassemia, sickle-cell anaemia.

Reminder: Please read the “Do not take” section of the Package Leaflet for the other medicines used 
in combination with this medicine.

Warnings and precautions
There are several serious adverse reactions associated with the combination therapy of ribavirin with 
(peg)interferon alfa. These include:
 Psychiatric and central nervous system effects (such as depression, suicidal thoughts, attempted 

suicide and aggressive behaviour, etc.). Be sure to seek emergency care if you notice that you 
are becoming depressed or have suicidal thoughts or change in your behaviour. You may want 
to consider asking a family member or close friend to help you stay alert to signs of depression 
or changes in your behaviour

 Severe eye disorders
 Dental and periodontal disorders: Dental and gum disorders have been reported in patients 

receiving Rebetol in combination with (peg)interferon alfa-2b. You should brush your teeth 
thoroughly twice daily and have regular dental examinations. In addition some patients may 
experience vomiting. If you have this reaction, be sure to rinse your mouth thoroughly 
afterwards

 Inability to achieve full adult height may occur in some children and adolescents
 Increased hormone related to your thyroid (TSH) in children and adolescents

Paediatric population
If you are caring for a child and your doctor decides not to defer combination treatment with 
peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to understand that this 
combination therapy induces a growth inhibition that may be irreversible in some patients. 

In addition these events have occurred in patients taking Rebetol:
Haemolysis: Rebetol can cause a break down in red blood cells causing anaemia which may impair 
your heart function or worsen symptoms of heart disease.
Pancytopenia: Rebetol can cause a decrease in your platelet and red and white blood cell count when 
used in combination with peginterferon. 

Standard blood tests will be taken to check your blood, kidney and liver function.
- Blood tests will be done regularly to help your doctor to know if this treatment is working.
- Depending upon the results of these tests, your doctor may change/adjust the number of hard 

capsules you or the child you are caring for take, prescribe a different pack size of this 
medicine, and/or change the length of time to take this treatment.

- If you have or develop severe kidney or liver problems, this treatment will be stopped.

Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as 
difficulty in breathing, wheezing or hives) while taking this treatment.

Talk to your doctor if you or the child you are caring for:
 are a woman of childbearing age (see section “Pregnancy and breast-feeding”).
 are a male and your female partner is of childbearing age (see section “Pregnancy and

breast-feeding”).
 had a previous heart condition or have heart disease.
 have another liver problem in addition to hepatitis C infection.
 have problems with your kidneys.
 have HIV (human immunodeficiency virus) or have ever had any other problems with your

immune system.

Please refer to the Package Leaflet of (peg)interferon alfa for more detailed information on these 
safety issues.

 



67

Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for the other 
medicines used in combination with Rebetol before you begin combination treatment. 

Use in children and adolescents
If the child is weighing less than 47 kg or unable to swallow an oral solution of Rebetol is available.

Other medicines with Rebetol
Tell your doctor or pharmacist if you or the child you are caring for are taking, have recently taken or 
might take: 
- azathioprine is a medicine that suppresses your immune system, using this medicine in 

combination with Rebetol may increase your risk of developing severe blood disorders.
- anti-Human Immunodeficiency Virus (HIV) medicines - [nucleoside reverse transcriptase 

inhibitor (NRTI), and/or combined anti-retroviral therapy (cART)]:
 Taking this medicine in combination with an alpha interferon and an anti-HIV medicine 

may increase the risk of lactic acidosis, liver failure, and blood abnormalities 
development (reduction in number of red blood cells which carry oxygen, certain white 
blood cells that fight infection, and blood clotting cells called platelets).

- With zidovudine or stavudine, it is not certain if this medicine will change the way 
these medicines work. Therefore, your blood will be checked regularly to be sure that the 
HIV infection is not getting worse. If it gets worse, your doctor will decide whether or 
not your Rebetol treatment needs to be changed. Additionally, patients receiving 
zidovudine with ribavirin in combination with alpha interferons could be at increased 
risk of developing anaemia (low number of red blood cells). Therefore the use of 
zidovudine and ribavirin in combination with alpha interferons is not recommended.

 Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis,
the use of ribavirin and didanosine is not recommended and the use of ribavirin and 
stavudine should be avoided.

 Co-infected patients with advanced liver disease receiving cART may be at increased 
risk of worsening liver function. Adding treatment with an alpha interferon alone or in 
combination with ribavirin may increase the risk in this patient subset.

Reminder: Please read the “Other medicines" section of the Package Leaflet for the other medicines 
used in combination with Rebetol before you begin combination treatment with this 
medicine.

Pregnancy and breast-feeding
If you are pregnant, you must not take this medicine. This medicine can be very damaging to your 
unborn baby (embryo).

Both female and male patients must take special precautions in their sexual activity if there is any 
possibility for pregnancy to occur:
- Girl or woman of childbearing age:

You must have a negative pregnancy test before treatment, each month during treatment, and 
for the 4 months after treatment is stopped. This should be discussed with your doctor. 

- Men:
Do not have sex with a pregnant woman unless you use a condom. This will lessen the 
possibility for ribavirin to be left in the woman’s body. 
If your female partner is not pregnant now but is of childbearing age, she must be tested for 
pregnancy each month during treatment and for the 7 months after treatment has stopped. 
You or your female partner must use an effective contraceptive during the time you are taking 
Rebetol and for 7 months after stopping treatment. This should be discussed with your doctor 
(see section “Do not take Rebetol”).

 



68

If you are a woman who is breast-feeding, you must not take this medicine. Discontinue 
breast-feeding before starting to take this medicine.

Driving and using machines
This medicine does not affect your ability to drive or use machines; however, other medicines used in 
combination with Rebetol may affect your ability to drive or use machines. Therefore, do not drive or 
use machines if you become tired, sleepy, or confused from this treatment. 

Rebetol contains lactose
Each capsule contains a small amount of lactose.
If you have been told by your doctor that you have an intolerance to some sugars, discuss with your 
doctor before taking this medicine.

3. How to use Rebetol

General information about taking this medicine:

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.
Do not take more than the recommended dosage and take the medicine for as long as prescribed.
Your doctor has determined the correct dose of this medicine based on how much you or the child you 
are caring for weighs. 

Adults
The recommended dose and duration of Rebetol depends on how much the patient weighs and the 
medicines that are used in combination.

Use in children and adolescents
Dosing for children above 3 years of age and adolescents depends on how much the person weighs 
and the medicines that are used in combination. The recommended dose of Rebetol combined with 
interferon alfa-2b or peginterferon alfa-2b, is shown in the below table. 

Rebetol dose based on body weight when used in combination with interferon alfa-2b or peginterferon 
alfa-2b in children above 3 years of age and adolescents

If the child/adolescent weighs 
(kg)

Usual daily Rebetol dose Number of 200 mg capsules

47 - 49 600 mg 1 capsule in the morning and 
2 capsules in the evening

50 - 65 800 mg 2 capsules in the morning and 
2 capsules in the evening

> 65 See adult dose 

Take your prescribed dose by mouth with water and during your meal. Do not chew the hard capsules. 
For children or adolescents who cannot swallow a hard capsule, an oral solution of this medicine is 
available.

Reminder: This medicine is used in combination with other medicines for hepatitis C virus infection. 
For complete information be sure to read the “How to use” section of the Package Leaflet 
for the other medicines used in combination with Rebetol.

If you take more Rebetol than you should
Tell your doctor or pharmacist as soon as possible.

 



69

If you forget to take Rebetol
Take/administer the missed dose as soon as possible during the same day. If an entire day has gone 
by, check with your doctor. Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in 
combination with Rebetol.

Like all medicines, this medicine used in combination with other medicines can cause side effects, 
although not everybody gets them. Although not all of these unwanted effects may occur, they may 
need medical attention if they do occur.

Contact your doctor immediately if you notice any of the following side effects occurring during 
combination treatment with other medicines:
 chest pain or persistent cough; changes in the way your heart beats, fainting,
 confusion, feeling depressed; suicidal thoughts or aggressive behaviour, attempt suicide, 

thoughts about threatening the life of others,
 feelings of numbness or tingling,
 trouble sleeping, thinking or concentrating,
 severe stomach pain, black or tar-like stools, blood in stool or urine, lower back or side pain,
 painful or difficult urination,
 severe bleeding from your nose,
 fever or chills beginning after a few weeks of treatment,
 problems with your eyesight or hearing,
 severe skin rash or redness.

The following side effects have been reported with the combination of this medicine hard capsules 
and an alpha interferon product in adults:

Very commonly reported side effects (may affect more than 1 in 10 people):
 decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 

dizziness), decrease in neutrophils (that make you more susceptible to different infections),
 difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or 

irritable, tired feeling, trouble falling asleep or staying asleep,
 cough, dry mouth, pharyngitis (sore throat),
 diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus infection, 

vomiting, weakness, 
 loss of appetite, loss of weight, stomach pain,
 dry skin, irritation, hair loss, itching, muscle pain, muscle aches, pain in joints and muscles, 

rash.

Commonly reported side effects (may affect up to 1 in 10 people):
 decrease in blood clotting cells called platelets that may result in easy bruising and spontaneous 

bleeding, decrease in certain white blood cells called lymphocytes that help fight infection,
decrease in thyroid gland activity (which may make you feel tired, depressed, increase your 
sensitivity to cold and other symptoms), excess of sugar or uric acid (as in gout) in the blood, low 
calcium level in the blood, severe anaemia,

 fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness, 
abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental 
disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble 
sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling),

 blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in your
hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex), change in 

 



70

taste, taste loss, bleeding gums or sores in mouth, burning sensation on tongue, sore tongue, 
inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose bleed, 
nonproductive cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth disorder,

 cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling 
unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high 
blood pressure, palpitations (pounding heart beat), rapid heart rate,

 bloating, constipation, indigestion, intestinal gas (flatus), increased appetite, irritated colon, 
irritation of prostate gland, jaundice (yellow skin), loose stools, pain on the right side around 
your ribs, enlarged liver, stomach upset, frequent need to urinate, passing more urine than usual, 
urinary tract infection, abnormal urine,

 difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, 
painful menstruation, disorder of ovary or vagina, breast pain, erectile problem,

 abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of the 
skin with possible oozing lesions), hives, increased or decreased sensitivity to touch, nail disorder,
muscle spasms, numbness or tingling feeling, limb pain, pain in joints, shaky hands, psoriasis, 
puffy or swollen hands and ankles, sensitivity to sunlight, rash with raised spotted lesions, 
redness of skin or skin disorder, swollen face, swollen glands (swollen lymph nodes), tense 
muscles, tumour (unspecified), unsteady when walking, water impairment.

Uncommonly reported side effects (may affect up to 1 in 100 people):
 hearing or seeing images that are not present,
 heart attack, panic attack, 
 hypersensitivity reaction to the medication,
 inflammation of pancreas, pain in bone, diabetes mellitus,
 muscle weakness.

Rarely reported side effects (may affect up to 1 in 1,000 people):
 seizure (convulsions)
 pneumonia,
 rheumatoid arthritis, kidney problems,
 dark or bloody stools, intense abdominal pain,
 sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, 

skin lesions and swollen glands),
 vasculitis.

Very rarely reported side effects (may affect up to 1 in 10,000 people): 
 suicide,
 stroke (cerebrovascular events).

Not known side effects (frequency cannot be estimated from the available data):
 thoughts about threatening the life of others,
 mania (excessive or unreasonable enthusiasm),
 pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection that 

develops between the pericardium (the lining of the heart) and the heart itself],
 change in colour of the tongue.

Side effects in children and adolescents
The following side effects have been reported with the combination of this medicine and an interferon 
alfa-2b product in children and adolescents:

Very commonly reported side effects (may affect more than 1 in 10 people):
 decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 

dizziness), decrease in neutrophils (that make you more susceptible to different infections), 

 



71

 decrease in thyroid gland activity (which may make you feel tired, depressed, increase your 
sensitivity to cold and other symptoms),

 feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired 
feeling, trouble falling asleep or staying asleep, virus infection, weakness,

 diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss of 
weight, decrease in the rate of growth (height and weight), pain on right side of ribs, 
pharyngitis (sore throat), shaking chills, stomach pain, vomiting,

 dry skin, hair loss, irritation, itching, muscle pain, muscle aches, pain in joints and muscles, 
rash.

Commonly reported side effects (may affect up to 1 in 10 people):
 decrease in blood clotting cells called platelets (that may result in easy bruising and 

spontaneous bleeding), 
 excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in

thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, 
weight loss, palpitation, tremors),

 agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional 
instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of 
restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality sleep, 
sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm yourself, 

 bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear 
infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores, 
coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore throat), rapid 
breathing, respiratory infections, scaling lips and clefts in the corners of the mouth, shortness of 
breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny nose, throat pain, 
toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), weakness,

 chest pain, flushing, palpitations (pounding heart beat), rapid heart rate,
 abnormal liver function,
 acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder, 

incontinence, increased appetite, inflammation of the membrane of the stomach and intestine, 
stomach upset, loose stools,

 urination disorders, urinary tract infection,
 difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, 

disorder of vagina, inflammation of the vagina, testis pain, development of male body traits,
 acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), 

increased or decreased sensitivity to touch, increased sweating, increase in muscle movement, 
tense muscle, limb pain, nail disorder, numbness or tingling feeling, pale skin, rash with raised 
spotted lesions, shaky hands, redness of skin or skin disorder, skin discolouration, skin sensitive 
to sunlight, skin wound, swelling due to a build-up of excess water, swollen glands (swollen 
lymph nodes), tremor, tumour (unspecified).

Uncommonly reported side effects (may affect up to 1 in 100 people):
 abnormal behaviour, emotional disorder, fear, nightmare,
 bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision, 

drowsiness, intolerance to light, itchy eyes, facial pain, inflamed gums, 
 chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia, wheezing,
 low blood pressure,
 enlarged liver,
 painful menstruation,
 itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to touch,

muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling.

The attempt to self-harm has also been reported in adults, children, and adolescents.

 



72

This medicine in combination with an alpha interferon product may also cause:
 aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the 

production of red blood cells); this causes severe anaemia, symptoms of which would include 
unusual tiredness and a lack of energy,

 delusions, 
 upper and lower respiratory tract infection,
 inflammation of the pancreas,
 severe rashes which may be associated with blisters in the mouth, nose, eyes and other mucosal 

membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal necrolysis 
(blistering and peeling of the top layer of skin).

The following other side effects have also been reported with the combination of this medicine and an 
alpha interferon product:
 abnormal thoughts, hearing or seeing images that are not present, altered mental status, 

disorientation,
 angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause 

difficulty in swallowing or breathing),
 Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin 

and the membranes of the ears, brain and spinal cord),
 bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,
 eye problems including damage to the retina, obstruction of the retinal artery, inflammation of 

the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),
 enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel 

movement,
 acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg 

or thigh pain, loss of range of motion, stiffness, sarcoidosis (a disease characterised by 
persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands).

This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause: 
 dark, cloudy or abnormally coloured urine, 
 difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw 

pain,
 loss of consciousness,
 loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,
 loss of vision.
You or your caregiver should call your doctor immediately if you have any of these side effects.

If you are a HCV/HIV co-infected adult patient receiving anti-HIV treatment, the addition of this 
medicine and peginterferon alfa may increase your risk of worsening liver function (combined
anti-retroviral therapy (cART)) and increase your risk of lactic acidosis, liver failure, and blood 
abnormalities development (reduction in number of red blood cells which carry oxygen, certain white 
blood cells that fight infection, and blood clotting cells called platelets) (NRTI).
In HCV/HIV co-infected patients receivingcART, the following other side effects have occurred with 
the combination of Rebetol hard capsules and peginterferon alfa-2b (not listed above in adults side 
effects):
 appetite decreased,
 back pain, 
 CD4 lymphocytes decreased,
 defective metabolism of fat,
 hepatitis,
 limb pain,
 oral candidiasis (oral thrush),
 various laboratory blood values abnormalities.

 



73

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can also help provide more information on 
the safety of this medicine.

5. How to store Rebetol

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to 
the last day of that month.

Do not store above 30ºC. 

Do not use this medicine without advice of your doctor or pharmacist if you notice any change in the 
appearance of the hard capsules.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Rebetol contains

- The active substance is ribavirin 200 mg.
- The other ingredients are microcrystalline cellulose, lactose monohydrate (40 mg), 

croscarmellose sodium, magnesium stearate. The capsule shell contains gelatine, titanium 
dioxide. The capsule shell imprint contains shellac, propylene glycol, ammonium hydroxide, 
colouring agent (E 132).

What Rebetol looks like and contents of the pack

This medicine is a white, opaque, hard capsule imprinted with blue ink.
This medicine is available in different pack sizes containing 84, 112, 140 or 168 capsules of 200 mg 
to be swallowed.
Not all pack sizes may be marketed.

Your physician will prescribe the pack size which is best for you.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V. SP Labo N.V.
Waarderweg 39 Industriepark 30
2031 BN Haarlem B-2220 Heist-op-den-Berg
The Netherlands Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. +370 5 278 02 47
msd_lietuva@merck.com

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


74

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel.: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 2900
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 70 00

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

 



75

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 



76

Package leaflet: Information for the user

Rebetol 40 mg/mL oral solution
ribavirin

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Rebetol is and what it is used for
2. What you need to know before you use Rebetol 
3. How to use Rebetol
4. Possible side effects
5. How to store Rebetol
6. Contents of the pack and other information

This Package Leaflet contains information for the paediatric patient (child or adolescent, 3 through 
17 years of age), or for his or her parent or caregiver.

1. What Rebetol is and what it is used for

Rebetol contains the active substance ribavirin. This medicine stops the multiplication of hepatitis C 
virus. Rebetol must not be used alone.

The combination of Rebetol and other medicines is used to treat patients who have chronic hepatitis C 
(HCV).
Rebetol may be used in paediatric patients (children 3 years of age and older and adolescents), who 
are not previously treated and without severe liver disease.

2. What you need to know before you use Rebetol 

Do not take Rebetol
Do not take Rebetol if any of the following apply to you or the child you are caring for.

If you are not sure, talk to your doctor or pharmacist before taking Rebetol.
 are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6).
 are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”).
 are breast-feeding.
 had a serious heart problem during the past 6 months.
 have any blood disorders, such as anaemia (low blood count), thalassemia, sickle-cell anaemia.

Reminder: Please read the “Do not take” section of the Package Leaflet for the other medicines used 
in combination  with this medicine.

 



77

Warnings and precautions
There are several serious adverse reactions associated with the combination therapy of ribavirin with 
(peg)interferon alfa. These include:
 Psychiatric and central nervous system effects (such as depression, suicidal thoughts, attempted 

suicide and aggressive behaviour, etc.). Be sure to seek emergency care if you notice that you 
are becoming depressed or have suicidal thoughts or change in your behaviour. You may want 
to consider asking a family member or close friend to help you stay alert to signs of depression 
or changes in your behaviour

 Severe eye disorders
 Dental and periodontal disorders: Dental and gum disorders have been reported in patients 

receiving Rebetol in combination with (peg)interferon alfa-2b. You should brush your teeth 
thoroughly twice daily and have regular dental examinations. In addition some patients may 
experience vomiting. If you have this reaction, be sure to rinse your mouth thoroughly 
afterwards

 Inability to achieve full adult height may occur in some children and adolescents
 Increased hormone related to your thyroid (TSH) in children and adolescents

Paediatric population
If you are caring for a child and your doctor decides not to defer combination treatment with 
peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to understand that this 
combination therapy induces a growth inhibition that may be irreversible in some patients. 

In addition these events have occurred in patients taking Rebetol:
Haemolysis: Rebetol can cause a break down in red blood cells causing anaemia which may impair 
your heart function or worsen symptoms of heart disease.
Pancytopenia: Rebetol can cause a decrease in your platelet and red and white blood cell count when 
used in combination with peginterferon. 

Standard blood tests will be taken to check your blood, kidney and liver function.
- Blood tests will be done regularly to help your doctor to know if this treatment is working.
- Depending upon the results of these tests, your doctor may change/adjust the number of hard 

capsules you or the child you are caring for take, prescribe a different pack size of this 
medicine, and/or change the length of time to take this treatment.

- If you have or develop severe kidney or liver problems, this treatment will be stopped.

Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as 
difficulty in breathing, wheezing or hives) while taking this treatment.

Talk to your doctor if you or the child you are caring for:
 are a woman of childbearing age (see section “Pregnancy and breast-feeding”).
 are a male and your female partner is of childbearing age (see section “Pregnancy and 

breast-feeding”).
 had a previous heart condition or have heart disease.
 have another liver problem in addition to hepatitis C infection.
 have problems with your kidneys.
 have HIV (human immunodeficiency virus) or have ever had any other problems with your

immune system.

Please refer to the Package Leaflet of (peg)interferon alfa for more detailed information on these 
safety issues.

Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for the other 
medicines used in combination with Rebetol before you begin combination treatment. 

 



78

Other medicines with Rebetol
Tell your doctor or pharmacist if you or the child you are caring for are taking, have recently taken or 
might take:
- azathioprine is a medicine that suppresses your immune system, using this medicine in 

combination with Rebetol may increase your risk of developing severe blood disorders.
- anti-Human Immunodeficiency Virus (HIV) medicines - [nucleoside reverse transcriptase 

inhibitor (NRTI), and/or combined anti-retroviral therapy (cART)]:
 Taking this medicine in combination with an alpha interferon and an anti-HIV medicine

may increase the risk of lactic acidosis, liver failure, and blood abnormalities 
development (reduction in number of red blood cells which carry oxygen, certain white 
blood cells that fight infection, and blood clotting cells called platelets).

 With zidovudine or stavudine, it is not certain if this medicine will change the way 
these medicines work. Therefore, your blood will be checked regularly to be sure that the 
HIV infection is not getting worse. If it gets worse, your doctor will decide whether or 
not your Rebetol treatment needs to be changed. Additionally, patients receiving 
zidovudine with ribavirin in combination with alpha interferons could be at increased 
risk of developing anaemia (low number of red blood cells). Therefore the use of 
zidovudine and ribavirin in combination with alpha interferons is not recommended.

 Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis,
the use of ribavirin and didanosine is not recommended and the use of ribavirin and 
stavudine should be avoided.

 Co-infected patients with advanced liver disease receiving cART may be at increased 
risk of worsening liver function. Adding treatment with an alpha interferon alone or in 
combination with ribavirin may increase the risk in this patient subset.

Reminder: Please read the “Other medicines” section of the Package Leaflet for the other medicines 
used in combination with Rebetol before you begin combination treatment with this 
medicine.

Pregnancy and breast-feeding 
If you are pregnant, you must not take this medicine. This medicine can be very damaging to your 
unborn baby (embryo).

Both female and male patients must take special precautions in their sexual activity if there is any 
possibility for pregnancy to occur:
- Girl or woman of childbearing age:

You must have a negative pregnancy test before treatment, each month during treatment, and 
for the 4 months after treatment is stopped. This should be discussed with your doctor. 

- Men:
Do not have sex with a pregnant woman unless you use a condom. This will lessen the 
possibility for ribavirin to be left in the woman’s body. 
If your female partner is not pregnant now but is of childbearing age, she must be tested for 
pregnancy each month during treatment and for the 7 months after treatment has stopped. 
You or your female partner must use an effective contraceptive during the time you are taking 
Rebetol and for 7 months after stopping treatment. This should be discussed with your doctor 
(see section “Do not take Rebetol”). 

If you are a woman who is breast-feeding, you must not take this medicine. Discontinue 
breast-feeding before starting to take this medicine.

Driving and using machines
This medicine does not affect your ability to drive or use machines; however, other medicines used in 
combination with Rebetol may affect your ability to drive or use machines. Therefore, do not drive or 
use machines if you become tired, sleepy, or confused from this treatment. 

 



79

Rebetol contains sucrose and sorbitol
This medicine contains sucrose and sorbitol, these are types of sugars. 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine.

3. How to use Rebetol

General information about taking this medicine:

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
Do not take more than the recommended dosage and take the medicine for as long as prescribed.
Your doctor has determined the correct dose of this medicine based on how much you or the child you 
are caring for weighs.

Use in children and adolescents
Dosing for children above 3 years of age and adolescents depends on how much the person weighs 
and the medicines that are used in combination. The recommended dose of Rebetol combined with 
interferon alfa-2b or peginterferon alfa-2b, is shown in the below table. 

Rebetol oral solution -
Usual dosage to be used with interferon alfa-2b or peginterferon alfa-2b in children above 3 years of 
age and adolescents
If the patient weighs this many kg Measure and give this dose

Morning Dose Evening Dose
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

1. Measure:
You can measure the dose with the oral dosing syringe provided.

 



80

The plastic oral dosing syringe consists of two parts, an opaque barrel, and a white plunger rod that 
fits into the barrel. 
The rod is marked with 0.5 mL markings starting at 1.5 mL (at the very top of the rod) and ending at 
10 mL.

A. Insert the assembled dosing syringe into the bottle of Rebetol oral 
solution.

B. While keeping the tip in the liquid, pull the rod out. As the solution 
fills the syringe, you will see the numbers on the rod go up, such as 
1.5 mL, 2.0 mL, 2.5 mL, etc.

Reminder: Your doctor may have changed the amount based on 
recent test results.

C. Pull the rod out until you can read the correct number of mL for the 
dose you are measuring.

D. Take the oral syringe out of the bottle and check to see that the correct 
amount appears in the bottom of the syringe. If you have too much or 
too little, try again until you have the correct amount.

2. Deliver: Try not to let the oral syringe touch the inside of the mouth.
Hold the syringe to your mouth and release the dose into your mouth (or 
the mouth of the patient you are caring for) by pushing in the rod. 
Swallow the dose.

3. Rinse: If the syringe has touched the inside of the mouth, rinse it with water 
before inserting it in the bottle again.
The syringe should be rinsed with water after each use to avoid 
stickiness.

4. Taking all your medicine:
Take or give the prescribed dose by mouth in the morning and evening, with a meal. 

Reminder: This medicine is used in combination with other medicines for hepatitis C virus infection. 
For complete information be sure to read the “How to use” section of the Package Leaflet 
for the other medicines used in combination with Rebetol.

If you take more Rebetol than you should
Tell your doctor or pharmacist as soon as possible.

If you forget to take Rebetol
Take/administer the missed dose as soon as possible during the same day. If an entire day has gone 
by, check with your doctor. Do not take a double dose to make up for a forgotten dose.

 



81

4. Possible side effects

Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in 
combination with Rebetol.

Like all medicines, this medicine used in combination with other medicines can cause side effects, 
although not everybody gets them. Although not all of these unwanted effects may occur, they may 
need medical attention if they do occur.

Contact your doctor immediately if you notice any of the following side effects occurring during 
combination treatment with other medicines:
 chest pain or persistent cough, changes in the way your heart beats, fainting,
 confusion, feeling depressed, suicidal thoughts or aggressive behaviour, attempt suicide, 

thoughts about threatening the life of others,
 feelings of numbness or tingling,
 trouble sleeping, thinking or concentrating,
 severe stomach pain; black or tar-like stools, blood in stool or urine, lower back or side pain,
 painful or difficult urination,
 severe bleeding from your nose,
 fever or chills beginning after a few weeks of treatment,
 problems with your eyesight or hearing,
 severe skin rash or redness.

Children and adolescents
The following side effects have been reported with the combination of this medicine and an interferon 
alfa-2b product in children and adolescents:

Very commonly reported side effects (may affect more than 1 in 10 people):
 decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 

dizziness), decrease in neutrophils (that make you more susceptible to different infections), 
 decrease in thyroid gland activity (which may make you feel tired, depressed, increase your 

sensitivity to cold and other symptoms),
 feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired 

feeling, trouble falling asleep or staying asleep, virus infection, weakness,
 diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss of 

weight, decrease in the rate of growth (height and weight), pain on right side of ribs, 
pharyngitis (sore throat), shaking chills, stomach pain, vomiting,

 dry skin, hair loss, irritation, itching, muscle pain, muscle aches, pain in joints and muscles, 
rash.

Commonly reported side effects (may affect up to 1 in 10 people): 
 decrease in blood clotting cells called platelets (that may result in easy bruising and 

spontaneous bleeding),
 excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in

thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, 
weight loss, palpitation, tremors),

 agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional 
instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of 
restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality sleep, 
sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm yourself, 

 bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear 
infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores, 
coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore throat), rapid 
breathing, respiratory infections, scaling lips and clefts in the corners of the mouth, shortness of 

 



82

breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny nose, throat pain, 
toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), weakness,

 chest pain, flushing, palpitations (pounding heart beat), rapid heart rate,
 abnormal liver function,
 acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder, 

incontinence, increased appetite, inflammation of the membrane of the stomach and intestine, 
stomach upset, loose stools,

 urination disorders, urinary tract infection,
 difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, 

disorder of vagina, inflammation of the vagina, testis pain, development of male body traits,
 acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), 

increased or decreased sensitivity to touch, increased sweating, increase in muscle movement, 
tense muscle, limb pain, nail disorder, numbness or tingling feeling, pale skin, rash with raised 
spotted lesions, shaky hands, redness of skin or skin disorder, skin discolouration, skin sensitive 
to sunlight, skin wound, swelling due to a build-up of excess water, swollen glands (swollen 
lymph nodes), tremor, tumour (unspecified).

Uncommonly reported side effects (may affect up to 1 in 100 people):
 abnormal behaviour, emotional disorder, fear, nightmare,
 bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision, 

drowsiness, intolerance to light, itchy eyes, facial pain,
 chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia, wheezing,
 low blood pressure,
 enlarged liver,
 painful menstruation,
 itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to touch,

muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling.

Adults
The additional following side effects have occurred with the combination of this medicine and an 
alpha interferon product in adults but not in children:

Commonly reported side effects (may affect up to 1 in 10 people):
 decrease in certain white blood cells called leukocytes that help fight infection, excess of sugar in 

the blood, low calcium level in the blood,
 amnesia, crying, bleeding gums, feeling faint, anger, memory impaired, mental disorder,
 cardiac murmur (abnormal heart beat sounds), difficult breathing, low or high blood pressure,
 blurred vision, changes in your hearing, ringing in ears, earache, bloating, burning sensation on 

tongue, change in taste, taste loss, dry mouth, migraine, nonproductive cough, thirst,
 abnormal urine, passing more urine than usual,
 irritated colon, irritation of prostate gland, intestinal gas (flatus),
 jaundice (yellow skin),
 disorder of ovary, breast pain, lack of interest in sex or inability to perform, erectile problem,
 abnormal hair texture, arthritis, psoriasis, muscle spasm, puffy or swollen hands and ankles, 

swollen face, unsteady when walking, water impairment.

Uncommonly reported side effects (may affect up to 1 in 100 people):
 hearing or seeing images that are not present,
 heart attack, panic attack, 
 hypersensitivity reaction to the medication,
 inflammation of pancreas, pain in bone, diabetes mellitus,
 muscle weakness.

 



83

Rarely reported side effects (may affect up to 1 in 1,000 people):
 seizure (convulsions),
 pneumonia,
 rheumatoid arthritis, kidney problems,
 dark or bloody stools, intense abdominal pain,
 sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, 

skin lesions and swollen glands),
 vasculitis.

Very rarely reported side effects (may affect up to 1 in 10,000 people):
 suicide,
 stroke (cerebrovascular events).

Not known side effects (frequency cannot be estimated from the available data):
 thoughts about threatening the life of others,
 mania (excessive or unreasonable enthusiasm),
 pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection that 

develops between the pericardium (the lining of the heart) and the heart itself],
 change in colour of the tongue.

The attempt to self-harm has also been reported in adults, children, and adolescents.

This medicine in combination with an alpha interferon product may also cause:
 aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the 

production of red blood cells); this causes severe anaemia, symptoms of which would include 
unusual tiredness and a lack of energy,

 delusions, 
 upper and lower respiratory tract infection,
 inflammation of the pancreas,
 severe rashes which may be associated with blisters in the mouth, nose, eyes and other mucosal 

membranes (erythema multiforme, Stevens Johnson syndrome), and toxic epidermal necrolysis 
(blistering and peeling of the top layer of skin).

The following other side effects have also been reported with the combination of this medicine and an 
alpha interferon product:
 abnormal thoughts, hearing or seeing images that are not present, altered mental status, 

disorientation,
 angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause 

difficulty in swallowing or breathing),
 Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin 

and the membranes of the ears, brain and spinal cord),
 bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,
 eye problems including damage to the retina, obstruction of the retinal artery, inflammation of 

the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),
 enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel 

movement,
 acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg 

or thigh pain, loss of range of motion, stiffness, sarcoidosis (a disease characterised by 
persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands).

This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause: 
 dark, cloudy or abnormally coloured urine,
 difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw 

pain,

 



84

 loss of consciousness,
 loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,
 loss of vision.
You or your caregiver should call your doctor immediately if you have any of these side effects.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can also help provide more information on 
the safety of this medicine.

5. How to store Rebetol

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to 
the last day of that month. Once the bottle has been opened, the oral solution can be used for 1 month.

Do not store above 30ºC.

Do not use this medicine without advice of your doctor or pharmacist if you notice any change in the 
appearance of the solution.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Rebetol contains

- The active substance is ribavirin 40 mg/mL.
- The other ingredients are: sodium citrate, citric acid, anhydrous, sodium benzoate, glycerol, 

sucrose, sorbitol liquid (crystallising), propylene glycol, purified water, natural and artificial 
bubble gum flavouring 

What Rebetol looks like and contents of the pack

This solution is packaged in 118 mL size amber glass bottles containing 100 mL of oral solution.
A 10 mL oral dosing syringe is provided to measure the dose. 

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V. Cenexi HSC
Waarderweg 39 2, rue Louis Pasteur
2031 BN Haarlem 14200 Hérouville-Saint-Clair
The Netherlands France

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. +370 5 278 02 47
msd_lietuva@merck.com

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


85

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel: +420 233 010 111 
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 4482 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel.: 8007 4433 (+356 99917558)
malta_info@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: + 33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 2900
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o.
Tel: +386 1 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 70 00

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

 



86

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in 

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET