Ribavirin Teva Pharma B.V.

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 200 mg film-coated tablets 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each Ribavirin Teva Pharma B.V. tablet contains 200 mg of ribavirin 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Light pink to pink, (debossed with “93” on one side and “7232” on the other). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ribavirin Teva Pharma B.V. is indicated for the treatment of chronic hepatitis C virus (HCV) infection 
in adults, children 3-years of age or older and adolescents and must only be used as part of a 
combination regimen with interferon alfa-2b. Ribavirin monotherapy must not be used.  
 
There is no safety or efficacy information on the use of ribavirin with other forms of interferon (i.e. 
not alfa-2b). 
 
Naïve patients  
Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for 
the treatment of adult patients with all types of chronic hepatitis C except genotype 1, not previously 
treated, without liver decompensation, with elevated alanine aminotransferase (ALT), who are positive 
for hepatitis C viral ribonucleic acid HCV-RNA (see section 4.4).  
 
Paediatric patients (children 3 years of age and older and adolescents: Ribavirin Teva Pharma B.V. is 
indicated in a combination regimen with interferon alfa2b, for the treatment of children and 
adolescents 3 years of age and older, who have all types of chronic hepatitis C except genotype 1, not 
previously treated, without liver decompensation, and who are positive for HCV-RNA.  
When deciding not to defer treatment until adulthood, it is important to consider that the 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 basis (see section 4.4).  
 
Previous treatment failure patients  
Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, for 
the treatment of adult patients with chronic hepatitis C who have previously responded (with 
normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have 
subsequently relapsed (see section 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 
 



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Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. for prescribing information particular to that 
product and for further dosage recommendations on co-administration with Ribavirin Teva Pharma 
B.V..  
 
Ribavirin Teva Pharma B.V. tablets are to be administered orally each day in two divided doses 
(morning and evening) with food. 
 
Adults:  
The recommended dose and duration of Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V.. 
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. 
 
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 tablets, ribavirin oral solution is 
available and should be used if appropriate. 
 
Dosing of ribavirin 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 is shown in Table 1. 
Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin as 
some combination regimens do not adhere to the ribavirin dosing guidance provided in Table 1. 
 
Table 1  Ribavirin Teva Pharma B.V. dose based on body weight when used in combination 
with interferon alfa-2b in paediatric patients 

Patient weight (kg) Daily ribavirin dose Number of 200 mg tablets 
47-49 600 mg 3 x 200 mg tabletsa 
50-65 800 mg 4 x 200 mg tabletsb 
> 65 Refer to adult dose recommendation 

a: 1 morning, 2 evening 
b: 2 morning, 2 evening 
 
Dose modification for adverse reactions 
 
Dose modification for adults 
Dose reduction of ribavirin depends on the initial ribavirin posology which depends on the medicinal 
product that is used in combination with ribavirin. 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin 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. 
 



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

if: 
Discontinue 
ribavirin 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, ribavirin dose should be 
reduced to 600 mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets in 
the evening). If the abnormality is reversed, ribavirin 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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. is by an additional 200 mg/day. Patients whose dose of 
Ribavirin Teva Pharma B.V. is reduced to 600 mg daily receive one 200 mg tablet in the morning and 
two 200 mg tablets in the evening. 
 
In case of serious adverse reaction potentially related to medicinal products used in combination with 
ribavirin, refer to the corresponding SmPC of these medicinal products as some combination regimens 
do not adhere to the ribavirin 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 ribavirin 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 ribavirin. 
However, as in younger patients, renal function must be determined prior to administration of ribavirin 
(see section 5.2). 
 
Paediatric patients (children 3 years of age and older and adolescents) 
Ribavirin may be used in combination with interferon alfa-2b (see section 4.4). The selection of 
ribavirin formulation is based on individual characteristics of the patient.  



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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 ribavirin for 
further dosage recommendations on co-administration. 
 
Renal impairment  
The pharmacokinetics of ribavirin 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 ribavirin. 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 ribavirin 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 Ribavirin 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 ribavirin 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 ribavirin. 
 
Method of administration 
Ribavirin Teva Pharma B.V. tablets 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, Ribavirin Teva 

Pharma B.V. 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 Ribavirin 
Teva Pharma B.V. for contraindications specific to these products. 
 
4.4 Special warnings and precautions for use 
 
Ribavirin 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 ribavirin with 
(peg)interferon alfa. These include: 



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- 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 ribavirin in combination with peginterferon alfa-2b or 
interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia 
associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the 
symptoms of coronary disease, or both. Thus, ribavirin 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 ribavirin the physician must comprehensively inform both male 
and female patients of the teratogenic risk of ribavirin, 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 ribavirin (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, Ribavirin Teva Pharma B.V. 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 
Ribavirin Teva Pharma B.V. for discontinuation or dose modification recommendations. 
 
Renal impairment 
The pharmacokinetics of ribavirin 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 ribavirin. Due to substantial increases in ribavirin plasma 
concentrations in patients with moderate and severe renal impairment, ribavirin 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). 



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Potential to exacerbate immunosuppression 
Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 
weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This 
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and 
concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 
4.5). 
 
HCV/HIV Co-infection  
Mitochondrial toxicity and lactic acidosis: Caution should be taken in HIV-positive subjects 
co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment 
(especially ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive 
population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial 
toxicity and lactic acidosis when ribavirin is administered. 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 ribavirin 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 ribavirin and zidovudine are at increased risk of developing anaemia; therefore, 
the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5). 
 
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 ribavirin.  
 
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 ribavirin 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). 



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Uric acid may increase with ribavirin due to haemolysis; therefore, the potential for development of 
gout must be carefully monitored in pre-disposed patients. 
 
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 ribavirin. Ribavirin does not inhibit cytochrome 
P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. 
Therefore, there is a minimal potential for P450 enzyme-based interactions.  
 
Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere 
with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine 
monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with 
azathioprine. The use of pegylated alpha interferons and ribavirin concomitantly with azathioprine 
should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with 
azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done 
during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with 
these medicines should be stopped (see section 4.4). 
 
No interaction studies have been conducted with ribavirin and other medicinal products, except for 
peginterferon alfa-2b, interferon alfa-2b and antacids.  
 
No pharmacokinetic interactions were noted between ribavirin and peginterferon alfa-2b or interferon 
alfa-2b in a multiple-dose pharmacokinetic study.  
 
Antacid 
The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing 
magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased 
bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is 
not considered to be clinically relevant.  
 
Nucleoside analogues 
Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic 
acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in 
vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs 
(e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. 
Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, 
have been reported (see section 4.4).  
The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen 
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of 
ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 
4.4).Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment 
(ART) regimen if this is already established. This would be particularly important in patients with  a 
known history of zidovudine induced anaemia. 
 
Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after 
cessation of ribavirin therapy due to the long half-life (see section 5.2).  
 
There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or 
protease inhibitors.  
 
Conflicting findings are reported in literature on co-administration between abacavir and ribavirin. 
Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 



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risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised 
when both medicines are co-administered. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception in males and females 
 
Female patients  
Ribavirin Teva Pharma B.V. must not be used by females who are pregnant (see sections 4.3, 4.4 and 
5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Ribavirin 
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 (see section 4.4). If pregnancy does occur during treatment or 
within four months from stopping treatment, the patient must be advised of the significant teratogenic 
risk of ribavirin to the foetus (see section 4.4).  
 
Male patients and their female partners 
Extreme care must be taken to avoid pregnancy in partners of male patients taking Ribavirin Teva 
Pharma B.V. (see sections 4.3, 4.4 and 5.3). Ribavirin accumulates intracellularly and is cleared from 
the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its 
potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on 
approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not 
shown an increased risk of malformation compared to the general population, nor any specific pattern 
of malformation, either male patients or their female partners of childbearing age must be advised to 
use an effective contraceptive during treatment with ribavirin 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 ribavirin to the partner.  
 
Pregnancy 
The use of Ribavirin Teva Pharma B.V. is contraindicated during pregnancy. Ribavirin 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 ribavirin is excreted in human milk. Because of the potential for adverse 
reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.  
 
Fertility 
Preclinical data:  
- Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section 

5.3).  
- Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for 

ribavirin in all animal species in which adequate studies have been conducted, occurring at 
doses as low as one twentieth of the recommended human dose (see section 5.3).  

- Genotoxicity: Ribavirin induces genotoxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Ribavirin Teva Pharma B.V. 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 
 



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Summary of the safety profile 
The salient safety issue of ribavirin is haemolytic anaemia occurring within the first weeks of therapy. 
The haemolytic anaemia associated with ribavirin 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 ribavirin 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 
ribavirin for additional undesirable effects reported with these products. 
 
Adults 
The safety of ribavirin is evaluated from data from four clinical trials in patients with no previous 
exposure to interferon (interferon-naïve patients): two trials studied ribavirin in combination with 
interferon alfa-2b, two trials studied ribavirin in combination with peginterferon alfa-2b.  
 
Patients who are treated with interferon alfa-2b and ribavirin 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 ribavirin) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b 
and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferon 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 ribavirin 

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 



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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* 

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* 



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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, gastroesophageal 
reflux*, glossitis, cheilitis, abdominal distension, gingival 
bleeding, gingivitis, loose stools, tooth disorder, 
constipation, flatulence 

Uncommon:  Pancreatitis, oral pain 
Rare: Ischaemic colitis 
Very rare: Ulcerative colitis* 
Not Known: Periodontal disorder, dental disorder, tongue pigmentation 
Hepatobiliary disorders 
Common: Hepatomegaly, jaundice, hyperbilirubinemia* 
Very rare: Hepatotoxicity (including fatalities)* 
Skin and subcutaneous tissue disorders 
Very common: Alopecia, pruritus, skin dry, rash 
Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity 

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

Rare:  Cutaneous sarcoidosis 
Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, 

erythema multiforme* 
Musculoskeletal and  
connective tissue disorders 
Very common: Arthralgia, myalgia, musculoskeletal pain 
Common: Arthritis, back pain, muscle spasms, pain in extremity 
Uncommon: Bone pain, muscle weakness 
Rare: Rhabdomyolysis*, myositis* 
Renal and urinary disorders 
Common: Micturition frequency, polyuria, urine abnormality 
Rare: Renal failure, renal insufficiency* 
Very rare: Nephrotic syndrome* 
Reproductive system and breast disorders 
Common: Female: amenorrhea, menorrhagia, menstrual disorder, 

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

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

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

feeling abnormal, thirst 



13 

Uncommon: Face oedema 
Investigations 
Very common: Weight decrease 
Common: Cardiac murmur 
* Since ribavirin 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 ribavirin in combination with interferon alfa-2b (pegylated or nonpegylated). 
 
Description of selected adverse reactions 
A reduction in haemoglobin concentrations by > 4 g/dL was observed in 30 % of patients treated with 
ribavirin and peginterferon alfa-2b and 37 % of patients treated with ribavirin 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 ribavirin 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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. 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 ribavirin 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 %).   
 
Mitochondrial toxicity 
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI 
regimen and associated-ribavirin 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 ribavirin in combination with peginterferon 
alfa-2b when compared to patients receiving ribavirin 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 ribavirin in combination with peginterferon alfa-2b. Anaemia a (haemoglobin < 9.4 
g/dL) was reported in 12 % (23/194) of patients treated with ribavirin in combination with 
peginterferon alfa-2b. 
 
CD4 lymphocytes decrease 
Treatment with ribavirin 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 



14 

ribavirin 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 Summary of Product Characteristics 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 Ribavirin Teva 
Pharma B.V 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 ribavirin, 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 ribavirin, growth inhibition was observed that resulted 
in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very 
common during the treatment (at the end of treatment, mean decrease from baseline in weight and in 
height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was 
inhibited (< 3rd percentile in 70 % of the patients). 
 
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height 
percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued 
to have inhibited growth (growth velocity < 3rd percentile). Ninety four of 107 children enrolled in the 
5 year long-term follow up trial. The effects on growth were less in those children treated for 24 weeks 
than those treated for 48 weeks. From pre-treatment to end of long-term follow up among children 
treated for 24 or 48 weeks, height for age percentiles decreased 1.3 and 9.0 percentiles, respectively. 
Twenty four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 
48 weeks had a > 15 percentile height for age decrease from pre-treatment to the end of 5 year long 
term follow up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) 
treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a 
decrease from pre-treatment baseline > 30 height for age percentiles to the end of the 5 year long term 
follow-up. For weight, pre-treatment to end of long term follow up, weight for age percentiles 
decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For 
BMI, pre-treatment to end of long-term follow up, BMI for age percentiles decreased 1.8 and 7.5 
percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height 
percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The 
decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a 
normative population did not fully recover at the end of long-term follow-up period for children 
treated with 48 weeks of therapy (see section 4.4). 
 
In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia 
(80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site 
erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction 
(thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in 
severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection 
site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). 
Important treatment-emergent adverse reactions that occurred in this patient population were 
nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and 
hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated 
TSH.  
  
In combination with interferon alfa-2b 
In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy 
of interferon alfa-2b and ribavirin 6 % discontinued therapy due to adverse events. In general, the 



15 

adverse event 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 growth velocity 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 ribavirin, 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 events (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 ribavirin 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 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical 

trials in children and adolescents with ribavirin 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 liability 



16 

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

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

Nervous system disorders 
Very common: Headache, dizziness 
Common: Hyperkinesia, tremor, dysphonia, paresthaesia, 

hypoaesthesia, hyperaesthesia, concentration impaired, 
somnolence, disturbance in attention, poor quality of sleep 

Uncommon: Neuralgia, lethargy, psychomotor hyperactivity 
Eye disorders 
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland 

disorder 
Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision 

blurred, photophobia 
Ear and labyrinth disorders 
Common: Vertigo 
Cardiac disorders 
Common: Tachycardia, palpitations 
Vascular disorders 
Common: Pallor, flushing 
Uncommon: Hypotension 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, 

nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal 
pain 

Uncommon: Wheezing, nasal discomfort 
Gastro-intestinal disorders 
Very common: Abdominal pain, abdominal pain upper, vomiting , 

diarrhoea, nausea 
Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous 

stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal 
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, 

hyperhidrosis, eczema, 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 



17 

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 ribavirin/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 ribavirin 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. 
 
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 ribavirin used in combination with peginterferon alfa-2b or interferon alfa-2b, the 
maximum overdose reported was a total dose of 10 g of ribavirin (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, nucleosides and nucleotides excl.reverse 
transcriptase inhibitors, ATC code: J05AB04.  
 
Mechanism of action 
Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and 
DNA viruses. The mechanism by which ribavirin in combination with other medicinal products exerts 
its effects against HCV is unknown. Oral formulations of ribavirin monotherapy have been 
investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations 
showed that ribavirin 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.  

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


18 

 
Clinical efficacy and safety 
The use of ribavirin in combination treatment with 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 ribavirin + interferon alfa-2b 
(C95-132 and I95-143) and one with ribavirin + 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 ribavirin to interferon alfa-2b (41 % vs 16 %, 
p < 0.001).  
 
In clinical trials C95-132 and I95-143, ribavirin + 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.  
 
In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following 
combination regimens:  
 Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).  
 Ribavirin (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). 
 Ribavirin (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).  
 
In this trial, the combination of ribavirin and peginterferon alfa-2b (1.5 micrograms/kg/week) was 
significantly more effective than the combination of ribavirin 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 ribavirin 
administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that 
received > 10.6 mg/kg ribavirin (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 
ribavirin (Table 7), while response rates in patients that received > 13.2 mg/kg ribavirin were even 
higher.  
 
Table 7  Sustained response rates with ribavirin + peginterferon alfa-2b  
  (by ribavirin dose [mg/kg], genotype and viral load)  
HCV Genotype  Ribavirin dose 

(mg/kg) 
P 1.5/R P 0.5/R I/R 

All Genotypes  All 
≤ 10.6 
> 10.6 

54 % 
50 % 
61 % 

47 % 
41 % 
48 % 

47 % 
27 % 
47 % 

Genotype 1  All 
≤ 10.6 
> 10.6 

42 % 
38 % 
48 % 

34 % 
25 % 
34 % 

33 % 
20 % 
34 % 

Genotype 1  ≤ 600,000 
IU/mL  

All 
≤ 10.6 
> 10.6 

73 % 
74 % 
71 % 

51 % 
25 % 
52 % 

45 % 
33 % 
45 % 

 Genotype 1 > 600,000 
IU/mL  

All 
≤ 10.6 
> 10.6 

30 % 
27 % 
37 % 

27 % 
25 % 
27 % 

29 % 
17 % 
29 % 



19 

Genotype 2/3  All 
≤ 10.6 
> 10.6 

82 % 
79 % 
88 % 

80 % 
73 % 
80 % 

79 % 
50 % 
80 % 

P1.5/R   Ribavirin (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)  
P0.5/R   Ribavirin (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)  
I/R   Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU) 
 
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 8. 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 ribavirin (800 mg/day) plus 
peginterferon alfa-2b (1.5 µg/kg/week) or ribavirin (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 ribavirin (800-1,200 mg/day based on 
weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or ribavirin (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 8 Sustained virological response based on genotype after ribavirin in combination 

with peginterferon alfa-2b in HCV/HIV co-infected patients  
 

 Study 11  Study 22   
 

Ribavirin 
(800 mg/day) 
+ 
peginterferon 
alfa-2b (1.5 
µg /kg/ week) 

Ribavirin 
(800 mg/day) + 
interferon alfa-
2b (3 MIU 
TIW) p 

valuea  

Ribavirin 
(800-
1,200 mg/day) 
d + 
peginterferon 
alfa-2b (100 
or 150c 
µg/week) 

Ribavirin 
(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: Ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.  
1
Carrat 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 
ribavirin in combination with peginterferon alfa-2b. This decline was significant among responders 
(-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) 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.   



20 

 
Retreatment of relapse patients with Ribavirin and interferon alfa-2b combination treatment  
Two trials examined the use of ribavirin 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 ribavirin 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.  
 
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 nonpegylated interferon alfa-2b (with or without ribavirin) and pegylated interferon alfa-
2b (with or without ribavirin), 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 nonpegylated interferon alfa-2b (with or without ribavirin), and is 99 % (95 % 
CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without ribavirin). 
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated, with or 
without ribavirin) 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 
Ribavirin 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 ribavirin 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 
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 ribavirin 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 9.  
 
Table 9.  Sustained virological response in previously untreated children and 

adolescents  
 Ribavirin 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  



21 

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 
Ribavirin 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.  
 
Ribavirin 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 ribavirin 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 
 
Absorption 
Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax=1.5 hours), 
followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, 
distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with 
approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability 
is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear 
relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume of 
distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.  
 
Distribution 
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and 
has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of 
transporter is present on virtually all cell types and may account for the high volume of distribution of 
ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess 
of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.  
 
Biotransformation 
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative 
pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. 
Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted 
renally.  



22 

 
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.  
 
Older people (≥ 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  
Ribavirin in combination with interferon alfa-2b 
Multiple-dose pharmacokinetic properties for ribavirin and interferon alfa-2b in children and 
adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The 



23 

pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) is similar in adults and children 
or adolescents.  
 
Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and 
ribavirin when administered to paediatric patients with chronic hepatitis C  

Parameter Ribavirin 
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 Ribavirin; AUC0-24 (IU.hr/mL) for interferon alfa-2b  
 
5.3 Preclinical safety data 
 
Ribavirin 
Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in 
all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, 
limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects 
increased with escalation of the dose. Survival of foetuses and offspring was reduced.  
 
In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of 
ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested 
as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery 
period, tibial and femoral changes were minimal although generally statistically significant compared 
to controls in males at all dose levels and in females dosed with the two highest doses compared to 
controls. No histopathological effects on bone were observed. No ribavirin effects were observed 
regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups 
were below human plasma concentrations at the therapeutic dose.  
 
Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly 
after initiation of dosing, but is rapidly reversible upon cessation of treatment.  
In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, 
abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce 
systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of 
treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or 
two spermatogenic cycles (see section 4.6).  
 
Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin 
was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the 
mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant 
lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted 
through male gametes.  
 
Conventional carcinogenicity rodent studies with low exposures compared to human exposure under 
therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In 
addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin 
did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor 
approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential 
of ribavirin in humans is unlikely.  
 
Ribavirin plus interferon 



24 

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 
 
Tablet core 
Calcium hydrogen phosphate anhydrous 
Croscarmellose sodium 
Povidone 
Magnesium stearate 
 
Tablet coating 
Polyvinyl alcohol – partly hydrolysed 
Macrogol / Polyethylene glycol 3350 
Titanium dioxide (E171) 
Talc 
Iron oxide red 
Iron oxide yellow 
Iron oxide black 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Ribavirin Teva Pharma B.V. tablets are packaged in aluminium blisters consisting of polyvinyl 
chloride (PVC)/polyethylene (PE)/polyvinyl Acetate (PVAc) 
 
Packs of 14, 28, 42, 56, 84, 112, 140 and 168 tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 



25 

2031GA Haarlem 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/527/001 - 14 tablets 
EU/1/09/527/002 - 28 tablets 
EU/1/09/527/003 - 42 tablets 
EU/1/09/527/004 - 56 tablets 
EU/1/09/527/005 - 84 tablets 
EU/1/09/527/006 - 112 tablets 
EU/1/09/527/007 - 140 tablets 
EU/1/09/527/008 - 168 tablets 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation : 01 July 2009 
 
Date of latest renewal : 16 January 2014  
 
 
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/. 

http://www.emea.europa.eu/�


26 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 400 mg film coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each Ribavirin Teva Pharma B.V. tablet contains 400 mg of ribavirin 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Light pink to pink, (debossed with “R” on one side and “400” on the other). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ribavirin Teva Pharma B.V. is indicated for the treatment of chronic hepatitis C virus (HCV) infection 
in adults, children 3-years of age or older and adolescents and must only be used as part of a 
combination regimen with interferon alfa-2b. Ribavirin monotherapy must not be used.  
 
There is no safety or efficacy information on the use of ribavirin with other forms of interferon (i.e. 
not alfa-2b). 
 
Naïve patients  
 Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, 

for the treatment of adult patients with all types of chronic hepatitis C except genotype 1 , not 
previously treated, without liver decompensation, with elevated alanine aminotransferase 
(ALT), who are positive for hepatitis C viral ribonucleic acid HCV-RNA (see section 4.4).  

 
Paediatric patients (children 3 years of age and older  and adolescents: Ribavirin Teva Pharma B.V. 
is indicated, in a combination regimen with interferon alfa-2b, for the treatment of children and 
adolescents 3 years of age and older, who have all types of chronic hepatitis C except genotype 1, not 
previously treated, without liver decompensation, and who are positive for serum HCV-RNA.  
When deciding not to defer treatment until adulthood, it is important to consider that the 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 basis (see section 4.4). 
 
Previous treatment failure patients  
 Adult patients: Ribavirin Teva Pharma B.V. is indicated, in combination with interferon alfa-2b, 

for the treatment of adult patients with chronic hepatitis C who have previously responded (with 
normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have 
subsequently relapsed.(see section 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  
 



27 

Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. for prescribing information particular to that 
product and for further dosage recommendations on co-administration with Ribavirin Teva Pharma 
B.V.. 
 
Ribavirin Teva Pharma B.V. tablets are to be administered orally each day in two divided doses 
(morning and evening) with food. 
 
Adults:  
The recommended dose and duration of Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V.. 
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. 
 
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 tablets, ribavirin oral solution is 
available and should be used if appropriate. 
 
Dosing of ribavirin 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 is shown in Table 1. 
Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin as 
some combination regimens do not adhere to the ribavirin dosing guidance provided in Table 1. 
 
Table 1  Ribavirin Teva Pharma B.V. dose based on body weight when used in combination 
with interferon alfa-2b in paediatric patients 

Patient weight (kg) Daily ribavirin dose Number of 200 mg tablets* 
47-49 600 mg 3 x 200 mg tabletsa 
50-65 800 mg 4 x 200 mg tabletsb 
> 65 Refer to adult dose recommendation 

a: 1 morning, 2 evening 
b: 2 morning, 2 evening 
 
Ribavirin Teva Pharma B.V. 400 mg Tablets 
*Nb: for 800 mg daily dose, 2 x 200 mg tablets can be substituted for 1 x 400 mg tablet. 
 
Dose modification for adverse reactions 
 
Dose modification for adults 
Dose reduction of ribavirin depends on the initial ribavirin posology which depends on the medicinal 
product that is used in combination with ribavirin. 
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin 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. 
 



28 

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

if: 
Discontinue 
ribavirin 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, ribavirin dose should be 
reduced to 600 mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets in 
the evening). If the abnormality is reversed, ribavirin 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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. is by an additional 200 mg/day. Patients whose dose of 
Ribavirin Teva Pharma B.V. is reduced to 600 mg daily receive one 200 mg tablet in the morning and 
two 200 mg tablets in the evening. 
 
In case of serious adverse reaction potentially related to medicinal products used in combination with 
ribavirin, refer to the corresponding SmPC of these medicinal products as some combination regimens 
do not adhere to the ribavirin 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 ribavirin 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 ribavirin. 
However, as in younger patients, renal function must be determined prior to administration of ribavirin 
(see section 5.2). 
 
Paediatric patients (children 3 years of age and older and adolescents) 
Ribavirin may be used in combination with interferon alfa-2b (see section 4.4). The selection of 
ribavirin 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. 



29 

Please refer to the corresponding SmPC of medicinal products used in combination with ribavirin for 
further dosage recommendations on co-administration. 
 
Renal impairment  
The pharmacokinetics of ribavirin 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 ribavirin. 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 ribavirin 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 Ribavirin 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 ribavirin 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 ribavirin. 
 
Method of administration 
Ribavirin Teva Pharma B.V. tablets 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, Ribavirin Teva 

Pharma B.V. 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 Ribavirin 
Teva Pharma B.V. for contraindications specific to these products. 
 
4.4 Special warnings and precautions for use 
 
Ribavirin 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 ribavirin 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 



30 

- 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 ribavirin in combination with peginterferon alfa-2b or 
interferon alfa-2b in clinical trials. Although ribavirin has no direct cardiovascular effects, anaemia 
associated with ribavirin may result in deterioration of cardiac function, or exacerbation of the 
symptoms of coronary disease, or both. Thus, ribavirin 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 ribavirin the physician must comprehensively inform both male 
and female patients of the teratogenic risk of ribavirin, 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 ribavirin (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, Ribavirin Teva Pharma B.V. 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 
Ribavirin Teva Pharma B.V. for discontinuation or dose modification recommendations. 
 
Renal impairment 
The pharmacokinetics of ribavirin 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 ribavirin. Due to substantial increases in ribavirin plasma 
concentrations in patients with moderate and severe renal impairment, ribavirin 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 



31 

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 
weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This 
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and 
concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 
4.5). 
 
HCV/HIV Co-infection  
Mitochondrial toxicity and lactic acidosis: Caution should be taken in HIV-positive subjects co-
infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially 
ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive population 
receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity 
and lactic acidosis when ribavirin is administered. 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 ribavirin 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 ribavirin and zidovudine are at increased risk of developing anaemia; therefore, 
the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5). 
 
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 ribavirin.  
 
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 ribavirin 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). 
 



32 

Uric acid may increase with ribavirin due to haemolysis; therefore, the potential for development of 
gout must be carefully monitored in pre-disposed patients. 
 
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 ribavirin. Ribavirin does not inhibit cytochrome 
P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes. 
Therefore, there is a minimal potential for P450 enzyme-based interactions.  
 
Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere 
with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine 
monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with 
azathioprine. The use of pegylated alpha interferons and ribavirin concomitantly with azathioprine 
should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with 
azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done 
during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with 
these medicines should be stopped (see section 4.4). 
 
No interaction studies have been conducted with ribavirin and other medicinal products, except for 
peginterferon alfa-2b, interferon alfa-2b and antacids.  
 
No pharmacokinetic interactions were noted between ribavirin and peginterferon alfa-2b or interferon 
alfa-2b in a multiple-dose pharmacokinetic study.  
 
Antacid 
The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing 
magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased 
bioavailability in this study was due to delayed transit of ribavirin or modified pH. This interaction is 
not considered to be clinically relevant.  
 
Nucleoside analogues 
Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic 
acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in 
vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs 
(e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. 
Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, 
have been reported (see section 4.4).  
The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen 
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of 
ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 
4.4).Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment 
(ART) regimen if this is already established. This would be particularly important in patients with  a 
known history of zidovudine induced anaemia. 
 
Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after 
cessation of ribavirin therapy due to the long half-life (see section 5.2).  
 
There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or 
protease inhibitors.  
 
Conflicting findings are reported in literature on co-administration between abacavir and ribavirin. 
Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 



33 

risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised 
when both medicines are co-administered. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception in males and females 
 
Female patients 
Ribavirin Teva Pharma B.V. must not be used by females who are pregnant (see sections 4.3, 4.4 and 
5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Ribavirin 
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 (see section 4.4). If pregnancy does occur during treatment or 
within four months from stopping treatment, the patient must be advised of the significant teratogenic 
risk of ribavirin to the foetus (see section 4.4).  
 
Male patients and their female partners 
Extreme care must be taken to avoid pregnancy in partners of male patients taking Ribavirin Teva 
Pharma B.V. (see sections 4.3, 4.4 and 5.3). Ribavirin accumulates intracellularly and is cleared from 
the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its 
potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on 
approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not 
shown an increased risk of malformation compared to the general population, nor any specific pattern 
of malformation, either male patients or their female partners of childbearing age must be advised to 
use an effective contraceptive during treatment with ribavirin 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 ribavirin to the partner.  
 
Pregnancy 
The use of Ribavirin Teva Pharma B.V. is contraindicated during pregnancy. Ribavirin 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 ribavirin is excreted in human milk. Because of the potential for adverse 
reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.  
 
Fertility 
Preclinical data:  
- Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section 

5.3).  
- Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for 

ribavirin in all animal species in which adequate studies have been conducted, occurring at 
doses as low as one twentieth of the recommended human dose (see section 5.3).  

- Genotoxicity: Ribavirin induces genotoxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Ribavirin Teva Pharma B.V. 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 
 



34 

Summary of the safety profile 
The salient safety issue of ribavirin is haemolytic anaemia occurring within the first weeks of therapy. 
The haemolytic anaemia associated with ribavirin 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 ribavirin 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 
ribavirin for additional undesirable effects reported with these products. 
 
Adults 
The safety of ribavirin is evaluated from data from four clinical trials in patients with no previous 
exposure to interferon (interferon-naïve patients): two trials studied ribavirin in combination with 
interferon alfa-2b, two trials studied ribavirin in combination with peginterferon alfa-2b.  
 
Patients who are treated with interferon alfa-2b and ribavirin 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 ribavirin) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b 
and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferon 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 ribavirin 

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 



35 

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* 

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* 



36 

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, gastroesophageal 
reflux*, glossitis, cheilitis, abdominal distension, gingival 
bleeding, gingivitis, loose stools, tooth disorder,  
constipation, flatulence 

Uncommon:  Pancreatitis, oral pain 
Rare: Ischaemic colitis 
Very rare: Ulcerative colitis* 
Not Known: Periodontal disorder, dental disorder, tongue pigmentation 
Hepatobiliary disorders 
Common: Hepatomegaly, jaundice, hyperbilirubinemia* 
Very rare: Hepatotoxicity (including fatalities)* 
Skin and subcutaneous tissue disorders 
Very common: Alopecia, pruritus, skin dry, rash 
Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity 

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

Rare:  Cutaneous sarcoidosis 
Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, 

erythema multiforme* 
Musculoskeletal and  
connective tissue disorders 
Very common: Arthralgia, myalgia, musculoskeletal pain 
Common: Arthritis, back pain, muscle spasms, pain in extremity 
Uncommon: Bone pain, muscle weakness 
Rare: Rhabdomyolysis*, myositis* 
Renal and urinary disorders 
Common: Micturition frequency, polyuria, urine abnormality 
Rare: Renal failure*, renal insufficiency* 
Very rare: Nephrotic syndrome* 
Reproductive system and breast disorders 
Common: Female: amenorrhea, menorrhagia, menstrual disorder, 

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

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

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

feeling abnormal, thirst 



37 

Uncommon: Face oedema 
Investigations 
Very common: Weight decrease 
Common: Cardiac murmur 
* Since ribavirin 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 ribavirin in combination with interferon alfa-2b (pegylated or nonpegylated). 
 
Description of selected adverse reactions 
A reduction in haemoglobin concentrations by > 4 g/dL was observed in 30 % of patients treated with 
ribavirin and peginterferon alfa-2b and 37 % of patients treated with ribavirin 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 ribavirin 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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. 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 ribavirin 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 %).   
 
Mitochondrial toxicity 
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI 
regimen and associated-ribavirin 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 ribavirin in combination with peginterferon alfa-
2b when compared to patients receiving ribavirin 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 ribavirin in combination with peginterferon alfa-2b. Anaemia a (haemoglobin < 9.4 
g/dL) was reported in 12 % (23/194) of patients treated with ribavirin in combination with 
peginterferon alfa-2b. 
 
CD4 lymphocytes decrease 
Treatment with ribavirin 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 



38 

ribavirin 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 Summary of Product Characteristics 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 Ribavirin Teva 
Pharma B.V 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 ribavirin, 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 ribavirin, growth inhibition was observed that resulted 
in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very 
common during the treatment (at the end of treatment, mean decrease from baseline in weight and in 
height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was 
inhibited (< 3rd percentile in 70 % of the patients). 
 
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height 
percentiles were still 3 percentiles and 7 percentiles, respectively, and 20% of the children continued 
to have inhibited growth (growth velocity < 3rd percentile). Ninety four of 107 children enrolled in the 
5 year long-term follow up trial. The effects on growth were less in those children treated for 24 weeks 
than those treated for 48 weeks. From pre-treatment to end of long-term follow up among children 
treated for 24 or 48 weeks, height for age percentiles decreased 1.3 and 9.0 percentiles, respectively. 
Twenty four percent of children (11/46) treated for 24 weeks and 40 % of children (19/48) treated for 
48 weeks had a > 15 percentile height for age decrease from pre-treatment to the end of 5 year long 
term follow up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) 
treated for 24 weeks and 13 % of children (6/48) treated for 48 weeks were observed to have a 
decrease from pre-treatment baseline > 30 height for age percentiles to the end of the 5 year long term 
follow-up. For weight, pre-treatment to end of long term follow up, weight for age percentiles 
decreased 1.3 and 5.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. For 
BMI, pre-treatment to end of long-term follow up, BMI for age percentiles decreased 1.8 and 7.5 
percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height 
percentile at year 1 of long term follow-up was most prominent in prepubertal age children. The 
decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a 
normative population did not fully recover at the end of long-term follow-up period for children 
treated with 48 weeks of therapy (see section 4.4). 
 
In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia 
(80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site 
erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction 
(thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in 
severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection 
site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). 
Important treatment-emergent adverse reactions that occurred in this patient population were 
nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and 
hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated 
TSH.  
  
In combination with interferon alfa-2b 
In clinical trials of 118 children and adolescents 3 to 16 years of age, treated with combination therapy 
of interferon alfa-2b and ribavirin, 6 % discontinued therapy due to adverse events. In general, the 



39 

adverse event 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 growth velocity 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 ribavirin, 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 events (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 ribavirin 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 6 Adverse reactions very commonly, commonly and uncommonly reported during clinical 

trials in children and adolescents with ribavirin 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 liability 



40 

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

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

Nervous system disorders 
Very common: Headache, dizziness 
Common: Hyperkinesia, tremor, dysphonia, paresthaesia, 

hypoaesthesia, hyperaesthesia, concentration impaired, 
somnolence, disturbance in attention, poor quality of sleep 

Uncommon: Neuralgia, lethargy, psychomotor hyperactivity 
Eye disorders 
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland 

disorder 
Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision 

blurred, photophobia 
Ear and labyrinth disorders 
Common: Vertigo 
Cardiac disorders 
Common: Tachycardia, palpitations 
Vascular disorders 
Common: Pallor, flushing 
Uncommon: Hypotension 
Respiratory, thoracic and mediastinal disorders 
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, 

nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal 
pain. 

Uncommon: Wheezing, nasal discomfort 
Gastro-intestinal disorders 
Very common: Abdominal pain, abdominal pain upper, vomiting , 

diarrhoea, nausea 
Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous 

stomatitis, dyspepsia, cheilosis, glossitis, gastroesophageal 
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, 

hyperhidrosis, eczema, 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 



41 

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 ribavirin/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 ribavirin 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. 
 
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 ribavirin used in combination with peginterferon alfa-2b or interferon alfa-2b, the 
maximum overdose reported was a total dose of 10 g of ribavirin (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, nucleosides and nucleotides excl.reverse 
transcriptase inhibitors, ATC code: J05AB04.  
 
Mechanism of action 
Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and 
DNA viruses. The mechanism by which ribavirin in combination with other medicinal products exerts 
its effects against HCV is unknown. Oral formulations of ribavirin monotherapy have been 
investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations 
showed that ribavirin 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.  
 

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


42 

Clinical efficacy and safety 
The use of ribavirin in combination treatment with 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 ribavirin + interferon alfa-2b 
(C95-132 and I95-143) and one with ribavirin + 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 ribavirin to interferon alfa-2b (41 % vs 16 %, 
p < 0.001).  
 
In clinical trials C95-132 and I95-143, ribavirin + 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.  
 
In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following 
combination regimens:  
 Ribavirin (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).  
 Ribavirin (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). 
 Ribavirin (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).  
 
In this trial, the combination of ribavirin and peginterferon alfa-2b (1.5 micrograms/kg/week) was 
significantly more effective than the combination of ribavirin 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 ribavirin 
administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that 
received > 10.6 mg/kg ribavirin (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 
ribavirin (Table 7), while response rates in patients that received > 13.2 mg/kg ribavirin were even 
higher.  
 
Table 7  Sustained response rates with ribavirin + peginterferon alfa-2b  
  (by ribavirin dose [mg/kg], genotype and viral load)  
HCV Genotype  Ribavirin dose 

(mg/kg) 
P 1.5/R P 0.5/R I/R 

All Genotypes  All 
≤ 10.6 
> 10.6 

54 % 
50 % 
61 % 

47 % 
41 % 
48 % 

47 % 
27 % 
47 % 

Genotype 1  All 
≤ 10.6 
> 10.6 

42 % 
38 % 
48 % 

34 % 
25 % 
34 % 

33 % 
20 % 
34 % 

Genotype 1  ≤ 600,000 
IU/mL  

All 
≤ 10.6 
> 10.6 

73 % 
74 % 
71 % 

51 % 
25 % 
52 % 

45 % 
33 % 
45 % 

 Genotype 1 > 600,000 
IU/mL  

All 
≤ 10.6 
> 10.6 

30 % 
27 % 
37 % 

27 % 
25 % 
27 % 

29 % 
17 % 
29 % 



43 

Genotype 2/3  All 
≤ 10.6 
> 10.6 

82 % 
79 % 
88 % 

80 % 
73 % 
80 % 

79 % 
50 % 
80 % 

P1.5/R   Ribavirin (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)  
P0.5/R   Ribavirin (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)  
I/R   Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU) 
 
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 8. 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 ribavirin (800 mg/day) plus 
peginterferon alfa-2b (1.5 µg/kg/week) or ribavirin (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 ribavirin (800-1,200 mg/day based on 
weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or ribavirin (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 8 Sustained virological response based on genotype after ribavirin in combination 

with peginterferon alfa-2b in HCV/HIV co-infected patients  
 

 Study 11  Study 22   
 

Ribavirin 
(800 mg/day) 
+ 
peginterferon 
alfa-2b (1.5 
µg /kg/ week) 

Ribavirin 
(800 mg/day) + 
interferon alfa-
2b (3 MIU 
TIW) p 

valuea  

Ribavirin 
(800-
1,200 mg/day) 
d + 
peginterferon 
alfa-2b (100 
or 150c 
µg/week) 

Ribavirin 
(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: Ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.  
1
Carrat 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 
ribavirin in combination with peginterferon alfa-2b. This decline was significant among responders (-
0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) 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. 



44 

 
Retreatment of relapse patients with Ribavirin and interferon alfa-2b combination treatment 
Two trials examined the use of ribavirin 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 ribavirin 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.  
 
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 nonpegylated interferon alfa-2b (with or without ribavirin) and pegylated interferon alfa-
2b (with or without ribavirin), 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 nonpegylated interferon alfa-2b (with or without ribavirin), and is 99 % (95 % 
CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without ribavirin). 
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated, with or 
without ribavirin) 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 
Ribavirin 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 ribavirin 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 
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 ribavirin 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 9.  
 
Table 9.  Sustained virological response in previously untreated children and 
adolescents  
 Ribavirin 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  



45 

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 
Ribavirin 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.  
 
Ribavirin 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 ribavirin 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 
 
Absorption 
Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax=1.5 hours), 
followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, 
distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with 
approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability 
is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear 
relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume of 
distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.  
 
Distribution 
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and 
has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of 
transporter is present on virtually all cell types and may account for the high volume of distribution of 
ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess 
of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.  
 
Biotransformation 
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative 
pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. 
Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted 
renally.  



46 

 
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.  
 
Older people (≥ 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  
Ribavirin in combination with interferon alfa-2b 
Multiple-dose pharmacokinetic properties for ribavirin and interferon alfa-2b in children and 
adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The 



47 

pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) is similar in adults and children 
or adolescents.  
 
Table 10. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and 
ribavirin when administered to paediatric patients with chronic hepatitis C  

Parameter Ribavirin 
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 Ribavirin; AUC0-24 (IU.hr/mL) for interferon alfa-2b  
 
5.3 Preclinical safety data 
 
Ribavirin 
Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in 
all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, 
limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects 
increased with escalation of the dose. Survival of foetuses and offspring was reduced.  
 
In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of 
ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested 
as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery 
period, tibial and femoral changes were minimal although generally statistically significant compared 
to controls in males at all dose levels and in females dosed with the two highest doses compared to 
controls. No histopathological effects on bone were observed. No ribavirin effects were observed 
regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups 
were below human plasma concentrations at the therapeutic dose.  
 
Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly 
after initiation of dosing, but is rapidly reversible upon cessation of treatment.  
In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, 
abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce 
systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of 
treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or 
two spermatogenic cycles (see section 4.6).  
 
Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin 
was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the 
mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant 
lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted 
through male gametes.  
 
Conventional carcinogenicity rodent studies with low exposures compared to human exposure under 
therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In 
addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin 
did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor 
approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential 
of ribavirin in humans is unlikely.  
 
Ribavirin plus interferon 



48 

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 
 
Tablet core 
Calcium hydrogen phosphate anhydrous 
Croscarmellose sodium 
Povidone 
Magnesium stearate 
 
Tablet coating 
Polyvinyl alcohol – partly hydrolysed 
Macrogol / Polyethylene glycol 3350 
Titanium dioxide (E171) 
Talc 
Iron oxide red 
Iron oxide yellow 
Iron oxide black 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Ribavirin Teva Pharma B.V. tablets are packaged in aluminium blisters consisting of polyvinyl 
chloride (PVC)/polyethylene (PE)/polyvinyl Acetate (PVAc) 
 
Packs of 14, 28, 42, 56, 84, 112, 140 and 168 tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
Swensweg 5 



49 

2031GA Haarlem 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/527/009 - 14 tablets 
EU/1/09/527/010 - 28 tablets 
EU/1/09/527/011 - 42 tablets 
EU/1/09/527/012 - 56 tablets 
EU/1/09/527/013 - 84 tablets 
EU/1/09/527/014 - 112 tablets 
EU/1/09/527/015 - 140 tablets 
EU/1/09/527/016 - 168 tablets 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation : 01 July 2009 
 
Date of latest renewal : 16 January 2014 
 
 
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/. 

http://www.emea.europa.eu/�


50 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER  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 

 
 

 
 



51 

A. MANUFACTURERS  RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Teva Pharmaceutical Works Private Limited Company 
Pallagi Street 13 
H-4042 Debrecen 
Hungary 

Teva UK Ltd. 
Brampton Road,  
Hampden Park, Eastbourne,  
East Sussex, BN22 9AG 
United Kingdom 

Pharmachemie BV 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 
Teva Pharma SLU 
C/ C, n° 4, Polígono Industrial Malpica,  
50016 Zaragoza 
Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
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) 
 
Not applicable. 



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



53 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



54 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton for 14, 28, 42, 56, 84, 112, 140 and 168 film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 200 mg film-coated tablets 
ribavirin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of ribavirin 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
28 film-coated tablets 
42 film-coated tablets 
56 film-coated tablets 
84 film-coated tablets 
112 film-coated tablets 
140 film-coated tablets 
168 film-coated tablets 
 
 
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  
 
 



55 

9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/527/001 (14 tablets) 
EU/1/09/527/002 (28 tablets) 
EU/1/09/527/003 (42 tablets) 
EU/1/09/527/004 (56 tablets) 
EU/1/09/527/005 (84 tablets) 
EU/1/09/527/006 (112 tablets) 
EU/1/09/527/007 (140 tablets) 
EU/1/09/527/008 (168 tablets) 
 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Ribavirin Teva Pharma B.V. 200mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



56 

 
PC: 
SN: 
NN: 



57 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Immediate packaging (blister foil) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 200 mg film-coated tablets 
ribavirin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 



58 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton for 14, 28, 42, 56, 84, 112, 140 and 168 film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 400 mg film-coated tablets 
ribavirin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 400 mg of ribavirin 
 
 
3. LIST OF EXCIPIENTS 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
28 film-coated tablets 
42 film-coated tablets 
56 film-coated tablets 
84 film-coated tablets 
112 film-coated tablets 
140 film-coated tablets 
168 film-coated tablets 
 
 
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 



59 

 
 
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 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/527/009 (14 tablets) 
EU/1/09/527/010 (28 tablets) 
EU/1/09/527/011 (42 tablets) 
EU/1/09/527/012 (56 tablets) 
EU/1/09/527/013 (84 tablets) 
EU/1/09/527/014 (112 tablets) 
EU/1/09/527/015 (140 tablets) 
EU/1/09/527/016 (168 tablets) 
 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Ribavirin Teva Pharma B.V. 400mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



60 

PC: 
SN: 
NN: 



61 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Immediate packaging (blister foil) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ribavirin Teva Pharma B.V. 400 mg film-coated tablets 
ribavirin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 



62 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



63 

Package leaflet: Information for the user 
 

Ribavirin Teva Pharma B.V. 200 mg film-coated tablets 
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 illsness 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 Ribavirin Teva Pharma B.V. is and what it is used for 
2. What you need to know before you use Ribavirin Teva Pharma B.V. 
3. How to use Ribavirin Teva Pharma B.V. 
4. Possible side effects 
5. How to store Ribavirin Teva Pharma B.V. 
6. Contents of the pack and other information 
 
 
1. What Ribavirin Teva Pharma B.V. is and what it is used for 
Ribavirin Teva Pharma B.V. contains the active substance ribavirin. This medicine stops the 
multiplication of many types of viruses, including hepatitis C virus. This medicine must not be used 
without interferon alfa-2b, i.e. Ribavirin Teva Pharma B.V. must not be used alone. 
 
Previously untreated patients: 
The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat patients 3 
years of age and older who have chronic hepatitis C (HCV) infection. For paediatric patients (children 
and adolescents) weighing less than 47 kg a solution formulation is available. 
 
Previously treated adult patients: 
The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat adult patients 
with chronic hepatitis C, who have previously responded to treatment with an alpha interferon alone, 
but whose condition has recurred. 
 
There is no safety or efficacy information on the use of ribavirin with pegylated or other forms of 
interferon (i.e., not alfa-2b). 
 
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 Ribavirin Teva Pharma B.V. 
 
Do not take Ribavirin Teva Pharma B.V. 
 
Do not take Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. if 
you: 
- 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 



64 

- have any blood disorder such as anaemia (low blood count), thalassemia or sickle-cell anaemia 
 
Reminder: Please read the “Do not take” section of the Package leaflet for the other medicines used in 

combination before you begin combination treatment 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 ribavirin 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 Ribavirin Teva Pharma B.V.: 
Haemolysis: Ribavirin Teva Pharma B.V. can cause a break down in red blood cells causing anaemia 
which may impair your heart function or worsen symptoms of heart disease. 
Pancytopenia: Ribavirin Teva Pharma B.V. 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 tablets 

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 your 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. 



65 

 
Reminder: Please read the “Warnings and precautions” section of the Package Leaflet for the other 

medicines used in combination with Ribavirin Teva Pharma B.V. before you begin 
combination treatment. 

 
Use in children and adolescents 
If the child is weighing less than 47 kg or unable to swallow tablets an oral solution of ribavirin should 
be used. 
 
Other medicines and Ribavirin Teva Pharma B.V. 
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 ribavirin 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 Ribavirin Teva Pharma B.V. 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 alfa interferons 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 Ribavirin Teva Pharma B.V. 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 this medicine and for 
7 months after stopping treatment. This should be discussed with your doctor (see “Do not take 
Ribavirin Teva Pharma B.V.”). 
 



66 

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 effect your ability to drive or use machines; 
however, other medicines used in combination with Ribavirin Teva Pharma B.V. may cause 
sleepiness, tiredness or confusion. 
Do not drive or use any tools or machines if you feel tired or sleepy, or are confused. 
 
 
3. How to use Ribavirin Teva Pharma B.V. 
 
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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma 
B.V. combined with interferon alfa-2b, is shown in the below table. 
 
Ribavirin Teva Pharma B.V. 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 Ribavirin Teva 

Pharma B.V. dose 
Number of 200 mg tablets 

47 - 49 600 mg  1 tablet in the morning and 
2 tablets in the evening 

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

> 65 See adult dose  
 
Take your prescribed dose by mouth with water and during your meal. Do not chew the film-coated 
tablets. For children or adolescents who cannot swallow a film-coated tablet, an oral solution of 
ribavirin is available. 
 
Reminder: This medicine is only to be 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 Ribavirin Teva Pharma 
B.V.. 

 
If you take more Ribavirin Teva Pharma B.V. than you should 
Tell your doctor or pharmacist as soon as possible. 
 
If you forget to take Ribavirin Teva Pharma B.V. 
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. 
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 



67 

 
4. Possible side effects 
 
Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in 
combination with Ribavirin Teva Pharma B.V.. 
 
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 occuring 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 ribavirin 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 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, 



68 

 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 ribavirin 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, 



69 

 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. 
 
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, 



70 

 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), stroke (cerebrovascular events),  
 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-2b 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 receiving cART, the following other side effects have occurred with 
the combination of ribavirin 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. 
 
Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. 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 help provide more information on the safety of 
this medicine. 
 
 
5. How to store Ribavirin Teva Pharma B.V. 
 

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


71 

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 outer packaging. The expiry date 
refers to the last day of that month. 
 
This medicinal product requires no special storage conditions. 
 
Do not use this medicine if you notice any change in the appearance of the tablets. 
 
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 to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Ribavirin Teva Pharma B.V. contains 
 
The active substance is Ribavirin. Each film-coated tablet contains 200 mg of ribavirin. 
 
The other ingredients are  
 
 Tablet core; Calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, 

magnesium stearate.   
 Film coating, composed of :  polyvinyl alcohol – partly hydrolysed, macrogol / polyethylene 

glycol 3350, titanium dioxide (E171), talc, iron oxide red, iron oxide yellow, iron oxide black. 
 
What Ribavirin Teva Pharma B.V. looks like and contents of the pack 
 
Ribavirin Teva Pharma B.V. 200 mg film-coated tablets are light-pink to pink, (debossed with “93” on 
one side and “7232” on the other). 
 
Ribavirin Teva Pharma B.V. is available in different pack sizes containing 14, 28, 42, 56, 84, 112, 140 
or 168 tablets. 
 
Not all pack sizes may be marketed. 
 
Your physician will prescribe the pack size which is best for you. 
 
Marketing Authorisation Holder 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
Manufacturer 
Teva Pharmaceutical Works Private Limited Company 
Pallagi út 13 
Debrecen H-4042 
Hungary 
 
TEVA UK Ltd 
Brampton Road 
Hampden Park 
Eastbourne, East Sussex 
BN22 9AG UK 



72 

 
Pharmachemie B.V. 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 
Teva Pharma SLU 
C/ C, n° 4, Polígono Industrial Malpica,  
50016 Zaragoza 
Spain 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 
 

België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG  
Tel/Tél: +32 3 820 73 73  
 

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 
 

България  
Тева Фармасютикълс България ЕООД 
Teл: +359 2 489 95 82  
 

Luxembourg/Luxemburg  
Teva Pharma Belgium N.V./S.A./AG  
Belgien/ Belgique 
Tél/Tel: +32 3 820 73 73 
 

Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251 007 111 
 

Magyarország  
Teva Gyógyszergyár Zrt. 
Tel: (36) 1 288 6400 
 
 

Danmark  
Teva Denmark A/S  
Tlf: +45 44 98 55 11  
 

Malta  
Teva Pharmaceuticals Ireland 
Tel: +353 51 321740 
L-Irlanda 
 

Deutschland 
TEVA GmbH 
Tel: +49 731 402 08 
 

Nederland  
Teva Nederland B.V. 
Tel: +31 (0) 800 0228400  
 

Eesti 
Teva Eesti esindus UAB Sicor Biotech 
Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 (0)1 97007 0 
 

España 
Teva Pharma, S.L.U 
Tél: +(34) 91 387 32 80   
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +(48) 22 345 93 00 
 

France 
Teva Santé 
Tél: +(33) 1 55 91 7800 
 

Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: +351 21 476 75 50 
 



73 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel:+ 385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +4021 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)51 321 740 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
ratiopharm Oy 
Finnland 
Sími: +358 20 180 5900 
 

Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +(421) 2 5726 7911 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 
 

Κύπρος 
Teva Ελλάς Α.Ε. 
Ελλάδα 
Τηλ: +30 210 72 79 099 
 

Sverige 
Teva Sweden AB 
Tel: +(46) 42 12 11 00 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā  
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977628500 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Other sources of information 
 
Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

http://www.ema.europa.eu/�


74 

Package leaflet: Information for the user 
 

Ribavirin Teva Pharma B.V. 400 mg film-coated tablets 
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 illsness 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 Ribavirin Teva Pharma B.V. is and what it is used for 
2. What you need to know before you use Ribavirin Teva Pharma B.V. 
3. How to use Ribavirin Teva Pharma B.V. 
4. Possible side effects 
5. How to store Ribavirin Teva Pharma B.V. 
6. Contents of the pack and other information 
 
 
1. What Ribavirin Teva Pharma B.V. is and what it is used for 
Ribavirin Teva Pharma B.V. contains the active substance ribavirin. This medicine stops the 
multiplication of many types of viruses, including hepatitis C virus. This medicine must not be used 
without interferon alfa-2b, i.e. Ribavirin Teva Pharma B.V. must not be used alone. 
 
Previously untreated patients: 
The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat patients 3 
years of age and older who have chronic hepatitis C (HCV) infection. For paediatric patients (children 
and adolescents) weighing less than 47 kg a solution formulation is available. 
 
Previously treated adult patients: 
The combination of Ribavirin Teva Pharma B.V. with interferon alfa-2b is used to treat adult patients 
with chronic hepatitis C, who have previously responded to treatment with an alpha interferon alone, 
but whose condition has recurred. 
 
There is no safety or efficacy information on the use of ribavirin with pegylated or other forms of 
interferon (i.e., not alfa-2b). 
 
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 Ribavirin Teva Pharma B.V. 
 
Do not take Ribavirin Teva Pharma B.V. 
 
Do not take Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma B.V. if 
you: 
- 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 



75 

- have any blood disorder, such as anaemia (low blood count), thalassemia or sickle-cell 
anaemia 

 
Reminder: Please read the “Do not take” section of the Package leaflet for the other medicines used in 

combination before you begin combination treatment 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 ribavirin 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 Ribavirin Teva Pharma B.V.: 
Haemolysis: Ribavirin Teva Pharma B.V. can cause a break down in red blood cells causing anaemia 
which may impair your heart function or worsen symptoms of heart disease. 
Pancytopenia: Ribavirin Teva Pharma B.V. 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 tablets 

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 your 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. 
 



76 

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 Ribavirin Teva Pharma B.V. before you begin 
combination treatment. 

 
Use in children and adolescents 
If the child is weighing less than 47 kg or unable to swallow tablets an oral solution of ribavirin should 
be used. 
 
Other medicines and Ribavirin Teva Pharma B.V. 
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 ribavirin 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 Ribavirin Teva Pharma B.V. 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 alfa interferons 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 Ribavirin Teva Pharma B.V. 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 this medicine and for 



77 

7 months after stopping treatment. This should be discussed with your doctor (see “Do not take 
Ribavirin Teva Pharma B.V.”). 
 
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 effect your ability to drive or use machines;  
However, other medicines used in combination with Ribavirin Teva Pharma B.V. may cause 
sleepiness, tiredness or confusion. 
Do not drive or use any tools or machines if you feel tired or sleepy, or are confused. 
 
 
3. How to use Ribavirin Teva Pharma B.V. 
 
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 Ribavirin Teva Pharma B.V. 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 Ribavirin Teva Pharma 
B.V. combined with interferon alfa-2b, is shown in the below table.  
 
Ribavirin Teva Pharma B.V. 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 Ribavirin Teva 

Pharma B.V. dose 
Number of 200 mg tablets 

47 - 49 600 mg  1 tablet in the morning and 
2 tablets in the evening 

50 - 65 800 mg 2 tablets in the morning and 
2 tablets in the evening or 1 (400 
mg) tablet in the morning and 1 
(400 mg) tablet in the evening 

> 65 See adult dose  
 
Take your prescribed dose by mouth with water and during your meal. Do not chew the film-coated 
tablets. For children or adolescents who cannot swallow a film-coated tablet, an oral solution of 
ribavirin is available. 
 
Reminder: This medicine is only to be 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 Ribavirin Teva Pharma 
B.V.. 

 
If you take more Ribavirin Teva Pharma B.V. than you should 
Tell your doctor or pharmacist as soon as possible. 
 
If you forget to take Ribavirin Teva Pharma B.V. 



78 

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. 
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Please read the “Possible side effects” section of the Package Leaflet for the other medicines used in 
combination with Ribavirin Teva Pharma B.V.. 
 
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 occuring 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 ribavirin 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 taste, 



79 

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 ribavirin 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), 



80 

 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. 
 
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, 



81 

 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), stroke (cerebrovascular events),  
 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-2b 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 receiving cART, the following other side effects have occurred with 
the combination of ribavirin 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. 
 
Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. 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 help provide more information on the safety of 
this medicine.  
 
 

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


82 

5. How to store Ribavirin Teva Pharma B.V. 
 
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 outer packaging. The expiry date 
refers to the last day of that month. 
 
This medicinal product requires no special storage conditions. 
 
Do not use this medicine if you notice any change in the appearance of the tablets. 
 
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 to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Ribavirin Teva Pharma B.V. contains 
 
The active substance is Ribavirin. Each film-coated tablet contains 400 mg of ribavirin. 
 
The other ingredients are  
 
 Tablet core; Calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, 

magnesium stearate.   
 Film coating, composed of :  polyvinyl alcohol – partly hydrolysed, macrogol / polyethylene 

glycol 3350, titanium dioxide (E171), talc, iron oxide red, iron oxide yellow, iron oxide black. 
 
What Ribavirin Teva Pharma B.V. looks like and contents of the pack 
 
Ribavirin Teva Pharma B.V. 400 mg film-coated tablets are light-pink to pink, (debossed with “R” on 
one side and “400” on the other). 
 
Ribavirin Teva Pharma B.V. is available in different pack sizes containing 14, 28, 42, 56, 84, 112, 140 
or 168 tablets. 
 
Not all pack sizes may be marketed. 
 
Your physician will prescribe the pack size which is best for you. 
 
Marketing Authorisation Holder 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
 
Manufacturer 
Teva Pharmaceutical Works Private Limited Company 
Pallagi út 13 
Debrecen H-4042 
Hungary 
 
TEVA UK Ltd 
Brampton Road 



83 

Hampden Park 
Eastbourne, East Sussex 
BN22 9AG UK 
 
Pharmachemie B.V. 
Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 
Teva Pharma SLU 
C/ C, n° 4, Polígono Industrial Malpica,  
50016 Zaragoza 
Spain 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 
 

België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG  
Tel/Tél: +32 3 820 73 73  
 

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 
 

България  
Тева Фармасютикълс България ЕООД 
Teл: +359 2 489 95 82  
 

Luxembourg/Luxemburg  
Teva Pharma Belgium N.V./S.A./AG  
Belgien/ Belgique 
Tél/Tel: +32 3 820 73 73 
 

Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251 007 111 
 

Magyarország  
Teva Gyógyszergyár Zrt. 
Tel: (36) 1 288 6400 
 
 

Danmark  
Teva Denmark A/S  
Tlf: +45 44 98 55 11  
 

Malta  
Teva Pharmaceuticals Ireland 
Tel: +353 51 321740 
L-Irlanda 
 

Deutschland 
TEVA GmbH 
Tel: +49 731 402 08 
 

Nederland  
Teva Nederland B.V. 
Tel: +31 (0) 800 0228400  
 

Eesti 
Teva Eesti esindus UAB Sicor Biotech 
Eesti filiaal 
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 (0)1 97007 0 
 

España 
Teva Pharma, S.L.U 
Tél: +(34) 91 387 32 80   
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +(48) 22 345 93 00 
 



84 

France 
Teva Santé 
Tél: +(33) 1 55 91 7800 
 

Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: +351 21 476 75 50 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel:+ 385 1 37 20 000 
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +4021 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)51 321 740 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
ratiopharm Oy 
Finnland 
Sími: +358 20 180 5900 
 

Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +(421) 2 5726 7911 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 20 180 5900 
 

Κύπρος 
Teva Ελλάς Α.Ε. 
Ελλάδα 
Τηλ: +30 210 72 79 099 
 

Sverige 
Teva Sweden AB 
Tel: +(46) 42 12 11 00 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā  
Tel: +371 673 23 666 
 

United Kingdom 
Teva UK Limited 
Tel: +44 1977628500 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Other sources of information 
 
Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 

http://www.ema.europa.eu/�

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS  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