Ribavirin Mylan

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Ribavirin Mylan 200 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 200 mg of ribavirin.  

 

Excipient with known effect: each hard capsule contains 15 mg of lactose monohydrate. 

 

For the full list of excipients, see section 6.1.  

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

White opaque body imprinted "riba/200" in green and a white opaque cap imprinted "riba/200" in 

green. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Ribavirin Mylan is indicated for the treatment of chronic hepatitis C (CHC) and must only be used as 

part of a combination regimen with interferon alfa-2b (adults, children (3 years of age and older) and 

adolescents).  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). 

 

Please refer also to the interferon alfa-2b Summary of Product Characteristics (SmPC) for prescribing 

information particular to that product. 

 

Naïve patients 

Adult Patients (18 years of age or older): Ribavirin Mylan 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 serum HCV-RNA (see section 4.4).  

 

Paediatric patients (children 3 years of age and older and adolescents): Ribavirin Mylan 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 can induce 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). 

 

Previously treatment failure patients 

Adult patients: Ribavirin Mylan 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). 

 



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4.2 Posology and method of administration 
 

Treatment should be initiated, and monitored, by a physician experienced in the management of 

chronic hepatitis C.  

 

Ribavirin Mylan must be used in combination with interferon alfa-2b. 

 

Please refer also to the interferon alfa-2b Summary of Product Characteristics (SmPC) for prescribing 

information particular to that product. 

 

Posology 

 

Ribavirin Mylan 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 for additional prescribing information particular to that product and 

for further dosage recommendations on co-administration with ribavirin.  

 

Ribavirin capsules are to be administered orally each day in two divided doses (morning and evening) 

with food.  

 

Adults 

The recommended dose and duration of ribavirin 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.  

 

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. 

 

Ribavirin Mylan must be used in combination with interferon alfa-2b (3 million international units 

[MIU] three times a week). 

 

The regimen administered should be selected based on the anticipated efficacy and safety of the 

combination treatment for an individual patient (see section 5.1).  

 

Ribavirin in combination with interferon alfa-2b: 

 

Based on the results of clinical trials, it is recommended that patients be treated for at least six months.  

During those clinical trials in which patients were treated for one year, patients who failed to show a 

virological response after six months of treatment (HCV-RNA below lower limit of detection) were 

unlikely to become sustained virological responders (HCV-RNA below lower limit of detection six 

months after withdrawal of treatment). 

 

Duration of treatment – Naïve patients  

 

• Genotypes Non-1: The decision to extend therapy to one year in patients with negative HCV-
RNA after six months of treatment should be based on other prognostic factors (e.g., age >40 

years, male gender, bridging fibrosis). 

 

Duration of treatment – Retreatment 

 

• Genotype 1: Treatment should be continued for another six month period (i.e., a total of one year) 
in patients who exhibit negative HCV-RNA after six months of treatment. 

 

• Genotypes Non-1: The decision to extend therapy to one year in patients with negative HCVRNA 
after six months of treatment should be based on other prognostic factors (e.g., age > 40 years, 

male gender, bridging fibrosis). 

 



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Paediatric population  

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

 

Note: For patients who weigh < 47 kg, or are unable to swallow capsules, 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 or peginterferon 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.  

 

 

In clinical studies performed in this population ribavirin and interferon alfa-2b were used in doses of 

15 mg/kg/day and 3 million international units (MIU)/m2 three times a week respectively (Table 1).   

 

Table 1 Ribavirin Mylan dose based on body weight when used in combination with interferon 

alfa-2b or peginterferon alfa-2b in paediatric patients 

Patient weight (kg) Daily Ribavirin dose Number of 200 mg capsules 

47 - 49 600 mg 3 capsules a 

50 - 65 800 mg 4 capsules b 

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

 

Duration of treatment in children and adolescents 

 

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

  

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 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 Mylan 

dose* 

 if: 

Reduce only interferon 

alfa-2b dose (see note 2) 

if:  

Discontinue Ribavirin 

Mylan 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 capsule in the morning and two 200 mg capsules 

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 Mylan 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 

Mylan is by an additional 200 mg/day. Patients whose dose of Ribavirin Mylan is reduced to 600 mg 

daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.  

In children and adolescent patients treated with Ribavirin Mylan plus interferon alfa-2b, reduce 

Ribavirin Mylan dose to 7.5 mg/kg/day. 

Note 2: In adult patients and children and adolescent patients treated with Ribavirin Mylan plus 

interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose. 

 

In case of serious adverse reaction potentially related to medicinal products used in combination with 

Ribavirin Mylan, 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 Mylan 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 

 



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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 Mylan (see section 5.2).  

 

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

Ribavirin Mylan may be used in combination with peginterferon alfa-2b or interferon alfa-2b (see 

section 4.4).   

The selection of formulation is based on individual characteristics of the patient. 

The safety and efficacy of ribavirin used together with direct-acting-anti-virals in these patients has 

not been established. No data are available. 

Please refer to the corresponding SmPC of medicinal products used in combination with 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 Mylan. 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 Mylan 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.  If serum creatinine rises to > 2 mg/dl 

(Table 2) Ribavirin Mylan and interferon alfa-2b must be discontinued. 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 Mylan 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 Mylan. 

 

Paediatric population (patients under the age of 18 years):  Ribavirin Mylan may be used in 

combination with interferon alfa-2b in children (3 years of age and older) and adolescents.  The 

selection of formulation is based on individual characteristics of the patient (see section 4.1).  Safety 

and effectiveness of Ribavirin Mylan with pegylated or other forms of interferon (i.e. not alfa-2b) in 

these patients have not been evaluated. 

    

Patients co-infected with HCV/HIV: Patients taking NRTI treatment in association with ribavirin and 

interferon alfa-2b may be at increased risk of mitochondrial toxicity, lactic acidosis and hepatic 

decompensation (see section 4.4).  Please refer also to the relevant product information for 

antiretroviral medicinal products. 

Method of administration  

 

Ribavirin Mylan 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. 



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- Pregnancy (see sections 4.4, 4.6 and 5.3).  In females of childbearing potential, Ribavirin Mylan 

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).  

Initiation of peginterferon alfa-2b is contraindicated in HCV/HIV patients with cirrhosis and a Child-

Pugh score ≥ 6. 

 

Children and adolescents: 

Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation, or suicide attempt.  

 

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

- Autoimmune hepatitis; or history of autoimmune disease. 
 

4.4 Special warnings and precautions for use 

 

Psychiatric and Central Nervous System (CNS):  

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 

observed in some patients during Ribavirin combination therapy with peginterferon alfa-2b or 

interferon alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up 

period. Among children and adolescents, treated with Ribavirin in combination with interferon alfa-

2b, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4% 

versus 1%) during treatment and during the 6-month follow-up after treatment. As in adult patients, 

children and adolescents experienced other psychiatric adverse reactions (e.g., depression, emotional 

lability, and somnolence).  Other CNS effects including aggressive behaviour (sometimes directed 

against others such as homicidal ideation), bipolar disorder, mania, confusion and alterations of mental 

status have been observed with alpha interferons.  Patients should be closely monitored for any signs 

or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these 

undesirable effects must be borne in mind by the prescribing physician and the need for adequate 

therapeutic management should be considered.  If psychiatric symptoms persist or worsen, or suicidal 

ideation is identified, it is recommended that treatment with Ribavirin and peginterferon alfa-2b or 

interferon alfa-2b be discontinued, and the patient followed, with psychiatric intervention as 

appropriate.  

 

Patients with existence of, or history of severe psychiatric conditions:  If treatment with Ribavirin in 

combination with peginterferon alfa-2b or interferon alfa-2b is judged necessary in adult patients with 

existence or history of severe psychiatric conditions, this should only be initiated after having ensured 

appropriate individualised diagnostic and therapeutic management of the psychiatric condition.   

- The use of Ribavirin and interferon alfa-2b or peginterferon alfa-2b in children and adolescents with 

existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). 

 

Patients with substance use/abuse: 

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 

increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric 

disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in 

these patients, the presence of psychiatric co-morbidities and the potential for other substance use 

should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-

disciplinary approach including a mental health care provider or addiction specialist should be 

considered to evaluate, treat and follow the patient. Patients should be closely monitored during 

therapy and even after treatment discontinuation. Early intervention for re-emergence or development 

of psychiatric disorders and substance use is recommended. 

 

Paediatric population: Growth and development: 



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During the course of interferon (standard and pegylated)/ribavirin therapy lasting up to 48 weeks in 

patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data 

available in children treated with the combination therapy of pegylated interferon/ribavirin are 

indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated > 15 

percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 

and 5.1).  

The longer term data available in children treated with the combination therapy with standard 

interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in 

height percentile as compared to baseline) in 21 % (n=20) of children despite being off treatment for 

more than 5 years. Final adult height was available for 14 of those children and show that 12 

continued to have height deficits > 15 percentiles, 10 to 12 years after the end of treatment. 

 

Case by case benefit/risk assessment in children: 

The expected benefit of treatment should be carefully weighed against the safety findings observed for 

children and adolescents in the clinical trials (see sections 4.8 and 5.1). 

−  It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced height in some patients. 

−  This risk should be weighed against the disease characteristics of the child, such as evidence of 

disease progression (notably fibrosis), co-morbidities that may negatively influence the disease 

progression (such as HIV-co-infection), as well as prognostic factors of response (HCV 

genotype and viral load). 

 

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 

risk of growth inhibition. Although data are limited, no evidence of long-term effects on sexual 

maturation was noted in the 5 year observational follow-up study. 

 

Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Ribavirin 

must not be used alone.  The safety and efficacy of this combination have been established only using 

ribavirin capsules together with peginterferon alfa-2b or interferon alfa-2b solution for injection.  

 

All patients in selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain 

cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological 

confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed 

prior to commencing treatment. 

 

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 Mylan 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 



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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 Mylan must be discontinued immediately and appropriate medical therapy 

instituted. Transient rashes do not necessitate interruption of treatment.  

 

Ocular changes: Ribavirin is used in combination therapy with alpha interferons. Retinopathy 

including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery or 

vein occlusion which may result in loss of vision have been reported in rare instances with 

combination therapy with alpha interferons.  All patients should have a baseline eye examination.  

Any patient complaining of decrease or loss of vision must have a prompt and complete eye 

examination. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive 

retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha 

interferons. Combination therapy with alpha interferons should be discontinued in patients who 

develop new or worsening ophthalmologic disorders.  

 

Liver function 

Any patient developing significant liver function abnormalities during treatment must be monitored 

closely. Discontinue treatment in patients who develop prolongation of coagulation markers which 

might indicate liver decompensation. Please refer to the corresponding SmPC of medicinal products 

used in combination with ribavirin 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 Mylan dose 

adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are 

available regarding dose modification for paediatric patients with renal impairment (see sections 4.2 

and 5.2). Haemoglobin concentrations should be monitored closely during treatment and corrective 

action taken as necessary (see section 4.2). 

 

Potential to exacerbate immunosuppression 

Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 

weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This 

myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and 

concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 

4.5). 

 

Thyroid supplemental monitoring specific for children and adolescents: Approximately 12% to 21% of 

children treated with Ribavirin and interferon alfa-2b (pegylated and non-pegylated) developed 

increase in thyroid stimulating hormone (TSH). Another approximately 4% had a transient decrease 

below the lower limit of normal. Prior to initiation of interferon alfa-2b therapy, TSH levels must be 

evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy.  

Interferon alfa-2b (pegylated and non-pegylated) therapy may be initiated if TSH levels can be 

maintained in the normal range by medication. Thyroid dysfunction during treatment with Ribavirin 

and interferon alfa-2b and during treatment with Ribavirin and peginterferon alfa-2b has been 

observed. If thyroid abnormalities are detected, the patient's thyroid status should be evaluated and 

treated as clinically appropriate. Children and adolescents should be monitored every 3 months for 

evidence of thyroid dysfunction (e.g. TSH).  

  



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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. Adding treatment with alfa interferons alone 

or in combination with ribavirin may increase the risk in this patient subset. 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 and peginterferon alfa-2b.  

 

Dental and periodontal disorders: Dental and periodontal disorders, which may lead to loss of teeth, 

have been reported in patients receiving Ribavirin and peginterferon alfa-2b or interferon alfa-2b 

combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous 

membranes of the mouth during long-term treatment with the combination of Ribavirin and 

peginterferon alfa-2b or interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and 

have regular dental examinations. In addition some patients may experience vomiting. If this reaction 

occurs, they should be advised to rinse out their mouth thoroughly afterwards.  

 

Laboratory tests 

Standard 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 Mylan therapy:  

 

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

  

  

 



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Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as 

clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).  

 

Uric acid may increase with Ribavirin Mylan due to haemolysis; therefore, the potential for 

development of gout must be carefully monitored in pre-disposed patients.  

 

Information on excipients 

Each Ribavirin Mylan hard capsule contains 15 mg of lactose monohydrate.  Patients with rare 

hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose 

malabsorption should not take this medicine. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Interaction studies have only been performed in adults. 

 

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.  

 

Interferon alfa-2b: 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 Mylan 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 Mylan therapy due to the long half-life (see section 5.2).  



12 

 

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 

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 Mylan must not be used by females who are pregnant (see sections 4.3 and 5.3). Extreme 

care must be taken to avoid pregnancy in female patients (see section 5.3). Ribavirin Mylan therapy 

must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to 

initiation of therapy. Females of childbearing potential must use an effective contraceptive during 

treatment and for four months after treatment has been concluded; routine monthly pregnancy tests 

must be performed during this time. If pregnancy does occur during treatment or within four months 

from stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to 

the foetus (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 Mylan 

(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 Mylan 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 Mylan 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 Mylan has no or negligible influence on the ability to drive and use machines; however, 

peginterferon alfa-2b or interferon alfa-2b used in combination may have an effect.  Thus, patients 



13 

who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or 

operating machinery. 

 

4.8 Undesirable effects 
 

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  

 

Bitherapy with peginterferon alfa-2b or interferon alfa-2b 

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 capsules in combination 

with interferon alfa-2b, two trials studied ribavirin capsules 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 SmPCs for adverse reactions that may be attributable to interferons 

monotherapy. Within the organ system classes, adverse reactions are listed under headings of 

frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); 

uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known. 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.  

 
Table 5 Adverse reactions reported during clinical trials or following the marketing use of 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 



14 

Very rare: Aplastic anaemia* 

Not known: Pure red cell aplasia, idiopathic thrombocytopenic purpura, 

thrombotic thrombocytopenic purpura 

Immune system disorders 

Uncommon: Drug hypersensitivity 

Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated) 

Not known: Vogt-Koyanagi-Harada syndrome, systemic lupus 

erythematosus, vasculitis, acute hypersensitivity reactions 

including urticaria, angioedema, bronchoconstriction, 

anaphylaxis 

Endocrine disorders 

Common: Hypothyroidism, hyperthyroidism 

Metabolism and nutrition disorders 

Very common: Anorexia 

Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, 

increased appetite 

Uncommon: Diabetes mellitus, hypertriglyceridemia* 

Psychiatric disorders 

Very common: Depression, anxiety, emotional lability, insomnia 

Common: Suicidal ideation, psychosis, aggressive behaviour, confusion, 

agitation, anger, mood altered, abnormal behaviour, 

nervousness, sleep disorder, decreased libido, apathy, abnormal 

dreams, crying 

Uncommon: Suicide attempts, panic attack, hallucination 

Rare: Bipolar disorder* 

Very rare: Suicide* 

Not known: Homicidal ideation*, mania*, mental status change 

Nervous system disorders 

Very common: Headache, dizziness, dry mouth, concentration impaired 

Common: Amnesia, memory impairment, syncope, migraine, ataxia, 

paraesthaesia, dysphonia, taste loss, hypoaesthesia, 

hyperaesthesia, hypertonia, somnolence, disturbance in 

attention, tremor, dysgeusia 

Uncommon: Neuropathy, peripheral neuropathy 

Rare: Seizure (convulsion)* 

Very rare: Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, 

encephalopathy*, polyneuropathy* 

Not known: 

 

Facial palsy, mononeuropathies 

Eye disorders 

Common: Visual disturbance, blurred vision, conjunctivitis, eye irritation, 

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

Rare: Retinal haemorrhages*, retinopathies (including macular 

oedema)*, retinal artery occlusion*, retinal vein occlusion*, 

optic neuritis*, papilloedema*, loss of visual acuity or visual 

field*, retinal exudates 

Ear and labyrinth disorders 

Common: Vertigo, hearing impaired/loss, tinnitus, ear pain 

Cardiac disorders 

Common: Palpitation, tachycardia 

Uncommon: Myocardial infarction 

Rare: Cardiomyopathy, arrhythmia* 

Very rare: Cardiac ischaemia* 

Not known: Pericardial effusion*, pericarditis* 

Vascular disorders 

Common: Hypotension, hypertension, flushing 

Rare: Vasculitis 

Very rare: Peripheral ischaemia* 

Respiratory, thoracic and mediastinal disorders 

Very common: Dyspnoea, coughing 



15 

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* 

Gastrointestinal disorders 

Very common: Diarrhoea, vomiting, nausea, abdominal pain 

Common: Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, 

upper right quadrant pain, dyspepsia, gastroesophoageal 

reflux*, glossitis, cheilitis, abdominal distension, gingival 

bleeding, gingivitis, loose stools, tooth disorder, constipation, 

flatulence 

Uncommon: Pancreatitis, oral pain 

Rare: Ischaemic colitis 

Very rare: Ulcerative colitis* 

Not Known: Periodontal disorder, dental disorder, tongue pigmentation 

Hepatobiliary disorders 

Common: Hepatomegaly, jaundice, hyperbilirubinemia* 

Very rare: Hepatotoxicity (including fatalities)* 

Skin and subcutaneous tissue disorders 

Very common: Alopecia, pruritus, skin dry, rash 

Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity 

reaction, maculopapular rash, erythematous rash, night sweats, 

hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, 

skin disorder, bruise, sweating increased, abnormal hair texture, 

nail disorder* 

Rare: Cutaneous sarcoidosis 

Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, 

erythema multiforme* 

Musculoskeletal and connective tissue disorders 

Very common: Arthralgia, myalgia, musculoskeletal pain 

Common: Arthritis, back pain, muscle spasms, pain in extremity 

Uncommon: Bone pain, muscle weakness 

Rare: Rhabdomyolysis*, myositis* 

Renal and urinary disorders 

Common: Micturition frequency, polyuria, urine abnormality 

Rare: Renal failure, renal insufficiency* 

Very rare: Nephrotic syndrome* 

Reproductive system and breast disorders 

Common: Female: amenorrhea, menorrhagia, menstrual disorder, 

dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. 

Male: impotence, prostatitis, erectile dysfunction. Sexual 

dysfunction (not specified)* 

General disorders and administration site conditions 

Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia, 

irritability 

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

feeling abnormal, thirst 

Uncommon: Face oedema 

  

Investigations 

Very common: Weight decrease 

Common: Cardiac murmur 

*  Since 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 non-pegylated).  

 

Description of selected adverse reactions 

 



16 

A reduction in haemoglobin concentrations by > 4g/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 capsules 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 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 capsules in combination with peginterferon alfa-2b.  Anaemia 

(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 

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 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 in combination with peginterferon alfa-2b. 

  

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 % 



17 

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 reactions.  In general, the 

adverse reaction profile in the limited children and adolescent population studied was similar to that 

observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as 

decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean 

percentile decrease of 13 percentile) were observed during treatment Within the 5 years follow-up 

post-treatment period, the children had a mean height of 44th percentile, which was below the median 

of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) 

of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a 

> 30 percentile decrease in their height percentile from the start of treatment to the end of long-term 

follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated 

that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. 

During combination therapy for up to 48 weeks with interferon alfa-2b and ribavirin, growth inhibition 

was observed that resulted in reduced final adult height in some patients. In particular, decrease in 



18 

mean height percentile from baseline to the end of the long-term follow-up was most prominent in 

prepubertal age children (see section 4.4). 

 

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 

(2.4% vs 1%) during treatment and during the 6 month follow-up after treatment.  As in adult patients, 

children and adolescents also experienced other psychiatric adverse reactions (e.g., depression, 

emotional lability, and somnolence) (see section 4.4).  In addition, injection site disorders, pyrexia, 

anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 

compared to adult patients.  Dose modifications were required in 30% of patients, most commonly for 

anaemia and neutropenia. 

 

Tabulated list of adverse reactions in paediatric population  

 

Reported adverse reactions listed in Table 6 are based on experience from the two multicentre 

children and adolescents clinical trials using 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 lability 

Common: Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, 

agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep 

disorder, abnormal dreaming, apathy 

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

Nervous system disorders 

Very common: Headache, dizziness 



19 

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 

Gastrointestinal disorders 

Very common: Abdominal pain, abdominal pain upper, vomiting, diarrhoea, nausea  

Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, 

cheilosis, glossitis, gastroesophoageal reflux, rectal disorder, gastrointestinal 

disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, 

oral pain 

Uncommon: Gingivitis 

Hepatobiliary disorders 

Common: Hepatic function abnormal 

Uncommon: Hepatomegaly 

Skin and subcutaneous tissue disorders 

Very common: Alopecia, rash 

Common: Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, 

acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise  

Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation 

Musculoskeletal and connective tissue disorders 

Very common: Arthralgia, myalgia, musculoskeletal pain 

Common: Pain in extremity, back pain, muscle contracture 

Renal and urinary disorders 

Common: Enuresis, micturition disorder, urinary incontinence, proteinuria 

Reproductive system and breast disorders 

Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: 

testicular pain 

Uncommon: Female: dysmenorrhoea 

General disorders and administration site conditions 

Very common: Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability 

Common: Chest pain, oedema, pain, feeling cold 

Uncommon: Chest discomfort, facial pain 

Investigations 

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

Common: Blood thyroid stimulating hormone increased, thyroglobulin increased 

Uncommon: Anti-thyroid antibody positive 



20 

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 (Ribavirin Mylan) 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 

peginterferon alfa-2b or interferon alfa-2b 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.  

 

Clinical efficacy and safety 

 

Ribavirin in combination with Direct Antiviral Agent (DAA): 

Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with such 

combination. 

Only the description of the use of ribavirin from the original development with (peg)interferon alfa-2b 

is detailed in the current SmPC. 
Bitherapy with peginterferon alfa-2b or interferon alfa-2b: 

The use of ribavirin in combination treatment with peginterferon alfa-2b or interferon alfa-2b was 

evaluated in a number of clinical trials.  Eligible patients for these trials had chronic hepatitis C 

confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver 

biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic 

hepatitis, and abnormal serum ALT.  

 

Naïve patients 

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


21 

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 capsules 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, 

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

2b monotherapy.  

 

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following 

combination regimens:  

• 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 54 % 47 % 47 % 

≤ 10.6 50 % 41 % 27 % 

> 10.6 61 % 48 % 47 % 

Genotype 1 All 42 % 34 % 33 % 

≤ 10.6 38 % 25 % 20 % 

> 10.6 48 % 34 % 34 % 

Genotype 1  

≤ 600,000 IU/ml 

All 73 % 51 % 45 % 

≤ 10.6 74 % 25 % 33 % 

> 10.6 71 % 52 % 45 % 

Genotype 1 

> 600,000 IU/ml 

All 30 % 27 % 29 % 

≤ 10.6 27 % 25 % 17 % 

> 10.6 37 % 27 % 29 % 

Genotype 2/3 All 82 % 80 % 79 % 

≤ 10.6 79 % 73 % 50 % 

> 10.6 88 % 80 % 80 % 

P1.5/R  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)  

 

In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b, 1.5 microgram/kg 

subcutaneously, once weekly, in combination with ribavirin 800 mg-1,400 mg p.o. for 6 months 



22 

(based on body weight, only three patients weighing >105 kg, received the 1,400 mg dose) (Table 8). 

Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).  

 

Table 8 Virologic Response at End of Treatment, Sustained Virologic Response and Relapse by 

HCV Genotype and Viral Load* 

  

  

Ribavirin 800-1,400 mg/day plus peginterferon alfa-2b 1.5 μg/kg once 

weekly 

End of treatment 

response 

Sustained virologic response Relapse 

All Subjects 94% (211/224) 81% (182/224) 12% (27/224) 

HCV 2 100% (42/42) 93% (39/42) 7% (3/42) 

≤ 600,000 IU/ml 100% (20/20) 95% (19/20) 5% (1/20) 

> 600,000 IU/mL 100% (22/22) 91% (20/22) 9% (2/22) 

HCV 3 93% (169/182) 79% (143/182) 14% (24/166) 

≤ 600,000 IU/ml 93% (92/99) 86% (85/99) 8% (7/91) 

> 600,000 IU/ml 93% (77/83) 70% (58/83) 23% (17/75) 

*  Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 

24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window 

was considered to be a non-responder at week 24 of follow-up.  

 

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the 

pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.  

 

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received 

peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight 

adjusted ribavirin.  The overall sustained response rate after a 24-week treatment duration was 50%.  

Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and 

week 24 of therapy.   In this subgroup, there was a 92% (89/97) sustained virological response rate.  

The high sustained response rate in this subgroup of patients was identified in an interim analysis 

(n=49) and prospectively confirmed (n=48).  

Limited historical data indicate that treatment for 48 weeks might be associated with a higher 

sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 

24 weeks of treatment).  

 

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two 

peginterferon alfa-2b/ ribavirin regimens [peginterferon alfa-2b 1.5 µg/kg and 1 µg/kg subcutaneously 

once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and 

peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily 

(in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response 

to the treatment was measured by Sustained Virologic Response (SVR) which is defined as 

undetectable HCV-RNA at 24 weeks post-treatment (see Table 9). 

 

Table 9  Virologic response at treatment week 12, end of treatment response, relapse rate* and 

Sustained Virologic Response (SVR) 

 

Treatment group % (number) of patients 

 

peginterferon alfa-2b 

1.5 µg/kg  

+ Ribavirin  

peginterferon alfa-2b  

1 µg/kg  

+ Ribavirin 

peginterferon alfa-2a 

180 µg 

+ Ribavirin  

Undetectable HCV-RNA 

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

End of treatment 

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

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



23 

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

SVR in patients with 

undetectable HCV-RNA 

at treatment week 12 

81 (328/407) 83 (303/366) 74 (344/466) 

 *HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml 

Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from 

baseline) was a criterion for discontinuation of treatment. 

 

In all three treatment groups, sustained virologic response rates were similar. In patients of African 

American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with 

peginterferon alfa-2b (1.5 µg/kg)/ ribavirin combination therapy resulted in a higher sustained 

virologic response rate compared to peginterferon alfa-2b 1 µg/kg dose. At the peginterferon alfa-2b 

1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, 

in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml and in 

patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to 

the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the 

relapse rate was 24 %.  
 

Predictability of sustained virological response in naïve patients 

Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels 

of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or 

undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have 

been shown to be predictive for sustained response (Table 10).  

  



24 

Table 10 Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b 1.5 µg/kg/ 

Ribavirin 800-1,400 mg Combination Therapy 

 Negative Positive 

No 

response at 

Treatment 

Week 

No 

sustained 

Response 

Predictive 

Value 

Response 

at 

Treatment 

Week 

Sustained 

Response 

Predictive 

Value 

Genotype 1* 

By Week 4*** 

(n= 950) 

      

HCV-RNA negative 834 539 65% 

(539/834) 

116 107 92% 

(107/116) 

HCV-RNA negative 

or 

≥ 1 log decrease in 

viral load 

220 210 95% 

(210/220) 

730 392 54% 

(392/730) 

By Week 12*** 

(n= 915) 

      

HCV-RNA negative 508 433 85% 

(433/508) 

407 328 81% 

(328/407) 

HCV-RNA negative 

or 

≥ 2 log decrease in 

viral load 

206 205 N/A† 

 

709 402 57% 

(402/709) 

Genotype 2, 3** 

By Week 12 

(n=215) 

      

HCV-RNA negative  

or  

≥ 2 log decrease in 

viral load  

2 1 50% 

(1/2) 

213 177 83% 

(177/213) 

*Genotype 1 receive 48 weeks treatment 

**Genotype 2, 3 receive 24 weeks treatment 

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 

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

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

and if positive, patients to stop therapy. 

. 

 

HCV/HIV Co-infected patients 

Two trials have been conducted in patients co-infected with HIV and HCV.  The response to treatment 

in both of these trials is presented in Table 11.  Study 1 (RIBAVIC; P01017) was a randomized, 

multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who 

were co-infected with HIV.  Patients were randomized to receive either 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.  

 



25 

Table 11 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/da

y)d + 

peginterferon 

alfa-2b (100 or 

150cµg/week) 

Ribavirin 

(800-1,200 mg/da

y)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 800mg 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. 

 

Previously treated patients  

- Retreatment of prior treatment failures (relapse and non-responder patients) with peginterferon alfa-

2b in combination with ribavirin: 

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous 

treatment with combination alpha interferon/ribavirin were retreated with peginterferon alfa-2b, 1.5 

microgram/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin.  Failure to 

prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 

12 weeks of treatment).  

 

Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks and 

were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-

RNA after 12 weeks of treatment.  Sustained Virologic Response (SVR) is defined as undetectable 

HCV-RNA at 24 weeks post-treatment (Table 12).  

 

Table 12  Rates of Response to retreatment in prior treatment failures 

 

 Patients with undetectable HCV-RNA at treatment week 12 and SVR 

upon retreatment 

Overall 

Population* 

 interferon alpha/ribavirin peginterferon alpha/ribavirin 

 Response week 

12 % (n/N) 

SVR% (n/N) 

99% CI 

Response week 

12 % (n/N) 

SVR% (n/N) 

99% CI 

SVR% (n/N) 

99% CI 

Overall 38.6(549/1,423) 59.4 (326/549) 

54.0, 64.8 

31.5(272/863) 50.4 (137/272) 

42.6, 58.2 

21.7 

(497/2,293) 

19.5, 23.9 



26 

Prior Response      

Relapse 67.7 (203/300) 59.6 (121/203) 

50.7, 68.5 

58.1 (200/344) 

 

52.5 (105/200) 

43.4, 61.6 

37.7 (243/645) 

32.8, 42.6 

Genotype 1/4 

 

59.7 (129/216) 51.2 (66/129) 

39.8, 62.5 

48.6 (122/251) 

 

44.3 (54/122) 

32.7, 55.8 

28.6 (134/468) 

23.3, 34.0 

Genotype 2/3 88.9 (72/81) 73.6 (53/72) 

(60.2, 87.0) 

83.7 (77/92) 

 

64.9 (50/77) 

50.9, 78.9 

61.3 (106/173) 

51.7, 70.8 

NR 28.6 (258/903) 57.0 (147/258) 

49.0, 64.9 

12.4 (59/476) 

 

44.1 (26/59) 

27.4, 60.7 

13.6 

(188/1,385) 

11.2, 15.9 

Genotype 1/4 

 

23.0 (182/790) 51.6 (94/182) 

42.1, 61.2 

9.9 (44/446) 

 

38.6 (17/44) 

19.7, 57.5 

9.9 (123/1,242) 

7.7, 12.1 

Genotype 2/3 67.9 (74/109) 70.3 (52/74) 

56.6, 84.0 

53.6 (15/28) 

 

60.0 (9/15) 

27.4, 92.6 

46.0 (63/137) 

35.0, 57.0 

Genotype      

1 30.2 (343/1,135)  51.3 (176/343) 

44.4, 58.3 

23.0 (162/704) 42.6 (69/162) 

32.6, 52.6 

 

14.6 

(270/1,846) 

12.5, 16.7 

2/3 77.1 (185/240)  

  

73.0 (135/185) 

64.6, 81.4 

75.6 (96/127) 63.5 (61/96) 

50.9, 76.2 

 

55.3 (203/367) 

48.6, 62.0 

 

4 42.5 (17/40) 70.6 (12/17) 

42.1, 99.1 

44.4 (12/27) 50.0 (6/12) 

12.8, 87.2 

28.4 (19/67) 

14.2, 42.5 

METAVIR 

Fibrosis Score 

     

F2 46.0 (193/420)  66.8 (129/193) 

58.1, 75.6 

33.6 (78/232) 57.7 (45/78) 

43.3, 72.1 

29.2 (191/653) 

24.7, 33.8 

F3 38.0 (163/429)  62.6 (102/163) 

52.8, 72.3 

32.4 (78/241) 51.3 (40/78) 

36.7, 65.9 

 

21.9 (147/672) 

17.8, 26.0 

 

F4 33.6 (192/572)  49.5 (95/192) 

40.2, 58.8 

29.7 (116/390) 44.8 (52/116) 

32.9, 56.7 

16.5 (159/966) 

13.4, 19.5 

Baseline Viral 

Load 

     

HVL 

(>600,000 

IU/ml) 

32.4 (280/864) 56.1 (157/280) 

48.4, 63.7 

26.5 (152/573) 41.4 (63/152) 

31.2, 51.7 

16.6 

(239/1,441) 

14.1, 19.1 

LVL 

(≤600,000 

IU/ml) 

48.3 (269/557) 62.8 (169/269) 

55.2, 70.4 

41.0 (118/288) 61.0 (72/118) 

49.5, 72.6 

 

30.2 (256/848) 

26.1, 34.2 

 

NR: Non-responder- defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.  

Plasma HCV -RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory  

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

 

Overall, approximately 36% (821/2,286) of patients had undetectable plasma HCV-RNA levels at 

week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml).  In this 

subgroup, there was a 56 % (463/823) sustained virological response rate.  For patients with prior 

failure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12, the 

sustained response rates were 59 % and 50 %, respectively.  Among 480 patients with > 2 log viral 

reduction but detectable virus at week 12, altogether 188 patients continued therapy.  In those patients 

the SVR was 12 %.  

 

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a 

week 12 response to retreatment than non-responders to non-pegylated interferon alpha/ribavirin 

(12.4% vs. 28.6%).  However, if a week 12 response was achieved, there was little difference in SVR 

regardless of prior treatment or prior response. 

 

- Retreatment of relapse patients with 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 



27 

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 non-pegylated 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 non-pegylated 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 non-pegylated, 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 peginterferon alfa-2b 

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-

RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus pegylated 

interferon alfa-2b 60 µg/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral 

load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % 

< 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis 

C. Due to the lack of data in children with severe progression of the disease, and the potential for 

undesirable effects, the benefit/risk of the combination of ribavirin and pegylated interferon alfa-2b 

needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are 

summarized in Table 13. 

 

Table 13 Sustained virological response rates (na,b (%)) in previously untreated children and 

adolescents by genotype and treatment duration – All subjects 

n = 107 

 24 weeks 48 weeks 

All Genotypes 26/27 (96 %) 44/80 (55 %) 

Genotype 1 - 38/72 (53 %) 

Genotype 2 14/15 (93 %) - 

Genotype 3c 12/12 (100 %) 2/3 (67 %) 

Genotype 4 - 4/5 (80 %) 

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

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

c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while 

those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment. 

 

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 



28 

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 14.  

 

Table 14 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 

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 

 



29 

Absorption 

Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), 

followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, 

distribution and elimination are 0.05, 3.73 and 79 hours, respectively).  Absorption is extensive with 

approximately 10% of a radiolabelled dose excreted in the faeces.   However, absolute bioavailability 

is approximately 45%-65%, which appears to be due to first pass metabolism.  There is a linear 

relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin.  Volume of 

distribution is approximately 5,000 l.  Ribavirin does not bind to plasma proteins.  

 

Distribution 

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and 

has been identified to be primarily via an es-type equilibrative nucleoside transporter.  This type of 

transporter is present on virtually all cell types and may account for the high volume of distribution of 

ribavirin.  The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess 

of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.  

 

Biotransformation 

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative 

pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite.  

Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted 

renally.  

 

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability 

following single oral doses (intrasubject variability of approximately 30% for both AUC and Cmax), 

which may be due to extensive first pass metabolism and transfer within and beyond the blood 

compartment.  

 

Elimination 

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-

dose to single-dose AUC12hr.  Following oral dosing with 600 mg BID, steady-state was reached by 

approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml.  

Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects 

slow elimination from non-plasma compartments.  

 

Transfer into seminal fluid 

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 

approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 

partner after sexual intercourse with a treated patient has been estimated and remains extremely 

limited compared to therapeutic plasma concentration of ribavirin. 

 

Food effect 

The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat 

meal (AUCtf and Cmax both increased by 70%).  It is possible that the increased bioavailability in this 

study was due to delayed transit of ribavirin or modified pH.  The clinical relevance of results from 

this single dose study is unknown.  In the pivotal clinical efficacy trial, patients were instructed to take 

ribavirin with food to achieve the maximal plasma concentration of ribavirin.  

 

Renal function 

Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUCtf and 

Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance 

>90 ml/minute).  The mean AUCtf was threefold greater in subjects with creatinine clearance between 

10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 

and 50 mL/min, AUCtf was twofold greater compared with control subjects. This appears to be due to 

reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged 

by haemodialysis.    

 

Hepatic function 



30 

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.  

 

Elderly patients (≥ 65 years of age) 

Specific pharmacokinetic evaluations for elderly subjects have not been performed.  However, in a 

population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function 

is the determining factor.  

 

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration 

values from four controlled clinical trials.  The clearance model developed showed that body weight, 

gender, age, and serum creatinine were the main covariates.  For males, clearance was approximately 

20 % higher than for females.  Clearance increased as a function of body weight and was reduced at 

ages greater than 40 years.  Effects of these covariates on ribavirin clearance appear to be of limited 

clinical significance due to the substantial residual variability not accounted for by the model.  

 

Paediatric population  

Ribavirin in combination with peginterferon alfa-2b 

Multiple-dose pharmacokinetic properties for ribavirin and peginterferon alfa-2b in children and 

adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children 

and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 

60 µg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted 

to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 µg/kg/week. The 

pharmacokinetics of ribavirin (dose-normalized) in this trial was similar to those reported in a prior 

study of ribavirin in combination with interferon alfa-2b in children and adolescent patients and in 

adult patients. 

 

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 15. The 

pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) is similar in adults and children 

or adolescents. 

 

Table 15  Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and 

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 



31 

controls.  No histopathological effects on bone were observed.  No ribavirin effects were observed 

regarding neurobehavioural or reproductive development.  Plasma concentrations achieved in rat pups 

were below human plasma concentrations at the therapeutic dose.  

 

Erythrocytes are a primary target of toxicity for ribavirin in animal studies.  Anaemia occurs shortly 

after initiation of dosing, but is rapidly reversible upon cessation of treatment.  

 

In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, 

abnormalities in sperm, occurred at doses of 15 mg/kg and above.  These doses in animals produce 

systemic exposures well below those achieved in humans at therapeutic doses.  Upon cessation of 

treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or 

two spermatogenic cycles (see section 4.6).  

 

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity.  Ribavirin 

was active in the Balb/3T3 in vitro Transformation Assay.  Genotoxic activity was observed in the 

mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay.  A dominant 

lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted 

through male gametes.  

 

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under 

therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin.  In 

addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin 

did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor 

approximately 2.5 compared to human exposure).  These studies suggest that a carcinogenic potential 

of ribavirin in humans is unlikely.  

 

Ribavirin plus interferon 

When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any 

effects not previously seen with either active substance alone.  The major treatment-related change 

was a reversible mild to moderate anaemia, the severity of which was greater than that produced by 

either active substance alone. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule contents: 

 Microcrystalline cellulose  

 Lactose monohydrate 

 Croscarmellose sodium  

 Povidone 

Capsule shell:  

 Gelatine 

 Titanium dioxide (E171) 

Capsule imprint: 

 Shellac 

 Propylene glycol 

 Ammonia solution, concentrated 

 Yellow iron oxide (E172) 

 Indigotine (E132) 

 Titanium dioxide (E171) 

 

6.2 Incompatibilities 

 

Not applicable. 

 



32 

6.3 Shelf life 

 

Bottles:  36 months 

Blisters:  36 months 

 

6.4 Special precautions for storage 

 

Bottles:  Do not store above 30°C. 

Blisters:  No special storage conditions. 

 

6.5 Nature and contents of container 
 

Ribavirin Mylan capsules are packaged in: 

 

High-density polyethylene (HDPE) bottle, closed with a child-resistant (CR) polypropylene (PP) 

screw cap.  

 

Pack sizes of 84, 112, 140 and 168 capsules. 

 

Blisters: 

Cardboard box containing 56 or 168 hard capsules in PVC/Aclar – Aluminium foil blisters 

 

 

Unit Dose Blisters: 

Cardboard box containing 56x1, 84x1, 112x1, 140x1, 168x1 hard capsules in PVC/Aclar – Aluminium 

foil perforated unit dose blisters 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal  

 

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

requirements.  

 

7. MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/10/634/001 

EU/1/10/634/002 

EU/1/10/634/003 

EU/1/10/634/004 

EU/1/10/634/005 

EU/1/10/634/006 

EU/1/10/634/007 

EU/1/10/634/008 

EU/1/10/634/009 

EU/1/10/634/010 

EU/1/10/634/011 

 

 



33 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 10 June 2010 

Date of latest renewal: 11 February 2015 

 

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.eu.int/
http://www.emea.eu.int/


34 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



35 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Penn Pharmaceutical Services Ltd. 

23-24 Tafarnaubach Industrial Estate 

Tredegar, Gwent NP2 3AA 

United Kingdom 

 

McDermott Laboratories Ltd t/a Gerard Laboratories 

35/36 Baldoyle Industrial Estate,  

Grange Road, Dublin 13 

Ireland 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

• Conditions or restrictions regarding supply and use imposed on the marketing 

authorisation holder 

 

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 

Pharmacovigilance system 

The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the 

Marketing Authorisation, is in place and functioning before and whilst the product is on the market. 

 

PSURs  

 

The marketing authorisation holder shall submit periodic safety update reports for this product in 

accordance with the requirements set out in the list of Union reference dates (EURD list) ) provided 

for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-

portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

 EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

Not applicable 

 

  



36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

  



37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

  



38 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

Carton 

 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Ribavirin Mylan 200 mg hard capsules 

ribavirin 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each hard capsule contains 200 mg ribavirin. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. 

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

56x1 hard capsules 

84x1 hard capsules 

112x1 hard capsules 

140x1 hard capsules 

168x1 hard capsules56 hard capsules 

84 hard capsules 

112 hard capsules 

140 hard capsules 

168 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use. 

Read the package leaflet before 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 



39 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Bottles - Do not store above 30°C. 

Blisters - No special storage conditions. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/10/634/001 

EU/1/10/634/002 

EU/1/10/634/003 

EU/1/10/634/004 

EU/1/10/634/005 

EU/1/10/634/006 

EU/1/10/634/007 

EU/1/10/634/008 

EU/1/10/634/009 

EU/1/10/634/010 

EU/1/10/634/011 

 

 

13. BATCH NUMBER 

 

Batch 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 



40 

Ribavirin Mylan hard capsules 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: {number} 

SN: {number}  

NN: {number}  

 

 

 



41 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  

 

Bottle 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Ribavirin Mylan 200 mg hard capsules 

ribavirin 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 200 mg ribavirin. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose.  

See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

84 hard capsules 

112 hard capsules 

140 hard capsules 

168 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Oral use 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30°C. 

 



42 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

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

requirements 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/10/634/001 

EU/1/10/634/002 

EU/1/10/634/003 

EU/1/10/634/004 

 

 

13. BATCH NUMBER 

 

Batch 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: {number} 

SN: {number}  

NN: {number}  

 

 

 

 



43 

MINIMUM PARTICULARS TO APPEAR ON UNIT DOSE BLISTERS 

 

PVC/Aclar® - Aluminium 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Ribavirin Mylan 200 mg hard capsules 

ribavirin 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Mylan S.A.S. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Batch 

 

 

5. OTHER 

 

 

 

  



44 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 



45 

Package leaflet: Information for the patient 

 

Ribavirin Mylan 200 mg hard capsules 

ribavirin 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness  are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet:  

1. What Ribavirin Mylan is and what it is used for 

2. What you need to know before you take Ribavirin Mylan 

3. How to take Ribavirin Mylan 

4. Possible side effects 

5. How to store Ribavirin Mylan 
6. Contents of the pack and other information 

 

 

1. What Ribavirin Mylan is and what it is used for 
 

Ribavirin Mylan contains the active substance ribavirin.  This medicine stops the multiplication of 

hepatitis C virus. Ribavirin Mylan must not be used without interferon alfa-2b, i.e. Ribavirin Mylan 

must not be used alone. 

 

Depending on the genotype of the hepatitis C virus that you have, your doctor may choose to treat you 

with a combination of  this medicine with other medicines. There may be some further treatment 

limitations if you have or have not been previously treated for chronic hepatitis C infection. Your 

doctor will recommend the best course of therapy.  

 

The combination of Ribavirin Mylan and other medicines is used to treat adult patients who have 

chronic hepatitis C (HCV). 

 

Previously untreated patients: 

The combination of Ribavirin Mylan with interferon alfa-2b is used in paedriatic patientes (children 

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 Mylan 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 Mylan 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 take Ribavirin Mylan  
 

Do not take Ribavirin Mylan 

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



46 

 

If you are not sure, talk to your doctor or pharmacist before taking Ribavirin Mylan. 

-  are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6). 

-  are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). 

-  are breast-feeding. 

-  had a serious heart problem during the past 6 months. 

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

 

 

Children and adolescents must not take combination therapy with Ribavirin Mylan and alpha 

interferon when there is existence or history of serious nervous or mental problems, such as severe 

depression, thoughts of suicide or attempted suicide. 

 

Reminder: Please read the “Do not take” section of the Package Leaflet for interferon alfa-2b before 

you begin used in combination with this medicine. 

 

Warnings and precautions  

 

Talk to your doctor or pharmacist before taking Ribavirin Mylan. 

 

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 Mylan: 

Haemolysis: Ribavirin Mylan 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 Mylan can cause a decrease in your platelet and red and white blood cell 

count when used in combination with peginterferon. 

  

Standard blood tests will be taken to check your blood, kidney and liver function. 

- Blood tests will be done regularly to help your doctor to know if this treatment is working. 

- Depending upon the results of these tests, your doctor may change/adjust the number of hard 

capsules you or the child you are caring for take, prescribe a different pack size of this medicine, 

and/or change the length of time to take this treatment. 

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

 

Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as 

difficulty in breathing, wheezing or hives) while taking this treatment.  

 



47 

 

Talk to your doctor if you or the child you are caring for: 

• are a woman of childbearing age (see section “Pregnancy and breast-feeding”). 

• are a male and your female partner is of childbearing age (see section “Pregnancy and breast-
feeding”) 

• had a previous heart condition or have heart disease. 

• have another liver problem in addition to hepatitis C infection.  

• have problems with your kidneys. 

• have HIV (human immunodeficiency virus) or have ever had any other problems with your 
immune system. 

 

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

safety issues. 

 

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

alfa-2b before you begin combination treatment. 

 

Use in children and adolescents 

If the child is weighing less than 47 kg or unable to swallow an oral solution of Ribavirin is available. 

 

Other medicines and Ribavirin Mylan 

 

Tell your doctor or pharmacist if you or the child you are caring for are taking, have recently taken or 

might take any other medicines: 

 

- azathioprine is a medicine that suppresses your immune system, using this medicine in 

combination with ribavirin and pegylated alpha interferons and, therefore 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 Mylan treatment needs to be changed. Additionally, patients receiving 

zidovudine with ribavirin in combination with alpha interferons could be at increased 

risk of developing anaemia (low number of red blood cells).  Therefore the use of 

zidovudine and ribavirin in combination with alpha interferons is not recommended. 

- Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis, 

the use of ribavirin and didanosine is not recommended and the use of ribavirin and 

stavudine should be avoided. 

- Co-infected patients with advanced liver disease receiving cART may be at increased risk 

of worsening liver function. Adding treatment with an alpha interferon alone or in 

combination with ribavirin may increase the risk in this patient subset. 

 

Reminder: Please read the “Other medicines” section of the Package Leaflet for interferon alfa-2b 

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: 



48 

 

• 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 

ribavirin and for 7 months after stopping treatment. This should be discussed with your doctor 

(see section “Do not take Ribavirin Mylan”). 

 

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

feeding before starting to take this medicine. 

 

Driving and using machines 

This medicine does not affect your ability to drive or use machines; however, interferon alfa-2b may 

affect your ability to drive or use machines. Therefore, do not drive or use machines if you become 

tired, sleepy, or confused from this treatment. 

 

Ribavirin Mylan contains lactose  

Each Ribavirin Mylan hard capsule contains a small amount of lactose.  If you have been told by your 

doctor that you have an intolerance to some sugars, discuss with your doctor before taking this 

medicine. 

 

 

3. How to take Ribavirin Mylan 
 

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 Ribavirin Mylan based on how much you or the child 

you are caring for weighs. 

Adults 

The recommended dose and duration of Ribavirin Mylan 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 Mylan combined with 

interferon alfa-2b or peginterferon alfa-2b, is shown in the below table. 

 

Ribavirin Mylan 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 

Mylan dose Number of 200 mg capsules 

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

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

> 65 See adult dose 

 

 



49 

Take your prescribed dose by mouth with water and during your meal. Do not chew the hard capsules. 

For children or adolescents who cannot swallow a hard capsule, an oral solution of ribavirin is 

available. 

 

Reminder: This medicine  is used in combination with interferon alfa-2b for hepatitis C virus 

infection. For complete information be sure to read the “How to use” section of the 

Package Leaflet for interferon alfa-2b. 

 

Interferon medicine that is used in combination with Ribavirin Mylan may cause unusual tiredness; if 

you are injecting this medicine yourself or giving it to a child, use it at bedtime. 

 

If you take more Ribavirin Mylan than you should 

Tell your doctor or pharmacist as soon as possible. 

 

If you forget to take Ribavirin Mylan  

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 questions on the use of this medicine, ask your doctor or pharmacists. 

 

 

4. Possible side effects 

 

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

combination with Ribavirin Mylan. 

 

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. 

Psychiatric and Central Nervous System: 

Some people get depressed when taking Ribavirin in combination treatment with an interferon, and in 

some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 

behaviour (sometimes directed against others). Some patients have actually committed suicide. 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. 

 

Children and adolescents are particularly prone to develop depression when being treated with 

ribavirin and interferon alpha. Immediately contact the doctor or seek emergency treatment if they 

display any unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or 

others. 

 

Growth and development (children and adolescents): 

During the one year of treatment with Ribavirin in combination with interferon alfa-2b, some children 

and adolescents did not grow or gain weight as much as expected. Some children did not reach their 

projected height within 1-12 years after completing treatment. 

 

Contact your doctor immediately if you notice any of the following side effects occurring during 

combination treatment with an alpha interferon product:  

 

- 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, 



50 

- painful or difficult urination,  
- severe bleeding from your nose,  
- fever or chills beginning after a few weeks of treatment,  
- problems with your eyesight or hearing,  
- severe skin rash or redness. 

 

The following side effects have been reported with the combination of this medicine 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,  

 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,  



51 

 inflammation of pancreas, pain in bone, diabetes mellitus, 

 muscle weakness. 
 

Rarely reported side effects (may affect up to 1 in 1,000 people): 

 seizure (convulsions), 

 pneumonia, 

 rheumatoid arthritis, kidney problems,  

 dark or bloody stools, intense abdominal pain, 

 sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, 
skin lesions and swollen glands), 

 vasculitis. 
 

Very rarely reported side effects (may affect up to 1 in 10,000 people):  

 suicide, 

 stroke (cerebrovascular events). 
 

 

Not known side effects (frequency cannot be estimated from the available data): 

 thoughts about threatening the life of others, 

 mania (excessive or unreasonable enthusiasm), 

 pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection 
that develops between the pericardium (the lining of the heart) and the heart itself, 

 change in colour of the tongue. 
 

 

Side effects in children and adolescents 

 

The following side effects have been reported with the combination of this medicine and an interferon 

alfa-2b product in children and adolescents: 

 

Very commonly reported side effects (may affect more than 1 in 10 people): 

 decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 
dizziness), decrease in neutrophils (that make you more susceptible to different infections), 

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

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

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

pharyngitis (sore throat), shaking chills, stomach pain, vomiting, 

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

 

Commonly reported side effects (may affect up to 1 in 10 people): 

 decrease in blood clotting cells called platelets (that may result in easy bruising and 
spontaneous bleeding),  

 excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in 
thyroid gland activity (which may cause nervousness, heat intolerance and excessive sweating, 

weight loss, palpitation, tremors), 

 agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, emotional 
instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, feeling of 

restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor quality 

sleep, sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to harm 

yourself, 

 bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear 
infection, eye irritation or pain or infection, change in taste, changes in your voice, cold sores, 



52 

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,  

 severe rashes which may be associated with blisters in the mouth, nose, eyes and other 
mucosal membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal 

necrolysis (blistering and peeling of the top layer of skin).  

 

The following other side effects have also been reported with the combination of this medicine and an 

alpha interferon product: 

 abnormal thoughts, hearing or seeing images that are not present, altered mental status, 
disorientation, 

 angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause 
difficulty in swallowing or breathing),  

 Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, 
skin and the membranes of the ears, brain and spinal cord), 

 bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,   

 eye problems including damage to the retina, obstruction of the retinal artery, inflammation of 
the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),  

 enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel 
movement,  



53 

 acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg 
or thigh pain, loss of range of motion, stiffness, sarcoidosis, (a disease characterised by 

persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands).  

 

 This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause:  

 dark, cloudy or abnormally coloured urine, 

 difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw 
pain,  

 loss of consciousness,  

 loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,  

 loss of vision. 
You or your caregiver should call your doctor immediately if you have any of  these side effects. 

 

If you are a HCV/HIV co-infected adult patient receiving anti-HIV treatment, the addition of this 

medicine and peginterferon alfa may increase your risk of worsening liver function (combined anti-

retroviral therapy (cART)) and increase your risk of lactic acidosis, liver failure and blood 

abnormalities development (reduction in number of red blood cells which carry oxygen, certain white 

blood cells that fight infection, and blood clotting cells called platelets) (NRTI). 

 

In HCV/HIV co-infected patients 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, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V*. By reporting side effects, you can also help provide more information 

on the safety of this medicine. 

 

 

5. How to store Ribavirin Mylan  

 

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 bottle or blister after EXP. The 

expiry date refers to the last day of that month. 

 

Do not store the bottles above 30°C. 

 

There are no special storage conditions for capsules packed in blisters. 

 

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

appearance of the hard capsules. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

6. Contents of the pack and other information 

 

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


54 

What Ribavirin Mylan contains 

 

- The active substance is ribavirin 200 mg. 
- The other ingredients are croscarmellose sodium, lactose monohydrate, microcrystalline 

cellulose, povidone. The capsule shell contains gelatine and titanium dioxide (E171). The 

capsule shell imprint contains shellac, propylene glycol, strong ammonia solution, colouring 

agents (E172, E132, E171).  

 

What Ribavirin Mylan looks like and contents of the pack 

 

The Ribavirin Mylan hard capsule is a white, opaque, hard capsule imprinted with green ink. 

 

The Ribavirin Mylan hard capsule is available in different pack sizes: 

 

High-density polyethylene (HDPE) bottle, closed with a child-resistant (CR) polypropylene (PP) 

screw cap.  Pack sizes of 84, 112, 140 and 168 capsules. 

 

Blisters: 

Cardboard box containing 56 or 168 hard capsules in PVC/Aclar – Aluminium foil blisters 

 

Unit Dose Blisters: 

Cardboard box containing 56x1, 84x1, 112x1, 140x1, 168x1 hard capsules in PVC/Aclar – Aluminium 

foil perforated unit dose blisters 

  

 

Not all pack sizes may be marketed. 

 

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

 

Marketing Authorisation Holder  

 

Mylan S.A.S. 

117 Allée des Parcs 

69800 Saint-Priest 

France 

 

Manufacturer 

 

Penn Pharmaceutical Services Ltd      

23-24 Tafarnaubach Industrial Estate,  

Tredegar,  

Gwent, NP22 3AA     

United Kingom     

 

McDermott Laboratories Ltd t/a Gerard Laboratories 

35/36 Baldoyle Industrial Estate,  

Grange Road, Dublin 13 

Ireland 

 

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

Authorisation Holder: 

 

België/Belgique/Belgien 

Mylan bvba/sprl 

Tél/Tel: + 32 (0)2 658 61 00 

 

Lietuva 

BGP Products UAB  

Tel: +370 5 205 1288 

 



55 

България 

Майлан ЕООД 

Тел: +359 2 44 55 400 

 

Luxembourg/Luxemburg 

Mylan bvba/sprl 

Tel: + 32 (0)2 658 61 00 

 (Belgique/Belgien) 

 

Česká republika 

Mylan Pharmaceuticals s.r.o. 

Tel: + 420 222 004 400 

Magyarország 

Mylan EPD Kft. 

Tel: +36 1 465 2100 

 

Danmark 

Mylan AB 

Tlf: + 46 855 522 750 

(Sverige) 

 

Malta 

V.J. Salomone Pharma Ltd 

Tel: + 356 21 22 01 74 

 

Deutschland 

Mylan dura GmbH 

Tel: + 49-(0) 6172 888 01 

 

Nederland 

Mylan BV 

Tel: +31 (0)20 426 3300 

 

Eesti 

BGP Products Switzerland GmbH Eesti filiaal  

Tel: + 372 6363 052 

 

Norge 

Mylan AB 

Tel: + 46 855 522 750 

(Sverige) 

 

Ελλάδα 

Generics Pharma Hellas ΕΠΕ 

Τηλ:  +30 210 993 6410 

Österreich 

Arcana Arzneimittel GmbH 

Tel: +43 1 416 2418 

 

España 

Mylan Pharmaceuticals, S.L. 

tel: + 34 900 102 712 

Polska 

Mylan Healthcare Sp. z.o.o. 

Tel: +48 22 546 64 00 

 

France 

Mylan S.A.S 

Tel: +33 4 37 25 75 00 

 

Portugal 

Mylan Lda. 

Tel: + 351 21 412 72 56 

Hrvatska  

Mylan Hrvatska d.o.o.   

Tel: +385 1 23 50 599 

 

România 

BGP Products  

SRLTel: +40 372 579 000 

 

Ireland 

Mylan Ireland 

Tel: +353 (0) 87 1694982 

 

Slovenija 

GSP Proizvodi d.o.o  

Tel: +386 1 236 31 85 

 

Ísland 

Mylan AB 

Tel: +46 855 522 750 

(Svíþjóð) 

 

 

Slovenská republika 

Mylan s.r.o. 

Tel: +421 2 32 199 100 

Italia 

Mylan S.p.A 

Tel: +39 02 612 46921 

Suomi/Finland 

Mylan OY 

Puh/Tel: +358 20 720 9555 

 

  

Κύπρος Sverige 



56 

Pharmaceutical Trading Co Ltd 

Τηλ: +357 99403969 

 

Mylan AB 

Tel: +46 855 522 750 

Latvija 

BGP Products SIA  

Tel: +371 676 055 80 

 

United Kingdom 

Generics [UK] Ltd 

Tel: +44 1707 853000 

 

 

This Leaflet was Last Approved In. 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

http://www.ema.europa.eu/


57 

 


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