Informations for option: Ribavirin 200 Mg Capsules Hard, show other option

Select option:

1. Ribavirin 200 Mg Capsules Hard
2. Ribavirin 200 Mg Capsules Hard

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ribavirin 200 mg capsules, hard

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of ribavirin.

Excipient with known effect: Ribavirin contains 45 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsule, hard

White/white, size ‘1’ hard gelatine capsule filled with white to off-white granular powder and imprinted with ‘E” on white cap and ‘81’ on white body with black ink.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ribavirin is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults, children 3 years of age and older and adolescents and must only be used as part of a combination regimen with interferon alfa-2b. Ribavirin monotherapy must not be used.

There is no safety or efficacy information on the use of Ribavirin with other forms of interferon (i.e., not alfa-2b).

Naive patients

Adult patients: Ribavirin is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with all types of chronic hepatitis C except genotype 1, not previously treated, without liver decompensation, with elevated alanine aminotransferase (ALT), who are positive for hepatitis C viral ribonucleic acid HCV-RNA (see section 4.4).

Children 3 years of age and older and adolescents: Ribavirin is intended for use, 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 HCV-RNA.

When deciding to not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).

Previous treatment failure patients

Adult patients: Ribavirin 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 alfa monotherapy but who have subsequently relapsed. (see section 5.1).

4.2 Posology and method of administration

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

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

Please refer also to the interferon alfa-2b Summary of Product Characteristics (SPC) for prescribing information particular to that product.

Dose to be administered

The dose of Ribavirin is based on patient body weight. Ribavirin capsules are to be administered orally each day in two divided doses (morning and evening) with food.

Adult patients:

The dose of Ribavirin is based on patient body weight (Table 1).

Ribavirin must be used in combination with interferon alfa-2b (3 million international units [MIU] three times a week). The choice of combination regimen is based on the characteristics of the patient. 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).

Patient weight (kg)	Daily Ribavirin dose	Number of 200 mg capsules
< 65	800 mg	4 a
65 - 80	1,000 mg	5 b
81 - 105	1,200 mg	6 c
> 105	1,400 mg	7 d

a: 2 morning, 2 evening b: 2 morning, 3 evening c: 3 morning, 3 evening d: 3 morning, 4 evening

Ribavirin Capsules 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 virologic responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).

Duration of treatment - Naive 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 HCV-RNA after six months of treatment should be based on other prognostic factors (e.g., age >40 years, male gender, bridging fibrosis).

Children 3 years of age and older and adolescents:

Note: For patients who weigh < 47 kg, or are unable to swallow capsules, ribavirin oral solution is available and should be used in appropriate:

Dosing for children and adolescent patients is determined by body weight for Ribavirin and by body surface area for interferon alfa-2b.

Dose to be administered for the combination therapy with interferon alfa-2b:

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 2).

Table 2 Ribavirin dose based on body weight when used in combination with interferon alfa-2b in children and adolescents
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 dosing table (Table 1)

^a 1 morning, 2 evening ^b 2 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 all patients

If severe adverse reactions or laboratory abnormalities develop during therapy with ribavirin and interferon alfa-2b, modify the dosages of each product if appropriate, until the adverse reactions abate. Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines, Table 3). As adherence might be of importance for outcome of therapy, the dose should be kept as close as possible to the recommended standard dose. The potential negative impact of ribavirin dose reduction on efficacy results could not be ruled out.

Table 3 Dosage modification guidelines based on laboratory parameters
Laboratory values	Reduce only ribavirin daily dose (see note 1), if:	Reduce only interferon alfa-2b dose (see note 2) if:	Discontinue combination therapy when the below test value is reported:**
Haemoglobin	< 10 g/dl	-	< 8.5 g/dl
Adults: Haemoglobin in: patients with history of stable cardiac disease Children and adolescents: not applicable (see section 4.4)	> 2 g/dl decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction)		< 12 g/dl after 4 weeks of dose reduction
White blood cells	-	< 1.5 x 109 /l	< 1.0 x 109 /l
Neutrophils	-	< 0.75 x 109 /l	< 0.5 x 109 /l

Platelets		<    50 x 109 /l (adults) <    70 x 109 /l (children and adolescents)	<    25 x 109 /l (adults) <    50 x 109 /l (children and adolescents)
Bilirubin - Direct	-	-	2.5 x ULN*
Bilirubin - Indirect	> 5 mg/dl		>    4 mg/dl (adults) >    5 mg/dl (for > 4 weeks) (children and adolescents treated with interferon alfa-2b)
Creatinine	-	-	> 2.0 mg/dl
Alanine aminotransferase and Aspartate aminotransferase (ALT/AST)			2 x baseline and > 10 x ULN*

* Upper limit of normal

** Refer to the SPC for interferon alfa-2b for dose modification and discontinuation.

Note 1: In adult patients, 1^st dose reduction of Ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2^nd dose reduction of Ribavirin is by an additional 200 mg/day. Patients whose dose of Ribavirin 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 plus interferon alfa-2b, reduce Ribavirin dose to 7.5 mg/kg/day.

Note 2: In adult patients and children and adolescent patients treated with Ribavirin plus interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose.

Special populations

Use in renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2). Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of ribavirin. Patients with creatinine clearance < 50 ml/minute must not be treated with ribavirin (see section 4.3). Subjects with impaired renal function should be more carefully monitored with respect to the

development of anaemia. If serum creatinine rises to > 2.0 mg/dl (Table 3), ribavirin and interferon alfa-2b must be discontinued.

Use in hepatic impairment: No pharmacokinetic interaction appears between ribavirin and hepatic function (see section 5.2). Therefore, no dose adjustment of ribavirin is required in patients with hepatic impairment.

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

Use in patients under the age of 18 years: Ribavirin 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.Safety and effectiveness of ribavirin with other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.

Patients co-infected with HCV/HIV: Patients taking 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.

4.3 Contraindications

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

•    Pregnant women (see sections 4.4, 4.6 and 5.3). Ribavirin must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

•    Women who are breast-feeding.

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

•    Severe, debilitating medical conditions includingpatients with chronic renal failure, patients with creatinine clearance < 50 ml/minute and/or on haemodialysis.

•    Severe hepatic dysfunction or decompensated cirrhosis of the liver.

•    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 peginterferon alfa-2b or 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.

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 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 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.

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

Ocular changes: Ribavirin is used in combination therapy with alpha interferons. Retinopathy including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery or vein occlusion which may result in loss of vision have been reported in rare instances with combination therapy with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferons. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Liver function: Any patient developing significant liver function abnormalities during treatment must be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation markers which might indicate liver decompensation.

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

Thyroid supplemental monitoring 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).

HCV/HIV Co-infection:

Mitochondrial toxicity and lactic acidosis:

Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is administered. In particular:

•    co-administration of Ribavirin and didanosine is not recommended due to the risk of mitochondrial toxicity (see section 4.5).

•    co-administration of Ribavirin and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.

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

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. 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. 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 HAART 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/pl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin 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 and blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Ribavirin therapy:

Haemoglobin	Adult: > 12 g/dl (females); > 13 g/dl (males) Children and adolescents: > 11 g/dl (females); > 12 g/dl (males)
Platelets	> 100,000/mm3
Neutrophil Count	> 1,500/mm3

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

For females of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for four months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for seven months thereafter (see section 4.6).

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

Use in patients with rare hereditary disorders: Each Ribavirin capsule contains 40 mg of lactose.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 interferer with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myclotoxicity 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 azatioprine 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 analogs: Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see section 4.4).

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

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

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

Conflicting findings are reported in literature on co-administration between abacavir and ribavirin.

Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 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

Pregnancy

The use of Ribavirin is contraindicated during pregnancy.

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).

Women of childbearing potential/contraception in males and females

Female patients: Ribavirin 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 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.

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

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

4.7 Effects on ability to drive and use machines

Ribavirin 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 who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.

4.8 Undesirable effects

Adult patients:

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

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

The adverse reactions listed in Table 4 are based on experience from clinical trials in adult naive 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 4. Also, refer to peginterferon alfa-2b and interferon alfa-2b SPCs for adverse reactions that may be attributable to interferon monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to

<1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4 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	Injection site infection, lower respiratory tract infection
Rare:	Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common:	Neoplasm unspecified
Blood and lymphatic system disorders
Very common:	Anaemia, neutropenia
Common:	Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia
Very rare:	Aplastic anaemia*
Not known:	Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:	Drug hypersensitivity
Rare:	Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known:	Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis
Endocrine disorders
Common:	Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:	Anorexia
Common:	Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite
Uncommon:	Diabetes mellitus, hypertriglyceridemia*
Psychiatric disorders
Very common:	Depression, insomnia, anxiety, emotional lability
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 disort	ers
Common:	Vertigo, hearing impairment/loss, tinnitus, ear pain
Cardiac disorders
Common:	Palpitation, tachycardia
Uncommon:	Myocardial infarction
Rare:	Cardiomyopathy*, arrhythmia*
Very rare:	Cardiac ischaemia*
Not known:	Pericardial effusion*, pericarditis*
Vascular disorders
Common:	Hypotension, hypertension, flushing
Rare:	Vasculitis
Very rare:	Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:	Dyspnoea, coughing

Common:	Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough
Very rare:	Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*
Gastro-intestinal disorders
Very common:	Diarrhoea, vomiting, nausea, abdominal pain
Common:	Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophogeal 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 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 abnormally
Rare:	Renal failure renal insufficiency*
Very rare:	Nephrotic syndrome*
Reproductive system ant	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:	Injection site inflammation, injection site reaction, fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability
Common:	Chest pain, chest discomfort, peripheral oedema, malaise, injection site pain, feeling abnormal, thirst
Uncommon	Face oedema
Rare:	Injection site necrosis
Investigations
Very common:	Weight decrease
Common:	Cardiac murmur

* Since ribavirin is always 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).

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

Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with ribavirin 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 monoinfected 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/pl (see section 4.4).

Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin 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 % 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 is observed, the reversibility of which is uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3^rd 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 < 3^rd percentile). Based on interim data from the long-term follow-up portion of this study, 22 % (16/74) of children had a > 15 percentile decrease in height percentile, of whom 3 (4 %) children had a > 30 percentile decrease despite being off treatment for more than 1 year. In particular, decrease in mean height percentile at year 1 of long term follow-up was most prominent in prepubertal age children (see section 4.4).

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

In combination with interferon alfa-2b

In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and 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 growth velocity of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). During combination therapy for up to 48 weeks with interferon alfa-2b and ribavirin, growth inhibition is observed, the reversibility of which is uncertain. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4).

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

emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropenia.

Reported adverse reactions listed in Table 5 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 5 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, aggressiion, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy
Uncommon:	Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

Nervous system disorders
Very common:	Headache, dizziness
Common:	Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep
Uncommon:	Neuralgia, lethargy, psychomotor hyperactivity
Eye disorders
Common:	Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Uncommon:	Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Ear and labyrinth disorders
Common:	Vertigo
Cardiac disorders
Common:	Tachycardia, palpitations
Vascular disorders
Common:	Pallor, flushing
Uncommon:	Hypotension
Respiratory, thoracic and mediastinal disorders
Common:	Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain
Uncommon:	Wheezing, nasal discomfort
Gastro-intestinal disort	ers
Very common:	Abdominal pain, abdominal pain upper, vomiting, diarrhoea, nausea
Common:	Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophogeal 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
Uncommon:	Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise 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:	Injection site inflammation, injection site reaction, injection site erythema, injection site pain, fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability
Common:	Chest pain, oedema, pain, injection site pruritus, injection site rash, injection site dryness, feeling cold
Uncommon	Chest discomfort, facial pain, injection site induration
Investigations
Very common:	Growth rate decrease (height and/or weight decrease for age)
Common:	Blood thyroid stimulating hormone increased, thyroglobulin increased
Uncommon:	Anti-thyroid antibody positive
Injury, poisoning and procedural complications
Common:	Skin laceration
Uncommon:	Contusion

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

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: Direct acting antivirals, nucleosides and nucleotides (excl.reverse transcriptase inhibitors), ATC code: J05AB04.

Mechanism of action

Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin in combination with 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.

Ribavirin clinical trials in adults

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

Naive patients

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

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

In clinical trial C/I98-580, 1,530 naive 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 6), while response rates in patients that received > 13.2 mg/kg Ribavirin were even higher.

Table 6 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)

Ribavirin (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 7. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were coinfected with HIV. Patients were randomized to receive either ribavirin (800 mg/day) plus peginterferon alfa-2b (1.5 pg/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 pg/week based on weight) or ribavirin (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.

Table 7 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 pg/kg/week)	Ribavirin (800 mg/day) + interferon alfa-2b (3 MIU TIW)	p valuea	Ribavirin (800-1,200 mg/day)d + peginterferon alfa-2b (100 or 150cpg/week)	Ribavirin (800 1,200 mg/day)d + interferon alfa-2b (3 MIU TIW)	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 pg/week peginterferon alfa-2b and subjects > 75 kg received 150 pg/week peginterferon alfa-2b . d: Ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

¹Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.

² Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response

Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with 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.

3 Retreatment of relapse patients with Ribavirin and interferon alfa-2b combination treatment

Two trials examined the use of ribavirin and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with ribavirin and interferon alfa-2b resulted in a sustained virological response that was tenfold 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).

Ribavirin clinical trials in children and adolescents:

Ribavirin in combination with interferon alfa-2b Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received ribavirin 15 mg/kg per day plus interferon alfa-2b 3 MIU/m 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 8.

Table 8 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 - Children and adolescents

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

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

5.2 Pharmacokinetic properties

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean T_max= 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 AUC_tf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

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.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-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.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_J2hr. 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 coadministration of a high fat meal (AUC_tf and C_max 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: Single-dose ribavirin pharmacokinetics were altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.

Hepatic function: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are 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 interferon alfa-2b

Multiple-dose pharmacokinetic properties for ribavirin capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 9. The pharmacokinetics of ribavirin and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.

Table 9. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and ribavirin when administered to children or adolescents 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	0.27 (27)	Not done
l/hr/kg

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

5.3 Preclinical safety data

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

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

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

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

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro Transformation Assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20200 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,

Povidone K30 Magnesium stearate.

Capsule shell:

Gelatine,

Titanium dioxide (E171).

Sodium lauryl sulphate

Capsule imprint:

Shellac,

Propylene glycol,

Black iron oxide (E 172)

Potassium hydroxide,

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

This medicinal product does not require special storage conditions.

6.5    Nature and contents of container

Ribavirin is available in PVC/PE/PVDC/Aluminium blisters and HDPE containers in the pack sizes of

PVC/PE/PVDC/aluminium blister: 84, 112, 140 and 168 capsules HDPE bottle: 42 and 500 capsules

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares, Odyssey Business Park

West End Road

South Ruislip HA4 6QD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0233

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/03/2012

10    DATE OF REVISION OF THE TEXT

06/08/2014