4.1. Therapeutic indications

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

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

4.2. Posology and method of administration

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

Posology

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

Please refer also 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.

Paediatric population

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

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

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.

Table 1. Ribavirin 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

a: 1 morning, 2 evening

b: 2 morning, 2 evening

Dose modification for adverse reactions

Dose modification for adults

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

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

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

Table 2 Management of Adverse Reactions

Laboratory values

Reduce Ribavirin dose* if:

Discontinue Ribavirin if:

Haemoglobin in patients with No Cardiac Disease

< 10 g/dL

< 8.5 g/dL

Haemoglobin: Patients with History of Stable Cardiac Disease

≥ 2 g/dL decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction)

< 12 g/dL despite 4 weeks at reduced dose

Bilirubin – Indirect

> 5 mg/dL

> 4 mg/dL (adults)

* For patients receiving a 1,000 mg (< 75 kg) or 1,200 mg (> 75 kg) dose, ribavirin dose should be reduced to 600 mg/day (administered as one 200 mg 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 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 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 case of serious adverse reaction potentially related to medicinal products used in combination with ribavirin, refer to the corresponding SmPC of these medicinal products as some combination regimens do not adhere to the ribavirin dose modification and/or discontinuation guidelines as described in Table 2.

Dose modification for paediatric patients

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

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

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

Table 3 Management of Adverse Reactions

Laboratory values

Discontinue Ribavirin if:

Bilirubin – Indirect

> 5 mg/dL (for > 4 weeks)

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

Or

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

Special populations

Elderly (≥ 65 years of age)

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

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

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

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

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 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. Adult patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) should be administered alternating daily doses of 200 mg and 400 mg. Adult patients with severe renal impairment (creatinine clearance of < 30 mL/minute) and patients with End Stage Renal Disease (ESRD) or on haemodialysis should be administered ribavirin 200 mg/day. Table 4 provides guidelines for dose modification for patients with renal dysfunction. Patients with impaired renal function should be more carefully monitored with respect to the development of anaemia. No data are available regarding dose modification for paediatric patients with renal impairment.

Table 4 Dosage Modification for Renal Impairment in Adult Patients

Creatinine Clearance

Ribavirin Dose (daily)

30 to 50 mL/min

Alternating doses, 200 mg and 400 mg every other day

Less than 30 mL/min

200 mg daily

Haemodialysis (ESRD)

200 mg daily

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

Method of administration

Ribavirin should be administered orally with food.

4.3. Contraindications

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

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

• Breast-feeding.

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

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

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

4.4. Special warnings and precautions for use

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

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

There are several serious adverse reactions associated with the combination therapy of Ribavirin with (peg) interferon alfa.

These include:

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

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

• Increased thyroid stimulating hormone (TSH) in children and adolescents

• Severe ocular disorders

• Dental and periodontal disorders.

Paediatric population

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

Haemolysis:

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

Cardiovascular:

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

Teratogenic risk

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

Acute hypersensitivity:

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

Liver function:

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

Renal impairment

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

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

Potential to exacerbate immunosuppression:

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

HCV/HIV Co-infection:

Mitochondrial toxicity and lactic acidosis:

Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is administered. For additional details see section 4.5.

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

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

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

Haematological abnormalities in HCV/HIV co-infected patients

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

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

Patients with low CD4 counts:

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

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

Laboratory tests:

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

• Haemoglobin

Adult: ≥ 12 g/dL (females); ≥ 13 g/dL (males)

Children and adolescents: ≥ 11 g/dL (females); ≥ 12 g/dL (males)

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

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

Excipients

Lactose

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

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule that is to say essentially 'sodium free'

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

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

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

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

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

Antacid

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

Nucleoside analogues:

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

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

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

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

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

Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at 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 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 nine months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within nine 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 (see sections 4.3, 4.4 and 5.3). Ribavirin accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not shown an increased risk of malformation compared to the general population, nor any specific pattern of malformation, either male patients or their female partners of childbearing age must be advised to use an effective contraceptive during treatment with Ribavirin and for six 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 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 has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.

4.8. Undesirable effects

Summary of 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.

Use of Ribavirin in combination with direct antiviral agents (DAA)

Based on the review of safety data derived from clinical studies in adults with DAA in combination with ribavirin, the most frequent adverse reactions identified as associated with ribavirin were anaemia, nausea, vomiting, asthenia, fatigue, insomnia, cough, dyspnoea, pruritus and rash. Except anaemia, the majority of these adverse reactions were not serious and resolved without treatment discontinuation.

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

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

Tabulated list of adverse reactions for adults

The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b 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

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 disorders

Common:

Vertigo, hearing impaired/loss, tinnitus, ear pain

Cardiac disorders

Common:

Palpitation, tachycardia

Uncommon:

Myocardial infarction

Rare:

Cardiomyopathy*, arrhythmia*

Very rare:

Cardiac ischaemia*

Not known:

Pericardial effusion*, pericarditis*

Vascular disorders

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Very rare:

Peripheral ischaemia*

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea, coughing

Common:

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

Very rare:

Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*

Gastro-intestinal disorders

Very common:

Diarrhoea, vomiting, nausea, abdominal pain

Common:

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

Uncommon:

Pancreatitis, oral pain

Rare:

Ischaemic colitis

Very rare:

Ulcerative colitis *

Not Known:

Periodontal disorder, dental disorder, tongue pigmentation

Hepatobiliary disorders

Common:

Hepatomegaly, jaundice, hyperbilirubinemia*

Very rare:

Hepatotoxicity (including fatalities)*

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus, skin dry, rash

Common:

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

Rare:

Cutaneous sarcoidosis

Very rare:

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

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis*, myositis*

Renal and urinary disorders

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure renal insufficiency*

Very rare:

Nephrotic syndrome*

Reproductive system and breast disorders

Common:

Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder.

Male: impotence, prostatitis, erectile dysfunction, Sexual dysfunction (not specified)*

General disorders and administration site conditions

Very common:

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

Common:

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

Uncommon

Face oedema

Investigations

Very common:

Weight decrease

Common:

Cardiac murmur

* Since 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

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 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 withother medicinal products.

Paediatric population

In combination with peginterferon alfa-2b

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

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

For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among children treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long term followup 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 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, 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 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 Pigmentation disorder, dermatitis atopic, skin exfoliation

Uncommon

Pigmentation disorder, dermatitis atopic, skin exfoliation

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Pain in extremity, back pain, muscle contracture

Renal and urinary disorders

Common:

Enuresis, micturition disorder, urinary incontinence, proteinuria

Reproductive system and breast disorders

Common:

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

Male: testicular pain

Uncommon:

Female: dysmenorrhoea

General disorders and administration site conditions

Very common:

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

Common:

Chest pain, oedema, pain, feeling cold

Uncommon

Chest discomfort, facial pain

Investigations

Very common:

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

Common:

Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon:

Anti-thyroid antibody positive

Injury, poisoning and procedural complications

Common:

Skin laceration

Uncommon:

Contusion

Most of the changes in laboratory values in the 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 or search for MHRA Yellow Card in the Google Play or Apple App Store

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.