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Drug Details

REBETOL

• Drug Class Description
  Antivirals.
• Generic Name
  Ribavirin [tribavirin]
• Presentation
  Hard capsule White, opaque and imprinted with blue ink.
• Description
  Each Rebetol capsule contains 200 mg of ribavirin. For a full list of excipients. Rebetol contains 40 mg of lactose monohydrate.
• Indications
  

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

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

• Adult Dosage
  

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

  Dose to be administered

  The dose of Rebetol is based on patient body weight (Table 1). Rebetol capsules are to be administered orally each day in two divided doses (morning and evening) with food.

  Adult patients: Rebetol must be used in combination with either peginterferon alfa-2b (1.5 micrograms/kg/week) or 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.

  Table 1 Rebetol dose based on body weight
  < Patient weight (kg)	Daily Rebetol dose	Number of 200 mg capsules
  < 65	800 mg	4 a
  65 – 85	1,000 mg	5 b
  86 - 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

  Rebetol Capsules in combination with pegylated interferon alfa-2b:

  Duration of treatment – Naïve patients

  Predictability of sustained virological response: Patients infected with virus genotype 1 who fail to achieve virological response at Week 12 are highly unlikely to become sustained virological responders.

  Genotype 1: For patients who exhibit virological response at week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks).

  In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration.

  Genotypes 2 or 3: It is recommended that all patients be treated for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.

  Genotype 4: In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment as for genotype 1.

  HCV/HIV Co-infection

  The recommended duration of dosing for HCV/HIV co-infected patients is 48 weeks, regardless of genotype.

  Predictability of response and non-response in HCV/HIV Co-infection

  Early virological response by Week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with Rebetol in combination with peginterferon alfa-2b was 99 % (67/68; Study 1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving combination therapy.

  Duration of treatment - Retreatment

  Predictability of sustained virological response: All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at Week 12 should receive 48 weeks of therapy. Retreated patients who fail to achieve virological response at Week 12 are unlikely to become sustained virological responders after 48 weeks of therapy.

  Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

  Rebetol Capsules in combination with interferon alfa-2b:

  Duration of treatment: Based on the results of clinical trials, it is recommended that patients be treated for at least six months. During those clinical trials in which patients were treated for one year, patients who failed to show a virological response after six months of treatment (HCV-RNA below lower limit of detection) were unlikely to become sustained virological responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).

  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 aged three years and older, and adolescents: (for patients who weigh < 47 kg, or are unable to swallow capsules, please refer to the SPC for ribavirin 40 mg/ml oral solution).

  In clinical studies performed in this population ribavirin and interferon alfa-2b were used in doses of 15 mg/kg/day and 3 MIU/m² three times a week respectively (Table 2).

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

  Table 2 Rebetol paediatric dose based on body weight
  Patient weight (kg)	Daily Rebetol dose	Number of 200 mg capsules
  47 - 49	600 mg	3 capsules a
  50 - 65	800 mg	4 capsules b
  > 65	Refer to adult dosing table (Table 1)

  ^a1 morning, 2 evening ^b2 morning, 2 evening

  Duration of treatment in children and adolescents

  Genotype 1: The recommended duration of treatment is 1 year. Patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders (negative predictive value 96 %). Virological response is defined as absence of detectable HCV-RNA at Week 12 of treatment. Treatment should be discontinued in these patients.

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

  Virological responses after 1 year of treatment and 6 months of follow-up were 36 % for genotype 1 and 81 % for genotype 2/3/4.

  Dose modification for all patients

  If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol and peginterferon alfa-2b or 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
  Laboratory Values	Reduce only Rebetol daily dose adult to 600 mg/day* , paediatric to 7.5 mg/kg, if:	Reduce only peginterferon alfa-2b (adult) or interferon alfa-2b dose (adult and paediatric) to one-half dose, if:	Discontinue combination therapy if:
  Haemoglobin	< 10 g/dl	-	< 8.5 g/dl
  Adult: Haemoglobin in: patients with history of stable cardiac disease Paediatric: not applicable	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 /1
  Neutrophils	-	< 0.75 x 109 /l	< 0.5 x 109 /l
  Platelets	-	Adult < 50 x 109 /l Paediatric < 80 x 109 /l	Adult < 25 x 109 /l Paediatric < 50 x 109 /l
  Bilirubin – Direct	-	-	2.5 x ULN**
  Bilirubin – Indirect	> 5 mg/dl	-	Adult > 4 mg/dl Paediatric > 5 mg/dl (for > 4 weeks)
  Creatinine	-	-	> 2.0 mg/dl
  Alanine aminotransferase/ aspartate aminotransferase (ALT/AST)	-	-	2 x baseline and > 10 x ULN**

  ^* Administered in two divided doses, in the morning and in the evening.

  ^** Upper limit of normal

  Special populations

  Use in renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol. Subjects with impaired renal function should be more carefully monitored with respect to the development of anaemia. If serum creatinine rises to > 2 mg/dl (Table 3), Rebetol and peginterferon alfa-2b/interferon alfa-2b must be discontinued.

  Use in hepatic impairment: No pharmacokinetic interaction appears between ribavirin and hepatic function. Therefore, no dose adjustment of Rebetol 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 Rebetol.

  Use in patients under the age of 18 years: Rebetol as capsules or oral solution 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 Rebetol with pegylated or other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.

  Patients co-infected with HCV/HIV: Patients taking NRTI treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be at increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation. Please refer also to the relevant product information for antiretroviral medicinal products.

• Child Dosage
  Under 18 years, not recommended.
• Contra Indications
  

  - Hypersensitivity to the active substance or to any of the excipients.

  - Pregnant women. Rebetol 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.

  - Severe, debilitating medical conditions, including patients 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.

• Special Precautions
  

  Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Rebetol 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 Rebetol 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 Rebetol 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 Rebetol 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 Rebetol and interferon alfa-2b or peginterferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated.

   

  Growth and development (children and adolescents): During the course of interferon (standard and pegylated)/ribavirin therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment for more than 5 years.  Case by case benefit/risk assessment in children: The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials. −      It is important to consider that the combination therapy induced a growth inhibition, the reversibility of which is uncertain. −      This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV-co-infection), as well as prognostic factors of response (HCV genotype and viral load). Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.

  Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Rebetol must not be used alone. The safety and efficacy of this combination have been established only using ribavirin capsules together with peginterferon alfa-2b or interferon alfa-2b solution for injection.

  All patients in selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.

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

  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, Rebetol 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.

  Thyroid supplemental monitoring specific for children and adolescents:

  Approximately 12 to 21 % of children treated with Rebetol 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 Rebetol and interferon alfa-2b and during treatment with Rebetol 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 Rebetol and didanosine is not recommended due to the risk of mitochondrial toxicity.

  - co-administration of Rebetol 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 highly active anti-retroviral therapy (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.

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

  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 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 Rebetol 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 Rebetol 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 Rebetol 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 Rebetol 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.

  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.

  Uric acid may increase with Rebetol 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 Rebetol capsule contains 40 mg of lactose.

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

• Interactions
  

  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.

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

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

  Antacid: The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid containing magnesium aluminium and simethicone; AUC_tf 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 Rebetol and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported.

  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. 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 Rebetol therapy due to the long half-life.

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

• Adverse Drug Reactions
  

  Adult patients:

  The safety of Rebetol capsules is evaluated from data from three clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combination with interferon alfa-2b, one trial studied Rebetol 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 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 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 Rebetol with pegylated interferon alfa-2b or interferon alfa-2b injection
  System Organ Class	Adverse Reactions
  Infections and infestations
  Very common:	Viral infection, pharyngitis
  Common:	Fungal infection, otitis media, herpes simplex, urinary 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:	Thrombocytopenia, lymphadenopathy, lymphopenia
  Very rare:	Aplastic anaemia*
  Not known:	Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
  Immune system disorders
  Very rare:	Sarcoidosis*
  Not known:	Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis
  Endocrine disorders
  Common:	Hypothyroidism, hyperthyroidism
  Rare:	Diabetes
  Metabolism and nutrition disorders
  Very common:	Anorexia
  Common:	Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite, thirst
  Very rare:	Hypertriglyceridemia*
  Psychiatric disorders
  Very common:	Depression, insomnia, anxiety, emotional lability
  Common:	Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, nervousness, sleep disorder, abnormal dreaming, abnormal crying, apathy, decreased libido
  Uncommon:	Suicide attempts
  Rare:	Hallucination
  Very rare:	Suicide*
  Not known:	Mental status change
  Nervous system disorders
  Very common:	Headache, dizziness, dry mouth, concentration impaired
  Common:	Ataxia, tremor, paresthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, somnolence, migraine, hypertonia, dysgeusia
  Rare:	Seizure (convulsion)*, peripheral neuropathy*
  Very rare:	Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*
  Not known:	Facial palsy, neuropathies (including mononeuropathies)
  Eye disorders
  Common:	Blurred vision, conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
  Rare:	Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery obstruction*, retinal vein obstruction*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, cotton wool spots*
  Ear and labyrinth disorders
  Common:	Vertigo, hearing impairment/loss, tinnitus, earache
  Cardiac disorders
  Common:	Palpitation, tachycardia
  Rare:	Cardiomyopathy*, arrhythmia*
  Very rare:	Myocardial infarction*, cardiac ischaemia*
  Vascular disorders
  Common:	Hypotension, hypertension, syncope, flushing
  Very rare:	Peripheral ischaemia*
  Respiratory, thoracic and mediastinal disorders
  Very common:	Dyspnoea, coughing
  Common:	Sinusitis, bronchitis, epistaxis, rhinitis, respiratory disorder, nasal congestion, rhinorrhea, nonproductive cough
  Very rare:	Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*
  Gastro-intestinal disorders
  Very common:	Diarrhoea, vomiting, nausea, abdominal pain
  Common:	Ulcerative stomatitis, stomatitis, colitis, upper right quadrant pain, dyspepsia, gastroesophogeal reflux*, glossitis, gingival bleeding, gingivitis, loose stools, constipation, flatulence
  Rare:	Pancreatitis*
  Very rare:	Ischaemic colitus*, ulcerative colitus*
  Not Known:	Periodontal disorder, dental disorder
  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, dermatitis, acne, furunculosis*, erythema, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*
  Very rare:	Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*
  Musculoskeletal and connective tissue disorders
  Very common:	Arthralgia, myalgia, musculoskeletal pain
  Common:	Arthritis
  Rare:	Rhabdomyolysis*, myositis*
  Renal and urinary disorders
  Common:	Micturition frequency, polyuria
  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 Sexual dysfunction (not specified)*
  General disorders and administration site conditions
  Very common:	Injection site inflammation, injection site reaction, fatigue, rigors, fever, flu-like symptoms, asthenia, irritability
  Common:	Chest pain, peripheral oedema, malaise, injection site pain, face oedema*
  Very rare:	Injection site necrosis
  Investigations
  Very common:	Weight decrease
  Common:	Cardiac murmur, urine abnormal

  * 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 nonpegylated).

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

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

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

  HCV/HIV co-infected patients:

  For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other undesirable effects (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.

  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. Haematological abnormalities were more frequently reported in patients receiving Rebetol in combination with peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon alfa-2b. In Study 1, decrease in absolute neutrophil count levels below 500 cells/mm³ was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm³ was observed in 4 % (8/194) of patients receiving Rebetol in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Rebetol in combination with peginterferon alfa-2b.

  CD4 lymphocytes decrease:

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

  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 Rebetol in combination with peginterferon alfa-2b.

  Children and adolescents:

  In clinical trials of 118 children or adolescents 3 to 16 years of age, 6 % discontinued therapy due to adverse events. In general, the adverse event profile in the limited paediatric population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height (mean percentile decrease of growth velocity of 9 %) and weight (mean percentile decrease of 13 %) percentile were observed during treatment. Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence). In addition, injection site disorders, fever, 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 neutropaenia.

  Reported adverse reactions listed in Table 5 are based on experience from paediatric clinical trials. 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

  Table 5 Adverse reactions very commonly and commonly reported during clinical trials of Rebetol with interferon alfa-2b injection in paediatric patients
  System Organ Class	Adverse Reactions
  Infections and infestations
  Very common:	Viral infection, pharyngitis
  Common:	Fungal infection, bacterial infection, pulmonary infection, otitis media, tooth abscess, herpes simplex, urinary tract infection, vaginitis, gastroenteritis
  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
  	Hypertriglyceridemia, hyperuricemia, increased appetite
  Psychiatric disorders
  Very common:	Depression, insomnia, emotional lability
  Common:	Suicidal ideation, aggressive reaction, confusion, behaviour disorder, agitation, somnambulism, anxiety, nervousness, sleep disorder, abnormal dreaming, apathy
  Nervous system disorders
  Very common:	Headache, dizziness
  Common:	Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence
  Eye disorders
  Common:	Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
  Vascular disorders
  Common:	Raynaud's disease, flushing, pallor
  Respiratory, thoracic and mediastinal disorders
  Common:	Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhea, sneezing
  Gastro-intestinal disorders
  Very common:	Diarrhoea, vomiting, nausea, abdominal pain
  Common:	Mouth ulceration, stomatitis ulcerative, stomatitis, right upper quadrant pain, dyspepsia, glossitis, gastroesophogeal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder
  Hepatobiliary disorders
  Common:	Hepatic function abnormal
  Skin and subcutaneous tissue disorders
  Very common:	Alopecia, rash
  Common:	Photosensitivity reaction, maculopapular rash, eczema, acne, skin disorder, nail disorder, skin discolouration, pruritus, dry skin, erythema, bruise, sweating increased
  Musculoskeletal and connective tissue disorders
  Very common:	Arthralgia, myalgia, musculoskeletal pain
  Renal and urinary disorders
  Common:	Enuresis, micturition disorder, urinary incontinence
  Reproductive system and breast disorders
  Common:	Female : amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain
  General disorders and administration site conditions
  Very common:	Injection site inflammation, injection site reaction, fatigue, rigors, fever, influenza-like symptoms, malaise, irritability
  Common:	Chest pain, asthenia, oedema, injection site pain
  Investigations
  Very common:	Growth rate decrease (height and/or weight decrease for age)
  Injury, poisoning and procedural complications
  Common:	Skin laceration