Drug Class Description
Antiviral

Generic Name
Ribavirin

Drug Description
Each film-coated tablet contains 200 milligrams of ribavirin.

Presentation
Film-coated tabletLight pink, flat oval-shaped film-coated tablet (marked with RIB 200 on one side and ROCHE on the opposite side).

Indications
Copegus is indicated for the treatment of chronic hepatitis C and must only be used as part of a combination regimen with peginterferon alfa-2a or with interferon alfa-2a. Copegus monotherapy must not be used. The combination of Copegus with peginterferon alfa-2a or interferon alfa-2a is indicated in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis.The combination with peginterferon alfa-2a is also indicated in patients co- infected with clinically stable HIV, including patients with compensated cirrhosis. The combination regimens are indicated in previously untreated patients as well as in patients who have previously responded to interferon alpha therapy and subsequently relapsed after treatment was stopped.

Adult Dosage
Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.Method of AdministrationCopegus film-coated tablets are administered orally in two divided doses with food (morning and evening). Due to the teratogenic potential of ribavirin, the tablets should not be broken or crushed. As Copegus is available in a 200 mg tablet, there is no need for dividing or cutting the 400 mg tablet in half.PosologyCopegus is used in combination with peginterferon alfa-2a or interferon alfa-2a. The exact dose and duration of treatment depend on the interferon product used.Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on dosage and duration of treatment when Copegus is to be used in combination with either of these products.Posology in combination with peginterferon alfa-2a:Dose to be administeredThe recommended dose of Copegus in combination with peginterferon alfa-2a solution for injection depends on viral genotype and the patient's body weight (see Table 1).Duration of treatmentThe duration of combination therapy with peginterferon alfa-2a depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy.Treatment for 24 weeks may be considered in patients infected with- genotype 1 with low viral load (LVL) (800,000 IU/mL) at baseline or- genotype 4who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see 5.1). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL (800,000 IU/mL) at baseline who become HCV negative by week 4 of treatment and remain HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24 week treatment duration. In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (> 800,000 IU/mL) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1000/1200 mg of ribavirin for 48 weeks is recommended.Table 1 Copegus Dosing Recommendations in Combination with Peginterferon alfa-2a for HCV patientsGenotypeDaily Copegus DoseDuration of treatmentNumber of 200/400 mg tabletsGenotype 1 LVL with RVR*< 75 kg = 1000 mg75 kg = 1200 mg24 weeks or 48 weeks5 x 200 mg(2 morning, 3 evening)6 x 200 mg(3 morning, 3 evening)Genotype 1 HVL with RVR*<75 kg = 1000 mg75 kg = 1200 mg48 weeks5 x 200 mg(2 morning, 3 evening)6 x 200 mg(3 morning, 3 evening)Genotype 4 with RVR*<75 kg = 1000 mg75 kg = 1200 mg24 weeks or 48 weeks5 x 200 mg(2 morning, 3 evening)6 x 200 mg(3 morning, 3 evening)Genotype 1 or 4 without RVR*<75 kg = 1000 mg75 kg = 1200 mg48 weeks5 x 200 mg(2 morning, 3 evening)6 x 200 mg(3 morning, 3 evening)Genotype 2 or 3 LVL with RVR**800 mg(a)16 weeks(a)or 24 weeks4 x 200 mg(2 morning, 2 evening) or2 x 400 mg(1 morning, 1 evening)Genotype 2 or 3 HVL with RVR**800 mg24 weeks4 x 200 mg(2 morning, 2 evening) or2 x 400 mg(1 morning, 1 evening)Genotype 2 or 3 without RVR**800 mg24 weeks4 x 200 mg(2 morning, 2 evening) or2 x 400 mg(1 morning, 1 evening)*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;**RVR = rapid viral response (HCV RNA negative) by week 4LVL=800,000 IU/mL; HVL= > 800,000 IU/mL(a)It is presently not clear whether a higher dose of Copegus (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for retreating non-responding and relapsing patients.Chronic hepatitis C – treatment-experienced patientsThe recommended dose of Copegus, in combination with 180 micrograms once weekly of peginterferon alfa-2a, is 1000 milligrams daily or 1200 milligrams daily for patients <75 kg and75 kg, respectively, regardless of genotype.Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks.HIV-HCV Co-infectionThe recommended dosage for Copegus in combination with 180 micrograms once weekly of peginterferon alfa-2a is 800 milligrams, daily for 48 weeks, regardless of genotype. The safety and efficacy of combination therapy with ribavirin doses greater than 800 milligrams daily is currently being studied. A duration of therapy less than 48 weeks has not been adequately studied.Predictability of response and non-response – treatment-naive patientsEarly 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 (see Table 2).Table 2 Predictive Value of Week 12 Virological Response at the Recommended Dosing Regimen while receiving Copegus and peginterferon Combination TherapyGenotypeNegativePositiveNo response by week 12No sustained responsePredictive ValueResponse by week 12Sustained responsePredictive ValueGenotype 1 (N= 569)1029795%(97/102)46727158%(271/467)Genotype 2 and 3 (N=96)33100%(3/3)938187%(81/93)A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with peginterferon alfa-2a monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.Predictability of response and non-response – treatment-experienced patientsIn non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.Posology in combination with interferon alfa-2a:Dose to be administeredThe recommended dose of Copegus in combination with interferon alfa-2a solution for injection depends on the patient's body weight (see Table 3).Duration of treatment:Patients should be treated with combination therapy with interferon alfa-2a for at least six months. Patients with HCV genotype 1 infections should receive 48 weeks of combination therapy. In patients infected with HCV of other genotypes, the decision to extend therapy to 48 weeks should be based on other prognostic factors (such as high viral load at baseline, male gender, age > 40 years and evidence of bridging fibrosis).Table 3 Copegus Dosing Recommendations in Combination with Interferon alfa-2aPatient weight (kg)Daily Copegus doseDuration of treatmentNumber of 200 mg tablets<751,000 mg24 or 48 weeks5 (2 morning, 3 evening)751,200 mg24 or 48 weeks6 (3 morning, 3 evening)Dosage modification for adverse reactionsPlease refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on dose adjustment and discontinuation of treatment for either of these products.If severe adverse reactions or laboratory abnormalities develop during therapy with Copegus and peginterferon alfa-2a or interferon alfa-2a, modify the dosages of each product, until the adverse reactions abate. Guidelines were developed in clinical trials for dose modification (seeDosage Modification Guidelines for Management of Treatment-Emergent Anaemia, Table 4).If intolerance persists after dose adjustment, discontinuation of Copegus or both Copegus and peginterferon alfa-2a or interferon alfa-2a may be needed.Table 4 Dosage Modification Guidelines for Management of Treatment-Emergent AnaemiaLaboratory ValuesReduce only Copegus dose to 600 mg/day* if:Discontinue Copegus if:**Haemoglobin in Patients with No Cardiac Disease<10 g/dl<8.5 g/dlHaemoglobin: 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*Patients whose dose of Copegus is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening.**If the abnormality is reversed, Copegus 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.Special populationsUse in renal impairment:The recommended dose regimens (adjusted by the body weight cutoff of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment. There are insufficient data on the safety, efficacy and pharmacokinetics of ribavirin in patients with serum creatinine > 2 mg/dl or creatinine clearance < 50 ml/min, whether or not on haemodialysis, to support specific recommendations for dose adjustments. Therefore, ribavirin should be used in such patients only when this is considered to be essential. Therapy should be initiated (or continued if renal impairment develops while on therapy) with extreme caution and intensive monitoring of haemoglobin concentrations, with corrective action as may be necessary, should be employed throughout the treatment period.Use in hepatic impairment:Hepatic function does not affect the pharmacokinetics of ribavirin. Therefore, no dose adjustment of Copegus is required in patients with hepatic impairment. The use of peginterferon alfa-2a and interferon alfa-2a is contraindicated in patients with decompensated cirrhosis and other forms of severe hepatic impairment.Use in elderly patients over the age of 65: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 Copegus.Use in patients under the age of 18 years:Treatment with Copegus is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with peginterferon alfa-2a and interferon alfa-2a. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a.

Child Dosage
Use in patients under the age of 18 years:Treatment with Copegus is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with peginterferon alfa-2a and interferon alfa-2a. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a.

Elderly Dosage
Use in elderly patients over the age of 65: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 Copegus.

Contra Indications
See peginterferon alfa-2a or interferon alfa-2a prescribing information for contraindications related to either of these products.- hypersensitivity to ribavirin or to any of the excipients.- pregnant women. Copegus 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 hepatic dysfunction or decompensated cirrhosis of the liver.- haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).- Initiation of peginterferon alfa-2a is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score 6 (Please refer to the SPC of peginterferon alfa-2a for Child-Pugh assessment).

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 Copegus combination therapy with peginterferon alfa-2a or interferon alfa-2a, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, 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 Copegus and peginterferon alfa-2a or interferon alfa-2a be discontinued, and the patient followed, with psychiatric intervention as appropriate.Patients with existence of, or history of severe psychiatric conditions:If treatment with Copegus in combination with peginterferon alfa-2a or interferon alfa-2a is judged necessary in 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.Please refer to the SPC of peginterferon alfa-2a or interferon alfa-2a for further information on special warnings and precautions for use related to either of these products.All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (ie, patients with genotype 2 or 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.In patients with normal ALT, progression of fibrosis occurs on average at a slower rate than in patients with elevated ALT. This should be considered in conjunction with other factors, such as HCV genotype, age, extrahepatic manifestations, risk of transmission, etc. which influence the decision to treat or not.Teratogenic risk:See4.6 Pregnancy and lactation.Prior to initiation of treatment with ribavirin the physician must comprehensively inform the patient 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 treatment with ribavirin. For laboratory monitoring of pregnancy please refer to Laboratory tests.Carcinogenicity:Ribavirin is mutagenic in somein vivoandin vitrogenotoxicity assays. A potential carcinogenic effect of ribavirin cannot be excluded.Haemolysis and Cardiovascular system:A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Copegus 1000/1200 milligrams in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Copegus 800 milligram was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. The risk of developing anaemia is higher in the female population. Although ribavirin has no direct cardiovascular effects, anaemia associated with Copegus may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Copegus 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, stop therapy.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.Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of ribavirin and a peginterferon 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.The use of Copegus and peginterferon alfa-2a combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse events. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.Acute hypersensitivity:If an acute hypersensitivity reaction (e.g. urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Copegus must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.Liver function:In patients who develop evidence of hepatic decompensation during treatment, Copegus in combination with peginterferon alfa-2a or interferon alfa-2a should be discontinued. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued.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 eva luated in all patients prior to initiation of Copegus, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen at the recommended dosing regimen in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute. There are insufficient data on the safety, efficacy and pharmacokinetics of Copegus in such patients to support specific recommendations for dose adjustments. Copegus therapy should not be initiated (or continued if renal impairment occurs while on treatment) in such patients, whether or not on haemodialysis, unless it is considered to be essential. Extreme caution is required. Haemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary.Ocular changes:Copegus is used in combination therapy with alpha interferons. Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction 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 (eg, 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.HIV/HCV Co-infection: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 peginterferon alfa-2a with or without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).Chronic hepatitis C patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of serious adverse effects (e.g. lactic acidosis; peripheral neuropathy; pancreatitis).Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with Copegus in combination with interferons. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI). Caution should therefore be exercised when adding peginterferon alfa-2a and Copegus to HAART.The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia.Co-infected patients should be closely monitored, assessing their Child-Pugh score during treatment, and should be immediately discontinued if they progress to a Child-Pugh score of 7 or greater.Co-administration of Copegus and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-adminstration of Copegus and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.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 Copegus in combination with peginterferon alfa-2a or interferon alfa-2a:Haemoglobin12 g/dl (females);13 g/dl (males)Platelets90,000/mm3Neutrophil Count1,500/mm3In patients co-infected with HIV-HCV, limited efficacy and safety data (N = 51) 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.Laboratory eva luations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate.For women of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for 4 months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for 7 months thereafter.Uric acid may increase with Copegus due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.Dental and periodontal disorders:Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Copegus and peginterferon alfa-2a 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 Copegus and peginterferon alfa-2a. 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.

Interactions
Interaction studies have been conducted with ribavirin in combination with peginterferon alfa-2a, interferon alfa-2b and antacids. Ribavirin concentrations are similar when given alone or concomitantly with interferon alfa-2b or peginterferon alfa-2a.Any potential for interactions may persist for up to 2 months (5 half lives for ribavirin) after cessation of Copegus therapy due to the long half-life.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.Antacid: The bioavailability of ribavirin 600 milligrams was decreased by co-administration with an antacid containing magnesium, aluminium and methicone; 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: Ribavirin was shown in vitro to inhibit phosphorylation of zidovudine and stavudine. The clinical significance of these findings is unknown. However, these in vitro findings raise the possibility that concurrent use of Copegus with either zidovudine or stavudine might lead to increased HIV plasma viraemia. Therefore, it is recommended that plasma HIV RNA levels be closely monitored in patients treated with Copegus concurrently with either of these two agents. If HIV RNA levels increase, the use of Copegus concomitantly with reverse transcriptase inhibitors must be reviewed.Didanosine (ddI): Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased in vitro when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactataemia/lactic acidosis have been reported with use of ribavirin.HIV-HCV co-infected patients No apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12 week pharmacokinetic substudy to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or stavudine). However, due to high variability, the confidence intervals were quite wide. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of nucleoside reverse transcriptase inhibitors (NRTIs).

Adverse Reactions
See peginterferon alfa-2a or interferon alfa-2a prescribing information for additional undesirable effects for either of these products.Adverse events reported in patients receiving Copegus in combination with interferon alfa-2a are essentially the same as for those reported for Copegus in combination with peginterferon alfa-2a.Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Chronic Hepatitis CThe most frequently reported adverse events with Copegus in combination with peginterferon alfa-2a 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.Chronic Hepatitis C and Human Immunodeficiency Virus Co-infectionIn HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Copegus and peginterferon alfa-2a combination therapy other undesirable effects have been reported in 1% to 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a treatment 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 peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 51) are available in co-infected patients with CD4+ cell counts < 200/µl. (see peginterferon alfa-2a SPC).Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.Table 5 Undesirable Effects Reported with Copegus in combination with Peginterferon alfa-2a for HCV Patients Body systemVery Common CommonUncommon Rare Very rare 1 /10 1 /100 to < 1 /10 1 /1000 to < 1 /100 1 /10 ,000 to < 1 /1000 <1/10,000Infections and infestationsUpper respiratory infection, bronchitis, oral candidiasis, herpes simplexLower respiratory tract infection, urinary tract infection, skin infectionEndocarditis,Otitis externaNeoplasms benign and malignantMalignant hepatic neoplasmBlood and lymphatic system disordersAnaemiaThrombocytopenia, lymphadenopathyPancytopeniaAplastic anaemiaImmune system disordersSarcoidosis,thyroiditisAnaphylaxis, systemic lupus erythematosus, rheumatoid arthritisidiopathic or thrombotic thrombocytopenic purpuraEndocrine disordersHypothyroidism, hyperthyroidismDiabetesMetabolism and Nutrition DisordersAnorexiaDehydrationPsychiatric disordersDepression, insomniaMood alteration, emotional disorders, anxiety, aggression, nervousness, libido decreasedSuicidal ideation, hallucinations, angerSuicide, psychotic disorderNervous system disordersHeadache, dizziness, concentration impairedMemory impairment, syncope, weakness, migraine, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolenceHearing loss, peripheral neuropathyComa, convulsions, facial palsyEye disordersVision blurred, eye pain, eye inflammation, xerophthalmiaRetinal haemorrhage,Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcerVision lossEar and labyrinth disordersVertigo, earacheCardiac disordersTachycardia, palpitations, oedema peripheralMyocardial infarction, congestive heart failure, angina, Supraventricular tachycardia arrhythmia, atrial fibrillation, pericarditisVascular disordersFlushingHypertensionCerebral haemorrhageRespiratory, thoracic and mediastinal disordersDyspnoea, coughDyspnoea exertional, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throatWheezingInterstitial pneumonitis with fatal outcome, pulmonary embolismGastrointestinal disordersDiarrhoea, nausea, abdominal painVomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouthGastrointestinal bleeding, cheilitis, gingivitisPeptic ulcer, pancreatitisHepato-biliary disordersHepatic dysfunctionHepatic failure, cholangitis, fatty liverSkin and subcutaneous tissue disordersAlopecia, dermatitis, pruritis, dry skinRash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensitivity reaction, night sweatsToxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiformeMusculoskeletal connective tissue and bone disordersMyalgia, arthralgiaBack pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle crampsMyositisReproductive system and breast disordersImpotenceGeneral disorders and administration site conditionsPyrexia, rigors, pain, asthenia, fatigue, injection site reaction, irritabilityChest pain, influenza like illness, malaise, lethargy, hot flushes, thirstInvestigationsWeight decreasedInjury and poisoningSubstance overdoseLaboratory values: In clinical trials of Copegus in combination with peginterferon alfa-2a or interferon alfa-2a, the majority of cases of abnormal laboratory values were managed with dose modifications. With peginterferon alfa-2a and Copegus combination treatment, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of treatment.Haemolysis is the dose limiting toxicity of ribavirin therapy. A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Copegus 1000/1200 milligrams in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Copegus 800 milligram was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. It is not expected that patients will need to discontinue therapy because of decrease in haemoglobin levels alone. In most cases the decrease in haemoglobin occurred early in the treatment period and stabilised concurrently with a compensatory increase in reticulocytes.Most cases of anaemia, leucopenia and thrombocytopenia were mild (WHO grade 1). WHO grade 2 laboratory changes were reported for haemoglobin (4% of patients), leucocytes (24% of patients) and thrombocytes (2% of patients). Moderate (absolute neutrophil count (ANC): 0.749-0.5x109/L) and severe (ANC: <0.5x109/L) neutropenia was observed in 24% (216/887) and 5% (41/887) of patients receiving 48 weeks of Copegus 1000/1200 milligrams in combination with peginterferon alfa-2a.An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated with Copegus used in combination with peginterferon alfa-2a or interferon alfa-2a and values returned to baseline levels within 4 weeks after the end of therapy. In rare cases (2/755) this was associated with clinical manifestation (acute gout).Laboratory values for HIV-HCV co-infected patientsAlthough haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3 was observed in 10% and 8% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.

Manufacturer
Roche

Drug Availability
(POM)

Updated
21 November 2011