- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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.
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 4 who 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 section 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 (see section 5.1). 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 patients|
|Genotype||Daily Copegus Dose||Duration of treatment||Number of 200/400 mg tablets|
|Genotype 1 LVL with RVR*||<75 kg = 1000 mg ≥75 kg = 1200 mg||24 weeks or 48 weeks||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|Genotype 1 HVL with RVR*||<75 kg = 1000 mg ≥75 kg = 1200 mg||48 weeks||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|Genotype 4 with RVR*||<75 kg = 1000 mg ≥75 kg = 1200 mg||24 weeks or 48 weeks||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|Genotype 1 or 4 without RVR*||<75 kg = 1000 mg ≥75 kg = 1200 mg||48 weeks||5 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 weeks||4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening)|
|Genotype 2 or 3 HVL with RVR**||800 mg||24 weeks||4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening)|
|Genotype 2 or 3 without RVR**||800 mg||24 weeks||4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening)|
Chronic hepatitis C treatment-experienced patientsThe recommended dose of Copegus, in combination with 180 micrograms once weekly of peginterferon alfa-2a, is 1000 mg daily or 1200 mg daily for patients <75 kg and ≥75 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 (see section 5.1).
HIV-HCV Co-infectionThe recommended dosage for Copegus in combination with 180 micrograms once weekly, for 48 weeks, of peginterferon alfa-2a is as follows:- patients infected with HCV genotype 1 <75 kg: 1000 mg daily- patients infected with HCV genotype 1 ≥75 kg: 1200 mg daily- patients infected with HCV genotype other than 1 should receive 800 mg dailyA 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 Therapy|
|No response by week 12||No sustained response||Predictive Value||Response by week 12||Sustained response||Predictive Value|
|Genotype 1 (N= 569)||102||97||95% (97/102)||467||271||58% (271/467)|
|Genotype 2 and 3 (N=96)||3||3||100% (3/3)||93||81||87% (81/93)|
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 treatmentPatients 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-2a|
|Patient weight (kg)||Daily Copegus dose||Duration of treatment||Number of 200 mg tablets|
|<75||1,000 mg||24 or 48 weeks||5 (2 morning, 3 evening)|
|≥75||1,200 mg||24 or 48 weeks||6 (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 (see 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 Anaemia|
|Laboratory Values||Reduce only Copegus dose to 600 mg/day* if:||Discontinue Copegus 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|
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 (see section 5.2). 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. (see section 4.4).Use in hepatic impairment: Hepatic function does not affect the pharmacokinetics of ribavirin (see section 5.2). 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 (see section 5.1).
|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. Patients with substance use/abuse:HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended. Growth and development (children and adolescents): During the course of therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). At 2 years post-treatment with Pegasys, 16% of paediatric patients remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve. Case by case benefit/risk assessment in childrenThe expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1). - It is important to consider that the combination therapy induced a growth inhibition. - 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.|
Teratogenic risk: See section 4.6.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 some in vivo and in vitro genotoxicity assays. A potential carcinogenic effect of ribavirin cannot be excluded (see section 5.3). 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 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Copegus 800 mg 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 (see section 4.2). 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 (see section 4.5).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 evaluated 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 (see section 5.2). 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 (see section 4.2).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.Transplantation: The safety and efficacy of peginterferon-alfa-2a and Copegus treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with peginterferon-alfa-2a, alone or in combination with Copegus.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 (see section 4.5).The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).During treatment co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Copegus in combination with peginterferon alfa-2a or interferon alfa-2a should be discontinued immediately in patients with hepatic decompensation. Co-administration of Copegus and didanosine is not recommended due to the risk of mitochondrial toxicity (see Section 4.5). Moreover, co-administration 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:
|Haemoglobin||≥12 g/dl (females); ≥13 g/dl (males)|
HIV-HCV co-infected patientsNo 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).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 ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
Chronic hepatitis CThe most frequently reported adverse events with Copegus in combination with peginterferon alfa-2a 180 µg were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.
Chronic hepatitis C in prior non-responder patientsOverall, the safety profile for Copegus in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and Copegus treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and Copegus treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm3), and thrombocytopenia (13% experienced a platelet count <50,000/mm3) (see section 4.4).
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 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 system||Very common ≥1/10||Common≥1/100 to <1/10||Uncommon≥1/1000 to <1/100||Rare≥1/10,000 to <1/1000||Very rare<1/10,000||Frequency not known*|
|Infections and infestations||Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex||Lower respiratory tract infection, pneumonia, urinary tract infection, skin infection||Endocarditis, Otitis externa|
|Neoplasms benign and malignant||Malignant hepatic neoplasm|
|Blood and lymphatic system disorders||Anaemia||Thrombo-cytopenia, lymphadeno-pathy||Pancytopenia||Aplastic anaemia||Pure red cell aplasia|
|Immune system disorders||Sarcoidosis, thyroiditis||Anaphylaxis, systemic lupus erythemato-sus, rheumatoid arthritis||idiopathic or thrombotic thrombocyto-penic purpura||Liver and renal graft rejection, Vogt-Koyanagi-Harada disease|
|Endocrine disorders||Hypo-thyroidism, hyper-thyroidism||Diabetes|
|Metabolism and Nutrition Disorders||Anorexia||Dehydration|
|Psychiatric disorders||Depression, insomnia||Mood alteration, emotional disorders, anxiety, aggression, nervousness, libido decreased||Suicidal ideation, hallucina-tions, anger||Suicide, psychotic disorder||Mania, bipolar disorders, homicidal ideation|
|Nervous system disorders||Headache, dizziness, concentration impaired||Memory impairment, syncope, weakness, migraine, hypoaesthesia, hyperaesthe-sia, paraesthesia, tremor, taste disturbance, nightmares, somnolence||Peripheral neuropathy||Coma, convulsions, facial palsy|
|Eye disorders||Vision blurred, eye pain, eye inflammation, xerophthalmia||Retinal haemorrhage||Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer||Vision loss||Serous retinal detachment|
|Ear and labyrinth disorders||Vertigo, earache||Hearing loss|
|Cardiac disorders||Tachycardia, palpitations, oedema peripheral||Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis|
|Vascular disorders||Flushing||Hypertension||Cerebral haemorrhage|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea, cough||Dyspnoea exertional, epistaxis, nasopharyn-gitis, sinus congestion, nasal congestion, rhinitis, sore throat||Wheezing||Interstitial pneumonitis with fatal outcome, pulmonary embolism|
|Gastrointestinal disorders||Diarrhoea, nausea, abdominal pain||Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth||Gastrointes-tinal bleeding, cheilitis, gingivitis||Peptic ulcer, pancreatitis|
|Hepato-biliary disorders||Hepatic dysfunction||Hepatic failure, cholangitis, fatty liver|
|Skin and subcutaneous tissue disorders||Alopecia, dermatitis, pruritus, dry skin||Rash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensitivity reaction, night sweats||Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme|
|Musculoskeletal and connective tissue disorders||Myalgia, arthralgia||Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps||Myositis||Rhabdomyo-lysis|
|Renal and Urinary Disorders||Renal failure, nephrotic syndrome|
|Reproductive system and breast disorders||Impotence|
|General disorders and administration site conditions||Pyrexia, rigors, pain, asthenia, fatigue, injection site reaction, irritability||Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst|
|Injury and poisoning||Substance overdose|
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 <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.
Clinical efficacy and safety
Copegus in combination with peginterferon alfa-2a
Predictability of responsePlease refer to section 4.2, Table 2.
Study results in treatment-naive patientsEfficacy and safety of the combination of Copegus and peginterferon alfa-2a were established in two pivotal studies (NV15801 + NV15942), including a total of 2405 patients. The study population comprised interferon-naive patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT, and a liver biopsy consistent with chronic hepatitis C infection. Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 14). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl. Study NV15801 (1121 patients treated) compared the efficacy of 48 weeks of treatment with peginterferon alfa-2a (180 µg once weekly) and Copegus (1000/1200 mg daily) with either peginterferon alfa-2a monotherapy or combination therapy with interferon-alfa-2b and ribavirin. The combination of peginterferon alfa-2a and Copegus was significantly more efficacious than either the combination of interferon alfa-2b and ribavirin or peginterferon alfa-2a monotherapy. Study NV15942 (1284 patients treated) compared the efficacy of two durations of treatment (24 weeks with 48 weeks) and two dosages of Copegus (800 mg with 1000/1200 mg).For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see tables 6, 7, 8 and 14, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR™ HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after the end of therapy.
|Table 6 Virological Response in the overall population (including non-cirrhotic and cirrhotic patients)|
|Study NV15942||Study NV15801|
|Copegus 1,000/1,200 mg & Peginterferon alfa-2a 180 µg||Copegus 1,000/1,200 mg & Peginterferon alfa-2a 180 µg||Ribavirin 1,000/1,200 mg & Interferon alfa-2b 3 MIU|
|(N=436) 48 weeks||(N=453) 48 weeks||(N=444) 48 weeks|
|Response at End of Treatment||68%||69%||52%|
|Overall Sustained Response||63%||54%*||45%*|
|Table 7 Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Copegus Combination Therapy with peginterferon alfa-2a|
|Study NV15942||Study NV15801|
|Copegus800 mg & PEG-IFN alfa-2a180 µg 24 weeks||Copegus1000/1200 mg & PEG-IFN alfa-2a180 µg 24 weeks||Copegus800 mg & PEG-IFN alfa-2a180 µg 48 weeks||Copegus1000/1200 mg & PEG-IFN alfa-2a180 µg 48 weeks||Copegus1000/1200 mg & PEG-IFN alfa-2a180 µg 48 weeks||Ribavirin1000/1200 mg & Interferon alfa-2b3 MIU 48 weeks|
|Genotype 1||29 % (29/101)||42 % (49/118)||41 % (102/250)*||52 % (142/271)*||45 % (134/298)||36 % (103/285)|
|Low viral load||41 % (21/51)||52 % (37/71)||55 % (33/60)||65 % (55/85)||53 % (61/115)||44 % (41/94)|
|High viral load||16 % (8/50)||26 % (12/47)||36 % (69/190)||47 % (87/186)||40 % (73/182)||33 % (62/189)|
|Genotype 2/3||84 % (81/96)||81 % (117/144)||79 % (78/99)||80 % (123/153)||71 % (100/140)||61 % (88/145)|
|Low viral load||85 % (29/34)||83 % (39/47)||88 % (29/33)||77 % (37/48)||76 % (28/37)||65 % (34/52)|
|High viral load||84 % (52/62)||80 % (78/97)||74 % (49/66)||82 % (86/105)||70 % (72/103)||58 % (54/93)|
|Genotype 4||0 % (0/5)||67 % (8/12)||63 % (5/8)||82 % (9/11)||77 % (10/13)||45 % (5/11)|
|Table 8 Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype 1 and 4 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients|
|Study NV15942||Study ML17131|
|Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 24 weeks||Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 48 weeks||Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 24 weeks|
|Genotype 1 RVRLow viral load High viral load||90% (28/31) 93% (25/27) 75% (3/4)||92% (47/51) 96% (26/27) 88% (21/24)||77% (59/77) 80% (52/65) 58% (7/12)|
|Genotype 1 non RVRLow viral load High viral load||24% (21/87) 27% (12/44) 21% (9/43)||43% (95/220) 50% (31/62) 41% (64/158)||- - -|
|Genotype 4 RVR||(5/6)||(5/5)||92% (22/24)|
|Genotype 4 non RVR||(3/6)||(4/6)||-|
Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/mlRVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24 Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 9).
|Table 9 Relapse of Virological Response at the End of Treatment for Rapid Virological Response Population|
|Study NV15942||Study NV15801|
|Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 24 weeks||Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 48 weeks||Copegus1000/1200 mg & Peginterferon alfa-2a180 µg 48 weeks|
|Genotype 1 RVRLow viral load High viral load||6.7% (2/30) 3.8% (1/26) 25% (1/4)||4.3% (2/47) 0% (0/25) 9.1% (2/22)||0% (0/24) 0% (0/17) 0% (0/7)|
|Genotype 4 RVR||(0/5)||(0/5)||0% (0/4)|
|Table 10 Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients|
|Copegus 800 mg & Peginterferon alfa-2a 180 µg 16 weeks||Copegus 800 mg & Peginterferon alfa-2a 180 µg 24 weeks||Treatment difference95%CI||p value|
|Genotype 2 or 3||65% (443/679)||76% (478/630)||-10.6% [-15.5% ; -0.06%]||P<0.0001|
|Genotype 2 or 3 RVRLow viral loadHigh viral load||82% (378/461)89% (147/166)78% (231/295)||90% (370/410)94% (141/150)88% (229/260)||-8.2% [-12.8% ; -3.7%]-5.4% [-12% ; 0.9%]-9.7% [-15.9% ; -3.6%]||P=0.0006P=0.11P=0.002|
|Table 11 Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response|
|Copegus 800 mg & Peginterferon alfa-2a 180 µg 16 weeks||Copegus 800 mg & Peginterferon alfa-2a 180 µg 24 weeks||Treatment difference95%CI||p value|
|Genotype 2 or 3 RVRLow viral loadHigh viral load||15% (67/439)6% (10/155)20% (57/284)||6% (23/386)1% (2/141)9% (21/245)||9.3% [5.2% ; 13.6%]5% [0.6% ; 10.3%]11.5% [5.6% ; 17.4%]||P<0.0001P=0.04P=0.0002|
Chronic hepatitis C prior treatment non-responder patientsIn study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments: • peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 60 weeks • peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 36 weeks • peginterferon alfa-2a 180 µg/week for 72 weeks • peginterferon alfa-2a 180 µg/week for 48 weeks All patients received Copegus (1000 or 1200 mg/day) in combination with peginterferon alfa-2a. All treatment arms had 24 week treatment-free follow-up. Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 12.
|Table 12 Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Copegus and Peginterferon alfa-2a Combination Therapy in Non-Responders to Peginterferon alfa-2b plus Ribavirin|
|Copegus 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg 72 or 48 Weeks (N = 942) Pts with VR at Wk 12 a(N = 876)||Copegus 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg72 Weeks (N = 473) SVR in Pts with VR at Wk 12 b(N = 100)||Copegus 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg 48 Weeks (N = 469) SVR in Pts with VR at Wk 12 b(N = 57)|
|Overall Low viral load High viral load||18% (157/876) 35% (56/159) 14% (97/686)||57% (57/100) 63% (22/35) 54% (34/63)||35% (20/57) 38% (8/21) 32% (11/34)|
|Genotype 1/4 Low viral load High viral load||17% (140/846) 35% (54/154) 13% (84/663)||55% (52/94) 63% (22/35) 52% (30/58)||35% (16/46) 37% (7/19) 35% (9/26)|
|Genotype 2/3 Low viral load High viral load||58% (15/26) (2/5) (11/19)||(4/5) (3/4)||(3/10) (1/2) (1/7)|
|Cirrhosis StatusCirrhosis Noncirrhosis||8% (19/239) 22% (137/633)||(6/13) 59% (51/87)||(3/6) 34% (17/50)|
|Best Response during Previous Treatment≥2log10 decline in HCV RNA <2log10 decline in HCV RNA Missing best previous response||28% (34/121) 12% (39/323) 19% (84/432)||68% (15/22) 64% (16/25) 49% (26/53)||(6/12) (5/14) 29% (9/31)|
|Table 13 Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population|
|Previous Treatment||Copegus 1000/1200 mg & Peginterferon alfa-2a 180 µg 48 weeks|
|Pegylated interferon||34% (13/38)|
|Interferon plus ribavirin||13% (90/692)|
|Pegylated interferon plus ribavirin||11% (7/61)|
HCV patients with normal ALTIn study NR16071, HCV patients with normal ALT values were randomised to receive peginterferon alfa-2a 180 µg/week with a Copegus dose of 800 mg/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or an untreated control group for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.
Children and adolescentsIn the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with peginterferon alfa-2a 100 µg/m2 sc once weekly and Copegus 15 mg/kg/day, for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.
HIV-HCV co-infected patientsThe virological responses of patients treated with Copegus and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 14.
|Table 14 Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Copegus Combination Therapy with peginterferon alfa-2a in HIV-HCV co-infected patients|
|Interferon alfa-2a 3 MIU & Copegus 800 mg48 weeks||Peginterferon alfa-2a180 µg & Placebo48 weeks||Peginterferon alfa-2a180 µg & Copegus 800 mg48 weeks|
|All patients||12% (33/285)*||20% (58/286)*||40% (116/289)*|
|Genotype 1||7% (12/171)||14% (24/175)||29% (51/176)|
|Low viral load||19% (8/42)||38% (17/45)||61% (28/46)|
|High viral load||3% (4/129)||5% (7/130)||18% (23/130)|
|Genotype 2-3||20% (18/89)||36% (32/90)||62% (59/95)|
|Low viral load||27% (8/30)||38% (9/24)||61% (17/28)|
|High viral load||17% (10/59)||35% (23/66)||63% (42/67)|
Ribavirin in combination with interferon alfa-2aThe therapeutic efficacy of interferon alfa-2a alone and in combination with oral ribavirin was compared in clinical trials in naive (previously untreated) and relapsed patients who had virologically, biochemically and histologically documented chronic hepatitis C. Six months after end of treatment sustained biochemical and virological response as well as histological improvement were assessed.A statistically significant 10-fold increase (from 4% to 43%; p <0.01) in sustained virological and biochemical response was observed in relapsed patients (M23136; N=99). The favourable profile of the combination therapy was also reflected in the response rates relative to HCV genotype or baseline viral load. In the combination and interferon monotherapy arms, respectively, the sustained response rates in patients with HCV genotype-1 were 28% versus 0% and with genotype non-1 were 58% versus 8%. In addition the histological improvement favoured the combination therapy. Supportive favourable results (monotherapy vs combination; 6% vs 48%, p<0.04) from a small published study in naive patients (N=40) were reported using interferon alfa-2a (3 MIU 3 times per week) with ribavirin.
Tablet core:Pregelatinised maize starchSodium starch glycolate (type A)Microcrystalline cellulose Maize starchMagnesium stearate
Film-coating:HypromelloseTalcTitanium dioxide (E171) Yellow iron oxide (E172) Red iron oxide (E172)Ethylcellulose aqueous dispersionTriacetin
Roche Products Limited
Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW
+44 (0)1707 338 297
+44 (0)1707 384555
+44 (0)1707 366 000
+44 (0)800 328 1629
+44 (0)800 731 5711