- 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.
Dose to be administeredThe dose of Copegus is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1). Copegus tablets are to be administered orally each day in two divided doses (morning and evening) with food.
|Table 1. Copegus dosing recommendation according to the medicinal product used in combination|
|Medicinal product used in combination||Daily Copegus Dose||Number of 200/400mg tablets|
|Direct acting antivirals (DAA)||<75kg=1000mg =>75 kg = 1200 mg||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|PegIFN alfa-2a with DAA||<75kg=1000mg =>75 kg = 1200 mg||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|PegIFN alfa-2a without DAA||Genotype 2/3 treatment-naïveGenotype 2/3/4 with HIV-coinfection800mg||4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening)|
|Genotype 1/4Genotype 2/3 treatment-experiencedGenotype 1 HIV-coinfection<75kg=1000mg =>75 kg = 1200 mg||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|IFN alfa-2a without DAA||<75kg=1000mg =>75 kg = 1200 mg||5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening)|
|PegIFN alfa-2b with or without DAA||<65kg= 800 mg||4 x 200mg (2 morning, 2 evening) or 2 x 400(1 morning, 1 evening)|
|65-80kg= 1,000 mg||5 (2 morning, 3 evening)|
|81-105kg= 1,200 mg||6 (3 morning, 3 evening)|
|>105kg= 1,400 mg||7 (3 morning, 4 evening)|
Duration of treatmentDuration of treatment depends on medicinal products that it is being combined with and may depend on several patients or virus characteristics including genotype, co-infection status, previous history of treatment, on-treatment response. Refer to the SPC of the medicinal product that is used in combination with Copegus.
Dosage modification for adverse reactionsDose modification of Copegus depends on medicinal products that it is being combined with.If a patient has a severe adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
|Table 2 Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia|
|Laboratory Values||Reduce Copegus dose to   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. The total daily dose of Copegus should be reduced for patients with creatinine clearance less than or equal to 50 ml/min as shown in Table 3 (see also section 5.2).
|Table 3 Dosage Modification for Renal Impairment|
|Creatinine Clearance||Copegus Dose (daily)|
|30 to 50 ml/min||Alternating doses, 200 mg and 400 mg every other day|
|Less than 30 ml/min||200 mg daily|
|Hemodialysis||200 mg daily|
Combination therapy of ribavirin with (peg)interferon alfa.There are several severe adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa. These include: - Severe psychiatric and central nervous system effects (such as depression, suicidal ideation, attempted suicide and aggressive behavior, etc.) - Severe ocular disorders - Dental and periodontal disorders - Growth inhibition in children and adolescents that may be irreversible in some patients Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding these adverse reactions before initiating therapy.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 the 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 other medicinal products 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 in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute, therefore Copegus dose adjustments are recommended in these patients (see sections 4.2 and 5.2). Haemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary (see section 4.2).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 ribavirin and the other medicinal products. 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 other medicinal products 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, glucose, 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:Haemoglobin ≥12 g/dl (females); ≥13 g/dl (males)In patients co-infected with HIV-HCV, limited efficacy and safety data 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 evaluations 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.
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, 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 SmPC). Table 4 shows the undesirable effects reported in patients who have received Copegus primarily in combination with peginterferon alfa-2a or interferon alfa-2a.
|Table 4 Undesirable Effects Reported with Copegus primarily in combination with Peginterferon alfa-2a or Interferon 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|
|Blood and lymphatic system disorders||Anaemia, neutropenia||Thrombo-cytopenia, lymphadeno-pathy||Pancytopenia||Aplastic anaemia||Pure red cell aplasia|
|Immune system disorders||Sarcoidosis, thyroiditis||Anaphylaxis, systemic lupus erythematosus, 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, hallucinations, 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||Cerebral ischaemia|
|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, tinnitus||Hearing loss|
|Cardiac disorders||Tachycardia, palpitations, oedema peripheral||Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis|
|Vascular disorders||Flushing, hypotension||Hypertension||Cerebral haemorrhage, vasculitis|
|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||Gastrointestinal bleeding, cheilitis, gingivitis||Peptic ulcer, pancreatitis||Colitis ischaemic, colitis ulcerative, tongue pigmentation|
|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, 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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Clinical efficacy and safety
Copegus in combination with DAAPlease refer to the SmPC of the corresponding direct antiviral agent for a full description of the clinical data with such combination. Only the description of the use of Copegus with (peg)interferon are detailed in the current SmPC
Copegus in combination with peginterferon alfa-2a
Predictability of responsePlease refer to the peginterferon alfa-2a SmPC.
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 13). 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 5, 6, 7 and 13 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 5 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 6 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 1Low viral load High viral load||29% (29/101) 41% (21/51) 16% (8/50)||42% (49/118)52% (37/71) 26% (12/47)||41% (102/250)* 55% (33/60) 36% (69/190)||52% (142/271)*65% (55/85) 47% (87/186)||45% (134/298) 53% (61/115) 40% (73/182)||36%(103/285) 44% (41/94) 33% (62/189)|
|Genotype 2/3Low viral load High viral load||84% (81/96) 85% (29/34) 84% (52/62)||81% (117/144) 83% (39/47) 80% (78/97)||79% (78/99) 88% (29/33) 74% (49/66)||80% (123/153) 77% (37/48) 82% (86/105)||71% (100/140) 76% (28/37) 70% (72/103)||61% (88/145) 65% (34/52) 58% (54/93)|
|Genotype 4||0% (0/5)||67% (8/12)||63% (5/8)||82% (9/11)||77% (10/13)||45% (5/11)|
|Table 7 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)||-|
|Table 8 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 9 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-2a180 µg 16 weeks||Copegus 800 mg & Peginterferon alfa-2a180 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 load High 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=0.0006 P=0.11 P=0.002|
|Table 10 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-2a180 µg 16 weeks||Copegus 800 mg & Peginterferon alfa-2a180 µg 24 weeks||Treatment difference95%CI||p value|
|Genotype 2 or 3 RVRLow viral load High 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<0.0001 P=0.04 P=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 weeksAll 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 11.
|Table 11 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 µg 72 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 12 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 13.
|Table 13 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 celluloseMaize 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