Roche Products (Ireland) Ltd

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4.2     Posology and method of administration

^(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.

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).

5.1     Pharmacodynamic properties

Children and adolescents

In 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 mcg/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.

4.1     Therapeutic indications

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. (See section 4.4) The combination with peginterferon alfa-2a is also indicated in patients co- infected with clinically stable HIV, including patients with compensated cirrhosis (See section 4.3). The combination regimens are Copegus, in combination with peginterferon alfa-2a, is indicated in previously untreated naive patients as well as in and patients who have previously responded to failed previous treatment with interferon alpha therapy and subsequently relapsed after treatment was stopped (pegylated or non-pegylated) alone or in combination therapy with ribavirin.

4.2     Posology and method of administration

Chronic hepatitis C – treatment-experienced patients

The 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 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-infection

The 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 or a 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 patients

Predictability of response and non-response – treatment-experienced patients

In 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.

4.4     Special warnings and precautions for use

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.

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

Patients treated with Copegus and alpha interferon (standard and pegylated) combination therapy and zidovudine could be at increased risk of developing anaemia.

4.5     Interaction with other medicinal products and other forms of interaction

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.

4.8     Undesirable effects

Chronic hHepatitis C

The most frequently reported adverse events with Copegus in combination with peginterferon alfa-2a 180 micrograms were mostly mild to moderate in severity and were. Most of them were manageable without the need for modification of doses or discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients

Overall, 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 hHepatitis C and Human Immunodeficiency Virus Co-infection

Postmarketing adverse events

Eye Disorders:

Serous retinal detachment: frequency unknown

Serous retinal detachment has been reported with ribavirin in combination with interferons, including Pegasys.

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.

5.1     Pharmacodynamic properties

Study results in treatment-naive patients

Efficacy 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-naiïve 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 142). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.

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 142, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICORÔ 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.

Chronic hepatitis C prior treatment non-responder patients

In 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 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks

·  peginterferon alfa-2a 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks

·  peginterferon alfa-2a 180 mcg/week for 72 weeks

·  peginterferon alfa-2a 180 mcg/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.

High viral load = >800,000 IU/mL, low viral load =  £ 800,000 IU/mL.

a Patients who achieved viral suppression (undetectable HCV RNA, <50 IU/mL) at week 12 were considered to have a virological response at week 12.  Patients missing HCV RNA results at week 12 have been excluded from the analysis.

b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were considered to be non-responders

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 mcg/week and Copegus 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Copegus combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 13).

HIV-HCV co-infected patients

The 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 142.

Low viral load= ≤ 800,000 IU/mL; High viral load= > 800,000 IU/mL

* peginterferon alfa-2a 180 mcg Copegus 800mg vs. Interferon alfa-2a 3MIU ribavirin 800mg: Odds Ratio (95% CI) =  5.40 (3.42 to 8.54),  ….P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001

* peginterferon alfa-2a 180 mcg Copegus 800mg vs. peginterferon alfa-2a  180mg: Odds Ratio ( 95% CI) = 2.89 (1.93 to 4.32),….P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0001

* Interferon alfa-2a 3MIU Copegus 800mg vs. peginterferon alfa-2a 180mcg: Odds Ratio ( 95% CI) = 0.53 (0.33 to 0.85),  …P-value (stratified Cochran-Mantel-Haenszel test) = < 0.0084.

6.3     Shelf life

34 years

10.     DATE OF REVISION OF THE TEXT

UK: 15 July 200913 November 2009

Ireland: 15 July 20093 December 2009

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4.2     Posology and method of administration

Patients infected with HCV genotype 2/3 regardless of pre-treatment viral load should receive 24 weeks of therapy (see Table 1).

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).

5.1     Pharmacodynamic properties

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 10).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received peginterferon alfa-2a 180 µg sc qw and a Copegus dose of 800 mg and were randomised to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 10).

Low viral load= ≤ 800,000 IU/mL at baseline; High viral load= > 800,000 IU/mL at baseline

RVR = rapid viral response (HCV RNA negative) by week 4

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 11)