Roche Products Limited

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4.2      Posology and method of administration

[…]

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 is currently being studied. A duration of therapy less than 48 weeks has not been adequately studied.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 daily

A duration of therapy less than 48 weeks has not been adequately studied.

[…]

4.3      Contraindications

See peginterferon alfa-2a or interferon alfa-2a prescribing information for contraindications related to either of these products.

-           hypersensitivity to ribavirin or to any of the excipients.

-           pregnant women (see section 4.4). Copegus must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

-           women who are breast-feeding (see section 4.6).

-           a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.

-           severe hepatic dysfunction or decompensated cirrhosis of the liver.

-           haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).

-          Initiation of peginterferon alfa-2a is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir. (Please refer to the SPC of peginterferon alfa-2a section 4.4 for Child-Pugh assessment).

4.4      Special warnings and precautions for use

[…]

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.

[…]

During treatment Cco-infected patients should be closely monitored, for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic functions 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 assessing their Child-Pugh score during treatment, and should be immediately discontinued immediately in patients with hepatic decompensation. if they progress to a Child-Pugh score of 7 or greater.

[…]

4.8      Undesirable effects

[…]

Immune system disorders:

Liver and renal graft rejection: frequency unknown

Liver and renal graft rejections have been reported with Peginterferon-alfa2a, alone or in combination with Copegus.

[…]

5.1      Pharmacodynamic properties

[…]

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using peginterferon alfa-2a 180 mcg week and either Copegus 800 mg or 1000 mg (<75 kg/1200 mg (≥75 kg) daily for 48 weeks.  The study was not powered for efficacy considerations.  The safety profiles in both Copegus groups were consistent with the known safety profile of peginterferon alfa-2a plus Copegus combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Copegus arm.

[…]

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4.6      Fertility, pPregnancy and lactation

Preclinical data: Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted, occurring at doses well below the recommended human dose. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the ribavirin dose. Survival of foetuses and offspring was reduced.

Female patients: Copegus must not be used by women who are pregnant (see section 4.3 and section 4.4). Extreme care must be taken to avoid pregnancy in female patients. Copegus therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Any birth control method can fail. Therefore, it is critically important that women of childbearing potential and their partners must use 2a forms of effective contraception simultaneously, during treatment and for 4 months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within 4 months from stopping treatment the patient must be advised of the significant teratogenic risk of ribavirin to the foetus.

Male patients and their female partners: Extreme care must be taken to avoid pregnancy in partners of male patients taking Copegus. Ribavirin accumulates intracellularly and is cleared from the body very slowly. In animal studies, ribavirin produced changes in sperm at doses below the clinical dose. It is unknown whether the ribavirin that is contained in sperm will exert its known teratogenic effects upon fertilisation of the ova. Either Mmale patients andor their female partners of childbearing age must, therefore, be counselled to use 2a forms of effective contraception simultaneously during treatment with Copegus and for 7 months after treatment has been concluded. A pregnancy test must be performed before therapy is started. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin to the partner.

Lactation: It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment.

5.2      Pharmacokinetic properties

[…]

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentrations in seminal fluid are approximately two-fold higher compared to serum. However, ribavirin systemic of a female partner after a sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentrations of ribavirin.

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4.2     Posology and method of administration

[…]

Special populations

Use 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, and 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 and section 5.2).

4.4     Special warnings and precautions for use

[…]

Renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients (see section 5.2). 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, and 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. and section 5.2).

4.9     Overdose

No cases of overdose of Copegus have been reported in clinical trials. Hypocalcaemia and hypomagnesaemia have been observed in persons administered dosages greater than four times the maximal recommended dosages. In many of these instances ribavirin was administered intravenously. Ribavirin is not effectively removed by haemodialysis.Due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed by haemodialysis.

5.2     Pharmacokinetic properties

[…]

Renal function: Single-dose ribavirin pharmacokinetics were altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects whose creatinine clearance was greater than 90 ml/minute. The clearance of ribavirin is substantially reduced in patients with serum creatinine > 2 mg/dl or creatinine clearance < 50 ml/min. There are insufficient data on the safety and efficacy of ribavirin in such patients to support recommendations for dose adjustments. Plasma concentrations of ribavirin are essentially unchanged by haemodialysis.

Renal function: The apparent clearance of ribavirin is reduced in patients with creatinine clearance ≤50 ml/min, including patients with ESRD on chronic haemodialysis, exhibiting approximately 30% of the value found in patients with normal renal function. Based on a small study in patients with moderate or severe renal impairment (creatinine clearance ≤50 ml/min) receiving reduced daily doses of 600 mg and 400 mg of Copegus, respectively ribavirin plasma exposure (AUC) was found to be higher compared to patients with normal renal function (creatinine clearance >80 ml/min) receiving the standard Copegus dose. Patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Copegus, exhibited mean ribavirin exposure (AUC) approximately 80% of the value found in patients with normal renal function receiving the standard 1000/1200 mg Copegus daily dose. Plasma ribavirin is removed by haemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed from the body by haemodialysis. Increased rates of adverse drug reactions were observed in patients with moderate and severe renal impairment receiving the doses evaluated in this study. Though the dose of ribavirin would need to be reduced if used in patients with significant renal impairment, there are insufficient data on the safety and efficacy of ribavirin in such patients to support specific recommendations for dose adjustments (see section 4.2 and 4.4).

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4.4     Special warnings and precautions for use

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).

4.5     Interaction with other medicinal products and other forms of interaction

Azathioprine: Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine.  The use of Copegus and peginterferon alfa-2a concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering Copegus concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these drugs should be stopped (see section 4.4).

4.8     Undesirable effects

Table 5 shows the undesirable effects reported in patients who have received Copegus and peginterferon alfa-2a or interferon alfa-2a therapy.

Blood and lymphatic system disorders:

Pure red cell aplasia: frequency unknown.

Pure red cell aplasia has been reported with ribavirin in combination with interferons, including Pegasys.

Immune system disorders:

Vogt-Koyanagi-Harada Syndrome: frequency unknown. Vogt-Koyanagi-Harada Syndrome has been reported with ribavirin in combinations with interferons, including Pegasys.

Psychiatric disorders:

Homicidal ideation: frequency unknown.

Mania, bipolar disorders: frequency unknown.  Mania and bipolar disorders have been reported with ribavirin in combination with interferons, including Pegasys.

Musculoskelatal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.  Rhabdomyolysis has been reported with ribavirin in combination with interferons, including Pegasys.

10.     DATE OF REVISION OF THE TEXT

29 December 2010<[See Annex I - To be completed nationally]>

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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.

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4.1     Therapeutic indications

Copegus is indicated for the treatment of chronic hepatitis C and must only be used as part of a combination regimen with peginterferon alfa-2a or with interferon alfa-2a. Copegus monotherapy must not be used.

The combination of Copegus with peginterferon alfa-2a or interferon alfa-2a is indicated in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis. (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).

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 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).

Postmarketing adverse events

Eye Disorders:

Serous retinal detachment: frequency unknown

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

5.1     Pharmacodynamic properties

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).

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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)