Roche Products Limited

4.8     Undesirable effects

Experience from clinical trials

Chronic hepatitis C

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 4).The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.

Chronic hepatitis B

In clinical trials of 48 week treatment and 24 weeks follow-up, the safety profile for Pegasys in chronic hepatitis B was similar to that seen in chronic hepatitis C . With the exception of pyrexia the frequency of the majority of the reported adverse reactions was notably less in CHB patients treated with Pegasys monotherapy compared with HCV patients treated with Pegasys monotherapy (see Table 4). Adverse events were experienced by 88% of Pegasys-treated patients as compared with 53% of patients in the lamivudine comparator group, while 6% of the Pegasys-treated and 4% of the lamivudine-treated patients experienced serious adverse events during the studies. Adverse events or laboratory abnormalities led to 5% of patients withdrawing from Pegasys treatment, while less than 1% of patients withdrew from lamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew from treatment was similar to that of the overall population in each treatment group.

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Pegasys in combination with ribavirin in prior non-responder patients was similar to that in naïve 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 Pegasys treatment and ribavirin 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 Pegasys treatment and ribavirin 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 hematological toxicity were excluded from enrolling in this trial.

In another clinical trial, non-responder patients with advanced fibrosis 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 anemia (26% of patients experienced a hemoglobin 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 HIV co-infection

In HIV-HCV co-infected patients, the clinical adverse event profiles reported for Pegasys, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Pegasys and ribavirin 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. Pegasys 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 Pegasys 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.

Table 4 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC patients and with Pegasys in combination with ribavirin in CHC patients.

Table 4: Undesirable Effects Reported with Pegasys Monotherapy for HBV or HCV or iIn Combination with Ribavirin for HCV Patients in Clinical Trials and Post Marketing

*These adverse reactions were common (≥1/100 to < 1/10) in CHB patients treated with Pegasys monotherapy

Laboratory values

Pegasys treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase, electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia and elevated triglycerides (see section 4.4.). With both Pegasys monotherapy, and also the combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of the treatment.

Treatment with Pegasys was associated with decreases in haematological values (leucopenia, neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose modification, and returned to pre-treatment levels within 4‑8 weeks upon cessation of therapy (see sections 4.2 and 4.4).

Moderate (ANC: 0.749 ‑ 0.5 x 10⁹/l) and severe (ANC: < 0.5 x 10⁹/l) neutropenia was observed respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and ribavirin 1000/1200 milligrams for 48 weeks.

Anti-interferon antibodies

1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in chronic hepatitis B. However in neither disease was this correlated with lack of therapeutic response.

Thyroid function

Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients

Although 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 Pegasys monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm³ was observed in 10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anaemia (haemoglobin < 10 g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.

Post marketing adverse events

Infections and infestations:

Sepsis: frequency unknown.

As with other alpha interferons, sepsis has been reported with Pegasys.

Blood and lymphatic system disorders:

Pure red cell aplasia: frequency unknown.

As with other alpha interferons, pure red cell aplasia has been reported with Pegasys.

Immune system disorders:

Liver and renal graft rejection: frequency unknown.

Liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada disease (see also section 4.4, Autoimmune disease).

Psychiatric disorders:

Mania, bipolar disorders: frequency unknown.

As with other alpha interferons, mania and bipolar disorders have been reported with Pegasys.

Homicidal ideation: frequency unknown.

Nervous System Disorders:

Cerebral ischemia: frequency unknown.

Eye Disorders:

Serous retinal detachment: frequency unknown.

As with other alpha interferons, serous retinal detachment has been reported with Pegasys.

Vascular disorders:

Peripheral ischaemia: frequency unknown.

As with other alpha interferons, peripheral ischaemia has been reported with Pegasys.

Gastrointestinal disorders:

Ischaemic colitis: frequency unknown.

As with other alpha interferons, ischaemic colitis has been reported with Pegasys.

Musculoskeletal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.

6.5     Nature and contents of container

Available in packs containing 1, 4 or 12 pre-filled pens and 2, 4 or 12 alcohol pads. Not all pack-sizes may be marketed.

10.     DATE OF REVISION OF THE TEXT

29 June 201110 August 2011

4.6      Fertility, pregnancy and lactation

There are no adequate data on the use of peginterferon alfa-2a in pregnant women. Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and the potential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior to initiation of treatment.

Use with ribavirin

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Pegasys in combination with ribavirin. Female patients of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and or their female partners must each use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SPC.

4.3     Contraindications

·        Combination of Pegasys with telbivudine (see section 4.5).

4.5     Interaction with other medicinal products and other forms of interaction

A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established. Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).

10.     DATE OF REVISION OF THE TEXT

2 July 201018 April 2011

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4.2     Posology and method of administration

HIV-HCV co-infection

The recommended dosage for Pegasys, alone or in combination with 800 milligrams of ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks, regardless of genotype. For patients infected with HCV genotype 1 <75 kg and ³75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin.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.

4.3     Contraindications

Initiation of Pegasys is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinaemia caused by drugs such as atazanavir and indinavir

4.4     Special warnings and precautions for use

Transplantation

The safety and efficacy of Pegasys and Copegusribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, lLiver and renal graft rejections have been reported with Pegasys, alone or in combination with Copegusribavirin.

During treatment, cCo-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)., assessing their Child-Pugh score during treatment, and should be immediately discontinued if they progress to a 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 Pegasys should be discontinued immediately in patients with hepatic decompensation.

4.8       Undesirable effects

Laboratory values

Pegasys treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase, electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia and elevated triglycerides (see section 4.4.). With both Pegasys monotherapy, and also the combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of the treatment.

Treatment with Pegasys was associated with decreases in haematological values (leucopenia, neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose modification, and returned to pre-treatment levels within 4‑8 weeks upon cessation of therapy (see sections 4.2 and 4.4).

Moderate (ANC: 0.749 ‑ 0.5 x 10⁹/l) and severe (ANC: < 0.5 x 10⁹/l) neutropenia was observed respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and ribavirin 1000/1200 milligrams for 48 weeks.

Anti-interferon antibodies

1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in chronic hepatitis B. However in neither disease was this correlated with lack of therapeutic response.

Thyroid function

Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients

Although 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 Pegasys monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm³ was observed in 10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anaemia (haemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.

Immune system disorders:

Liver and renal graft rejection: frequency unknown.

As with other alpha interferons, lLiver and renal graft rejections have been reported with Pegasys, alone or in combination with Copegusribavirin.

5.1     Pharmacodynamic properties

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1000 mg (<75 kg)/1200 mg (³75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus ribavirin combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose ribavirin arm.

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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 a peginterferon and ribavirin 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

HCV monoinfected patients and HBV monoinfected patients

In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg to 150 mg), treatment with Pegasys 180 micrograms sc once weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

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 peginterferon alfa-2a and ribavirin concomitantly with azathioprin should be avoided. In individual cases where the benefit of administering ribavirin 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

Psychiatric disorders:

Mania, bipolar disorders: frequency unknown.

As with other alpha interferons, mania and bipolar disorders have been reported with Pegasys.

Homicidal ideation: frequency unknown.

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4.2     Posology and method of administration

Table 1: Dosing Recommendations for Combination therapy for HCV Patients

*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;

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

LVL= ≤800,000 IU/mL; HVL= > 800,000 IU/mL

^(a) It is presently not clear whether a higher dose of ribavirin (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.

4.4     Special warnings and precautions for use

Psychiatric and Central Nervous System (CNS):

Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys 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.

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Fever/infections

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and sepsis have been reported during treatment with alpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

4.5     Interaction with other medicinal products and other forms of interaction

HCV monoinfected patients and HBV monoinfected patients

Results from pharmacokinetic substudies of pivotal phase III trials demonstrated no pharmacokinetic interaction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCV patients.

In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg to 150 mg), treatment with Pegasys 180 micrograms sc once weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

Results from pharmacokinetic substudies of pivotal phase III trials demonstrated no pharmacokinetic interaction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCV patients.

A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.

4.8     Undesirable effects

Post marketing adverse events

Infections and infestations:

Sepsis: frequency unknown.

As with other alpha interferons, sepsis has been reported with Pegasys.

Blood and lymphatic system disorders:

Pure red cell aplasia: frequency unknown.

As with other alpha interferons, pure red cell aplasia has been reported with Pegasys.

Immune system disorders:

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada disease (see also section 4.4. Autoimmune disease).

Psychiatric disorders:

Mania, bipolar disorders: frequency unknown.

As with other alpha interferons, mania and bipolar disorders have been reported with Pegasys.

Vascular disorders:

Peripheral ischaemia: frequency unknown.

As with other alpha interferons, peripheral ischaemia has been reported with Pegasys.

Gastrointestinal disorders:

Ischaemic colitis: frequency unknown.

As with other alpha interferons, ischaemic colitis has been reported with Pegasys.

5.1     Pharmacodynamic properties

It is presently not clear whether a higher does of ribavirin (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.

5.2     Pharmacokinetic properties

Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be used in combination with ribavirin.

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4.2       Posology and method of administration

Patients under the age of 18 years

The safety and efficacy of Pegasys have not been established in this population. Pegasys is contraindicated in neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see section 4.3 and 4.4).

Children and adolescents

Only limited safety and efficacy data are available in children and adolescents (6-18 years) (see section 5.1). Pegasys is contraindicated in neonates and young children up to 3 years old because of the excipient benzyl alcohol (see sections 4.3 and 4.4).

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 PEG-IFN alfa 2a 100 mcg/m² sc once weekly and ribavirin 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

Chronic hepatitis C:

Pegasys is indicated for the treatment of chronic hepatitis C in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4).

The optimal way to use Pegasys in patients with chronic hepatitis C is in combination with ribavirin. The combination of Pegasys and ribavirin is indicated in naive patients and patients who have failed previous treatment with interferon alpha (pegylated or non-pegylated) alone or in combination therapy with ribavirin.

This combination is indicated in previously untreated patients as well as in patients who have previously responded to interferon alpha therapy and subsequently relapsed after treatment was stopped.

4.2     Posology and method of administration

Chronic hepatitis C – treatment-experienced patients:

The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by subcutaneous administration. For patients <75 kg and ³75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered.

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 PEG-IFN and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).(see predictability of response and non-response in prior non-responder patients). Patients who have undetectable virus at week 12 should receive 48 weeks of treatment. For genotype 1 non-responder patients with undetectable virus at week 12, 72 weeks of treatment may also be considered but is associated with a continuation of the side effects (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 Pegasys and ribavirin 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.

4.8     Undesirable effects

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Pegasys in combination with ribavirin in prior non-responder patients was similar to that in naïve 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 Pegasys treatment and ribavirin 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 Pegasys treatment and ribavirin 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 fibrosis 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).

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 randomizsed to four different treatments:

·        Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks;

·        Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks;

·        Pegasys 180 mcg/week for 72 weeks; or

·        Pegasys 180 mcg/week for 48 weeks.

All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment arms had 24 week treatment-free follow-up.

The primary analysis of the study demonstrated that sustained virological response was higher in patients treated for 72 weeks with an induction dose than in patients treated for 48 weeks without an induction dose (p=0.006). 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, and demographics and best responses to previous treatment are displayed in Table 12.

Table 12          Sustained Virological Response after Treatment with Pegasys and Ribavirin Combination Therapy in Non-responders to Previous Treatment with Peginterferon alfa 2b/Ribavirin

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

Table 12: Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Pegasys and Ribavirin Combination Therapy in Non-responders to Peginterferon alfa-2b plus Ribavirin.

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 Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on Pegasys plus ribavirin 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.

Table 13          Sustained Virological Response in HALT-C by Previous Treatment
Regimen in Non-responder Population

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4.4     Special warnings and precautions for use

Use of peginterferon as long term maintenance monotherapy (unapproved use)

In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was studied, no significant reductions were observed in the rate of fibrosis progression or related clinical events.

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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 remains 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).

*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;

LVL= ≤ 800,000 IU/mL; HVL= > 800,000 IU/mL

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

LVL= ≤800,000 IU/mL; HVL= > 800,000 IU/mL

The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for retreating non-responding and relapsing patients.

4.8 Undesirable effects

Post marketing adverse events

Nervous System Disorders:

Cerebral ischaemia: frequency unknown.

Eye Disorders:

Serous retinal detachment: frequency unknown.

As with other alpha interferons, serous retinal detachment has been reported with Pegasys.

Musculoskeletal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.

5.1 Pharmacodynamic properties

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on a 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 Pegasys 180 mg sc qw and a ribavirin dose of 800 mg and were randomizsed to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks was not equivalent to treatment for 24 weeks (see Table 10). 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 where HCV RNA negative by week 4 and had a LVL at baseline (see Table 10)However a retrospective analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline showed that the sustained viral response achieved with 16 weeks of treatment was comparable to that achieved with 24 weeks of treatment (89% and 94%, respectively) (see Table 10)

Table 10. Sustained Virological Response Overall and Based on Rapid Viral Response by Week

4 for Genotype 2 or 3 after Pegasys Combination Therapy with Ribavirin in HCV Patients

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).

Table 11: Relapse of Virological Response after the End of Treatment in Genotype 2 or 3

Patients with a Rapid Viral Response

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4.2              Posology and method of administration

HIV-HCV Co-infection

The recommended dosage for Pegasys, alone or in combination with 800 milligrams of ribavirin, is 180 micrograms once weekly subcutaneously 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.  Aor a  duration of therapy less than 48 weeks has not been adequately studied.

4.3              Special warnings and precautions for use

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

4.4              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

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4.4       Special warnings and precautions for use

Endocrine System

As with other interferons, hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys (see 4.8). Patients with these conditions who cannot be effectively controlled by medication should not being Pegasys monotherapy nor Pegasys/ribavirin combination therapy.

Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys or Pegasys/ribavirin therapy.

Fever/Infections

Serious infections (bacterial, viral, fungal) have been reported during treatment with alpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Dental and periodontal disorders:

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Pegasys and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

4.8       Undesirable effects

Table 6 – Nervous system disorders:

coma, peripheral neuropathy,coma

Very rarely, alpha interferons including Pegasys, used alone or in combination with ribavirin, may be associated with pancytopenia including aplastic anaemia.

After marketing, the following adverse events have beeen reported with Pegasys, used alone or in combination with ribavirin:

Blood and lymphatic system disorders:

Rarely: Pancytopenia

Very rarely: Aplastic anaemia

Endocrine disorders:

Very rarely: Diabetic ketoacidosis

Nervous system disorders:

Rarely: Convulsions, facial palsy