Pegasys · 4.4 Special warnings and precautions for use · 2

HOS-093272 · has-adverse-reaction-information · PDF-Seite 18

Summary of the safety profile Polycythaemia vera and essential thrombocythaemia Results from clinical studies and retrospective analyses in patients with polycythaemia vera and essential thrombocythaemia did not show any additional side effects than what is observed in patients with CHB or CHC, and as listed in Table 9. The most frequent side effects are flu-like symptoms, injection site reactions, peripheral sensory neuropathies, visual disturbances, Grade 1/2 depression, leukopenia, increases in hepatic ASAT transaminases, hypertension, fatigue, lymphopenia, anaemia and lymphocytopenia, diarrhoea, nausea, headache, musculoskeletal pain, skin toxicity, asthenia, and gastrointestinal symptoms. Chronic hepatitis B in adult patients In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in CHB was similar to that seen in CHC. 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 CHC patients treated with Pegasys monotherapy (see Table 9). 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 adult patients The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9). 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. 18 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 o

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HOS-093278 · has-adverse-reaction-information · PDF-Seite 56

Summary of the safety profile Chronic hepatitis B in adult patients In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in CHB was similar to that seen in CHC. 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 CHC patients treated with Pegasys monotherapy (see Table 9). 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 adult patients The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9). 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. 56 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 tr

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HOS-093268 · has-contraindication-information · PDF-Seite 11

• Hypersensitivity to the active substance, to alfa interferons, or to any of the excipients listed in section 6.1 • History or presence of autoimmune diseases • Pre-existing thyroid disease unless it can be controlled with conventional treatment • Severe hepatic dysfunction or decompensated cirrhosis of the liver • A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4) • HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by medicinal products such as atazanavir and indinavir • Combination with telbivudine (see section 4.5) 11 • Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see section 4.4 for benzyl alcohol • In paediatric patients, the presence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt

HOS-093274 · has-contraindication-information · PDF-Seite 49

• Hypersensitivity to the active substance, to alfa interferons, or to any of the excipients listed in section 6.1 • Autoimmune hepatitis • Severe hepatic dysfunction or decompensated cirrhosis of the liver • A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4) • HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6, except if only due to indirect hyperbilirubinemia caused by medicinal products such as atazanavir and indinavir • Combination with telbivudine (see section 4.5) 49 • Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see section 4.4 for benzyl alcohol) • In paediatric patients, the presence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt.

HOS-093267 · has-indication-information · PDF-Seite 2

Polycythaemia vera Pegasys is indicated as monotherapy in adults for the treatment of polycythaemia vera. Essential thrombocythaemia Pegasys is indicated as monotherapy in adults for the treatment of essential thrombocythaemia. 2 Chronic hepatitis B Adult patients Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg- negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased alanine aminotransferase (ALT) and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1). Paediatric patients 3 years of age and older Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 and 5.1. Chronic hepatitis C Adult patients Pegasys is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC) in patients with compensated liver disease (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype specific activity, see sections 4.2 and 5.1. Paediatric patients 5 years of age and older Pegasys in combination with ribavirin is indicated for the treatment of CHC in treatment-naïve children and adolescents 5 years of age and older who are positive for serum HCV-RNA. When deciding to initiate treatment in childhood, it is important to consider growth inhibition induced by combination therapy. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).

HOS-093273 · has-indication-information · PDF-Seite 41

Chronic hepatitis B Adult patients Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg- negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased alanine aminotransferase (ALT) and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1). Paediatric patients 3 years of age and older Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 and 5.1. 41 Chronic hepatitis C Adult patients Pegasys is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC) in patients with compensated liver disease (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype specific activity, see sections 4.2 and 5.1. Paediatric patients 5 years of age and older Pegasys in combination with ribavirin is indicated for the treatment of CHC in treatment-naïve children and adolescents 5 years of age and older who are positive for serum HCV-RNA. When deciding to initiate treatment in childhood, it is important to consider growth inhibition induced by combination therapy. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).

HOS-093276 · has-interaction-information · PDF-Seite 54

Interaction studies have only been performed in adults. Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 2C19 and 2D6 isozymes. In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. Serum concentrations of theophylline should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy. 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 54 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 medicinal products should be stopped (see section 4.4). 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 comb

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HOS-093270 · has-interaction-information · PDF-Seite 16

Interaction studies have only been performed in adults. Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 2C19 and 2D6 isozymes. In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. Serum concentrations of theophylline should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy. 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 16 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 medicinal products should be stopped (see section 4.4). 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 combin

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HOS-093277 · has-pregnancy-information · PDF-Seite 55

Pregnancy There are no or limited amount of data from 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. 55 Breastfeeding It is unknown whether peginterferon alfa-2a/metabolites are excreted in human milk. Because of the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued prior to initiation of treatment. Fertility There are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of the menstrual cycle has been seen with peginterferon alfa-2a in female monkeys (see section 5.3). 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 must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SmPC.

HOS-093271 · has-pregnancy-information · PDF-Seite 17

Pregnancy There are no or limited amount of data from 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. Breastfeeding It is unknown whether peginterferon alfa-2a/metabolites are excreted in human milk. Because of the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued prior to initiation of treatment. Fertility There are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of the menstrual cycle has been seen with peginterferon alfa-2a in female monkeys (see section 5.3). 17 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 must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SmPC.

HOS-093269 · has-warning-information · PDF-Seite 12

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Pegasys therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alfa interferons. All patients should be closely monitored for any signs or symptoms of psychiatric disorders. If symptoms of psychiatric disorders appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Pegasys be discontinued, and the patient followed, with psychiatric intervention as appropriate. 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. The use of Pegasys in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Patients with substance use/abuse: HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alfa interferon. If treatment with alfa interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is

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HOS-093275 · has-warning-information · PDF-Seite 50

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Pegasys therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alfa interferons. All patients should be closely monitored for any signs or symptoms of psychiatric disorders. If symptoms of psychiatric disorders appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Pegasys be discontinued, and the patient followed, with psychiatric intervention as appropriate. 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. The use of Pegasys in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Patients with substance use/abuse: HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alfa interferon. If treatment with alfa interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is

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