Harvoni

HOS-097215 · has-adverse-reaction-information · PDF-Seite 20

Summary of the safety profile in adults The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who received Harvoni in combination with ribavirin. The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively. In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions. Tabulated list of adverse events The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000). 20 Table 7: Adverse drug reactions identified with Harvoni Frequency Adverse drug reaction Nervous system disorders: Very common headache Skin and subcutaneous tissue disorders: Common rash Not known angioedema General disorders: Very common fatigue Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies (SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who w

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HOS-097221 · has-adverse-reaction-information · PDF-Seite 59

Summary of the safety profile in adults The safety assessment of Harvoni was mainly based on pooled Phase 3 clinical studies, without a control, in 1952 patients who received Harvoni for 8, 12 or 24 weeks, including 872 patients who received Harvoni in combination with ribavirin. The proportion of patients who permanently discontinued treatment due to adverse events was 0%, < 1% and 1% for patients receiving ledipasvir/sofosbuvir for 8, 12 and 24 weeks, respectively; and < 1%, 0%, and 2% for patients receiving ledipasvir/sofosbuvir + ribavirin combination therapy for 8, 12 and 24 weeks, respectively. In clinical studies, fatigue and headache were more common in patients treated with ledipasvir/sofosbuvir compared to placebo. When ledipasvir/sofosbuvir was studied with ribavirin, the most frequent adverse drug reactions to ledipasvir/sofosbuvir + ribavirin combination therapy were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions. Tabulated list of adverse events The following adverse drug reactions have been identified with Harvoni (Table 7). The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000). Table 7: Adverse drug reactions identified with Harvoni Frequency Adverse drug reaction Nervous system disorders: Very common headache Skin and subcutaneous tissue disorders: Common rash Not known angioedema General disorders: Very common fatigue Adults with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant The safety profile of ledipasvir/sofosbuvir with ribavirin for 12 or 24 weeks in adults with decompensated liver disease and/or those post-liver transplant was assessed in two open-label studies (SOLAR-1 and SOLAR-2). No new adverse drug reactions were detected among patients with decompensated cirrhosis and/or who were post-liver transplant and who received ledipasvir/sofosbuvir with ribavirin. Although adverse events, including serious adverse events, occurred more frequently in this study compared to studies that excluded decompensated patients and/or patients who were post- liver transplantation, the adverse events observed were t

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HOS-097211 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with rosuvastatin (see section 4.5). Use with strong P-gp inducers Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni (see section 4.5).

HOS-097217 · has-contraindication-information · PDF-Seite 43

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with rosuvastatin (see section 4.5). 43 Use with strong P-gp inducers Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will significantly decrease ledipasvir and sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni (see section 4.5).

HOS-097216 · has-indication-information · PDF-Seite 40

Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.

HOS-097210 · has-indication-information · PDF-Seite 2

Harvoni is indicated for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype-specific activity see sections 4.4 and 5.1.

HOS-097219 · has-interaction-information · PDF-Seite 46

As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni. Potential for Harvoni to affect other medicinal products Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters. Potential for other medicinal products to affect Harvoni Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected. Patients treated with vitamin K antagonists As liver function may change during treatment with Harvoni, a close monitoring of International Normalised Ratio (INR) values is recommended. 46 Impact of DAA therapy on drugs metabolized by the liver The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Interactions between Harvoni and other medicinal products Table 6 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The medicinal product

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HOS-097213 · has-interaction-information · PDF-Seite 8

As Harvoni contains ledipasvir and sofosbuvir, any interactions that have been identified with these active substances individually may occur with Harvoni. Potential for Harvoni to affect other medicinal products Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters. Potential for other medicinal products to affect Harvoni Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. Medicinal products that are strong P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of ledipasvir/sofosbuvir and thus are contraindicated with Harvoni (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni. Co-administration with such medicinal products is not recommended with Harvoni (see section 4.4). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Clinically significant medicinal product interactions with ledipasvir/sofosbuvir mediated by CYP450s or UGT1A1 enzymes are not expected. Patients treated with vitamin K antagonists As liver function may change during treatment with Harvoni, a close monitoring of International Normalised Ratio (INR) values is recommended. Impact of DAA therapy on drugs metabolized by the liver The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. Interactions between Harvoni and other medicinal products Table 6 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The medicinal product interactions described are based on studies conducted with

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HOS-097214 · has-pregnancy-information · PDF-Seite 19

Women of childbearing potential / contraception in males and females When Harvoni is used in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information. Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or Harvoni in pregnant women. 19 Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy. Breast-feeding It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of sofosbuvir in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during breast-feeding. Fertility No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility. If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin).

HOS-097220 · has-pregnancy-information · PDF-Seite 58

Women of childbearing potential / contraception in males and females When Harvoni is used in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information. Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or Harvoni in pregnant women. Animal studies do not indicate direct harmful effects with respect to reproductive toxicity. No significant effects on foetal development have been observed with ledipasvir or sofosbuvir in rats and rabbits. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy. Breast-feeding It is unknown whether ledipasvir or sofosbuvir and its metabolites are excreted in human milk. Available pharmacokinetic data in animals has shown excretion of ledipasvir and metabolites of sofosbuvir in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Therefore, Harvoni should not be used during breast-feeding. Fertility No human data on the effect of Harvoni on fertility are available. Animal studies do not indicate harmful effects of ledipasvir or sofosbuvir on fertility. If ribavirin is co-administered with Harvoni, the contraindications regarding use of ribavirin during pregnancy and breast-feeding apply (see also the Summary of Product Characteristics for ribavirin).

HOS-097218 · has-warning-information · PDF-Seite 44

Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir. Genotype-specific activity Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1. The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options. The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are limited (see section 5.1). Severe bradycardia and heart block Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment. Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated. Should concomitant use of amiodarone be considered necessary it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Harvoni. All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them. Use in diabetic patients Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglyc

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HOS-097212 · has-warning-information · PDF-Seite 5

Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir. Genotype-specific activity Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1. 5 The clinical data to support the use of Harvoni in adults infected with HCV genotype 3 are limited (see section 5.1). The relative efficacy of a 12-week regimen consisting of ledipasvir/sofosbuvir + ribavirin, compared to a 24-week regimen of sofosbuvir + ribavirin has not been investigated. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis (see section 4.2). In genotype 3-infection, the use of Harvoni (always in combination with ribavirin) should only be considered for patients who are deemed at high risk for clinical disease progression and who do not have alternative treatment options. The clinical data to support the use of Harvoni in adults infected with HCV genotype 2 and 6 are limited (see section 5.1). Severe bradycardia and heart block Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir- containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment. Amiodarone should only be used in patients on Harvoni when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated. Should concomitant use of amiodarone be considered necessary it is recommended that patients undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Harvoni. All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them. Use in diabetic patients Diabetics may experience improved glu

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