Sovaldi · 4.8 Undesirable effects · 2

HOS-096816 · has-adverse-reaction-information · PDF-Seite 45

Summary of the safety profile in adults Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled). Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa. In this context, no adverse drug reactions specific to sofosbuvir have been identified. The most common 45 adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia. Tabulated summary of adverse reactions The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). 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 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin Frequency SOFa + RBVb SOF + PEGc + RBV Infections and infestations: Common nasopharyngitis Blood and lymphatic system disorders: anaemia, neutropenia, lymphocyte count Very common haemoglobin decreased decreased, platelet count decreased Common anaemia Metabolism and nutrition disorders: Very common decreased appetited decreased appetite Common weight decreased Psychiatric disorders: Very common insomnia insomnia Common depression depression, anxiety, agitation Nervous system disorders: Very common headache dizziness, headache migraine, memory impairment, Common disturbance in attention disturbance in attention Eye disorders: Common

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HOS-096810 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile in adults Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled). Sovaldi has been studied in combination with ribavirin, with or without peginterferon alfa. In this context, no adverse drug reactions specific to sofosbuvir have been identified. The most common adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia. Tabulated summary of adverse reactions The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). 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 6: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin Frequency SOFa + RBVb SOF + PEGc + RBV Infections and infestations: Common nasopharyngitis Blood and lymphatic system disorders: Very common haemoglobin decreased anaemia, neutropenia, lymphocyte count decreased, platelet count decreased Common anaemia Metabolism and nutrition disorders: Very common decreased appetited decreased appetite Common weight decreased Psychiatric disorders: Very common insomnia insomnia Common depression depression, anxiety, agitation Nervous system disorders: Very common headache dizziness, headache Common disturbance in attention migraine, memory impairment, disturbance in attention 14 Eye disorders: Common vision blurred Respiratory, thoracic and mediastinal disorders: Very common

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HOS-096812 · has-contraindication-information · PDF-Seite 37

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

HOS-096806 · has-contraindication-information · PDF-Seite 6

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

HOS-096805 · has-indication-information · PDF-Seite 2

Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults 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-096811 · has-indication-information · PDF-Seite 33

Sovaldi is indicated in combination with other medicinal products 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-096814 · has-interaction-information · PDF-Seite 39

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters. The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see section 5.2). Patients treated with vitamin K antagonists As liver function may change during treatment with Sovaldi, a close monitoring of International Normalised Ratio (INR) values is recommended. Impact

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HOS-096808 · has-interaction-information · PDF-Seite 8

Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters. The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see section 5.2). Patients treated with vitamin K antagonists As liver function may change during treatment with Sovaldi, a close monitoring of International Normalised Ratio (INR) values is recommended. Impact

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HOS-096809 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential / contraception in males and females When Sovaldi is used in combination with ribavirin or peginterferon alfa/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 (see section 4.4). 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 sofosbuvir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. 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 Sovaldi during pregnancy. However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin). Breast-feeding It is unknown whether sofosbuvir and its metabolites are excreted in human milk. 13 Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details see section 5.3). A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during breast-feeding. Fertility No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicate harmful effects on fertility.

HOS-096815 · has-pregnancy-information · PDF-Seite 45

Women of childbearing potential / contraception in males and females When Sovaldi is used in combination with ribavirin or peginterferon alfa/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 (see section 4.4). 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 sofosbuvir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. 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 Sovaldi during pregnancy. However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin). Breast-feeding It is unknown whether sofosbuvir and its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details see section 5.3). A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during breast-feeding. Fertility No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicate harmful effects on fertility.

HOS-096813 · has-warning-information · PDF-Seite 37

General Sovaldi is not recommended for administration as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C infection. If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi. 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 Sovaldi 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 Sovaldi. 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. HCV/HBV (hepatitis B virus) co-infection Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines. 37 Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see also sections 4.2 an

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HOS-096807 · has-warning-information · PDF-Seite 6

General Sovaldi is not recommended for administration as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C infection. If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi. 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 Sovaldi 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 Sovaldi. 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. HCV/HBV (hepatitis B virus) co-infection Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines. Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see also sections 4.2 and 5.1).

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