Prevymis · 4.1 Therapeutic indications · 3

HOS-098421 · has-adverse-reaction-information · PDF-Seite 50

Summary of the safety profile The safety assessment of letermovir was based on three Phase 3 clinical trials. HSCT In P001, 565 adult HSCT recipients received letermovir or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant (see section 5.1). The most commonly reported adverse reactions occurring in at least 1% of subjects in the letermovir group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently reported adverse reactions that led to discontinuation of letermovir were: nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%). In P040, 218 adult HSCT recipients received letermovir or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT (see section 5.1). The adverse reactions reported were consistent with the safety profile of letermovir as characterised in study P001. Kidney transplant In P002, 292 adult kidney transplant recipients received letermovir through Week 28 (~200 days) post- transplant (see section 5.1). Tabulated summary of adverse reactions The following adverse reactions were identified in adult patients taking letermovir in clinical trials. The adverse reactions are listed below by body system organ class and frequency. Frequencies are 50 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 3: Adverse reactions identified with letermovir Frequency Adverse reactions Immune system disorders Uncommon hypersensitivity Metabolism and nutrition disorders Uncommon decreased appetite Nervous system disorders Uncommon dysgeusia, headache Ear and labyrinth disorders Uncommon vertigo Gastrointestinal disorders Common nausea, diarrhoea, vomiting Uncommon abdominal pain Hepatobiliary disorders Uncommon alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders Uncommon muscle spasms Renal and uri

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HOS-098415 · has-adverse-reaction-information · PDF-Seite 18

Summary of the safety profile The safety assessment of letermovir was based on three Phase 3 clinical trials. HSCT In P001, 565 adult HSCT recipients received letermovir or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant (see section 5.1). The most commonly reported adverse reactions occurring in at least 1% of subjects in the letermovir group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently reported adverse reactions that led to discontinuation of letermovir were: nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%). In P040, 218 adult HSCT recipients received letermovir or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT (see section 5.1). The adverse reactions reported were consistent with the safety profile of letermovir as characterised in study P001. Kidney transplant In P002, 292 adult kidney transplant recipients received letermovir through Week 28 (~200 days) post- transplant (see section 5.1). Tabulated summary of adverse reactions The following adverse reactions were identified in adult patients taking letermovir in clinical trials. 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 2: Adverse reactions identified with letermovir Frequency Adverse reactions Immune system disorders Uncommon hypersensitivity Metabolism and nutrition disorders Uncommon decreased appetite Nervous system disorders Uncommon dysgeusia, headache Ear and labyrinth disorders Uncommon vertigo Gastrointestinal disorders Common nausea, diarrhoea, vomiting Uncommon abdominal pain Hepatobiliary disorders Uncommon alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders Uncommon muscle spasms Renal and urinary disorders Uncommon blood

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HOS-098427 · has-adverse-reaction-information · PDF-Seite 84

Summary of the safety profile The safety assessment of letermovir was based on three Phase 3 clinical trials. HSCT In P001, 565 adult HSCT recipients received letermovir or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant (see section 5.1). The most commonly reported adverse reactions occurring in at least 1% of subjects in the letermovir group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently reported adverse reactions that led to discontinuation of letermovir were: nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%). In P040, 218 adult HSCT recipients received letermovir or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT (see section 5.1). The adverse reactions reported were consistent with the safety profile of letermovir as characterised in study P001. Kidney transplant In P002, 292 adult kidney transplant recipients received letermovir through Week 28 (~200 days) post- transplant (see section 5.1). Tabulated summary of adverse reactions The following adverse reactions were identified in adult patients taking letermovir in clinical trials. The adverse reactions are listed below by body system organ class and frequency. Frequencies are 84 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 3: Adverse reactions identified with letermovir Frequency Adverse reactions Immune system disorders Uncommon hypersensitivity Metabolism and nutrition disorders Uncommon decreased appetite Nervous system disorders Uncommon dysgeusia, headache Ear and labyrinth disorders Uncommon vertigo Gastrointestinal disorders Common nausea, diarrhoea, vomiting Uncommon abdominal pain Hepatobiliary disorders Uncommon alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders Uncommon muscle spasms Renal and urin

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HOS-098411 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration with pimozide (see sections 4.4 and 4.5). Concomitant administration with ergot alkaloids (see sections 4.4 and 4.5). Concomitant administration with St. John’s wort (Hypericum perforatum) (see section 4.5). When letermovir is combined with cyclosporine: • Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated (see section 4.5).

HOS-098417 · has-contraindication-information · PDF-Seite 37

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration with pimozide (see sections 4.4 and 4.5). Concomitant administration with ergot alkaloids (see sections 4.4 and 4.5). Concomitant administration with St. John’s wort (Hypericum perforatum) (see section 4.5). When letermovir is combined with cyclosporine: • Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated (see section 4.5).

HOS-098423 · has-contraindication-information · PDF-Seite 71

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant administration with pimozide (see sections 4.4 and 4.5). Concomitant administration with ergot alkaloids (see sections 4.4 and 4.5). Concomitant administration with St. John’s wort (Hypericum perforatum) (see section 4.5). When letermovir is combined with cyclosporine: • Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated (see section 4.5).

HOS-098416 · has-indication-information · PDF-Seite 34

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult and paediatric patients weighing at least 5 kg who are CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT). PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adult and paediatric patients weighing at least 40 kg who have received a kidney transplant from a CMV-seropositive donor [D+/R-]. Consideration should be given to official guidance on the appropriate use of antiviral agents.

HOS-098410 · has-indication-information · PDF-Seite 2

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult and paediatric patients weighing at least 15 kg who are CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT). PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adult and paediatric patients weighing at least 40 kg who have received a kidney transplant from a CMV-seropositive donor [D+/R-]. Consideration should be given to official guidance on the appropriate use of antiviral agents. 2

HOS-098422 · has-indication-information · PDF-Seite 68

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult and paediatric patients weighing at least 5 kg who are CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT). PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adult and paediatric patients weighing at least 40 kg who have received a kidney transplant from a CMV-seropositive donor [D+/R-]. Consideration should be given to official guidance on the appropriate use of antiviral agents.

HOS-098419 · has-interaction-information · PDF-Seite 38

General information about differences in exposure between different letermovir treatment regimens -The estimated letermovir plasma exposure is different depending on the dose regimen used (see table in section 5.2). Therefore, the clinical consequences of drug interactions for letermovir will be dependent on which letermovir regimen is used and whether or not letermovir is combined with cyclosporine. -The combination of cyclosporine and letermovir may lead to more marked or additional effects on concomitant medicinal products as compared to letermovir alone (see Table 2). Effect of other medicinal products on letermovir The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. The relative importance of these pathways is unknown. Both elimination pathways involve active uptake into the hepatocyte through the hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation of letermovir is mediated by UGT1A1 and 3. Letermovir also appears to be subject to P-gp and BCRP mediated efflux in the liver and intestine (see section 5.2). 38 Inducers of drug metabolising enzymes or transporters Co-administration of letermovir (with or without cyclosporine) with strong and moderate inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended, as it may lead to subtherapeutic letermovir exposure (see Table 2). -Examples of strong inducers include rifampicin, phenytoin, carbamazepine, rifabutin and phenobarbital. -Examples of moderate inducers include thioridazine, modafinil, ritonavir, lopinavir, efavirenz and etravirine. Rifampicin co-administration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 and/or P-gp inhibition) that is not clinically relevant, followed by clinically relevant decreases in letermovir plasma concentrations (due to induction of P-gp/UGT) with continued rifampicin co-administration (see Table 2). Additional effects of other products on letermovir relevant when combined with cyclosporine Inhibitors of OATP1B1 or 3 Co-administration of letermovir with medicinal products that are inhibitors of OATP1B1/3 transporters may result in increased letermovir plasma concentrations. If letermovir is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of letermovir is 240 mg once daily in adult and paediatric patients weighing at least 30 kg (see Table 2 and sections

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HOS-098413 · has-interaction-information · PDF-Seite 6

General information about differences in exposure between different letermovir treatment regimens -The estimated letermovir plasma exposure is different depending on the dose regimen used (see table in section 5.2). Therefore, the clinical consequences of drug interactions for letermovir will be dependent on which letermovir regimen is used and whether or not letermovir is combined with cyclosporine. -The combination of cyclosporine and letermovir may lead to more marked or additional effects on concomitant medicinal products as compared to letermovir alone (see Table 1). Effect of other medicinal products on letermovir The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. The relative importance of these pathways is unknown. Both elimination pathways involve active uptake into the hepatocyte through the hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation of letermovir is mediated by UGT1A1 and 3. Letermovir also appears to be subject to P-gp and BCRP mediated efflux in the liver and intestine (see section 5.2). Inducers of drug metabolising enzymes or transporters Co-administration of letermovir (with or without cyclosporine) with strong and moderate inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended, as it may lead to subtherapeutic letermovir exposure (see Table 1). -Examples of strong inducers include rifampicin, phenytoin, carbamazepine, rifabutin and phenobarbital. -Examples of moderate inducers include thioridazine, modafinil, ritonavir, lopinavir, efavirenz and etravirine. Rifampicin co-administration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 and/or P-gp inhibition) that is not clinically relevant, followed by clinically relevant decreases in letermovir plasma concentrations (due to induction of P-gp/UGT) with continued rifampicin co-administration (see Table 1). 6 Additional effects of other products on letermovir relevant when combined with cyclosporine Inhibitors of OATP1B1 or 3 Co-administration of letermovir with medicinal products that are inhibitors of OATP1B1/3 transporters may result in increased letermovir plasma concentrations. If letermovir is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of letermovir is 240 mg once daily in adult and paediatric patients weighing at least 30 kg (see Table 1 and sections 4

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HOS-098425 · has-interaction-information · PDF-Seite 72

General information about differences in exposure between different letermovir treatment regimens -The estimated letermovir plasma exposure is different depending on the dose regimen used (see table in section 5.2). Therefore, the clinical consequences of drug interactions for letermovir will be dependent on which letermovir regimen is used and whether or not letermovir is combined with cyclosporine. -The combination of cyclosporine and letermovir may lead to more marked or additional effects on concomitant medicinal products as compared to letermovir alone (see Table 2). Effect of other medicinal products on letermovir The elimination pathways of letermovir in vivo are biliary excretion and glucuronidation. The relative importance of these pathways is unknown. Both elimination pathways involve active uptake into the hepatocyte through the hepatic uptake transporters OATP1B1/3. After uptake, glucuronidation of letermovir is mediated by UGT1A1 and 3. Letermovir also appears to be subject to P-gp and BCRP mediated efflux in the liver and intestine (see section 5.2). Inducers of drug metabolising enzymes or transporters Co-administration of letermovir (with or without cyclosporine) with strong and moderate inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended, as it may lead to subtherapeutic letermovir exposure (see Table 2). -Examples of strong inducers include rifampicin, phenytoin, carbamazepine, rifabutin and phenobarbital. -Examples of moderate inducers include thioridazine, modafinil, ritonavir, lopinavir, efavirenz and etravirine. Rifampicin co-administration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 and/or P-gp inhibition) that is not clinically relevant, followed by clinically relevant decreases in letermovir plasma concentrations (due to induction of P-gp/UGT) with continued rifampicin co-administration (see Table 2). 72 Additional effects of other products on letermovir relevant when combined with cyclosporine Inhibitors of OATP1B1 or 3 Co-administration of letermovir with medicinal products that are inhibitors of OATP1B1/3 transporters may result in increased letermovir plasma concentrations. If letermovir is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of letermovir is 240 mg once daily in adult and paediatric patients weighing at least 30 kg (see Table 2 and sections

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HOS-098426 · has-pregnancy-information · PDF-Seite 83

Pregnancy There are no data from the use of letermovir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Letermovir is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether letermovir is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to 83 discontinue breast-feeding or to discontinue/abstain from letermovir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment of fertility was observed in male rats, but not in male mice or male monkeys (see section 5.3).

HOS-098414 · has-pregnancy-information · PDF-Seite 17

Pregnancy There are no data from the use of letermovir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Letermovir is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is unknown whether letermovir is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from letermovir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment of fertility was observed in male rats, but not in male mice or male monkeys (see section 5.3).

HOS-098420 · has-pregnancy-information · PDF-Seite 49

Pregnancy There are no data from the use of letermovir in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Letermovir is not recommended during pregnancy and in women of childbearing potential not using contraception. 49 Breast-feeding It is unknown whether letermovir is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from letermovir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment of fertility was observed in male rats, but not in male mice or male monkeys (see section 5.3).

HOS-098412 · has-warning-information · PDF-Seite 5

Monitoring of CMV DNA in HSCT recipients In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met (see section 5.1). Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions The concomitant use of letermovir and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: • possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir. • significant decrease of concomitant medicinal product plasma concentrations which may lead to reduced therapeutic effect of the concomitant medicinal product. See Table 1 for steps to prevent or manage these known or potentially significant medicinal product interactions, including dosing recommendations (see sections 4.3 and 4.5). Drug interactions Letermovir should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended (see section 4.5). Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending letermovir (see section 4.5) as well as after changing route of administration of letermovir. Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reduced plasma concentrations of some metabolised and transported medicinal products (see section 4.5). Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole. Concomitant use of dabigatran should be avoided due to risk of reduced dabigatran efficacy. 5 L

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HOS-098418 · has-warning-information · PDF-Seite 37

Monitoring of CMV DNA in HSCT recipients In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met (see section 5.1). Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions The concomitant use of letermovir and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: • possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir. • significant decrease of concomitant medicinal product plasma concentrations which may lead to reduced therapeutic effect of the concomitant medicinal product. See Table 2 for steps to prevent or manage these known or potentially significant medicinal product interactions, including dosing recommendations (see sections 4.3 and 4.5). Drug interactions Letermovir should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended (see section 4.5). Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending letermovir (see section 4.5) as well as after changing route of administration of letermovir. Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reduced plasma concentrations of some metabolised and transported medicinal products (see section 4.5). 37 Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole. Concomitant use of dabigatran should be avoided due to risk of reduced dabigatran efficacy.

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HOS-098424 · has-warning-information · PDF-Seite 71

Monitoring of CMV DNA in HSCT recipients In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met (see section 5.1). Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions The concomitant use of letermovir and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to: • possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir. • significant decrease of concomitant medicinal product plasma concentrations which may lead to reduced therapeutic effect of the concomitant medicinal product. See Table 2 for steps to prevent or manage these known or potentially significant medicinal product interactions, including dosing recommendations (see sections 4.3 and 4.5). Drug interactions Letermovir should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended (see section 4.5). Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending letermovir (see section 4.5) as well as after changing route of administration of letermovir. 71 Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reduced plasma concentrations of some metabolised and transported medicinal products (see section 4.5). Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole. Concomitant use of dabigatran should be avoided due to risk of reduced dabigatran efficacy. L

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