Erleada · 4.1 Therapeutic indications · 2

HOS-098343 · has-adverse-reaction-information · PDF-Seite 28

Summary of the safety profile The most common adverse reactions are fatigue (26%), skin rash (26% of any grade and 6% Grade 3 or 4), hypertension (22%), hot flush (18%), arthralgia (17%), diarrhoea (16%), fall (13%), and weight decreased (13%). Other important adverse reactions include fractures (11%), decreased appetite (11%) and hypothyroidism (8%). Tabulated list of adverse reactions Adverse reactions observed during clinical studies and/or in post-marketing experience are listed below by frequency category. Frequency categories 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); very rare (< 1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions System Organ Class Adverse reaction and frequency Blood and lymphatic system disorders common: neutropenia not known: agranulocytosis Endocrine disorders common: hypothyroidisma Metabolism and nutrition disorders very common: decreased appetite common: hypercholesterolaemia, hypertriglyceridaemia Nervous system disorders common: dysgeusia, ischaemic cerebrovascular disordersb uncommon: seizurec (see section 4.4), restless legs syndrome Cardiac disorders common: ischaemic heart diseased not known: QT prolongation (see sections 4.4 and 4.5) Vascular disorders very common: hot flush, hypertension Respiratory, thoracic and mediastinal not known: interstitial lung diseasee disorders Gastrointestinal disorders very common: diarrhoea Skin and subcutaneous tissue disorders very common: skin rashf common: pruritus, alopecia 28 

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HOS-098337 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions are fatigue (26%), skin rash (26% of any grade and 6% Grade 3 or 4), hypertension (22%), hot flush (18%), arthralgia (17%), diarrhoea (16%), fall (13%), and weight decreased (13%). Other important adverse reactions include fractures (11%), decreased appetite (11%) and hypothyroidism (8%). Tabulated list of adverse reactions Adverse reactions observed during clinical studies and/or in post-marketing experience are listed below by frequency category. Frequency categories 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); very rare (< 1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 8  Table 1: Adverse reactions System Organ Class Adverse reaction and frequency Blood and lymphatic system disorders common: neutropenia not known: agranulocytosis Endocrine disorders common: hypothyroidisma Metabolism and nutrition disorders very common: decreased appetite common: hypercholesterolaemia, hypertriglyceridaemia Nervous system disorders common: dysgeusia, ischaemic cerebrovascular disordersb uncommon: seizurec (see section 4.4), restless legs syndrome Cardiac disorders common: ischaemic heart diseased not known: QT prolongation (see sections 4.4 and 4.5) Vascular disorders very common: hot flush, hypertension Respiratory, thoracic and mediastinal not known: interstitial lung diseasee disorders Gastrointestinal disorders

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HOS-098333 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 3 Women who are or may become pregnant (see section 4.6).

HOS-098339 · has-contraindication-information · PDF-Seite 23

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 23 Women who are or may become pregnant (see section 4.6).

HOS-098332 · has-indication-information · PDF-Seite 2

Erleada is indicated:  in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease (see section 5.1).  in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) (see section 5.1).

HOS-098338 · has-indication-information · PDF-Seite 22

Erleada is indicated:  in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease (see section 5.1).  in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) (see section 5.1).

HOS-098341 · has-interaction-information · PDF-Seite 25

The elimination of apalutamide and formation of its active metabolite, N-desmethyl apalutamide, is mediated by both CYP2C8 and CYP3A4 to a similar extent at steady-state. No clinically meaningful changes in their overall exposure is expected as a result of drug interaction with inhibitors or inducers of CYP2C8 or CYP3A4. Apalutamide is an inducer of enzymes and transporters and may lead to an increase in elimination of many commonly used medicinal products. Potential for other medicinal products to affect apalutamide exposures Medicinal products that inhibit CYP2C8 CYP2C8 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 21% while AUC increased by 68% following co-administration of apalutamide 240 mg single dose with gemfibrozil (strong CYP2C8 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 21% while AUC increased by 45%. No initial dose adjustment is necessary when Erleada is co-administered with a strong inhibitor of CYP2C8 (e.g., gemfibrozil, clopidogrel) however, a reduction of the Erleada dose based on tolerability should be considered (see section 4.2). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide. 25 Medicinal products that inhibit CYP3A4 CYP3A4 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 22% while AUC was similar following co-administration of Erleada as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 22% while AUC was again similar. No initial dose adjustment is necessary when Erleada is co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) however, a reduction of the Erleada dose based on tolerability should be considered (see section 4.2). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide. Medicinal products that induce CYP3A4 or CYP2C8 The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Based on the drug-drug interaction study results with strong CYP3A4 inhibitor or

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HOS-098335 · has-interaction-information · PDF-Seite 5

The elimination of apalutamide and formation of its active metabolite, N-desmethyl apalutamide, is mediated by both CYP2C8 and CYP3A4 to a similar extent at steady-state. No clinically meaningful changes in their overall exposure is expected as a result of drug interaction with inhibitors or inducers of CYP2C8 or CYP3A4. Apalutamide is an inducer of enzymes and transporters and may lead to an increase in elimination of many commonly used medicinal products. Potential for other medicinal products to affect apalutamide exposures Medicinal products that inhibit CYP2C8 CYP2C8 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 21% while AUC increased by 68% following co-administration of apalutamide 240 mg single dose with gemfibrozil (strong CYP2C8 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 21% while AUC increased by 45%. No initial dose adjustment is necessary when Erleada is co-administered with a strong inhibitor of CYP2C8 (e.g., gemfibrozil, clopidogrel) however, a reduction of the Erleada dose based on tolerability should be considered (see section 4.2). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide. 5 Medicinal products that inhibit CYP3A4 CYP3A4 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 22% while AUC was similar following co-administration of Erleada as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 22% while AUC was again similar. No initial dose adjustment is necessary when Erleada is co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) however, a reduction of the Erleada dose based on tolerability should be considered (see section 4.2). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide. Medicinal products that induce CYP3A4 or CYP2C8 The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Based on the drug-drug interaction study results with strong CYP3A4 inhibitor or

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HOS-098336 · has-pregnancy-information · PDF-Seite 7

Contraception in males and females It is not known whether apalutamide or its metabolites are present in semen. Erleada may be harmful to a developing foetus. For patients having sex with female partners of reproductive potential, a condom should be used along with another highly effective contraceptive method during treatment and for 3 months after the last dose of Erleada. Pregnancy Erleada is contraindicated in women who are or may become pregnant (see section 4.3). Based on an animal reproductive study and its mechanism of action, Erleada may cause foetal harm and loss of pregnancy when administered to a pregnant woman. There are no data available from the use of Erleada in pregnant women. 7 Breast-feeding It is unknown whether apalutamide/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Erleada should not be used during breast-feeding. Fertility Based on animal studies, Erleada may decrease fertility in males of reproductive potential (see section 5.3).

HOS-098342 · has-pregnancy-information · PDF-Seite 27

Contraception in males and females It is not known whether apalutamide or its metabolites are present in semen. Erleada may be harmful to a developing foetus. For patients having sex with female partners of reproductive potential, a condom should be used along with another highly effective contraceptive method during treatment and for 3 months after the last dose of Erleada. Pregnancy Erleada is contraindicated in women who are or may become pregnant (see section 4.3). Based on an animal reproductive study and its mechanism of action, Erleada may cause foetal harm and loss of pregnancy when administered to a pregnant woman. There are no data available from the use of Erleada in pregnant women. 27 Breast-feeding It is unknown whether apalutamide/metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Erleada should not be used during breast-feeding. Fertility Based on animal studies, Erleada may decrease fertility in males of reproductive potential (see section 5.3).

HOS-098340 · has-warning-information · PDF-Seite 24

Seizure Erleada is not recommended in patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, recent stroke (within one year), primary brain tumours or brain metastases. If a seizure develops during treatment with Erleada, treatment should be discontinued permanently. The risk of seizure may be increased in patients receiving concomitant medicinal products that lower the seizure threshold. In two randomised studies (SPARTAN and TITAN), seizure occurred in 0.6% of patients receiving apalutamide and in 0.2% of patients treated with placebo. These studies excluded patients with a history of seizure or predisposing factors for seizure. There is no clinical experience in re-administering Erleada to patients who experienced a seizure. Falls and fractures Falls and fractures occurred in patients receiving apalutamide (see section 4.8). Patients should be evaluated for fracture and fall risk before starting Erleada and should continue to be monitored and managed according to established treatment guidelines and use of bone-targeted agents should be considered. Ischaemic heart disease and ischaemic cerebrovascular disorders Ischaemic heart disease and ischaemic cerebrovascular disorders, including events leading to death, occurred in patients treated with apalutamide (see section 4.8). The majority of patients had cardiac/cerebrovascular ischaemic disease risk factors. Patients should be monitored for signs and symptoms of ischaemic heart disease and ischaemic cerebrovascular disorders. Management of risk factors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care. Concomitant use with other medicinal products Apalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see section 4.5). A review of concomitant medicinal products should therefore be conducted when apalutamide treatment is initiated. Concomitant use of apalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters (see section 4.5) should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations. Co-administration of apalutamide with warfarin and coumarin-like anticoagulants should be avoided. If Erleada is co-administered with an anticoagulant meta

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HOS-098334 · has-warning-information · PDF-Seite 4

Seizure Erleada is not recommended in patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, recent stroke (within one year), primary brain tumours or brain metastases. If a seizure develops during treatment with Erleada, treatment should be discontinued permanently. The risk of seizure may be increased in patients receiving concomitant medicinal products that lower the seizure threshold. In two randomised studies (SPARTAN and TITAN), seizure occurred in 0.6% of patients receiving apalutamide and in 0.2% of patients treated with placebo. These studies excluded patients with a history of seizure or predisposing factors for seizure. There is no clinical experience in re-administering Erleada to patients who experienced a seizure. Falls and fractures Falls and fractures occurred in patients receiving apalutamide (see section 4.8). Patients should be evaluated for fracture and fall risk before starting Erleada and should continue to be monitored and managed according to established treatment guidelines and use of bone-targeted agents should be considered. Ischaemic heart disease and ischaemic cerebrovascular disorders Ischaemic heart disease and ischaemic cerebrovascular disorders, including events leading to death, occurred in patients treated with apalutamide (see section 4.8). The majority of patients had cardiac/cerebrovascular ischaemic disease risk factors. Patients should be monitored for signs and symptoms of ischaemic heart disease and ischaemic cerebrovascular disorders. Management of risk factors, such as hypertension, diabetes, or dyslipidaemia should be optimised as per standard of care. Concomitant use with other medicinal products Apalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see section 4.5). A review of concomitant medicinal products should therefore be conducted when apalutamide treatment is initiated. Concomitant use of apalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters (see section 4.5) should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations. Co-administration of apalutamide with warfarin and coumarin-like anticoagulants should be avoided. If Erleada is co-administered with an anticoagulant meta

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