Xtandi · 4.4 Special warnings and precautions for use · 2

HOS-096486 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fractures, fall, and headache. Other important adverse reactions include ischemic heart disease and seizure. Seizure occurred in 0.6% of enzalutamide-treated patients, 0.1% of placebo-treated patients and 0.3% in bicalutamide-treated patients. Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients (see section 4.4). Stevens-Johnson syndrome has been reported with enzalutamide treatment (see section 4.4). Tabulated list of adverse reactions Adverse reactions observed during clinical studies 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); not known (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 identified in controlled clinical trials and post-marketing MedDRA System organ class Adverse reaction and frequency Blood and lymphatic system Uncommon: leucopenia, neutropenia disorders Not known*: thrombocytopenia Immune system disorders Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema Metabolism and nutrition Not known*: decreased appetite disorders Psychiatric disorders Common: anxiety Uncommon: visual hallucination Nervous system disorders Very common: headache Common: memory impairment, amnesia, disturbance in attention, dysgeusia, restless legs syndrome, cognitive disorder Uncommon: seizure¥ Not known*: posterior reversible encephalopathy syndrome Cardiac disorders Common: ischemic heart disease† Not known*: QT-prolongation (see sections 4.4 and 4.5) Vascular disorders Very common: hot flush

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HOS-096492 · has-adverse-reaction-information · PDF-Seite 38

Summary of the safety profile The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fractures, fall, and headache. Other important adverse reactions include ischemic heart disease and seizure. Seizure occurred in 0.6% of enzalutamide-treated patients, 0.1% of placebo-treated patients and 0.3% in bicalutamide-treated patients. Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide- treated patients (see section 4.4). Stevens-Johnson syndrome has been reported with enzalutamide treatment (see section 4.4). Tabulated list of adverse reactions Adverse reactions observed during clinical studies 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 38 Table 1: Adverse reactions identified in controlled clinical trials and post-marketing MedDRA System organ class Adverse reaction and frequency Blood and lymphatic system Uncommon: leucopenia, neutropenia disorders Not known*: thrombocytopenia Immune system disorders Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema Metabolism and nutrition Not known*: decreased appetite disorders Psychiatric disorders Common: anxiety Uncommon: visual hallucination Nervous system disorders Very common: headache Common: memory impairment, amnesia, disturbance in attention, dysgeusia, restless legs syndrome, cognitive disorder Uncommon: seizure¥ Not known*: posterior reversible encephalopathy syndrome Cardiac disorders Common: ischemic heart disease† Not known*: QT-prolongation (see sections 4.4 and 4.5) Vascular disorders Very common: hot flus

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HOS-096488 · has-contraindication-information · PDF-Seite 33

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. Women who are or may become pregnant (see sections 4.6 and 6.6).

HOS-096482 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. Women who are or may become pregnant (see sections 4.6 and 6.6).

HOS-096487 · has-indication-information · PDF-Seite 32

Xtandi is indicated: • as monotherapy or in combination with androgen deprivation therapy for the treatment of adult men with high-risk biochemical recurrent (BCR) non-metastatic hormone-sensitive prostate cancer (nmHSPC) who are unsuitable for salvage-radiotherapy (see section 5.1). • in combination with androgen deprivation therapy for the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) (see section 5.1). • for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC) (see section 5.1). • for the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1). • for the treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.

HOS-096481 · has-indication-information · PDF-Seite 2

Xtandi is indicated: • as monotherapy or in combination with androgen deprivation therapy for the treatment of adult men with high-risk biochemical recurrent (BCR) non-metastatic hormone-sensitive prostate cancer (nmHSPC) who are unsuitable for salvage-radiotherapy (see section 5.1). • in combination with androgen deprivation therapy for the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) (see section 5.1). • for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC) (see section 5.1). • for the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1). • for the treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.

HOS-096484 · has-interaction-information · PDF-Seite 5

Potential for other medicinal products to affect enzalutamide exposures CYP2C8 inhibitors CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77% while Cmax decreased by 19%. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see section 4.2). CYP3A4 inhibitors CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No dose adjustment is necessary when Xtandi is co-administered with inhibitors of CYP3A4. CYP2C8 and CYP3A4 inducers Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by 37% while Cmax remained unchanged. No dose adjustment is necessary when Xtandi is co-administered with inducers of CYP2C8 or CYP3A4. 5 Potential for enzalutamide to affect exposures to other medicinal products Enzyme induction Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Some transporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and the organic anion transporting polyp

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HOS-096490 · has-interaction-information · PDF-Seite 35

Potential for other medicinal products to affect enzalutamide exposures CYP2C8 inhibitors CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77% while Cmax decreased by 19%. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see section 4.2). CYP3A4 inhibitors CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No dose adjustment is necessary when Xtandi is co-administered with inhibitors of CYP3A4. CYP2C8 and CYP3A4 inducers Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by 37% while Cmax remained unchanged. No dose adjustment is necessary when Xtandi is co- administered with inducers of CYP2C8 or CYP3A4. 35 Potential for enzalutamide to affect exposures to other medicinal products Enzyme induction Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Some transporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and the organic anion transporting poly

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HOS-096485 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential There are no human data on the use of Xtandi in pregnancy and this medicinal product is not for use in women of childbearing potential. This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant (see sections 4.3, 5.3, and 6.6). Contraception in males and females It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity (see section 5.3). Pregnancy Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant (see sections 4.3, 5.3, and 6.6). Breast-feeding Enzalutamide is not for use in women. It is not known if enzalutamide is present in human milk. Enzalutamide and/or its metabolites are secreted in rat milk (see section 5.3). Fertility Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs (see section 5.3).

HOS-096491 · has-pregnancy-information · PDF-Seite 38

Women of childbearing potential There are no human data on the use of Xtandi in pregnancy and this medicinal product is not for use in women of childbearing potential. This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant (see sections 4.3, 5.3, and 6.6). Contraception in males and females It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Studies in animals have shown reproductive toxicity (see section 5.3). Pregnancy Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant (see sections 4.3, 5.3, and 6.6). Breast-feeding Enzalutamide is not for use in women. It is not known if enzalutamide is present in human milk. Enzalutamide and/or its metabolites are secreted in rat milk (see section 5.3). Fertility Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs (see section 5.3).

HOS-096483 · has-warning-information · PDF-Seite 3

Risk of seizure Use of enzalutamide has been associated with seizure (see section 4.8). The decision to continue treatment in patients who develop seizures should be taken case by case. Posterior reversible encephalopathy syndrome There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xtandi (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xtandi in patients who develop PRES is recommended. 3 Second Primary Malignancies Cases of second primary malignancies have been reported in patients treated with enzalutamide in clinical studies. In phase 3 clinical studies, the most frequently reported events in enzalutamide treated patients, and greater than placebo, were bladder cancer (0.3%), adenocarcinoma of the colon (0.2%), transitional cell carcinoma (0.2%) and malignant melanoma (0.2%). Patients should be advised to promptly seek the attention of their physician if they notice signs of gastrointestinal bleeding, macroscopic haematuria, or other symptoms such as dysuria or urinary urgency develop during treatment with enzalutamide. Concomitant use with other medicinal products Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5). A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide 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 with warfarin and coumarin-like anticoagulants should be avoided. If Xtandi is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted (see section 4.5). Renal impairment Caution is required in patients with severe re

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HOS-096489 · has-warning-information · PDF-Seite 33

Risk of seizure Use of enzalutamide has been associated with seizure (see section 4.8). The decision to continue treatment in patients who develop seizures should be taken case by case. Posterior reversible encephalopathy syndrome There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xtandi (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires 33 confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xtandi in patients who develop PRES is recommended. Second Primary Malignancies Cases of second primary malignancies have been reported in patients treated with enzalutamide in clinical studies. In phase 3 clinical studies, the most frequently reported events in enzalutamide treated patients, and greater than placebo, were bladder cancer (0.3%), adenocarcinoma of the colon (0.2%), transitional cell carcinoma (0.2%) and malignant melanoma (0.2%). Patients should be advised to promptly seek the attention of their physician if they notice signs of gastrointestinal bleeding, macroscopic haematuria, or other symptoms such as dysuria or urinary urgency develop during treatment with enzalutamide. Concomitant use with other medicinal products Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5). A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide 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 with warfarin and coumarin-like anticoagulants should be avoided. If Xtandi is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted (see section 4.5). Renal impairment Caution is required in patients with severe re

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