enzalutamide: prescribing information – dosing, contraindications, interactions, side effects

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.

Treatment with enzalutamide should be initiated and supervised by specialist physicians experienced in the medical treatment of prostate cancer.
Posology
The recommended dose is 160 mg enzalutamide (four 40 mg soft capsules) as a single oral daily dose.

Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients with CRPC or mHSPC who are not surgically castrated.

Patients with high-risk BCR nmHSPC may be treated with Xtandi with or without a LHRH analogue.
For patients who receive Xtandi with or without a LHRH analogue, treatment can be suspended if PSA is undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Treatment should be reinitiated when PSA has increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior primary radiation therapy. If PSA is detectable (≥ 0.2 ng/mL) after 36 weeks of therapy, treatment should continue (see section 5.1).

If a patient misses taking Xtandi at the usual time, the prescribed dose should be taken as close as possible to the usual time. If a patient misses a dose for a whole day, treatment should be resumed the following day with the usual daily dose.

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduced dose (120 mg or 80 mg) if warranted.

Concomitant use with strong CYP2C8 inhibitors
The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor (see section 4.5).

Elderly
No dose adjustment is necessary for elderly patients (see sections 5.1 and 5.2).

Hepatic impairment
No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C, respectively). An increased half-life of enzalutamide has however been observed in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment (see section 5.2).
Caution is advised in patients with severe renal impairment or end-stage renal disease (see section 4.4).

Paediatric population
There is no relevant use of enzalutamide in the paediatric population in the indication of treatment of adult men with CRPC, mHSPC, or high-risk BCR nmHSPC.

Swallowing difficulties/history of dysphagia population
Enzalutamide is also available as tablets (40 mg and 80 mg) for patients who have difficulties swallowing large capsules or for patients with a history of dysphagia.
Method of administration
Xtandi is for oral use. The soft capsules should not be chewed, dissolved or opened but should be swallowed whole with a sufficient amount of water, and can be taken with or without food.

Treatment with enzalutamide should be initiated and supervised by specialist physicians experienced in the medical treatment of prostate cancer.
Posology
The recommended dose is 160 mg enzalutamide (four 40 mg film-coated tablets or two 80 mg film-coated tablets) as a single oral daily dose.

Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients with CRPC or mHSPC who are not surgically castrated.

Patients with high-risk BCR nmHSPC may be treated with Xtandi with or without a LHRH analogue.
For patients who receive Xtandi with or without a LHRH analogue, treatment can be suspended if PSA is undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Treatment should be reinitiated when PSA has increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior primary radiation therapy. If PSA is detectable (≥ 0.2 ng/mL) after 36 weeks of therapy, treatment should continue (see section 5.1).

If a patient misses taking Xtandi at the usual time, the prescribed dose should be taken as close as possible to the usual time. If a patient misses a dose for a whole day, treatment should be resumed the following day with the usual daily dose.

If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduced dose (120 mg or 80 mg) if warranted.

Concomitant use with strong CYP2C8 inhibitors
The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. If co-administration of the strong CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor (see section 4.5).

Elderly
No dose adjustment is necessary for elderly patients (see sections 5.1 and 5.2).

Hepatic impairment
No dose adjustment is necessary for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C, respectively). An increased half-life of enzalutamide has however been observed in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment (see section 5.2).
Caution is advised in patients with severe renal impairment or end-stage renal disease (see section 4.4).
Paediatric population
There is no relevant use of enzalutamide in the paediatric population in the indication of treatment of adult men with CRPC, mHSPC, or high-risk BCR nmHSPC.
Method of administration
Xtandi is for oral use. The film-coated tablets should not be cut, crushed or chewed but should be swallowed whole with a sufficient amount of water, and can be taken with or without food.

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).

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.

Table 1: Adverse reactions identified in controlled clinical trials and post-marketing MedDRA System organ class Adverse reaction and frequency Blood and lymphatic system disorders Uncommon: leucopenia, neutropenia Not known*: thrombocytopenia Immune system disorders Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema Metabolism and nutrition disorders Not known*: decreased appetite 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, hypertension Gastrointestinal disorders Not known*: dysphagia∞, nausea, vomiting, diarrhoea Hepatobiliary disorders Uncommon: hepatic enzymes increased Skin and subcutaneous tissue disorders Common: dry skin, pruritus Not known*: erythema multiforme, Stevens-Johnson syndrome, rash Musculoskeletal and connective tissue disorders Very common: fractures‡ Not known*: myalgia, muscle spasms, muscular weakness, back pain Reproductive system and breast disorder Common: gynaecomastia, nipple pain#, breast tenderness# General disorders and administration site conditions Very common: asthenia, fatigue Injury, poisoning and procedural complications Very common: fall * Spontaneous reports from post-marketing experience.
¥ As evaluated by narrow SMQs of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures, partial seizures, and status epilepticus. This includes rare cases of seizure with complications leading to death.
† As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery.
‡ Includes all preferred terms with the word ‘fracture’ in bones.
# Adverse reactions for enzalutamide as monotherapy.
∞ There have been reports of dysphagia, including reports of choking. Both events have mostly been reported with the capsule formulation, which could be related to a larger product size (see section 4.4).

Description of selected adverse reactions

Seizure
In controlled clinical studies, 31 patients (0.6%) experienced a seizure out of 5112 patients treated with a daily dose of 160 mg enzalutamide, whereas four patients (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide, experienced a seizure. Dose appears to be an important predictor of the risk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlled clinical studies, patients with prior seizure or risk factors for seizure were excluded.

In the 9785-CL-0403 (UPWARD) single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months.

The mechanism by which enzalutamide may lower the seizure threshold is not known but could be related to data from in vitro studies showing that enzalutamide and its active metabolite bind to and can inhibit the activity of the GABA-gated chloride channel.

Ischemic Heart Disease
In randomised placebo-controlled clinical studies, ischemic heart disease occurred in 3.5% of patients treated with enzalutamide plus ADT compared to 2.1% of patients treated with placebo plus ADT.
Fifteen (0.4%) patients treated with enzalutamide plus ADT and 3 (0.1%) patients treated with placebo plus ADT had an ischemic heart disease event that led to death.

In the EMBARK study, ischemic heart disease occurred in 6.2% of patients treated with enzalutamide plus leuprolide and 10.7% of patients treated with enzalutamide as monotherapy. One (0.3%) patient treated with enzalutamide plus leuprolide, one (0.3%) patient treated with placebo plus leuprolide and one (0.3%) patient treated with enzalutamide as monotherapy had an ischemic heart disease event that led to death.

Gynaecomastia
In the EMBARK study, gynaecomastia (all grades) was observed in 31 of 353 patients (8.8%) who were treated with enzalutamide plus leuprolide and 163 of 354 patients (46%) who were treated with enzalutamide as monotherapy. Grade 3 or higher gynaecomastia was not observed in any patients who were treated with enzalutamide plus leuprolide, and was observed in 1 patient (0.3%) treated with placebo plus leuprolide and 3 patients (0.8%) who were treated with enzalutamide as monotherapy.

Nipple pain
In the EMBARK study, nipple pain (all grades) was observed in 13 of 353 patients (3.7%) who were treated with enzalutamide plus leuprolide and 54 of 354 patients (15.3%) who were treated with enzalutamide as monotherapy. Grade 3 or higher nipple pain was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

Breast tenderness
In the EMBARK study, breast tenderness (all grades) was observed in 4 of 353 patients (1.1%) who were treated with enzalutamide plus leuprolide and 51 of 354 patients (14.4%) who were treated with enzalutamide as monotherapy. Grade 3 or higher breast tenderness was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

Table 1: Adverse reactions identified in controlled clinical trials and post-marketing MedDRA System organ class Adverse reaction and frequency Blood and lymphatic system disorders Uncommon: leucopenia, neutropenia Not known*: thrombocytopenia Immune system disorders Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema Metabolism and nutrition disorders Not known*: decreased appetite 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, hypertension Gastrointestinal disorders Not known*: dysphagia∞, nausea, vomiting, diarrhoea Hepatobiliary disorders Uncommon: hepatic enzymes increased Skin and subcutaneous tissue disorders Common: dry skin, pruritus Not known*: erythema multiforme, Stevens-Johnson syndrome, rash Musculoskeletal and connective tissue disorders Very common: fractures‡ Not known*: myalgia, muscle spasms, muscular weakness, back pain Reproductive system and breast disorder Common: gynaecomastia, nipple pain#, breast tenderness# General disorders and administration site conditions Very common: asthenia, fatigue Injury, poisoning and procedural complications Very common: fall * Spontaneous reports from post-marketing experience.
¥ As evaluated by narrow SMQs of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures, partial seizures, and status epilepticus. This includes rare cases of seizure with complications leading to death.
† As evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery.
‡ Includes all preferred terms with the word ‘fracture’ in bones.
# Adverse reactions for enzalutamide as monotherapy.
∞ There have been reports of dysphagia, including reports of choking. Both events have mostly been reported with the capsule formulation, which could be related to a larger product size (see section 4.4).

Description of selected adverse reactions

Seizure
In controlled clinical studies, 31 patients (0.6%) experienced a seizure out of 5112 patients treated with a daily dose of 160 mg enzalutamide, whereas four patients (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide, experienced a seizure. Dose appears to be an important predictor of the risk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlled clinical studies, patients with prior seizure or risk factors for seizure were excluded.

In the 9785-CL-0403 (UPWARD) single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months.

The mechanism by which enzalutamide may lower the seizure threshold is not known but could be related to data from in vitro studies showing that enzalutamide and its active metabolite bind to and can inhibit the activity of the GABA-gated chloride channel.

Ischemic Heart Disease
In randomised placebo-controlled clinical studies, ischemic heart disease occurred in 3.5% of patients treated with enzalutamide plus ADT compared to 2.1% of patients treated with placebo plus ADT.
Fifteen (0.4%) patients treated with enzalutamide plus ADT and 3 (0.1%) patients treated with placebo plus ADT had an ischemic heart disease event that led to death.

In the EMBARK study, ischemic heart disease occurred in 6.2% of patients treated with enzalutamide plus leuprolide and 10.7% of patients treated with enzalutamide as monotherapy. One (0.3%) patient treated with enzalutamide plus leuprolide, one (0.3%) patient treated with placebo plus leuprolide and one (0.3%) patient treated with enzalutamide as monotherapy had an ischemic heart disease event that led to death.

Gynaecomastia
In the EMBARK study, gynaecomastia (all grades) was observed in 31 of 353 patients (8.8%) who were treated with enzalutamide plus leuprolide and 163 of 354 patients (46%) who were treated with enzalutamide as monotherapy. Grade 3 or higher gynaecomastia was not observed in any patients who were treated with enzalutamide plus leuprolide, and was observed in 1 patient (0.3%) treated with placebo plus leuprolide and 3 patients (0.8%) who were treated with enzalutamide as monotherapy.

Nipple pain
In the EMBARK study, nipple pain (all grades) was observed in 13 of 353 patients (3.7%) who were treated with enzalutamide plus leuprolide and 54 of 354 patients (15.3%) who were treated with enzalutamide as monotherapy. Grade 3 or higher nipple pain was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

Breast tenderness
In the EMBARK study, breast tenderness (all grades) was observed in 4 of 353 patients (1.1%) who were treated with enzalutamide plus leuprolide and 51 of 354 patients (14.4%) who were treated with enzalutamide as monotherapy. Grade 3 or higher breast tenderness was not observed in any patients who were treated with enzalutamide plus leuprolide or with enzalutamide as monotherapy.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

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 renal impairment as enzalutamide has not been studied in this patient population.

Severe hepatic impairment
An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction (see section 4.5) may be increased.

Recent cardiovascular disease
The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if Xtandi is prescribed in these patients.

Androgen deprivation therapy may prolong the QT interval
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Xtandi.

Use with chemotherapy
The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel (see section 4.5); however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded.

Severe skin reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, which can be life threatening or fatal, has been reported with enzalutamide treatment.

At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of this reaction appear, enzalutamide should be withdrawn immediately and an alternative treatment considered (as appropriate).

Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide (see section 4.8).

Xtandi as monotherapy in patients with high-risk BCR nmHSPC
Results of the EMBARK study suggest that Xtandi as monotherapy and in combination with androgen deprivation therapy are not equivalent treatment options in patients with high-risk BCR nmHSPC (see sections 4.8 and 5.1). Xtandi in combination with androgen deprivation therapy is considered the preferred treatment option except for cases in which the addition of androgen deprivation therapy may result in unacceptable toxicity or risk.

Dysphagia related to product formulation
There have been reports of patients experiencing difficulty swallowing Xtandi, including reports of choking. The swallowing difficulties and choking events were mostly reported with the capsule formulation, which could be related to a larger product size. Patients should be advised to swallow the capsules whole with a sufficient amount of water.

In patients who have difficulties swallowing large capsules or patients with a history of dysphagia, it is recommended to use enzalutamide tablet formulations instead.

Excipients
Xtandi contains 57.8 mg sorbitol (E420) per soft capsule.

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.

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 renal impairment as enzalutamide has not been studied in this patient population.

Severe hepatic impairment
An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction (see section 4.5) may be increased.

Recent cardiovascular disease
The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if Xtandi is prescribed in these patients.

Androgen deprivation therapy may prolong the QT interval
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Xtandi.

Use with chemotherapy
The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel (see section 4.5); however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded.

Severe skin reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, which can be life threatening or fatal, has been reported with enzalutamide treatment.

At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of this reaction appear, enzalutamide should be withdrawn immediately and an alternative treatment considered (as appropriate).

Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema, have been observed with enzalutamide (see section 4.8).

Xtandi as monotherapy in patients with high-risk BCR nmHSPC
Results of the EMBARK study suggest that Xtandi as monotherapy and in combination with androgen deprivation therapy are not equivalent treatment options in patients with high-risk BCR nmHSPC (see sections 4.8 and 5.1). Xtandi in combination with androgen deprivation therapy is considered the preferred treatment option except for cases in which the addition of androgen deprivation therapy may result in unacceptable toxicity or risk.

Dysphagia related to product formulation
There have been reports of patients experiencing difficulty swallowing Xtandi, including reports of choking. The swallowing difficulties and choking events were mostly reported with the capsule formulation, which could be related to a larger product size. Patients should be advised to swallow the tablets whole with a sufficient amount of water.

Excipients
This medicine contains less than 1 mmol sodium (less than 23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

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.

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 polypeptide 1B1 (OATP1B1).

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In a clinical study in patients with metastatic CRPC, Xtandi (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m2 by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (GMR) = 0.882 (90% CI: 0.767, 1.02)] while Cmax decreased by 4% [GMR = 0.963 (90% CI:
0.834, 1.11)].

Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

Groups of medicinal products that can be affected include, but are not limited to:

• Analgesics (e.g. fentanyl, tramadol)
• Antibiotics (e.g. clarithromycin, doxycycline)
• Anticancer agents (e.g. cabazitaxel)
• Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)
• Betablockers (e.g. bisoprolol, propranolol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin)
• Corticosteroids (e.g. dexamethasone, prednisolone)
• HIV antivirals (e.g. indinavir, ritonavir)
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressant (e.g. tacrolimus)
• Proton pump inhibitor (e.g. omeprazole)
• Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)
• Thyroid agents (e.g. levothyroxine)

The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days, see section 5.2), effects on enzymes may

persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.

CYP1A2 and CYP2C8 substrates
Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4%, respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with Xtandi.

P-gp substrates
In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mild inhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients with prostate cancer that received a single oral dose of the probe P-gp substrate digoxin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The plasma levels of digoxin were measured using a validated liquid chromatography-tandem mass spectrometry assay. The AUC and Cmax of digoxin increased by 33% and 17%, respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Xtandi and may require dose adjustment to maintain optimal plasma concentrations.

Laboratory Test Interference
Falsely elevated digoxin plasma level results with the chemiluminescent microparticle immunoassay (CMIA) have been identified in patients treated with enzalutamide, independently of being treated with digoxin. Therefore, results of digoxin plasma levels obtained by CMIA should be interpreted with caution and confirmed by another type of assay before taking any action with digoxin doses.

BCRP substrates
At steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probe breast cancer resistance protein (BCRP) substrate rosuvastatin in patients with prostate cancer that received a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC of rosuvastatin decreased by 14% while Cmax increased by 6%. No dose adjustment is necessary when a BCRP substrate is co-administered with Xtandi.

MRP2, OAT3 and OCT1 substrates
Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.

Medicinal products which prolong the QT interval
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Effect of food on enzalutamide exposures
Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi was administered without regard to food.

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.

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 polypeptide 1B1 (OATP1B1).

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In a clinical study in patients with metastatic CRPC, Xtandi (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m2 by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (GMR) = 0.882 (90% CI: 0.767, 1.02)] while Cmax decreased by 4% [GMR = 0.963 (90% CI:
0.834, 1.11)].

Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

Groups of medicinal products that can be affected include, but are not limited to:

• Analgesics (e.g. fentanyl, tramadol)
• Antibiotics (e.g. clarithromycin, doxycycline)
• Anticancer agents (e.g. cabazitaxel)
• Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)
• Betablockers (e.g. bisoprolol, propranolol)
• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g. digoxin)
• Corticosteroids (e.g. dexamethasone, prednisolone)
• HIV antivirals (e.g. indinavir, ritonavir)
• Hypnotics (e.g. diazepam, midazolam, zolpidem)
• Immunosuppressant (e.g. tacrolimus)
• Proton pump inhibitor (e.g. omeprazole)
• Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)
• Thyroid agents (e.g. levothyroxine)

The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days, see section 5.2), effects on enzymes may

persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.

CYP1A2 and CYP2C8 substrates
Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4%, respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with Xtandi.

P-gp substrates
In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mild inhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients with prostate cancer that received a single oral dose of the probe P-gp substrate digoxin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The plasma levels of digoxin were measured using a validated liquid chromatography-tandem mass spectrometry assay. The AUC and Cmax of digoxin increased by 33% and 17%, respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Xtandi and may require dose adjustment to maintain optimal plasma concentrations.

Laboratory Test Interference
Falsely elevated digoxin plasma level results with the chemiluminescent microparticle immunoassay (CMIA) have been identified in patients treated with enzalutamide, independently of being treated with digoxin. Therefore, results of digoxin plasma levels obtained by CMIA should be interpreted with caution and confirmed by another type of assay before taking any action with digoxin doses.

BCRP substrates
At steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probe breast cancer resistance protein (BCRP) substrate rosuvastatin in patients with prostate cancer that received a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC of rosuvastatin decreased by 14% while Cmax increased by 6%. No dose adjustment is necessary when a BCRP substrate is co-administered with Xtandi.

MRP2, OAT3 and OCT1 substrates
Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.

Medicinal products which prolong the QT interval
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Effect of food on enzalutamide exposures
Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi was administered without regard to food.

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).

Xtandi may have moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported (see section 4.8). Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines. No studies to evaluate the effects of enzalutamide on the ability to drive and use machines have been conducted.

There is no antidote for enzalutamide. In the event of an overdose, treatment with enzalutamide should be stopped and general supportive measures initiated taking into consideration the half-life of 5.8 days.
Patients may be at increased risk of seizures following an overdose.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: hormone antagonists and related agents, anti-androgens, ATC code:
L02BB04.

Mechanism of action
Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen receptor signalling. Despite low or even undetectable levels of serum androgen, androgen receptor signalling continues to promote disease progression. Stimulation of tumour cell growth via the androgen receptor requires nuclear localization and DNA binding. Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway. Enzalutamide competitively inhibits androgen binding to androgen receptors, and consequently; inhibits nuclear translocation of activated receptors and inhibits the association of the activated androgen receptor with DNA even in the setting of androgen receptor overexpression and in prostate cancer cells resistant to anti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can induce cancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptor agonist activity.
Pharmacodynamic effects
In a phase 3 clinical trial (AFFIRM) of patients who failed prior chemotherapy with docetaxel, 54% of patients treated with enzalutamide, versus 1.5% of patients who received placebo, had at least a 50% decline from baseline in PSA levels.

In another phase 3 clinical trial (PREVAIL) in chemo-naïve patients, patients receiving enzalutamide demonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction from baseline), compared with patients receiving placebo, 78.0% versus 3.5% (difference = 74.5%, p < 0.0001).

In a phase 2 clinical trial (TERRAIN) in chemo-naïve patients, patients receiving enzalutamide demonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction from baseline), compared with patients receiving bicalutamide, 82.1% versus 20.9% (difference = 61.2%, p < 0.0001).

In a single arm trial (9785-CL-0410) of patients previously treated with at least 24 weeks of abiraterone (plus prednisone), 22.4% had a ≥ 50% decrease from baseline in PSA levels. According to prior chemotherapy history, the results proportion of patients with a ≥ 50% decrease in PSA levels were 22.1% and 23.2%, for the no prior chemotherapy and prior chemotherapy patient groups, respectively.

In the MDV3100-09 clinical trial (STRIVE) of non-metastatic and metastatic CRPC, patients receiving enzalutamide demonstrated a significantly higher total confirmed PSA response rate (defined as a ≥ 50% reduction from baseline) compared with patients receiving bicalutamide, 81.3% versus 31.3% (difference = 50.0%, p < 0.0001).

Enzalutamide is poorly water soluble. The solubility of enzalutamide is increased by caprylocaproyl macrogolglycerides as emulsifier/surfactant. In preclinical studies, the absorption of enzalutamide was increased when dissolved in caprylocaproyl macrogolglycerides.

The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one month. With daily oral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance of

enzalutamide is primarily via hepatic metabolism, producing an active metabolite that is equally as active as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide.
Absorption
Maximum plasma concentrations (Cmax) of enzalutamide in patients are observed 1 to 2 hours after administration. Based on a mass balance study in humans, oral absorption of enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. At steady state, the mean Cmax values for enzalutamide and its active metabolite are 16.6 μg/mL (23% coefficient of variation [CV]) and 12.7 μg/mL (30% CV), respectively.

Food has no clinically significant effect on the extent of absorption. In clinical trials, Xtandi was administered without regard to food.
Distribution
The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total body water, indicative of extensive extravascular distribution. Studies in rodents indicate that enzalutamide and its active metabolite can cross the blood brain barrier.

Enzalutamide is poorly water soluble. The solubility of enzalutamide is increased by caprylocaproyl macrogolglycerides as emulsifier/surfactant. In preclinical studies, the absorption of enzalutamide was increased when dissolved in caprylocaproyl macrogolglycerides.

The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one month. With daily oral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance of

enzalutamide is primarily via hepatic metabolism, producing an active metabolite that is equally as active as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide.
Absorption
Oral absorption of film-coated enzalutamide tablets was evaluated in healthy male volunteers after a single 160 mg dose of Xtandi film-coated tablets, and pharmacokinetic modelling and simulation were used to predict the pharmacokinetic profile at steady state. Based on these predictions, as well as other supportive data, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 2 hours (range 0.5 to 6 hours), and the steady-state pharmacokinetic profiles of enzalutamide and its active metabolite are similar for the film-coated tablets and the Xtandi soft capsules formulation.
Following oral administration of the soft capsule formulation (Xtandi 160 mg daily) in patients with metastatic CRPC, the steady-state plasma mean Cmax values for enzalutamide and its active metabolite are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively.