英文药名：Xtandi Capsules（enzalutamide）

中文药名：恩杂鲁胺胶囊

生产厂家：法国安斯泰来
药品介绍
Xtandi是一种新颖的、每日一次的口服雄激素受体信号传导抑制剂，该药能够抑制雄激素受体信号传导通路中的多个步骤，旨在干扰睾酮结合前列腺癌细胞的能力，已被证明能够降低癌细胞的生长，并能诱导肿瘤细胞死亡。睾酮是一种男性激素，能够激化前列腺癌细胞的生长。
欧洲人用药品委员会（CHMP）已经推荐enzalutamide（‍‍Xtandi，Astellas Pharma Europe Ltd‍‍‍‍）在前列腺癌治疗中增加新适用证。
Enzalutamide的新适用症推荐是，用于治疗雄激素治疗失败后、无症状或症状较轻、没有化疗指征的雄激素抵抗性转移性前列腺癌（mCRPC）的患者。这与美国批准的enzalutamide新适用证相似。
CHMP放宽了药物enzalutamide的适用证，允许其在疾病早期使用；之前enzalutamide的应用指征是用于已经接受多西他赛化疗的雄激素抵抗性转移性前列腺癌患者。2013年6月，enzalutamide在欧洲获得销售许可，而在美国在2012年8月获FDA批准用于经激素疗法及化疗后癌症已扩散的男性前列腺癌患者的治疗。
Xtandi 40mg soft capsules
1. Name of the medicinal product
Xtandi 40 mg soft capsules
2. Qualitative and quantitative composition
Each soft capsule contains 40 mg of enzalutamide.
Excipient with known effect:
Each soft capsule contains 52.4 mg of sorbitol.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Soft capsule.
White to off-white oblong soft capsules (approximately 20 mm x 9 mm) imprinted with “ENZ” in black ink on one side.
4. Clinical particulars
4.1 Therapeutic indications
Xtandi is indicated for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy.
4.2 Posology and method of administration
Posology
The recommended dose is 160 mg enzalutamide (four 40 mg capsules) as a single oral daily dose.
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).
Older people
No dose adjustment is necessary for older people (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment (Child Pugh Class A). Caution is advised in patients with moderate hepatic impairment (Child Pugh Class B). Xtandi is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 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 metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy.
Method of administration
Xtandi is for oral use. The capsules should be swallowed whole with water, and can be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Women who are or may become pregnant (see section 4.6).
4.4 Special warnings and precautions for use
Risk of seizure
Caution should be used in administering Xtandi to patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours or brain metastases, or alcoholism. In addition, the risk of seizure may be increased in patients receiving concomitant medicinal products that lower the seizure threshold.
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.
Hepatic impairment
Caution is required in patients with moderate hepatic impairment (Child-Pugh Class B) as data in moderate hepatic impairment are not fully conclusive (see section 5.2). As there are no data in patients with severe hepatic impairment and enzalutamide is primarily hepatically eliminated, Xtandi is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).
Recent cardiovascular disease
The AFFIRM study 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%, long QT, QTcF > 470 ms, bradycardia or uncontrolled hypertension. This should be taken into account if Xtandi is prescribed in these patients.
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.
Excipients
Xtandi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Potential for other medicinal products to affect enzalutamide exposures
CYP2C8 inhibitors and inducers
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) or inducers (e.g. rifampicin) 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 and inducers
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 or inducers of 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). The transport protein P-gp may also be induced, and probably other transporters as well, e.g. multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP) 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)
• Anticoagulants (e.g. acenocoumarol, warfarin)
• Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Betablockers (e.g. bisoprolol, propanolol)
• 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)
• Statins metabolized by CYP3A4 (e.g. atorvastatine, 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.
CYP2C8 substrates
Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. No dose adjustment is indicated when a 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. The effect of enzalutamide on P-gp substrates has not been evaluated in vivo; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of the nuclear pregnane receptor (PXR). 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.
BCRP, MRP2, OAT3 and OCT1 substrates
Based on in vitro data, inhibition of BCRP and 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.
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.
4.6 Fertility, pregnancy and lactation
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.
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 and 5.3).
Breast-feeding
Enzalutamide is not for use in women.
Fertility
Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs (see section 5.3).
4.7 Effects on ability to drive and use machines
Enzalutamide may have a moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizures have been reported (see section 4.8). Patients with a history of seizures or other predisposing factors (see section 4.4) should be advised of the risk of driving or operating machines. No studies to establish the effects of enzalutamide on the ability to drive and use machines have been conducted.
4.8 Undesirable effects
Summary of the safety profile
In the placebo-controlled phase 3 clinical trial (AFFIRM) of patients with metastatic castration-resistant prostate cancer who had received docetaxel therapy, enzalutamide was administered at a dose of 160 mg daily (N = 800) versus placebo (N = 399). The median duration of treatment with enzalutamide was 8.3 months while with placebo it was 3.0 months. Patients were allowed, but not required, to take prednisone.
Seizure occurred in 0.8% of patients receiving enzalutamide. The most common adverse reactions were hot flush and headache.
Tabulated summary of adverse reactions
Adverse reactions in AFFIRM 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions identified in the phase 3 clinical trial and post-marketing
MedDRA System organ class	Frequency
Blood and lymphatic system disorders	common: neutropenia uncommon: leucopenia
Psychiatric disorders	common: visual hallucinations, anxiety
Nervous system disorders	very common: headache common: cognitive disorder, memory impairment uncommon: seizure, amnesia, disturbance in attention
Vascular disorders	very common: hot flush common: hypertension
Skin and subcutaneous tissue disorders	common: dry skin, pruritus
Musculoskeletal and connective tissue disorders	common: fractures* not known**: myalgia, muscle spasms, muscular weakness, back pain
Injury, poisoning and procedural complications	common: falls

* Includes all fractures with the exception of pathological fractures
** Spontaneous reports from post-marketing experience
Description of selected adverse reactions
Seizures
In AFFIRM, six patients (0.8%) experienced a seizure out of 800 patients treated with a daily dose of 160 mg enzalutamide, whereas no seizures occurred in patients receiving placebo. Potentially contributing factors were present in several of these patients that may have independently increased their risk of seizure. The AFFIRM trial excluded patients with prior seizure or risk factors for 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. 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.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
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
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned
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 binding of androgens to androgen receptors, 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 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.
Clinical efficacy and safety
The efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and were using a gonadotropin-releasing hormone (GnRH) analogue or had undergone orchiectomy were assessed in a randomised, placebo-controlled, multicentre phase 3 clinical trial. A total of 1199 patients were randomised 2:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 800) or placebo once daily (N = 399). Patients were allowed but not required to take prednisone (maximum daily dose allowed was 10 mg prednisone or equivalent). Patients randomised to either arm were to continue treatment until disease progression (defined as confirmed radiographic progression or the occurrence of a skeletal-related event) and initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. The ECOG performance score was 0-1 in 91.5% of patients and 2 in 8.5% of patients; 28.4% had a mean Brief Pain Inventory score of ≥4 (mean of patient's reported worst pain over the previous 24 hours calculated for seven days prior to randomization). Most (91.2%) patients had metastases in bone and 23.2% had visceral lung and/or liver involvement. At study entry, 41% of randomized patients had PSA progression only, whereas 59% of patients had radiographic progression. 51% of patients were on bisphosphonates at baseline.
The phase 3 study excluded patients with medical conditions that may predispose them to seizures (see section 4.8) and medicinal products known to decrease the seizure threshold, as well as clinically significant cardiovascular disease such as uncontrolled hypertension, recent history of myocardial infarction or unstable angina, New York Heart Association class III or IV heart failure (unless ejection fraction was ≥ 45%), clinically significant ventricular arrhythmias or AV block (without permanent pacemaker).
Of the 800 patients in the phase 3 trial who received enzalutamide, 568 patients (71%) were 65 years and over and 199 patients (25%) were 75 years and over. No overall differences in safety or effectiveness were observed between these older patients and younger patients.
The protocol pre-specified interim analysis after 520 deaths showed a statistically significant superiority in overall survival in patients treated with enzalutamide compared to placebo (Table 2 and Figure 1).
Table 2: Overall survival of patients treated with either enzalutamide or placebo (intent-to-treat analysis)

Enzalutamide (N = 800)	Placebo (N = 399)
Deaths (%)	308 (38.5%)	212 (53.1%)
Median survival (months) (95% CI)	18.4 (17.3, NR)	13.6 (11.3, 15.8)
p valuea	< 0.0001
Hazard ratio (95% CI)b	0.631 (0.529, 0.752)

a P-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2) and mean pain score (< 4 vs. ≥ 4)
b Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours enzalutamide
Figure 1: Kaplan-Meier Overall Survival Curves (Intent-to-Treat Analysis)

Subgroup survival analysis showed a consistent survival benefit for treatment with enzalutamide (see Figure 2)
Figure 2: Overall Survival by Subgroup – Hazard Ratio and 95% Confidence Interval

ECOG: Eastern Cooperative Oncology Group; BPI-SF: Brief Pain Inventory-Short Form; PSA: Prostate Specific Antigen
In addition to the observed improvement in overall survival, key secondary endpoints (PSA progression, radiographic progression-free survival, and time to first skeletal-related event) favoured enzalutamide and were statistically significant after adjusting for multiple testing.
Radiographic progression-free survival as assessed by the investigator using RECIST v1.1 for soft tissue and appearance of 2 or more bone lesions in bone scan was 8.3 months for patients treated with enzalutamide and 2.9 months for patients who received placebo (HR = 0.404, 95% CI: [0.350, 0.466]); p < 0.0001). The analysis involved 216 deaths without documented progression and 645 documented progression events, of which 303 (47%) were due to soft tissue progression, 268 (42%) were due to bone lesion progression and 74 (11%) were due to both soft tissue and bone lesions.
Confirmed PSA decline of 50% or 90% were 54.0% and 24.8%, respectively, for patients treated with enzalutamide and 1.5% and 0.9%, respectively, for patients who received placebo (p < 0.0001). The median time to PSA progression was 8.3 months for patients treated with enzalutamide and 3.0 months for patients who received placebo (HR = 0.248, 95% CI: [0.204, 0.303]; p < 0.0001).
The median time to first skeletal-related event was 16.7 months for patients treated with enzalutamide and 13.3 months for patients who received placebo (HR = 0.688, 95% CI: [0.566, 0.835]; p < 0.0001). A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. The analysis involved 448 skeletal-related events, of which 277 events (62%) were radiation to bone, 95 events (21%) were spinal cord compression, 47 events (10%) were pathologic bone fracture, 36 events (8%) were change in anti-neoplastic therapy to treat bone pain and 7 events (2%) were surgery to bone.
The efficacy of enzalutamide in patients who have previously received abiraterone acetate has not been studied.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with enzalutamide in all subsets of the paediatric population in prostate carcinoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Enzalutamide is poorly water soluble. In this product, 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 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite is 95% bound to plasma proteins. There was no protein binding displacement between enzalutamide and other highly bound drugs (warfarin, ibuprofen and salicylic acid) in vitro.
Biotransformation
Enzalutamide is extensively metabolized. There are two major metabolites in human plasma: N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by CYP2C8 and to a lesser extent by CYP3A4/5 (see section 4.5), both of which play a role in the formation of the active metabolite. In vitro, N-desmethyl enzalutamide is metabolized to the carboxylic acid metabolite by carboxylesterase 1, which also plays a minor role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethyl enzalutamide was not metabolized by CYPs in vitro.
Under conditions of clinical use, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8 (see section 4.5).
Elimination
The mean apparent clearance (CL/F) of enzalutamide in patients ranges from 0.520 and 0.564 L/h.
Following oral administration of 14C-enzalutamide, 84.6% of the radioactivity is recovered by 77 days post dose: 71.0% is recovered in urine (primarily as the inactive metabolite, with trace amounts of enzalutamide and the active metabolite), and 13.6% is recovered in faeces (0.39% of dose as unchanged enzalutamide).
In vitro data indicate that enzalutamide is not a substrate for OATP1B1, OATP1B3, or OCT1; and N-desmethyl enzalutamide is not a substrate for P-gp or BCRP.
In vitro data indicate that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevant concentrations: OATP1B1, OATP1B3, OCT2, or OAT1.
Linearity
No major deviations from dose proportionality are observed over the dose range 40 to 160 mg. The steady-state Cmin values of enzalutamide and the active metabolite in individual patients remained constant during more than one year of chronic therapy, demonstrating time-linear pharmacokinetics once steady-state is achieved.
Renal impairment
No formal renal impairment study for enzalutamide has been completed. Patients with serum creatinine > 177 μmol/L (2 mg/dL) were excluded from clinical trials. Based on a population pharmacokinetic analysis, no dose adjustment is necessary for patients with calculated creatinine clearance (CrCL) values ≥ 30 mL/min (estimated by the Cockcroft and Gault formula). Enzalutamide has not been evaluated in patients with severe renal impairment (CrCL < 30 mL/min) or end-stage renal disease, and caution is advised when treating these patients. It is unlikely that enzalutamide will be significantly removed by intermittent haemodialysis or continuous ambulatory peritoneal dialysis.
Hepatic impairment
The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6) or moderate (N = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 14 matched control subjects with normal hepatic function. Following a single oral 160 mg dose of enzalutamide, the AUC and Cmax for enzalutamide in subjects with mild impairment increased by 5% and 24%, respectively, and the AUC and Cmax of enzalutamide in subjects with moderate impairment increased by 29% and decreased by 11%, respectively, compared to healthy control subjects. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC and Cmax in subjects with mild impairment increased by 14% and 19%, respectively, and the AUC and Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, compared to healthy control subjects. The patients in the moderate hepatic impairment group however had only modest impairment in parameters indicative of metabolic function (albumin, prothrombin time), and thus a larger effect in other patients with moderate hepatic impairment cannot be excluded.
Patients with baseline severe hepatic impairment (Child-Pugh C) were excluded from clinical trials.
Race
Most patients in the clinical trials (> 92%) were Caucasian. Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.
Older people
No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the population pharmacokinetic analysis.
5.3 Preclinical safety data
Enzalutamide treatment of pregnant mice resulted in an increased incidence of embryo-fetal deaths and external and skeletal changes. Reproductive toxicology studies were not conducted with enzalutamide, but in studies in rats (4 and 26 weeks) and dogs (4, 13, and 39 weeks), atrophy, aspermia/hypospermia, and hypertrophy/hyperplasia in the reproductive system were noted, consistent with the pharmacological activity of enzalutamide. In studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13, and 39 weeks), changes in the reproductive organs associated with enzalutamide were decreases in organ weight with atrophy of the prostate and epididymis. Leydig cell hypertrophy and/or hyperplasia were observed in mice (4 weeks) and dogs (39 weeks). Additional changes to reproductive tissues included hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in rats and testicular hypospermia and seminiferous tubule degeneration in dogs. Gender differences were noted in rat mammary glands (male atrophy and female lobular hyperplasia). Changes in the reproductive organs in both species were consistent with the pharmacological activity of enzalutamide and reversed or partially resolved after an 8-week recovery period. There were no other important changes in clinical pathology or histopathology in any other organ system, including the liver, in either species.
Enzalutamide did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in either the in vitro cytogenetic assay with mouse lymphoma cells or the in vivo mouse micronucleus assay. Long-term animal studies to evaluate the carcinogenic potential of enzalutamide have not been conducted. Enzalutamide was not phototoxic in vitro.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule contents
Caprylocaproyl macrogol-8 glycerides
Butylhydroxyanisole (E320)
Butylhydroxytoluene (E321)
Capsule shell
Gelatin
Sorbitol sorbitan solution
Glycerol
Titanium dioxide (E171)
Purified water
Printing ink
Iron oxide black (E172)
Polyvinyl acetate phthalate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Cardboard wallet incorporating a PVC/PCTFE/aluminium blister of 28 soft capsules. Each carton contains 4 wallets (112 soft capsules).
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands
8. Marketing authorisation number(s)
EU/1/13/846/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 21 June 2013
10. Date of revision of the text
25 September 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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产地国家：法国
原产地英文商品名:
Xtandi 40mg/cap 112caps/box
原产地英文药品名:
ESCITALOPRAM
中文参考商品译名:
Xtandi 40毫克/胶囊 112胶囊/盒
中文参考药品译名:
生产厂家中文参考译名:
恩杂鲁胺
生产厂家英文名:
ASTELLAS

-------------------------------------------------------
产地国家：美国
原产地英文商品名:
Xtandi 40mg/cap 120caps/box
原产地英文药品名:
ESCITALOPRAM
中文参考商品译名:
Xtandi 40毫克/胶囊 120胶囊/瓶
中文参考药品译名:
生产厂家中文参考译名:
恩杂鲁胺 
生产厂家英文名:
ASTELLAS

-------------------------------------------------------
产地国家：日本
原产地英文商品名:
Xtandi（イクスタンジカプセル）40mg/cap 56caps/box
原产地英文药品名:
ESCITALOPRAM
中文参考商品译名:
Xtandi（イクスタンジカプセル）40毫克/胶囊 56胶囊/盒
中文参考药品译名:
生产厂家中文参考译名:
恩杂鲁胺
生产厂家英文名:
ASTELLAS

-------------------------------------------------------
产地国家：英国
原产地英文商品名:
Xtandi 40mg/cap 112caps/box
原产地英文药品名:
ESCITALOPRAM
中文参考商品译名:
Xtandi 40毫克/胶囊 112胶囊/盒
中文参考药品译名:
生产厂家中文参考译名:
恩杂鲁胺
生产厂家英文名:
ASTELLAS