Xtandi

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ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT  
Xtandi - 40 mg soft capsules 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Xtandi - 40 mg soft capsules 
Each soft capsule contains 40 mg of enzalutamide. 

Excipient(s) with known effect  
Each soft capsule contains 57.8 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 high-risk non-metastatic castration-resistant prostate cancer 

(CRPC) (see section 5.1). 
• 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). 

• the treatment of adult men with metastatic CRPC whose disease has progressed on or after 
docetaxel therapy. 
 

 

4.2 Posology and method of administration 

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 not surgically castrated. 
 
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. 
 



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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. 

Method of administration  
Xtandi is for oral use. The soft capsules should not be chewed, dissolved or opened but should be 
swallowed whole with water, and can be taken with or without food. 

4.3 Contraindications  

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). 

4.4 Special warnings and precautions for use  

Risk of seizure 
Use of enzalutamide has been associated with seizure (see section 4.8). The decision to continue 
treatment in patients who develop seizure 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. 
 
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). 
 



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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. 
 
Excipients 
Xtandi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should 
not take this medicinal product. 
 
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). 

4.5 Interaction with other medicinal products and other forms of interaction  

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. 
 



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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). 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) 
• 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) 

 



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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. 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.  
 
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. 

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. 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). 



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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). 

4.7 Effects on ability to drive and use machines  

Xtandi has 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. 

4.8 Undesirable effects  

Summary of the safety profile  
The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other 
important adverse reactions include fall, cognitive disorder, and neutropenia. 
 
Seizure occurred in 0.4% 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). 
 
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. 
 



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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 

Psychiatric disorders Common: anxiety 
Uncommon: visual hallucination 

Nervous system disorders Common: headache, memory impairment, amnesia,  
disturbance in attention, restless legs syndrome 
Uncommon: cognitive disorder, 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*: nausea, vomiting, diarrhoea 
Skin and subcutaneous tissue 
disorders 

Common: dry skin, pruritus 
Not known*: 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 

General disorders and 
administration site conditions 

Very common: asthenia, fatigue 

Injury, poisoning and 
procedural complications 

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. 

 
Description of selected adverse reactions 
 
Seizure 
In controlled clinical studies, 13 patients (0.4%) experienced a seizure out of 3179 patients treated with 
a daily dose of 160 mg enzalutamide, whereas one patient (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 



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In randomized placebo-controlled clinical studies, ischemic heart disease occurred in 2.5% of patients 
treated with enzalutamide plus ADT compared to 1.3 % patients treated with placebo plus ADT.  
 

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. 

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: 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. 
 



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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). 
 
In the MDV3100-14 clinical trial (PROSPER) of non-metastatic CRPC, patients receiving 
enzalutamide demonstrated a significantly higher confirmed PSA response rate (defined as a ≥ 50% 
reduction from baseline), compared with patients receiving placebo, 76.3% versus 2.4% 
(difference = 73.9%, p < 0.0001). 

Clinical efficacy and safety  
Efficacy of enzalutamide was established in three randomised placebo-controlled multicentre phase 3 
clinical studies [MDV3100-14 (PROSPER), CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] of 
patients with progressive prostate cancer who had failed androgen deprivation therapy [LHRH 
analogue or after bilateral orchiectomy]. The PREVAIL study enrolled metastatic CRPC 
chemotherapy-naïve patients; whereas the AFFIRM study enrolled metastatic CRPC patients who had 
received prior docetaxel; and the PROSPER study enrolled patients with non-metastatic CRPC. All 
patients continued on a LHRH analogue or had prior bilateral orchiectomy. In the active treatment 
arm, Xtandi was administered orally at a dose of 160 mg daily. In the three clinical trials, patients 
received placebo in the control arm and patients were allowed, but not required, to take prednisone 
(maximum daily dose allowed was 10 mg prednisone or equivalent). 
 
Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore, 
in the three studies it was recommended that patients be maintained on their study treatments until 
discontinuation criteria were met as specified below for each study. 
 
MDV3100-14 (PROSPER) study (patients with non-metastatic CRPC) 
 
The PROSPER study enrolled 1401 patients with asymptomatic, high-risk non-metastatic CRPC who 
continued on androgen deprivation therapy (ADT; defined as LHRH analogue or prior bilateral 
orchiectomy).  Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and 
confirmation of non-metastatic disease by blinded independent central review (BICR). 
 
Patients with a history of mild to moderate heart failure (NYHA Class I or II), and patients taking 
medicinal products associated with lowering the seizure threshold were allowed. Patients were 
excluded with a previous history of seizure, a condition that might predispose them to seizure, or 
certain prior treatments for prostate cancer (i.e., chemotherapy, ketoconazole, abiraterone acetate, 
aminoglutethimide and/or enzalutamide). 
 
Patients were randomised 2:1 to receive either enzalutamide at a dose of 160 mg once daily (N = 933) 
or placebo (N = 468). Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time 
(PSADT) (< 6 months or ≥ 6 months) and the use of bone-targeting agents (yes or no). 
 
The demographic and baseline characteristics were well-balanced between the two treatment arms. 
The median age at randomisation was 74 years in the enzalutamide arm and 73 years in the placebo 
arm. Most patients (approximately 71%) in the study were Caucasian; 16% were Asian and 2% were 
Black. Eighty-one percent (81%) of patients had an ECOG performance status score of 0 and 19% 
patients had an ECOG performance status of 1. 
 
Metastasis-free survival (MFS) was the primary endpoint defined as the time from randomisation to 
radiographic progression or death within 112 days of treatment discontinuation without evidence of 
radiographic progression, whichever occurred first. Key secondary endpoints assessed in the study 
were time to PSA progression, time to first use of new antineoplastic therapy (TTA), overall survival 
(OS). Additional secondary endpoints included time to first use of cytotoxic chemotherapy and 
chemotherapy-free survival. See results below (Table 2).  
 



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Enzalutamide demonstrated a statistically significant 71% reduction in the relative risk of radiographic 
progression or death compared to placebo [HR = 0.29 (95% CI: 0.24, 0.35), p < 0.0001]. Median MFS 
was 36.6 months (95% CI: 33.1, NR) on the enzalutamide arm versus 14.7 months (95% CI: 14.2, 
15.0) on the placebo arm. Consistent MFS results were also observed in all pre-specified patient sub-
groups including PSADT (< 6 months or ≥ 6 months), demographic region (North America, Europe, 
rest of world), age (< 75 or ≥ 75), use of a prior bone-targeting agent (yes or no). 
 
Table 2: Summary of efficacy results in the PROSPER study (intent-to-treat analysis) 

 Enzalutamide 
N = 933 

Placebo 
N = 468 

Primary Endpoint 
Metastasis-free survival 

Number of Events (%) 219 (23.5) 228 (48.7) 
Median, months (95% CI)1 36.6 (33.1, NR) 14.7 (14.2, 15.0) 
Hazard Ratio (95% CI)2  0.29 (0.24, 0.35) 
P-value3  p < 0.0001 

Key Secondary Efficacy Endpoints 
Time to PSA progression 
Number of Events (%)  208 (22.3) 324 (69.2) 
Median, months (95% CI)1 37.2 (33.1, NR) 3.9 (3.8, 4.0) 
Hazard Ratio (95% CI)2 0.07 (0.05, 0.08) 
P-value3 p < 0.0001 

Time to first use of new antineoplastic therapy 
Number of Events (%)  142 (15.2) 226 (48.3) 
Median, months (95% CI)1 39.6 (37.7, NR) 17.7 (16.2, 19.7) 
Hazard Ratio (95% CI)2 0.21 (0.17, 0.26) 
P-value3 p < 0.0001 
NR = Not reached. 
1. Based on Kaplan-Meier estimates. 
2. HR is based on a Cox regression model (with treatment as the only covariate) stratified by PSA doubling time and 

prior or concurrent use of a bone targeting agent. The HR is relative to placebo with < 1 favouring enzalutamide. 
3. P-value is based on a stratified log-rank test by PSA doubling time (< 6 months, ≥ 6 months) and prior or 

concurrent use of a bone targeting agent (yes, no). 
 

 
Figure 1: Kaplan-Meier Curves of metastasis-free survival in the PROSPER study (intent-to-
treat analysis) 

 



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Overall survival was evaluated at two prespecified interim analyses to date; the first at the time of final 
MFS (n = 165) [HR = 0.80 (95% CI: 0.58, 1.09), p = 0.1519], and the second interim analysis 
(n = 288) [HR = 0.83 (95% CI: 0.65, 1.06), p = 0.1344]. The median was not reached in either 
treatment group and neither analysis showed a statistically significant difference between treatment 
arms. 
 
  
Enzalutamide demonstrated a statistically significant 93% reduction in the relative risk of PSA 
progression compared to placebo [HR = 0.07 (95% CI: 0.05, 0.08), p < 0.0001]. Median time to PSA 
progression was 37.2 months (95% CI: 33.1, NR) on the enzalutamide arm versus 3.9 months (95% 
CI: 3.8, 4.0) on the placebo arm. 
 
Enzalutamide demonstrated a statistically significant delay in the time to first use of new 
antineoplastic therapy compared to placebo [HR = 0.21 (95% CI: 0.17, 0.26), p < 0.0001]. Median 
time to first use of new antineoplastic therapy was 39.6 months (95% CI: 37.7, NR) on the 
enzalutamide arm versus 17.7 months (95% CI: 16.2, 19.7) on the placebo arm. 
 

 
Figure 2: Kaplan-Meier curves of time to first use of new antineoplastic therapy in the 
PROSPER study (intent-to-treat analysis) 

 
MDV3100-09 (STRIVE) study (chemotherapy-naïve patients with non-metastatic/metastatic CRPC) 
 
The STRIVE study enrolled 396 non-metastatic or metastatic CRPC patients who had serologic or 
radiographic disease progression despite primary androgen deprivation therapy who were randomised 
to receive either enzalutamide at a dose of 160 mg once daily (N = 198) or bicalutamide at a dose of 
50 mg once daily (N = 198). PFS was the primary endpoint defined as the time from randomisation to 
the earliest objective evidence of radiographic progression, PSA progression, or death on study. 
Median PFS was 19.4 months (95% CI: 16.5, not reached) in the enzalutamide group versus 
5.7 months (95% CI: 5.6, 8.1) in the bicalutamide group [HR = 0.24 (95% CI: 0.18, 0.32), p < 0.0001]. 
Consistent benefit of enzalutamide over bicalutamide on PFS was observed in all pre-specified patient 
subgroups. For the non-metastatic subgroup (N = 139) a total of 19 out of 70 (27.1%) patients treated 
with enzalutamide and 49 out of 69 (71.0%) patients treated with bicalutamide had PFS events 
(68 total events). The hazard ratio was 0.24 (95% CI: 0.14, 0.42) and the median time to a PFS event 
was not reached in the enzalutamide group versus 8.6 months in the bicalutamide group. 
 



13 

 
Figure 3: Kaplan-Meier Curves of progression-free survival in the STRIVE study (intent-to-
treat analysis) 

 
9785-CL-0222 (TERRAIN) study (chemotherapy-naïve patients with metastatic CRPC) 
 
The TERRAIN study enrolled 375 chemo- and antiandrogen-therapy naïve patients with metastatic 
CRPC who were randomised to receive either enzalutamide at a dose of 160 mg once daily (N = 184) 
or bicalutamide at a dose of 50 mg once daily (N = 191). Median PFS was 15.7 months for patients on 
enzalutamide versus 5.8 months for patients on bicalutamide [HR = 0.44 (95% CI: 0.34, 0.57), p < 
0.0001]. Progression-free survival was defined as objective evidence of radiographic disease 
progression by independent central review, skeletal-related events, initiation of new antineoplastic 
therapy or death by any cause, whichever occurred first. Consistent PFS benefit was observed across 
all pre-specified patient subgroups. 
 
MDV3100-03 (PREVAIL) study (chemotherapy-naïve patients with metastatic CRPC) 
 
A total of 1717 asymptomatic or mildly symptomatic chemotherapy-naïve patients were randomised 
1:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 872) or placebo orally 
once daily (N = 845). Patients with visceral disease, patients with a history of mild to moderate heart 
failure (NYHA Class I or II), and patients taking medicinal products associated with lowering the 
seizure threshold were allowed. Patients with a previous history of seizure or a condition that might 
predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. 
Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-
related event, or clinical progression) and the initiation of either a cytotoxic chemotherapy or an 
investigational agent, or until unacceptable toxicity. 
 
Patient demographics and baseline disease characteristics were balanced between the treatment arms. 
The median age was 71 years (range 42 - 93) and the racial distribution was 77% Caucasian, 
10% Asian, 2% Black and 11% other or unknown races. Sixty-eight percent (68%) of patients had an 
ECOG performance status score of 0 and 32% patients had an ECOG performance status of 1. 
Baseline pain assessment was 0 - 1 (asymptomatic) in 67% of patients and 2 - 3 (mildly symptomatic) 
in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours 
on a scale of 0 to 10). Approximately 45% of patients had measurable soft tissue disease at study 
entry, and 12% of patients had visceral (lung and/or liver) metastases. 
 
Co-primary efficacy endpoints were overall survival and radiographic progression-free survival 
(rPFS). In addition to the co-primary endpoints, benefit was also assessed using time to initiation of 
cytotoxic chemotherapy, best overall soft tissue response, time to first skeletal-related event, PSA 
response (≥ 50% decrease from baseline), time to PSA progression, and time to FACT-P total score 
degradation. 
 



14 

Radiographic progression was assessed with the use of sequential imaging studies as defined by 
Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (for bone lesions) and/or Response 
Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria (for soft tissue lesions). Analysis of rPFS 
utilised centrally-reviewed radiographic assessment of progression. 
 
At the pre-specified interim analysis for overall survival when 540 deaths were observed, treatment 
with enzalutamide demonstrated a statistically significant improvement in overall survival compared to 
treatment with placebo with a 29.4% reduction in risk of death [HR = 0.706 (95% CI: 0.60; 0.84), 
p < 0.0001].  An updated survival analysis was conducted when 784 deaths were observed. Results 
from this analysis were consistent with those from the interim analysis (Table 3, Figure 4). At the 
updated analysis 52% of enzalutamide-treated and 81% of placebo-treated patients had received 
subsequent therapies for metastatic CRPC that may prolong overall survival. 
 
Table 3: Overall survival of patients treated with either enzalutamide or placebo in the 
PREVAIL study (intent-to-treat analysis) 

 
Enzalutamide 

(N = 872) 
Placebo  

(N = 845) 
Pre-specified interim analysis   

Number of deaths (%) 241 (27.6%) 299 (35.4%) 
Median survival, months (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR) 

   P-value1 p < 0.0001 
   Hazard ratio (95% CI)2 0.71 (0.60, 0.84) 
Updated survival analysis   

Number of deaths (%) 368 (42.2%) 416 (49.2%) 
Median survival, months (95% CI) 35.3 (32.2, NR) 31.3 (28.8, 34.2) 
P-value1 p = 0.0002 

   Hazard ratio (95% CI)2 0.77 (0.67, 0.88) 
NR = Not reached. 
1. P-value is derived from an unstratified log-rank test. 
2. Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio < 1 favours enzalutamide. 

 

Figure 4: Kaplan-Meier curves of overall survival based on updated survival analysis in the 
PREVAIL study (intent-to-treat analysis) 



15 

 

 
Figure 5: Updated overall survival analysis by subgroup: Hazard ratio and 95% confidence 
interval in the PREVAIL study (intent-to-treat analysis) 

 
At the pre-specified rPFS analysis, a statistically significant improvement was demonstrated between 
the treatment groups with an 81.4% reduction in risk of radiographic progression or death [HR = 0.19 
(95% CI: 0.15, 0.23), p < 0.0001]. One hundred and eighteen (14%) enzalutamide-treated patients and 
321 (40%) of placebo-treated patients had an event. The median rPFS was not reached (95% CI: 13.8, 
not reached) in the enzalutamide-treated group and was 3.9 months (95% CI: 3.7, 5.4) in the placebo-
treated group (Figure 6). Consistent rPFS benefit was observed across all pre-specified patient 
subgroups (e.g. age, baseline ECOG performance, baseline PSA and LDH, Gleason score at diagnosis, 
and visceral disease at screening). A pre-specified follow-up rPFS analysis based on the investigator 
assessment of radiographic progression demonstrated a statistically significant improvement between 
the treatment groups with a 69.3% reduction in risk of radiographic progression or death [HR = 0.31 
(95% CI: 0.27, 0.35), p < 0.0001]. The median rPFS was 19.7 months in the enzalutamide group and 
5.4 months in the placebo group. 
 



16 

At the time of the primary analysis there were 1,633 patients randomised. 
 
Figure 6: Kaplan-Meier curves of radiographic progression-free survival in the PREVAIL study 
(intent-to-treat analysis) 

 
In addition to the co-primary efficacy endpoints, statistically significant improvements were also 
demonstrated in the following prospectively defined endpoints. 
 
The median time to initiation of cytotoxic chemotherapy was 28.0 months for patients receiving 
enzalutamide and 10.8 months for patients receiving placebo [HR = 0.35 (95% CI: 0.30, 0.40), 
p < 0.0001]. 
 
The proportion of enzalutamide-treated patients with measurable disease at baseline who had an 
objective soft tissue response was 58.8% (95% CI: 53.8, 63.7) compared with 5.0% (95% CI: 3.0, 7.7) 
of patients receiving placebo. The absolute difference in objective soft tissue response between 
enzalutamide and placebo arms was [53.9% (95% CI: 48.5, 59.1), p < 0.0001]. Complete responses 
were reported in 19.7% of enzalutamide-treated patients compared with 1.0% of placebo-treated 
patients, and partial responses were reported in 39.1% of enzalutamide-treated patients versus 3.9% of 
placebo-treated patients. 
 
Enzalutamide significantly decreased the risk of the first skeletal-related event by 28% [HR = 0.718 
(95% CI: 0.61, 0.84), p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgery 
to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of 
antineoplastic therapy to treat bone pain. The analysis included 587 skeletal-related events, of which 
389 events (66.3%) were radiation to bone, 79 events (13.5%) were spinal cord compression, 70 events 
(11.9%) were pathologic bone fracture, 45 events (7.6%) were change in antineoplastic therapy to treat 
bone pain, and 22 events (3.7%) were surgery to bone. 
 
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). 
 
The median time to PSA progression per PCWG2 criteria was 11.2 months for patients treated with 
enzalutamide and 2.8 months for patients who received placebo [HR = 0.17 (95% CI: 0.15, 0.20), 
p < 0.0001]. 



17 

 
Treatment with enzalutamide decreased the risk of FACT-P degradation by 37.5% compared with 
placebo (p < 0.0001). The median time to degradation in FACT-P was 11.3 months in the 
enzalutamide group and 5.6 months in the placebo group. 
 
CRPC2 (AFFIRM) study (patients with metastatic CRPC who previously received chemotherapy) 
 
The efficacy and safety of enzalutamide in patients with metastatic CRPC who had received docetaxel 
and were using a LHRH 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 93% 
Caucasian, 4% Black, 1% Asian, and 2% Other. The ECOG performance score was 0 - 1 in 91.5% of 
patients and 2 in 8.5% of patients; 28% 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 
randomisation). Most (91%) patients had metastases in bone and 23% had visceral lung and/or liver 
involvement. At study entry, 41% of randomised patients had PSA progression only, whereas 59% of 
patients had radiographic progression. Fifty-one percent (51%) of patients were on bisphosphonates at 
baseline. 
 
The AFFIRM 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). 
 
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 4 and 
Figures 7 and 8).  
 
Table 4: Overall survival of patients treated with either enzalutamide or placebo in the AFFIRM 
study (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-value1  p < 0.0001 
Hazard ratio (95% CI)2  0.63 (0.53, 0.75) 
NR = Not Reached. 
1. 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). 
2. Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours enzalutamide. 

 



18 

 
Figure 7: Kaplan-Meier curves of overall survival in the AFFIRM study (intent-to-treat 
analysis) 

 

 
ECOG: Eastern Cooperative Oncology Group; BPI-SF: Brief Pain Inventory-Short Form; PSA: Prostate Specific Antigen 
 
Figure 8: Overall survival by subgroup in the AFFIRM study – Hazard ratio and 95% 
confidence interval 

 
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. 



19 

 
Radiographic progression-free survival as assessed by the investigator using RECIST v 1.1 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 = 0.40 (95% CI: 0.35, 0.47), 
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 = 0.25 (95% CI: 0.20, 0.30), 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 = 0.69 (95% CI: 0.57, 0.84), 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 antineoplastic therapy to treat bone pain, and 7 events (2%) were surgery to bone. 
 
9785-CL-0410 study (enzalutamide post abiraterone in patients with metastatic CRPC) 
 
The study was a single-arm study in 214 patients with progressing metastatic CRPC who received 
enzalutamide (160 mg once daily) after at least 24 weeks of treatment with abiraterone acetate plus 
prednisone. Median rPFS (radiologic progression free survival, the study´s primary endpoint) was 
8.1 months (95% CI: 6.1, 8.3). Median OS was not reached. PSA Response (defined as ≥ 50% 
decrease from baseline) was 22.4% (95% CI: 17.0, 28.6). For the 69 patients who previously received 
chemotherapy, median rPFS was 7.9 months (95% CI: 5.5, 10.8). PSA Response was 23.2% (95% CI: 
13.9, 34.9). For the 145 patients who had no previous chemotherapy, median rPFS was 8.1 months 
(95% CI: 5.7, 8.3). PSA Response was 22.1% (95% CI: 15.6, 29.7). 
 
Although there was a limited response in some patients from treatment with enzalutamide after 
abiraterone, the reason for this finding is currently unknown. The study design could neither identify 
the patients who are likely to benefit, nor the order in which enzalutamide and abiraterone should be 
optimally sequenced. 
 
Elderly 
Of the 3179 patients in the controlled clinical trials who received enzalutamide, 2518 patients (79%) 
were 65 years and over and 1162 patients (37%) were 75 years and over. No overall differences in 
safety or effectiveness were observed between these elderly patients and younger patients. 

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. 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. 
 



20 

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 medicinal products (warfarin, ibuprofen and salicylic acid) in vitro. 

Biotransformation  
Enzalutamide is extensively metabolised. There are two major metabolites in human plasma: 
N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is 
metabolised 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 metabolised 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 metabolised 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. 



21 

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 
Hepatic impairment did not have a pronounced effect on the total exposure to enzalutamide or its 
active metabolite. The half-life of enzalutamide was however doubled in patients with severe hepatic 
impairment compared with healthy controls (10.4 days compared to 4.7 days), possibly related to an 
increased tissue distribution. 
 
The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6), 
moderate (N = 8) or severe (N = 8) hepatic impairment (Child-Pugh Class A, B or C, respectively) and 
in 22 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, the AUC and Cmax of enzalutamide in subjects with moderate impairment 
increased by 29% and decreased by 11%, respectively, and the AUC and Cmax of enzalutamide in 
subjects with severe impairment increased by 5% and decreased by 41%, 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, the AUC 
and Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, 
and the AUC and Cmax in subjects with severe hepatic impairment increased by 34% and decreased by 
27%, respectively, compared to healthy control subjects. 
 
Race 
Most patients in the controlled clinical trials (> 74%) were Caucasian. Based on pharmacokinetic data 
from studies in Japanese and Chinese patients with prostate cancer, there were no clinically relevant 
differences in exposure among the populations. There are insufficient data to evaluate potential 
differences in the pharmacokinetics of enzalutamide in other races. 
 
Elderly 
No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the elderly 
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 



22 

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. 
 
Studies in pregnant rats have shown that enzalutamide and/or its metabolites are transferred to fetuses. 
After oral administration of radiolabeled 14C-enzalutamide to rats on day 14 of pregnancy at a dose of 
30 mg/kg (~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in the 
fetus was reached 4 hours after administration and was lower than that in the maternal plasma with 
tissue/plasma ratio of 0.27. The radioactivity in the fetus decreased to 0.08 times the maximum 
concentration at 72 hours after administration. 
 
Studies in lactating rats have shown that enzalutamide and/or its metabolites are secreted in rat milk. 
After oral administration of radiolabeled 14C-enzalutamide to lactating rats at a dose of 30 mg/kg 
(~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in the milk was 
reached 4 hours after administration and was up to 3.54-fold higher than that in the maternal plasma. 
Study results also have shown that enzalutamide and/or its metabolites are transferred to infant rat 
tissues via milk and subsequently eliminated. 
 
Enzalutamide was negative for genotoxicity in a standard battery of in vitro and in vivo tests. In a 6-
month study in transgenic rasH2 mice, enzalutamide did not show carcinogenic potential (absence of 
neoplastic findings) at doses up to 20 mg/kg per day (AUC24h ~317 µg•h/mL), which resulted in 
plasma exposure levels similar to the clinical exposure (AUC24h 322 µg•h/mL) in mCRPC patients 
receiving 160 mg, daily.  
 
Daily dosing of rats for two years with enzalutamide at 10–100 mg/kg/day produced an increased 
incidence of several, mostly benign, tumour types. The most prominent of these were benign Leydig 
cell tumours, urothelium papilloma, and carcinoma of urinary bladder. Benign Leydig cell tumours are 
expected based on the pharmacological properties of this antiandrogen drug and not considered 
relevant to humans. Some urothelium papilloma and carcinoma of urinary bladder is expected in rats 
based on the horizontal structure of the rat urinary bladder, which can encounter concentrated urine 
and prolonged irritation from calculi. In the study, calculi and crystals were observed in rat urinary 
bladders. However, no obvious mechanistic rationale to explain specifically this malignancy can be 
established, and taking into account that exposure levels, based on AUC, achieved in the study, for 
enzalutamide plus its metabolites, were less than or similar to those in prostate cancer patients at the 
recommended dose of 160 mg/day, urinary bladder carcinogenicity potential of enzalutamide in 
humans cannot be excluded. Other tumours, which are also potentially related to the primary 
pharmacology include fibroadenoma of mammary glands and benign thymoma of thymus in males, 
benign granulosa cell tumours of ovaries in females, and adenoma of pituitary pars distalis in both 
sexes. The exposure levels achieved in this study in male rats at Week 26 at 100 mg/kg per day for 
enzalutamide plus its active metabolites M1 and M2 (AUC24: enzalutamide ~457 µg•h/mL, M1 ~321 
µg•h/mL, M2 ~35 µg•h/mL) were less than or similar to those in prostate cancer patients at the 
recommended dose (160 mg/day) of enzalutamide (AUC24: enzalutamide ~322 µg•h/mL, M1 ~193 
µg•h/mL, M2 ~278 µg•h/mL).  
 
Enzalutamide was not phototoxic in vitro. 

6. PHARMACEUTICAL PARTICULARS  

6.1 List of excipients  

Capsule contents 
Caprylocaproyl macrogol-8 glycerides  
Butylhydroxyanisole (E320) 
Butylhydroxytoluene (E321) 
 



23 

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  

3 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 

Xtandi should not be handled by persons other than the patient and his caregivers, and especially not 
by women who are or may become pregnant. The soft capsules should not be dissolved or opened. 

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 

EU/1/13/846/001 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  

Date of first authorisation: 21 June 2013 
Date of latest renewal: 8 February 2018 

10. DATE OF REVISION OF THE TEXT 

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



24 

1. NAME OF THE MEDICINAL PRODUCT  

Xtandi - 40 mg film-coated tablets 
Xtandi - 80 mg film-coated tablets 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Xtandi - 40 mg film-coated tablets 
Each film-coated tablet contains 40 mg of enzalutamide. 
 
Xtandi - 80 mg film-coated tablets 
Each film-coated tablet contains 80 mg of enzalutamide. 
 
For the full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM  

Film-coated tablet. 
Xtandi - 40 mg film-coated tablets 
Yellow round – film-coated tablets, debossed with E 40. 
 
Xtandi - 80 mg film-coated tablets 
Yellow oval – film-coated tablets, debossed with E 80. 

4. CLINICAL PARTICULARS  

4.1 Therapeutic indications  

Xtandi is indicated for: 
• the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer 

(CRPC) (see section 5.1). 
• 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). 

• the treatment of adult men with metastatic CRPC whose disease has progressed on or after 
docetaxel therapy. 

4.2 Posology and method of administration 

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 not surgically castrated. 
 
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. 



25 

 
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. 

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 water, and can be taken with or without food. 

4.3 Contraindications  

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). 

4.4 Special warnings and precautions for use  

Risk of seizure 
Use of enzalutamide has been associated with seizure (see section 4.8). The decision to continue 
treatment in patients who develop seizure 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. 
 
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. 



26 

 
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. 
 
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). 

4.5 Interaction with other medicinal products and other forms of interaction  

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. 



27 

 
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). 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) 
• 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) 

 



28 

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. 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.  
 
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. 

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. 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). 



29 

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). 

4.7 Effects on ability to drive and use machines  

Xtandi has 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. 

4.8 Undesirable effects  

Summary of the safety profile  
The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other 
important adverse reactions include fall, cognitive disorder, and neutropenia. 
 
Seizure occurred in 0.4% 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). 
 
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. 
 



30 

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 

Psychiatric disorders Common: anxiety 
Uncommon: visual hallucination 

Nervous system disorders Common: headache, memory impairment, amnesia,  
disturbance in attention, restless legs syndrome 
Uncommon: cognitive disorder, 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*: nausea, vomiting, diarrhoea 
Skin and subcutaneous tissue 
disorders 

Common: dry skin, pruritus 
Not known*: 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 

General disorders and 
administration site conditions 

Very common: asthenia, fatigue 

Injury, poisoning and 
procedural complications 

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. 

 
Description of selected adverse reactions 
 
Seizure 
In controlled clinical studies, 13 patients (0.4%) experienced a seizure out of 3179 patients treated with 
a daily dose of 160 mg enzalutamide, whereas one patient (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 



31 

In randomized placebo-controlled clinical studies, ischemic heart disease occurred in 2.5% of patients 
treated with enzalutamide plus ADT compared to 1.3 % patients treated with placebo plus ADT.  

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. 

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: 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. 
 



32 

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). 
 
In the MDV3100-14 clinical trial (PROSPER) of non-metastatic CRPC, patients receiving 
enzalutamide demonstrated a significantly higher confirmed PSA response rate (defined as a ≥ 50% 
reduction from baseline), compared with patients receiving placebo, 76.3% versus 2.4% 
(difference = 73.9%, p < 0.0001). 

Clinical efficacy and safety  
Efficacy of enzalutamide was established in three randomised placebo-controlled multicentre phase 3 
clinical studies [MDV3100-14 (PROSPER), CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] of 
patients with progressive prostate cancer who had failed androgen deprivation therapy [LHRH 
analogue or after bilateral orchiectomy]. The PREVAIL study enrolled metastatic CRPC 
chemotherapy-naïve patients; whereas the AFFIRM study enrolled metastatic CRPC patients who had 
received prior docetaxel; and the PROSPER study enrolled patients with non-metastatic CRPC. All 
patients continued on a LHRH analogue or had prior bilateral orchiectomy. In the active treatment 
arm, Xtandi was administered orally at a dose of 160 mg daily. In the three clinical trials, patients 
received placebo in the control arm and patients were allowed, but not required, to take prednisone 
(maximum daily dose allowed was 10 mg prednisone or equivalent). 
 
Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore, 
in the three studies it was recommended that patients be maintained on their study treatments until 
discontinuation criteria were met as specified below for each study. 
 
MDV3100-14 (PROSPER) study (patients with non-metastatic CRPC) 
 
The PROSPER study enrolled 1401 patients with asymptomatic, high-risk non-metastatic CRPC who 
continued on androgen deprivation therapy (ADT; defined as LHRH analogue or prior bilateral 
orchiectomy). Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and 
confirmation of non-metastatic disease by blinded independent central review (BICR). 
 
Patients with a history of mild to moderate heart failure (NYHA Class I or II), and patients taking 
medicinal products associated with lowering the seizure threshold were allowed. Patients were 
excluded with a previous history of seizure, a condition that might predispose them to seizure, or 
certain prior treatments for prostate cancer (i.e., chemotherapy, ketoconazole, abiraterone acetate, 
aminoglutethimide and/or enzalutamide). 
 
Patients were randomised 2:1 to receive either enzalutamide at a dose of 160 mg once daily (N = 933) 
or placebo (N = 468). Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time 
(PSADT) (< 6 months or ≥ 6 months) and the use of bone-targeting agents (yes or no). 
The demographic and baseline characteristics were well-balanced between the two treatment arms. 
The median age at randomisation was 74 years in the enzalutamide arm and 73 years in the placebo 
arm. Most patients (approximately 71%) in the study were Caucasian; 16% were Asian and 2% were 
Black. Eighty-one percent (81%) of patients had an ECOG performance status score of 0 and 19% 
patients had an ECOG performance status of 1. 
 
Metastasis-free survival (MFS) was the primary endpoint defined as the time from randomisation to 
radiographic progression or death within 112 days of treatment discontinuation without evidence of 
radiographic progression, whichever occurred first. Key secondary endpoints assessed in the study 
were time to PSA progression, time to first use of new antineoplastic therapy (TTA), overall survival 
(OS). Additional secondary endpoints included time to first use of cytotoxic chemotherapy and 
chemotherapy-free survival. See results below (Table 2).  
 
Enzalutamide demonstrated a statistically significant 71% reduction in the relative risk of radiographic 
progression or death compared to placebo [HR = 0.29 (95% CI: 0.24, 0.35), p < 0.0001]. Median MFS 



33 

was 36.6 months (95% CI: 33.1, NR) on the enzalutamide arm versus 14.7 months (95% CI: 14.2, 
15.0) on the placebo arm. Consistent MFS results were also observed in all pre-specified patient sub-
groups including PSADT (< 6 months or ≥ 6 months), demographic region (North America, Europe, 
rest of world), age (< 75 or ≥ 75), use of a prior bone-targeting agent (yes or no). 
 
Table 2: Summary of efficacy results in the PROSPER study (intent-to-treat analysis) 

 Enzalutamide 
N = 933 

Placebo 
N = 468 

Primary Endpoint 
Metastasis-free survival 

Number of Events (%) 219 (23.5) 228 (48.7) 
Median, months (95% CI)1 36.6 (33.1, NR) 14.7 (14.2, 15.0) 
Hazard Ratio (95% CI)2  0.29 (0.24, 0.35) 
P-value3  p < 0.0001 

Key Secondary Efficacy Endpoints 
Time to PSA progression 
Number of Events (%)  208 (22.3) 324 (69.2) 
Median, months (95% CI)1 37.2 (33.1, NR) 3.9 (3.8, 4.0) 
Hazard Ratio (95% CI)2 0.07 (0.05, 0.08) 
P-value3 p < 0.0001 

Time to first use of new antineoplastic therapy 
Number of Events (%)  142 (15.2) 226 (48.3) 
Median, months (95% CI)1 39.6 (37.7, NR) 17.7 (16.2, 19.7) 
Hazard Ratio (95% CI)2 0.21 (0.17, 0.26) 
P-value3 p < 0.0001 
NR = Not reached. 
1. Based on Kaplan-Meier estimates. 
2. HR is based on a Cox regression model (with treatment as the only covariate) stratified by PSA doubling time and 

prior or concurrent use of a bone targeting agent. The HR is relative to placebo with < 1 favouring enzalutamide. 
3. P-value is based on a stratified log-rank test by PSA doubling time (< 6 months, ≥ 6 months) and prior or 

concurrent use of a bone targeting agent (yes, no). 

 

 
Figure 1: Kaplan-Meier Curves of metastasis-free survival in the PROSPER study (intent-to-
treat analysis) 

 
Overall survival was evaluated at two prespecified interim analyses to date; the first at the time of final 
MFS (n = 165) [HR = 0.80 (95% CI: 0.58, 1.09), p = 0.1519], and the second interim analysis 
(n = 288) [HR = 0.83 (95% CI: 0.65, 1.06), p = 0.1344]. The median was not reached in either 



34 

treatment group and neither analysis showed a statistically significant difference between treatment 
arms. 
 
Enzalutamide demonstrated a statistically significant 93% reduction in the relative risk of PSA 
progression compared to placebo [HR = 0.07 (95% CI: 0.05, 0.08), p < 0.0001]. Median time to PSA 
progression was 37.2 months (95% CI: 33.1, NR) on the enzalutamide arm versus 3.9 months (95% 
CI: 3.8, 4.0) on the placebo arm. 
 
Enzalutamide demonstrated a statistically significant delay in the time to first use of new 
antineoplastic therapy compared to placebo [HR = 0.21 (95% CI: 0.17, 0.26), p < 0.0001]. Median 
time to first use of new antineoplastic therapy was 39.6 months (95% CI: 37.7, NR) on the 
enzalutamide arm versus 17.7 months (95% CI: 16.2, 19.7) on the placebo arm. 
 

 
Figure 2: Kaplan-Meier curves of time to first use of new antineoplastic therapy in the 
PROSPER study (intent-to-treat analysis) 

 
MDV3100-09 (STRIVE) study (chemotherapy-naïve patients with non-metastatic/metastatic CRPC) 
 
The STRIVE study enrolled 396 non-metastatic or metastatic CRPC patients who had serologic or 
radiographic disease progression despite primary androgen deprivation therapy who were randomised 
to receive either enzalutamide at a dose of 160 mg once daily (N = 198) or bicalutamide at a dose of 
50 mg once daily (N = 198). PFS was the primary endpoint defined as the time from randomisation to 
the earliest objective evidence of radiographic progression, PSA progression, or death on study. 
Median PFS was 19.4 months (95% CI: 16.5, not reached) in the enzalutamide group versus 
5.7 months (95% CI: 5.6, 8.1) in the bicalutamide group [HR = 0.24 (95% CI: 0.18, 0.32), p < 0.0001]. 
Consistent benefit of enzalutamide over bicalutamide on PFS was observed in all pre-specified patient 
subgroups. For the non-metastatic subgroup (N = 139) a total of 19 out of 70 (27.1%) patients treated 
with enzalutamide and 49 out of 69 (71.0%) patients treated with bicalutamide had PFS events 
(68 total events). The hazard ratio was 0.24 (95% CI: 0.14, 0.42) and the median time to a PFS event 
was not reached in the enzalutamide group versus 8.6 months in the bicalutamide group. 
 



35 

 
Figure 3: Kaplan-Meier Curves of progression-free survival in the STRIVE study (intent-to-
treat analysis) 

 
9785-CL-0222 (TERRAIN) study (chemotherapy-naïve patients with metastatic CRPC) 
 
The TERRAIN study enrolled 375 chemo- and antiandrogen-therapy naïve patients with metastatic 
CRPC who were randomised to receive either enzalutamide at a dose of 160 mg once daily (N = 184) 
or bicalutamide at a dose of 50 mg once daily (N = 191). Median PFS was 15.7 months for patients on 
enzalutamide versus 5.8 months for patients on bicalutamide [HR = 0.44 (95% CI: 0.34, 0.57), p < 
0.0001]. Progression-free survival was defined as objective evidence of radiographic disease 
progression by independent central review, skeletal-related events, initiation of new antineoplastic 
therapy or death by any cause, whichever occurred first. Consistent PFS benefit was observed across 
all pre-specified patient subgroups. 
 
MDV3100-03 (PREVAIL) study (chemotherapy-naïve patients with metastatic CRPC) 
 
A total of 1717 asymptomatic or mildly symptomatic chemotherapy-naïve patients were randomised 
1:1 to receive either enzalutamide orally at a dose of 160 mg once daily (N = 872) or placebo orally 
once daily (N = 845). Patients with visceral disease, patients with a history of mild to moderate heart 
failure (NYHA Class I or II), and patients taking medicinal products associated with lowering the 
seizure threshold were allowed. Patients with a previous history of seizure or a condition that might 
predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. 
Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-
related event, or clinical progression) and the initiation of either a cytotoxic chemotherapy or an 
investigational agent, or until unacceptable toxicity. 
 
Patient demographics and baseline disease characteristics were balanced between the treatment arms. 
The median age was 71 years (range 42 - 93) and the racial distribution was 77% Caucasian, 
10% Asian, 2% Black and 11% other or unknown races. Sixty-eight percent (68%) of patients had an 
ECOG performance status score of 0 and 32% patients had an ECOG performance status of 1. 
Baseline pain assessment was 0 - 1 (asymptomatic) in 67% of patients and 2 - 3 (mildly symptomatic) 
in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours 
on a scale of 0 to 10). Approximately 45% of patients had measurable soft tissue disease at study 
entry, and 12% of patients had visceral (lung and/or liver) metastases. 
 
Co-primary efficacy endpoints were overall survival and radiographic progression-free survival 
(rPFS). In addition to the co-primary endpoints, benefit was also assessed using time to initiation of 
cytotoxic chemotherapy, best overall soft tissue response, time to first skeletal-related event, PSA 
response (≥ 50% decrease from baseline), time to PSA progression, and time to FACT-P total score 
degradation. 
 



36 

Radiographic progression was assessed with the use of sequential imaging studies as defined by 
Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (for bone lesions) and/or Response 
Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria (for soft tissue lesions). Analysis of rPFS 
utilised centrally-reviewed radiographic assessment of progression. 
 
At the pre-specified interim analysis for overall survival when 540 deaths were observed, treatment 
with enzalutamide demonstrated a statistically significant improvement in overall survival compared to 
treatment with placebo with a 29.4% reduction in risk of death [HR = 0.706 (95% CI: 0.60; 0.84), 
p < 0.0001].  An updated survival analysis was conducted when 784 deaths were observed. Results 
from this analysis were consistent with those from the interim analysis (Table 3, Figure 4). At the 
updated analysis 52% of enzalutamide-treated and 81% of placebo-treated patients had received 
subsequent therapies for metastatic CRPC that may prolong overall survival. 
 
Table 3: Overall survival of patients treated with either enzalutamide or placebo in the 
PREVAIL study (intent-to-treat analysis) 

 
Enzalutamide 

(N = 872) 
Placebo  

(N = 845) 
Pre-specified interim analysis   

Number of deaths (%) 241 (27.6%) 299 (35.4%) 
Median survival, months (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR) 

   P-value1 p < 0.0001 
   Hazard ratio (95% CI)2 0.71 (0.60, 0.84) 
Updated survival analysis   

Number of deaths (%) 368 (42.2%) 416 (49.2%) 
Median survival, months (95% CI) 35.3 (32.2, NR) 31.3 (28.8, 34.2) 
P-value1 p = 0.0002 

   Hazard ratio (95% CI)2 0.77 (0.67, 0.88) 
NR = Not reached. 
1. P-value is derived from an unstratified log-rank test. 
2. Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio < 1 favours enzalutamide. 

 

Figure 4: Kaplan-Meier curves of overall survival based on updated survival analysis in the 
PREVAIL study (intent-to-treat analysis) 



37 

 

 
Figure 5: Updated overall survival analysis by subgroup: Hazard ratio and 95% confidence 
interval in the PREVAIL study (intent-to-treat analysis) 

 
At the pre-specified rPFS analysis, a statistically significant improvement was demonstrated between 
the treatment groups with an 81.4% reduction in risk of radiographic progression or death [HR = 0.19 
(95% CI: 0.15, 0.23), p < 0.0001]. One hundred and eighteen (14%) enzalutamide-treated patients and 
321 (40%) of placebo-treated patients had an event. The median rPFS was not reached (95% CI: 13.8, 
not reached) in the enzalutamide-treated group and was 3.9 months (95% CI: 3.7, 5.4) in the placebo-
treated group (Figure 6). Consistent rPFS benefit was observed across all pre-specified patient 
subgroups (e.g. age, baseline ECOG performance, baseline PSA and LDH, Gleason score at diagnosis, 
and visceral disease at screening). A pre-specified follow-up rPFS analysis based on the investigator 
assessment of radiographic progression demonstrated a statistically significant improvement between 
the treatment groups with a 69.3% reduction in risk of radiographic progression or death [HR = 0.31 
(95% CI: 0.27, 0.35), p < 0.0001]. The median rPFS was 19.7 months in the enzalutamide group and 
5.4 months in the placebo group. 
 



38 

At the time of the primary analysis there were 1,633 patients randomised. 
 
Figure 6: Kaplan-Meier curves of radiographic progression-free survival in the PREVAIL study 
(intent-to-treat analysis) 

 
In addition to the co-primary efficacy endpoints, statistically significant improvements were also 
demonstrated in the following prospectively defined endpoints. 
 
The median time to initiation of cytotoxic chemotherapy was 28.0 months for patients receiving 
enzalutamide and 10.8 months for patients receiving placebo [HR = 0.35 (95% CI: 0.30, 0.40), 
p < 0.0001]. 
 
The proportion of enzalutamide-treated patients with measurable disease at baseline who had an 
objective soft tissue response was 58.8% (95% CI: 53.8, 63.7) compared with 5.0% (95% CI: 3.0, 7.7) 
of patients receiving placebo. The absolute difference in objective soft tissue response between 
enzalutamide and placebo arms was [53.9% (95% CI: 48.5, 59.1), p < 0.0001]. Complete responses 
were reported in 19.7% of enzalutamide-treated patients compared with 1.0% of placebo-treated 
patients, and partial responses were reported in 39.1% of enzalutamide-treated patients versus 3.9% of 
placebo-treated patients. 
 
Enzalutamide significantly decreased the risk of the first skeletal-related event by 28% [HR = 0.718 
(95% CI: 0.61, 0.84), p < 0.0001]. A skeletal-related event was defined as radiation therapy or surgery 
to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of 
antineoplastic therapy to treat bone pain. The analysis included 587 skeletal-related events, of which 
389 events (66.3%) were radiation to bone, 79 events (13.5%) were spinal cord compression, 70 events 
(11.9%) were pathologic bone fracture, 45 events (7.6%) were change in antineoplastic therapy to treat 
bone pain, and 22 events (3.7%) were surgery to bone. 
 
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). 
 
The median time to PSA progression per PCWG2 criteria was 11.2 months for patients treated with 
enzalutamide and 2.8 months for patients who received placebo [HR = 0.17 (95% CI: 0.15, 0.20), 
p < 0.0001]. 



39 

 
Treatment with enzalutamide decreased the risk of FACT-P degradation by 37.5% compared with 
placebo (p < 0.0001). The median time to degradation in FACT-P was 11.3 months in the 
enzalutamide group and 5.6 months in the placebo group. 
 
CRPC2 (AFFIRM) study (patients with metastatic CRPC who previously received chemotherapy) 
 
The efficacy and safety of enzalutamide in patients with metastatic CRPC who had received docetaxel 
and were using a LHRH 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 93% 
Caucasian, 4% Black, 1% Asian, and 2% Other. The ECOG performance score was 0 - 1 in 91.5% of 
patients and 2 in 8.5% of patients; 28% 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 
randomisation). Most (91%) patients had metastases in bone and 23% had visceral lung and/or liver 
involvement. At study entry, 41% of randomised patients had PSA progression only, whereas 59% of 
patients had radiographic progression. Fifty-one percent (51%) of patients were on bisphosphonates at 
baseline. 
 
The AFFIRM 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). 
 
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 4 and 
Figures 7 and 8).  
 
Table 4: Overall survival of patients treated with either enzalutamide or placebo in the AFFIRM 
study (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-value1  p < 0.0001 
Hazard ratio (95% CI)2  0.63 (0.53, 0.75) 
NR = Not Reached. 
1. 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). 
2. Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours enzalutamide. 

 



40 

 
Figure 7: Kaplan-Meier curves of overall survival in the AFFIRM study (intent-to-treat 
analysis) 

 

 
ECOG: Eastern Cooperative Oncology Group; BPI-SF: Brief Pain Inventory-Short Form; PSA: Prostate Specific Antigen 
 
Figure 8: Overall survival by subgroup in the AFFIRM study – Hazard ratio and 95% 
confidence interval 

 
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. 



41 

 
Radiographic progression-free survival as assessed by the investigator using RECIST v 1.1 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 = 0.40 (95% CI: 0.35, 0.47), 
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 = 0.25 (95% CI: 0.20, 0.30), 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 = 0.69 (95% CI: 0.57, 0.84), 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 antineoplastic therapy to treat bone pain, and 7 events (2%) were surgery to bone. 
 
9785-CL-0410 study (enzalutamide post abiraterone in patients with metastatic CRPC) 
 
The study was a single-arm study in 214 patients with progressing metastatic CRPC who received 
enzalutamide (160 mg once daily) after at least 24 weeks of treatment with abiraterone acetate plus 
prednisone. Median rPFS (radiologic progression free survival, the study´s primary endpoint) was 
8.1 months (95% CI: 6.1, 8.3). Median OS was not reached. PSA Response (defined as ≥ 50% 
decrease from baseline) was 22.4% (95% CI: 17.0, 28.6). For the 69 patients who previously received 
chemotherapy, median rPFS was 7.9 months (95% CI: 5.5, 10.8). PSA Response was 23.2% (95% CI: 
13.9, 34.9). For the 145 patients who had no previous chemotherapy, median rPFS was 8.1 months 
(95% CI: 5.7, 8.3). PSA Response was 22.1% (95% CI: 15.6, 29.7). 
 
Although there was a limited response in some patients from treatment with enzalutamide after 
abiraterone, the reason for this finding is currently unknown. The study design could neither identify 
the patients who are likely to benefit, nor the order in which enzalutamide and abiraterone should be 
optimally sequenced. 
 
Elderly 
Of the 3179 patients in the controlled clinical trials who received enzalutamide, 2518 patients (79%) 
were 65 years and over and 1162 patients (37%) were 75 years and over. No overall differences in 
safety or effectiveness were observed between these elderly patients and younger patients. 

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. 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. 
 



42 

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. 
 
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.  
 
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 medicinal products (warfarin, ibuprofen and salicylic acid) in vitro. 

Biotransformation  
Enzalutamide is extensively metabolised. There are two major metabolites in human plasma: 
N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is 
metabolised 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 metabolised 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 metabolised 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. 
 



43 

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 
Hepatic impairment did not have a pronounced effect on the total exposure to enzalutamide or its 
active metabolite. The half-life of enzalutamide was however doubled in patients with severe hepatic 
impairment compared with healthy controls (10.4 days compared to 4.7 days), possibly related to an 
increased tissue distribution. 
 
The pharmacokinetics of enzalutamide were examined in subjects with baseline mild (N = 6), 
moderate (N = 8) or severe (N = 8) hepatic impairment (Child-Pugh Class A, B or C, respectively) and 
in 22 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, the AUC and Cmax of enzalutamide in subjects with moderate impairment 
increased by 29% and decreased by 11%, respectively, and the AUC and Cmax of enzalutamide in 
subjects with severe impairment increased by 5% and decreased by 41%, 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, the AUC 
and Cmax in subjects with moderate impairment increased by 14% and decreased by 17%, respectively, 
and the AUC and Cmax in subjects with severe hepatic impairment increased by 34% and decreased by 
27%, respectively, compared to healthy control subjects. 
 
Race 
Most patients in the controlled clinical trials (> 74%) were Caucasian. Based on pharmacokinetic data 
from studies in Japanese and Chinese patients with prostate cancer, there were no clinically relevant 
differences in exposure among the populations. There are insufficient data to evaluate potential 
differences in the pharmacokinetics of enzalutamide in other races. 
 
Elderly 
No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the elderly 
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 



44 

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. 
 
Studies in pregnant rats have shown that enzalutamide and/or its metabolites are transferred to fetuses. 
After oral administration of radiolabeled 14C-enzalutamide to rats on day 14 of pregnancy at a dose of 
30 mg/kg (~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in the 
fetus was reached 4 hours after administration and was lower than that in the maternal plasma with 
tissue/plasma ratio of 0.27. The radioactivity in the fetus decreased to 0.08 times the maximum 
concentration at 72 hours after administration. 
 
Studies in lactating rats have shown that enzalutamide and/or its metabolites are secreted in rat milk. 
After oral administration of radiolabeled 14C-enzalutamide to lactating rats at a dose of 30 mg/kg 
(~ 1.9 times the maximum dose indicated in humans), the maximum radioactivity in the milk was 
reached 4 hours after administration and was up to 3.54-fold higher than that in the maternal plasma. 
Study results also have shown that enzalutamide and/or its metabolites are transferred to infant rat 
tissues via milk and subsequently eliminated. 
 
Enzalutamide was negative for genotoxicity in a standard battery of in vitro and in vivo tests. In a 6-
month study in transgenic rasH2 mice, enzalutamide did not show carcinogenic potential (absence of 
neoplastic findings) at doses up to 20 mg/kg per day (AUC24h ~317 µg·h/mL), which resulted in plasma 
exposure levels similar to the clinical exposure (AUC24h 322 µg·h/mL) in mCRPC patients receiving 
160 mg, daily.  
 
Daily dosing of rats for two years with enzalutamide at 10–100 mg/kg/day produced an increased 
incidence of several, mostly benign, tumour types. The most prominent of these were benign Leydig 
cell tumours, urothelium papilloma, and carcinoma of urinary bladder. Benign Leydig cell tumours are 
expected based on the pharmacological properties of this antiandrogen drug and not considered 
relevant to humans. Some urothelium papilloma and carcinoma of urinary bladder is expected in rats 
based on the horizontal structure of the rat urinary bladder, which can encounter concentrated urine 
and prolonged irritation from calculi. In the study, calculi and crystals were observed in rat urinary 
bladders. However, no obvious mechanistic rationale to explain specifically this malignancy can be 
established, and taking into account that exposure levels, based on AUC, achieved in the study, for 
enzalutamide plus its metabolites, were less than or similar to those in prostate cancer patients at the 
recommended dose of 160 mg/day, urinary bladder carcinogenicity potential of enzalutamide in 
humans cannot be excluded. Other tumours, which are also potentially related to the primary 
pharmacology include fibroadenoma of mammary glands and benign thymoma of thymus in males, 
benign granulosa cell tumours of ovaries in females, and adenoma of pituitary pars distalis in both 
sexes. The exposure levels achieved in this study in male rats at Week 26 at 100 mg/kg per day for 
enzalutamide plus its active metabolites M1 and M2 (AUC24: enzalutamide ~457 µg·h/mL, M1 ~321 
µg·h/mL, M2 ~35 µg·h/mL) were less than or similar to those in prostate cancer patients at the 
recommended dose (160 mg/day) of enzalutamide (AUC24: enzalutamide ~322 µg·h/mL, M1 ~193 
µg·h/mL, M2 ~278 µg·h/mL).  
 
Enzalutamide was not phototoxic in vitro. 
 

6. PHARMACEUTICAL PARTICULARS  

6.1 List of excipients  

Tablet core 
Hypromellose acetate succinate 



45 

Microcrystalline cellulose 
Colloidal anhydrous silica 
Croscarmellose sodium 
Magnesium stearate 
 
Tablet coating 
Hypromellose 
Talc 
Macrogol (8000) 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 

6.2 Incompatibilities 

Not applicable. 

6.3 Shelf life  

3 years. 

6.4 Special precautions for storage  

This medicinal product does not require any special storage conditions. 

6.5 Nature and contents of container  

40 mg film-coated tablets 
Cardboard wallet incorporating a PVC/PCTFE/aluminium blister of 28 film-coated tablets. Each 
carton contains 112 film-coated tablets (4 wallets). 
 
80 mg film-coated tablets 
Cardboard wallet incorporating a PVC/PCTFE/aluminium blister of 14 film-coated tablets. Each 
carton contains 56 film-coated tablets (4 wallets). 

6.6 Special precautions for disposal and other handling 

Xtandi should not be handled by persons other than the patient and his caregivers, and especially not 
by women who are or may become pregnant. The film-coated tablets should not be cut or crushed. 

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 NUMBERS 

EU/1/13/846/002 (film-coated tablet 40 mg) 
EU/1/13/846/003 (film-coated tablet 80 mg) 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  

Date of first authorisation: 21 June 2013 



46 

Date of latest renewal: 8 February 2018 

10. DATE OF REVISION OF THE TEXT 

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



47 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



48 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62  
2333 BE Leiden 
The Netherlands 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports  
 
The  requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
Post-authorisation efficacy study (PAES):  In order to investigate the long-term 
effects of enzalutamide on Overall Survival and relevant secondary endpoints in 
adult men with high-risk non-metastatic castration-resistant prostate cancer, the 
MAH should submit the results of the MDV3100-14 (PROSPER) efficacy study:  
  

 

The Interim Analysis report of OS should be submitted by:  
 

July 2020 

The final clinical study report should be submitted by. 
 

December 2023 

 



49 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



50 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



51 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON WITH BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg soft capsules  
enzalutamide  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 40 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sorbitol (E420).  
See leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 soft capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
 



52 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/846/001 112 soft capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:



53 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
WALLET WITHOUT BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg soft capsules 
enzalutamide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 40 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sorbitol (E420).  
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 soft capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



54 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 40 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 



55 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 

 



56 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON WITH BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg film-coated tablets 
enzalutamide  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 40 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 



57 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/846/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 40 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:



58 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON WITH BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 80 mg film-coated tablets 
enzalutamide  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 80 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 



59 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/846/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 80 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN:



60 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
WALLET WITHOUT BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg film-coated tablets 
enzalutamide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 40 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 



61 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 40 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 



62 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
WALLET WITHOUT BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 80 mg film-coated tablets 
enzalutamide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 80 mg enzalutamide. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 



63 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62 
2333 BE Leiden 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
xtandi 80 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 



64 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 40 mg 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



65 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xtandi 80 mg 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



66 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET  



67 

Package leaflet: Information for the patient 
 

Xtandi 40 mg soft capsules 
enzalutamide 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in 

this leaflet. See section 4. 

What is in this leaflet 
  
1. What Xtandi is and what it is used for 
2. What you need to know before you take Xtandi 
3. How to take Xtandi 
4. Possible side effects 
5. How to store Xtandi 
6. Contents of the pack and other information 

1. What Xtandi is and what it is used for 

Xtandi contains the active substance enzalutamide. Xtandi is used to treat adult men with prostate 
cancer that no longer responds to androgen deprivation therapy. 
 
How Xtandi works 
Xtandi is a medicine that works by blocking the activity of hormones called androgens (such as 
testosterone). By blocking androgens, enzalutamide stops prostate cancer cells from growing and 
dividing. 
 
 
2. What you need to know before you take Xtandi  
 
Do not take Xtandi: 

- If you are allergic to enzalutamide or any of the other ingredients of this medicine (listed in 
section 6).  

- If you are pregnant or may become pregnant (see ‘Pregnancy, breast-feeding and fertility’) 
 
Warnings and precautions  
Seizures 
Seizures were reported in 4 in every 1,000 people taking Xtandi, and fewer than one in every 1,000 
people taking placebo (see ‘Other medicines and Xtandi’ below and section 4 ‘Possible side effects’).  
 
If you are taking a medicine that can cause seizures or that can increase the susceptibility for having 
seizures (see ‘Other medicines and Xtandi’ below) 
 
If you have a seizure during treatment: 
See your doctor as soon as possible. Your doctor may decide that you should stop taking Xtandi. 
 
Posterior reversible encephalopathy syndrome (PRES)  
There have been rare reports of PRES, a rare, reversible condition involving the brain, in patients 
treated with Xtandi. If you have a seizure, worsening headache, confusion, blindness or other vision 
problems, please contact your doctor as soon as possible. (See also section 4 ‘Possible side effects’).  



68 

 
Talk to your doctor before taking Xtandi  

- If you are taking any medicines to prevent blood clots (e.g. warfarin, acenocoumarol, 
clopidogrel) 

- If you use chemotherapy like docetaxel 
- If you have problems with your liver 
- If you have problems with your kidneys 

 
Please tell your doctor if you have any of the following:  
Any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being 
treated with medicines for these conditions. The risk of heart rhythm problems may be increased when 
using Xtandi. 
 
If you are allergic to enzalutamide, this may result in a rash or swelling of the face, tongue, lip or 
throat. If you are allergic to enzalutamide or any of the other ingredients of this medicine, do not take 
Xtandi. 
 
If any of the above applies to you or you are not sure, talk to your doctor before taking this 
medicine.  
 
Children and adolescents 
This medicine is not for use in children and adolescents. 
 
Other medicines and Xtandi 
Tell your doctor if you are taking, have recently taken or might take any other medicines. You need to 
know the names of the medicines you take. Keep a list of them with you to show to your doctor when 
you are prescribed a new medicine. You should not start or stop taking any medicine before you talk 
with the doctor that prescribed Xtandi. 
 
Tell your doctor if you are taking any of the following medicines. When taken at the same time as 
Xtandi, these medicines may increase the risk of a seizure: 
 
- Certain medicines used to treat asthma and other respiratory diseases (e.g. aminophylline, 

theophylline). 
- Medicines used to treat certain psychiatric disorders such as depression and schizophrenia (e.g. 

clozapine, olanzapine, risperidone, ziprasidone, bupropion, lithium, chlorpromazine, 
mesoridazine, thioridazine, amitriptyline, desipramine, doxepin, imipramine, maprotiline, 
mirtazapine). 

- Certain medicines for the treatment of pain (e.g. pethidine). 
 
Tell your doctor if you are taking the following medicines. These medicines may influence the effect 
of Xtandi, or Xtandi may influence the effect of these medicines. 
 
This includes certain medicines used to: 
- Lower cholesterol (e.g. gemfibrozil, atorvastatin, simvastatin) 
- Treat pain (e.g. fentanyl, tramadol) 
- Treat cancer (e.g. cabazitaxel) 
- Treat epilepsy (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid) 
- Treat certain psychiatric disorders such as severe anxiety or schizophrenia (e.g. diazepam, 

midazolam, haloperidol) 
- Treat sleep disorders (e.g. zolpidem) 
- Treat heart conditions or lower blood pressure (e.g. bisoprolol, digoxin, diltiazem, felodipine, 

nicardipine, nifedipine, propranolol, verapamil) 
- Treat serious disease related to inflammation (e.g. dexamethasone, prednisolone) 
- Treat HIV infection (e.g. indinavir, ritonavir) 
- Treat bacterial infections (e.g. clarithromycin, doxycycline) 
- Treat thyroid disorders (e.g. levothyroxine) 



69 

- Treat gout (e.g. colchicine) 
- Treat stomach disorders (e.g. omeprazole) 
- Prevent heart conditions or strokes (e.g. dabigatran etexilate) 
- Prevent organ rejection (e.g. tacrolimus) 
 
Xtandi might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, 
procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems when used 
with some other medicines (e.g. methadone, used for pain relief and part of drug addiction 
detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses). 
 
Tell your doctor if you are taking any of the medicines listed above. The dose of Xtandi or any other 
medicines that you are taking may need to be changed.  
 
Pregnancy, breast-feeding and fertility 
- Xtandi is not for use in women. This medicine may cause harm to the unborn child or potential 

loss of pregnancy if taken by women who are pregnant. It must not be taken by women who are 
pregnant, may become pregnant, or who are breast-feeding. 

- This medicine could possibly have an effect on male fertility.  
- If you are having sex with a woman who can become pregnant, use a condom and another 

effective birth control method, during treatment and for 3 months after treatment with this 
medicine. If you are having sex with a pregnant woman, use a condom to protect the unborn 
child. 

- Female caregivers see section 3 ‘How to take Xtandi’ for handling and use. 
 
Driving and using machines 
This medicine has moderate effect on your ability to drive or use any tools or machines as the side 
effects of Xtandi include psychiatric and neurological events including seizure. If you are at higher 
risk of seizures, talk to your doctor.  
 
Xtandi contains sorbitol 
This medicine contains 57.8 mg sorbitol (a type of sugar) per soft capsule. If you have been told by 
your doctor that you have an intolerance to some sugars, contact your doctor before taking this 
medicine.  
 
 
3. How to take Xtandi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.  
 
The usual dose is 160 mg (four soft capsules), taken at the same time once a day.  
 
Taking Xtandi 
- Swallow the soft capsules whole with water. 
- Do not chew, dissolve or open the soft capsules before swallowing. 
- Xtandi can be taken with or without food. 
- Xtandi should not be handled by persons other than the patient and his caregivers, and especially 

not by women who are or may become pregnant. 
 
Your doctor may also prescribe other medicines while you are taking Xtandi. 
 
If you take more Xtandi than you should 
If you take more soft capsules than prescribed, stop taking Xtandi and contact your doctor. You may 
have an increased risk of seizure or other side effects. 
 



70 

If you forget to take Xtandi 
- If you forget to take Xtandi at the usual time, take your usual dose as soon as you remember.  
- If you forget to take Xtandi for the whole day, take your usual dose the following day.  
- If you forget to take Xtandi for more than one day, talk to your doctor immediately.  
- Do not take a double dose to make up for the dose you forgot. 
 
If you stop taking Xtandi 
Do not stop taking this medicine unless your doctor tells you to.  
  
If you have any further questions on the use of this medicine, ask your doctor.  
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Seizures 
Seizures were reported in 4 in every 1,000 people taking Xtandi, and in fewer than one in every 1,000 
people taking placebo.  
 
Seizures are more likely if you take more than the recommended dose of this medicine, if you take 
certain other medicines, or if you are at higher than usual risk of seizure. 
 
If you have a seizure, see your doctor as soon as possible.  Your doctor may decide that you should 
stop taking Xtandi. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of PRES (may affect up to 1 in 1,000 people), a rare, 
reversible condition involving the brain, in patients treated with Xtandi. If you have a 
seizure, worsening headache, confusion, blindness or other vision problems, please contact 
your doctor as soon as possible.  
 
Other possible side effects include:  
 
Very common (may affect more than 1 in 10 people) 

Tiredness, broken bones, hot flushes, high blood pressure 
 
Common (may affect up to 1 in 10 people)  

Headache, fall, feeling anxious, dry skin, itching, difficulty remembering, blockage of the arteries 
in the heart (ischemic heart disease), breast enlargement in men (gynaecomastia), symptom of 
restless legs syndrome (an uncontrollable urge to move a part of the body, usually the leg), reduced 
concentration, forgetfulness 

 
Uncommon (may affect up to 1 in 100 people) 

Hallucinations, difficulty thinking clearly, low white blood cell count 
 
Not known (frequency cannot be estimated from the available data) 

Muscle pain, muscle spasms, muscular weakness, back pain, changes in ECG (QT prolongation), 
upset stomach including feeling sick (nausea), rash, being sick (vomiting), swelling of the face, 
lips, tongue and/or throat, reduction in blood platelets (which increases risk of bleeding or 
bruising), diarrhoea 

 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 



71 

 
5. How to store Xtandi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the cardboard wallet and outer carton 
after EXP. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not take any soft capsule that is leaking, damaged, or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Xtandi contains  
- The active substance is enzalutamide. Each soft capsule contains 40 mg of enzalutamide.  
- The other ingredients of the soft capsule are caprylocaproyl macrogol-8 glycerides, 

butylhydroxyanisole (E320), and butylhydroxytoluene (E321). 
- The ingredients of the soft capsule shell are gelatin, sorbitol sorbitan solution (see section 2), 

glycerol, titanium dioxide (E171), and purified water. 
- The ingredients of the ink are iron oxide black (E172) and polyvinyl acetate phthalate. 
 
What Xtandi looks like and contents of the pack 
- Xtandi soft capsules are white to off-white, oblong soft capsules (approximately 20 mm by 

9 mm) with “ENZ” written on one side.  
- Each carton contains 112 soft capsules in 4 blister wallets of 28 soft capsules each. 
 
Marketing Authorisation Holder and Manufacturer 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62  
2333 BE Leiden 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Astellas Pharma B.V. Branch 
Tél/Tel: + 32 (0)2 5580710 
 

Lietuva 
Biocodex UAB 
Tel: +370 37 408 681 
 

България 
Астелас Фарма ЕООД  
Teл.: + 359 2 862 53 72 
 

Luxembourg/Luxemburg 
Astellas Pharma B.V.Branch 
Belgique/Belgien 
Tél/Tel: + 32 (0)2 5580710 
 

Česká republika 
Astellas Pharma s.r.o. 
Tel: +420 236 080300 

Magyarország 
Astellas Pharma Kft. 
Tel.: + 36 1 577 8200 
 



72 

Danmark 
Astellas Pharma a/s 
Tlf: + 45 43 430355 
 

Malta 
E.J. Busuttil Ltd. 
Tel: +356 21 447184 

Deutschland 
Astellas Pharma GmbH 
Tel: + 49 (0)89 454401 
 

Nederland 
Astellas Pharma B.V. 
Tel: + 31 (0)71 5455745 
 

Eesti 
Biocodex OÜ 
Tel: +372 6 056 014 
 

Norge 
Astellas Pharma  
Tlf: + 47 66 76 46 00 
 

Ελλάδα 
Astellas Pharmaceuticals AEBE 
Τηλ: +30 210 8189900 
 

Österreich 
Astellas Pharma Ges.m.b.H. 
Tel: + 43 (0)1 8772668 
 

España 
Astellas Pharma S.A. 
Tel: + 34 91 4952700 
 

Polska 
Astellas Pharma Sp.z.o.o. 
Tel.: + 48 225451 111 
 

France 
Astellas Pharma S.A.S. 
Tél: + 33 (0)1 55917500 
 

Portugal 
Astellas Farma, Lda. 
Tel: + 351 21 4401320 
 

Hrvatska 
Astellas d.o.o. 
Tel: +385 1 670 01 02 
 

România 
S.C.Astellas Pharma SRL 
Tel: +40 (0)21 361 04 95 /96 /92 
 

Ireland 
Astellas Pharma Co. Ltd. 
Tel: + 353 (0)1 4671555 
 

Slovenija 
Astellas Pharma d.o.o. 
Tel: +386 14011 400 
 

Ísland 
Vistor hf 
Sími: + 354 535 7000 
 

Slovenská republika 
Astellas Pharma s.r.o.,  
Tel: +421 2 4444 2157 
 

Italia 
Astellas Pharma S.p.A. 
Tel: + 39 02 921381 
 

Suomi/Finland 
Astellas Pharma 
Puh/Tel: +358 (0)9 85606000 

Κύπρος 
Astellas Pharmaceuticals AEBE 
Ελλάδα 
Τηλ: +30 210 8189900 
 

Sverige 
Astellas Pharma AB 
Tel: + 46 (0)40-650 15 00 
 

Latvija 
Biocodex SIA 
Tel: +371 67 619365 
 

United Kingdom 
Astellas Pharma Ltd.  
Tel: +44 (0)203 379 8700 
 

 
This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  

 



73 

Package leaflet: Information for the patient 
 

Xtandi 40 mg film-coated tablets 
Xtandi 80 mg film-coated tablets 

enzalutamide 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Xtandi is and what it is used for  
2. What you need to know before you take Xtandi  
3. How to take Xtandi  
4. Possible side effects  
5. How to store Xtandi  
6. Contents of the pack and other information 
 
 
1. What Xtandi is and what it is used for 
 
Xtandi contains the active substance enzalutamide. Xtandi is used to treat adult men with prostate 
cancer that no longer responds to androgen deprivation therapy. 
 
How Xtandi works 
Xtandi is a medicine that works by blocking the activity of hormones called androgens (such as 
testosterone). By blocking androgens, enzalutamide stops prostate cancer cells from growing and 
dividing. 
 
 
2. What you need to know before you take Xtandi  
 
Do not take Xtandi: 

- If you are allergic to enzalutamide or any of the other ingredients of this medicine (listed in 
section 6).  

- If you are pregnant or may become pregnant (see ‘Pregnancy, breast-feeding and fertility’) 
 
Warnings and precautions  
Seizures 
Seizures were reported in 4 in every 1,000 people taking Xtandi, and fewer than one in every 
1,000 people taking placebo (see ‘Other medicines and Xtandi’ below and section 4 ‘Possible side 
effects’).  
 
If you are taking a medicine that can cause seizures or that can increase the susceptibility for having 
seizures (see ‘Other medicines and Xtandi’ below) 
 
If you have a seizure during treatment: 
See your doctor as soon as possible. Your doctor may decide that you should stop taking Xtandi. 
 



74 

Posterior reversible encephalopathy syndrome (PRES)  
There have been rare reports of PRES, a rare, reversible condition involving the brain, in patients 
treated with Xtandi. If you have a seizure, worsening headache, confusion, blindness or other vision 
problems, please contact your doctor as soon as possible. (See also section 4 ‘Possible side effects’).  
 
Talk to your doctor before taking Xtandi  

- If you are taking any medicines to prevent blood clots (e.g. warfarin, acenocoumarol, 
clopidogrel) 

- If you use chemotherapy like docetaxel 
- If you have problems with your liver 
- If you have problems with your kidneys 

 
Please tell your doctor if you have any of the following:  
Any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being 
treated with medicines for these conditions. The risk of heart rhythm problems may be increased when 
using Xtandi. 
 
If you are allergic to enzalutamide, this may result in a rash or swelling of the face, tongue, lip or 
throat. If you are allergic to enzalutamide or any of the other ingredients of this medicine, do not take 
Xtandi. 
 
If any of the above applies to you or you are not sure, talk to your doctor before taking this 
medicine.  
 
Children and adolescents 
This medicine is not for use in children and adolescents. 
 
Other medicines and Xtandi 
Tell your doctor if you are taking, have recently taken or might take any other medicines. You need to 
know the names of the medicines you take. Keep a list of them with you to show to your doctor when 
you are prescribed a new medicine. You should not start or stop taking any medicine before you talk 
with the doctor that prescribed Xtandi. 
 
Tell your doctor if you are taking any of the following medicines. When taken at the same time as 
Xtandi, these medicines may increase the risk of a seizure: 
 
- Certain medicines used to treat asthma and other respiratory diseases (e.g. aminophylline, 

theophylline). 
- Medicines used to treat certain psychiatric disorders such as depression and schizophrenia (e.g. 

clozapine, olanzapine, risperidone, ziprasidone, bupropion, lithium, chlorpromazine, 
mesoridazine, thioridazine, amitriptyline, desipramine, doxepin, imipramine, maprotiline, 
mirtazapine). 

- Certain medicines for the treatment of pain (e.g. pethidine). 
 
Tell your doctor if you are taking the following medicines. These medicines may influence the effect 
of Xtandi, or Xtandi may influence the effect of these medicines. 
 
This includes certain medicines used to: 
- Lower cholesterol (e.g. gemfibrozil, atorvastatin, simvastatin) 
- Treat pain (e.g. fentanyl, tramadol) 
- Treat cancer (e.g. cabazitaxel) 
- Treat epilepsy (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid) 
- Treat certain psychiatric disorders such as severe anxiety or schizophrenia (e.g. diazepam, 

midazolam, haloperidol) 
- Treat sleep disorders (e.g. zolpidem) 
- Treat heart conditions or lower blood pressure (e.g. bisoprolol, digoxin, diltiazem, felodipine, 

nicardipine, nifedipine, propranolol, verapamil) 



75 

- Treat serious disease related to inflammation (e.g. dexamethasone, prednisolone) 
- Treat HIV infection (e.g. indinavir, ritonavir) 
- Treat bacterial infections (e.g. clarithromycin, doxycycline) 
- Treat thyroid disorders (e.g. levothyroxine) 
- Treat gout (e.g. colchicine) 
- Treat stomach disorders (e.g. omeprazole) 
- Prevent heart conditions or strokes (e.g. dabigatran etexilate) 
- Prevent organ rejection (e.g. tacrolimus) 
 
Xtandi might interfere with some medicines used to treat heart rhythm problems (e.g. quinidine, 
procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems when used 
with some other medicines (e.g. methadone, used for pain relief and part of drug addiction 
detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses). 
 
Tell your doctor if you are taking any of the medicines listed above. The dose of Xtandi or any other 
medicines that you are taking may need to be changed.  
 
Pregnancy, breast-feeding and fertility 
- Xtandi is not for use in women. This medicine may cause harm to the unborn child or potential 

loss of pregnancy if taken by women who are pregnant. It must not be taken by women who are 
pregnant, may become pregnant, or who are breast-feeding. 

- This medicine could possibly have an effect on male fertility.  
- If you are having sex with a woman who can become pregnant, use a condom and another 

effective birth control method, during treatment and for 3 months after treatment with this 
medicine. If you are having sex with a pregnant woman, use a condom to protect the unborn 
child. 

- Female caregivers see section 3 ‘How to take Xtandi’ for handling and use. 
 
Driving and using machines 
This medicine has moderate effect on your ability to drive or use any tools or machines as the side 
effects of Xtandi include psychiatric and neurological events including seizure. If you are at higher 
risk of seizures, talk to your doctor.  
 
 
3. How to take Xtandi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure.  
 
The usual dose is 160 mg (four 40 mg film-coated tablets or two 80 mg film-coated tablets), taken at 
the same time once a day.  
 
Taking Xtandi 
- Swallow the tablets whole with water. 
- Do not cut, crush or chew the tablets before swallowing. 
- Xtandi can be taken with or without food. 
- Xtandi should not be handled by persons other than the patient and his caregivers, and especially 

not by women who are or may become pregnant. 
 
Your doctor may also prescribe other medicines while you are taking Xtandi. 
 
If you take more Xtandi than you should 
If you take more tablets than prescribed, stop taking Xtandi and contact your doctor. You may have an 
increased risk of seizure or other side effects. 
 



76 

If you forget to take Xtandi 
- If you forget to take Xtandi at the usual time, take your usual dose as soon as you remember.  
- If you forget to take Xtandi for the whole day, take your usual dose the following day.  
- If you forget to take Xtandi for more than one day, talk to your doctor immediately.  
- Do not take a double dose to make up for the dose you forgot. 
 
If you stop taking Xtandi 
Do not stop taking this medicine unless your doctor tells you to.  
  
If you have any further questions on the use of this medicine, ask your doctor.  
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Seizures 
Seizures were reported in 4 in every 1,000 people taking Xtandi, and in fewer than one in every 
1,000 people taking placebo. 
 
Seizures are more likely if you take more than the recommended dose of this medicine, if you take 
certain other medicines, or if you are at higher than usual risk of seizure. 
 
If you have a seizure, see your doctor as soon as possible.  Your doctor may decide that you should 
stop taking Xtandi. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of PRES (may affect up to 1 in 1,000 people), a rare, 
reversible condition involving the brain, in patients treated with Xtandi. If you have a 
seizure, worsening headache, confusion, blindness or other vision problems, please contact 
your doctor as soon as possible.  
 
Other possible side effects include:  
 
Very common (may affect more than 1 in 10 people) 

Tiredness, broken bones, hot flushes, high blood pressure 
 
Common (may affect up to 1 in 10 people)  

Headache, fall, feeling anxious, dry skin, itching, difficulty remembering, blockage of the arteries 
in the heart (ischemic heart disease), breast enlargement in men (gynaecomastia), symptom of 
restless legs syndrome (an uncontrollable urge to move a part of the body, usually the leg), reduced 
concentration, forgetfulness 

 
Uncommon (may affect up to 1 in  100 people) 

Hallucinations, difficulty thinking clearly, low white blood cell count 
 
Not known (frequency cannot be estimated from the available data) 

Muscle pain, muscle spasms, muscular weakness, back pain, changes in ECG (QT prolongation), 
upset stomach including feeling sick (nausea), rash, being sick (vomiting), swelling of the face, 
lips, tongue and/or throat, reduction in blood platelets (which increases risk of bleeding or 
bruising), diarrhoea 

 
Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 



77 

 
5. How to store Xtandi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the cardboard wallet and outer carton 
after EXP. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Xtandi contains  
The active substance is enzalutamide.  
Each Xtandi 40 mg film-coated tablet contains 40 mg of enzalutamide.  
Each Xtandi 80 mg film-coated tablet contains 80 mg of enzalutamide. 
 
The other ingredients of the film-coated tablets are: 

• Tablet core: Hypromellose acetate succinate, microcrystalline cellulose, colloidal anhydrous 
silica, croscarmellose sodium, magnesium stearate. 

• Tablet coating: Hypromellose, talc, macrogol 8000, titanium dioxide (E171), yellow iron 
oxide (E172). 

 
This medicine contains less than 1 mmol sodium (less than 23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
What Xtandi looks like and contents of the pack 
Xtandi 40 mg film-coated tablets are yellow round film-coated tablets, debossed with E 40. Each 
carton contains 112 tablets in 4 blister wallets of 28 tablets each. 
 
Xtandi 80 mg film-coated tablets are yellow oval film-coated tablets, debossed with E 80 
Each carton contains 56 tablets in 4 blister wallets of 14 tablets each. 
 
Marketing Authorisation Holder and Manufacturer 
 
Astellas Pharma Europe B.V. 
Sylviusweg 62  
2333 BE Leiden 
The Netherlands 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Astellas Pharma B.V. Branch 
Tél/Tel: + 32 (0)2 5580710 
 

Lietuva 
Biocodex UAB 
Tel: +370 37 408 681 
 

България 
Астелас Фарма ЕООД  
Teл.: + 359 2 862 53 72 
 

Luxembourg/Luxemburg 
Astellas Pharma B.V.Branch 
Belgique/Belgien 
Tél/Tel: + 32 (0)2 5580710 
 



78 

Česká republika 
Astellas Pharma s.r.o. 
Tel: +420 236 080300 

Magyarország 
Astellas Pharma Kft. 
Tel.: + 36 1 577 8200 
 

Danmark 
Astellas Pharma a/s 
Tlf: + 45 43 430355 
 

Malta 
E.J. Busuttil Ltd. 
Tel: +356 21 447184 

Deutschland 
Astellas Pharma GmbH 
Tel: + 49 (0)89 454401 
 

Nederland 
Astellas Pharma B.V. 
Tel: + 31 (0)71 5455745 
 

Eesti 
Biocodex OÜ 
Tel: +372 6 056 014 
 

Norge 
Astellas Pharma  
Tlf: + 47 66 76 46 00 
 

Ελλάδα 
Astellas Pharmaceuticals AEBE 
Τηλ: +30 210 8189900 
 

Österreich 
Astellas Pharma Ges.m.b.H. 
Tel: + 43 (0)1 8772668 
 

España 
Astellas Pharma S.A. 
Tel: + 34 91 4952700 
 

Polska 
Astellas Pharma Sp.z.o.o. 
Tel.: + 48 225451 111 
 

France 
Astellas Pharma S.A.S. 
Tél: + 33 (0)1 55917500 
 

Portugal 
Astellas Farma, Lda. 
Tel: + 351 21 4401320 
 

Hrvatska 
Astellas d.o.o. 
Tel: +385 1 670 01 02 
 

România 
S.C.Astellas Pharma SRL 
Tel: +40 (0)21 361 04 95 /96 /92 
 

Ireland 
Astellas Pharma Co. Ltd. 
Tel: + 353 (0)1 4671555 
 

Slovenija 
Astellas Pharma d.o.o. 
Tel: +386 14011 400 
 

Ísland 
Vistor hf 
Sími: + 354 535 7000 
 

Slovenská republika 
Astellas Pharma s.r.o.,  
Tel: +421 2 4444 2157 
 

Italia 
Astellas Pharma S.p.A. 
Tel: + 39 02 921381 
 

Suomi/Finland 
Astellas Pharma 
Puh/Tel: +358 (0)9 85606000 

Κύπρος 
Astellas Pharmaceuticals AEBE 
Ελλάδα 
Τηλ: +30 210 8189900 
 

Sverige 
Astellas Pharma AB 
Tel: + 46 (0)40-650 15 00 
 

Latvija 
Biocodex SIA 
Tel: +371 67 619365 
 

United Kingdom 
Astellas Pharma Ltd.  
Tel: +44 (0)203 379 8700 
 

 



79 

This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET