Enzalutamide is indicated for:

• the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC).

• the treatment of adult men with metastatic castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated

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

Treatment with enzalutamide should be initiated and supervised by specialist physicians experienced in the medical treatment of prostate cancer.

Posology

The recommended dose is 160 mg enzalutamide (four 40 mg soft capsules) as a single oral daily dose. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated.

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

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

Concomitant use with strong CYP2C8 inhibitors

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

Elderly

No dose adjustment is necessary for elderly patients.

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 may be observed in patients with severe hepatic impairment.

Renal impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is advised in patients with severe renal impairment or end-stage renal disease.

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

Enzalutamide 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.

Risk of seizure

Use of enzalutamide has been associated with seizure. 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 Enzalutamide. 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 Enzalutamide 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. 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 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 Enzalutamide is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted.

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 may be 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 may be increased.

Recent cardiovascular disease

Caution is required in patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months) as enzalutamide has not been studied in this patient population.

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 physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Enzalutamide.

Use with chemotherapy

The safety and efficacy of concomitant use of Enzalutamide with cytotoxic chemotherapy has not been established. Coadministration of enzalutamide has no clinically relevant effect on the pharmacokinetics of intravenous docetaxel; however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded.

Excipients

Enzalutamide contains sorbitol. 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.

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. 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.

CYP3A4 inhibitors

CYP3A4 plays a minor role in the metabolism of enzalutamide. No dose adjustment is necessary when Enzalutamide is co-administered with inhibitors of CYP3A4.

CYP2C8 and CYP3A4 inducers

No dose adjustment is necessary when Enzalutamide 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).

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

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

• Analgesics (e.g. fentanyl, tramadol)

• Antibiotics (e.g. clarithromycin, doxycycline)

• Anticancer agents (e.g. cabazitaxel)

• Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid)

• Antipsychotics (e.g. haloperidol)

• Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel)

• Betablockers (e.g. bisoprolol, propranolol)

• Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)

• Cardiac glycosides (e.g. digoxin)

• Corticosteroids (e.g. dexamethasone, prednisolone)

• HIV antivirals (e.g. indinavir, ritonavir)

• Hypnotics (e.g. diazepam, midazolam, zolpidem)

• Immunosuppressant (e.g. tacrolimus)

• Proton pump inhibitor (e.g. omeprazole)

• Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)

• Thyroid agents (e.g. levothyroxine)

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

In consideration of the long half-life of enzalutamide (5.8 days), 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

No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with Enzalutamide.

P-gp substrates

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 Enzalutamide and may require dose adjustment to maintain optimal plasma concentrations.

BCRP, MRP2, OAT3 and OCT1 substrates

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 Enzalutamide 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.

Effect of food on enzalutamide exposures

Food has no clinically significant effect on the extent of exposure to enzalutamide. Enzalutamide may be administered without regard to food.

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.

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.

Pregnancy

Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are or may become pregnant.

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.

Fertility

Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs.

Enzalutamide has moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure may be reported.

Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines.

No studies to establish the effects of enzalutamide on the ability to drive and use machines have been conducted.

The most common adverse reactions are asthenia/fatigue, hot flush, fractures, and hypertension. Other important adverse reactions include fall, cognitive disorder, and neutropenia.

Adverse reactions are listed below by frequency category. Frequency categories are defined as follows:

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table: Adverse reactions

* Spontaneous reports from post-marketing experience

** Includes all fractures with the exception of pathological fractures

To report any side effect(s):

• Saudi Arabia:

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.

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 binding of androgens to androgen receptors, inhibits nuclear translocation of activated receptors and inhibits the association of the activated androgen receptor with DNA even in the setting of androgen receptor overexpression and in prostate cancer cells resistant to anti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can induce cancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptor agonist activity.

Enzalutamide is poorly water soluble. The solubility of enzalutamide is increased by caprylocaproyl macrogolglycerides as emulsifier/surfactant.

The mean terminal half-life (t1/2) for enzalutamide is 5.8 days (range 2.8 to 10.2 days), and steady state will be 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 may be observed 1 to 2 hours after administration. 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. Enzalutamide may be 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, 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.

Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8.

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% will be 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).

Linearity

No major deviations from dose proportionality may be observed over the dose range 40 to 160 mg.

Renal impairment

No dose adjustment is necessary for patients with calculated creatinine clearance (CrCL) values ≥ 30 mL/min (estimated by the Cockcroft and Gault formula). Caution is advised when treating these patients with severe renal impairment (CrCL < 30 mL/min) or end-stage renal disease. 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.

Elderly

No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the elderly population pharmacokinetic analysis.

Enzalutamide treatment of pregnant mice resulted in an increased incidence of embryo-fetal deaths and external and skeletal changes. Reproductive toxicology studies were not conducted with Enzalutamide, but in studies in rats (4 and 26 weeks) and dogs (4, 13, and 39 weeks), atrophy, aspermia/hypospermia, and hypertrophy/hyperplasia in the reproductive system were noted, consistent with the pharmacological activity of Enzalutamide. In studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13, and 39 weeks), changes in the reproductive organs associated with Enzalutamide were decreases in organ weight with atrophy of the prostate and epididymis. Leydig cell hypertrophy and/or hyperplasia were observed in mice (4 weeks) and dogs (39 weeks). Additional changes to reproductive tissues included hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in rats and testicular hypospermia and seminiferous tubule degeneration in dogs. Gender differences were noted in rat mammary glands (male atrophy and female lobular hyperplasia). Changes in the reproductive organs in both species were consistent with the pharmacological activity of Enzalutamide and reversed or partially resolved after an 8-week recovery period. There were no other important changes in clinical pathology or histopathology in any other organ system, including the liver, in either species.

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.

Caprylocaproyl polyoxyglerides, Butylhydroxyanisole, Butylhydroxytoluene, Gelatin, Sorbitol Sorbitan Solution, Glycerin, Titanium Dioxide, Purified water, Opacode WB Black NS-78-17821, Triglycerides Medium-chain, KIMTECH pure W4 wipers, Isopropyl alcohol.

Not applicable.

Store below 30°C.

Keep out of the reach of children.

Each carton contains 112 soft capsules in 4 blister wallets of 28 soft capsules each.

No special requirements.