Enzutix 40 mg Capsule

ENZUTIX is indicated for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men.

Posology
The recommended dose of ENZUTIX is 160 mg (4 x 40 mg capsules) as a single oral daily dose.

Special Populations
Elderly
No dose adjustment is necessary for elderly patients (see section 5.1).
Hepatic impairment
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B, respectively. See section 5.2). Caution is advised in patients with severe hepatic impairment, as an increased half-life of enzalutamide has however been observed (Child-Pugh Class C (see section 4.4)).
Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment (see section 5.2). Caution is advised in patient 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, as prostate cancer is not present in children and adolescents.

Method of administration
ENZUTIX should be swallowed whole with water and can be taken with or without food. If a patient misses taking a dose 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 an entire day, treatment should be resumed the following day with the usual daily dose.

Hypersensitivity to enzalutamide or to any of the excipients listed in section 6.1. ENZUTIX is not for use in women (see sections 4.6 and 6.6).

Risk of seizure
Use of enzalutamide has been associated with seizure (see section 4.8). The risk of seizure may be increased in patients receiving concomitant medicines that lower the seizure threshold. Caution should be used in patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours or brain metastases, or alcoholism. The decision to continue treatment in patients who develop seizure should be taken on an individual basis.

Posterior reversible encephalopathy syndrome
There have been reports of posterior reversible encephalopathy syndrome (PRES) (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). Treatment discontinuation is recommended in patients who develop PRES.

Concomitant use with other medicines
Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicines (see examples in section 4.5). A review of concurrent medicines should therefore be conducted with enzalutamide treatment initiation. Concomitant use of enzalutamide with medicines 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 (see section 4.5).

Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If ENZUTIX is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin), 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
Caution is required in patients with 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 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
Phase 3 studies excluded patients (there is no data on the use in 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) u2265 45 %, bradycardia or uncontrolled hypertension. This should be taken into consideration when ENZUTIX is prescribed for 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 concurrent medicines that might prolong the QT interval (see section 4.5) medical practitioners should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating enzalutamide treatment.

Use with chemotherapy
The safety and efficacy of concomitant use of ENZUTIX 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).

Excipients
ENZUTIX contains sorbitol. Patients with hereditary fructose intolerance (HFI) should not take ENZUTIX.

Potential for other medicines to affect enzalutamide exposures
CYP2C8 inhibitors
CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Studies documented following oral administration of strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased by 326 % while C max of enzalutamide decreased by 18 %. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77 % while C max decreased by 19 %. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided, if possible, or used with caution during enzalutamide treatment.

CYP3A4 inhibitors
CYP3A4 plays a minor role in the metabolism of enzalutamide. Studies documented 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 C max was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27 % while C max was again unchanged. No dose adjustment is necessary when ENZUTIX is co-administered with CYP3A4 inhibitors.

CYP2C8 and CYP3A4 inducers
Studies documented following oral administration of 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 C max remained unchanged. No dose adjustment is necessary when ENZUTIX is co-administered with inducers of CYP3A4.

Potential for enzalutamide to affect exposures to other medicines
Enzyme induction
Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many medicines 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-glucuronosyl-transferase (UGTs - glucuronide conjugating enzymes). The transport protein P-gp may also be induced, and probably other transporters including 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.

Studies in patients with metastatic CRPC, enzalutamide (160 mg once daily) documented 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 %.

Interactions with certain medicines 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 medicines are to be avoided or used with caution. Groups of medicines 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, irinotecan, sunitinib)
• Antiepileptics (e.g. carbamazepine, clonazepam, phenobarbitone, phenytoin, primidone, valproic acid)
• Antipsychotics (e.g. haloperidol)
• Antithrombotics (e.g. 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. ciclosporin, tacrolimus)
• Proton pump inhibitor (e.g. omeprazole)
• Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin)
• Thyroid agents (e.g. levothyroxine)

Medicines with a narrow therapeutic range that are substrates of CYP3A4, CYP2C9, CYP2C19, and UGT1A1 should be used with caution when administered concomitantly with ENZUTIX and may require dose adjustment to maintain therapeutic plasma concentrations. The full induction potential of enzalutamide may not occur until approximately 1 month after treatment initiation, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicines 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 ENZUTIX treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide of 5,8 days (see section 5.2), effects on enzymes may persist for one month or longer after enzalutamide treatment discontinuation. A gradual dose reduction of the concomitant medicine may be necessary when stopping enzalutamide treatment. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

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

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). Medicines with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concurrently with ENZUTIX 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. ENZUTIX may increase the plasma concentrations of co-administered medicines that are BCRP or MRP2 substrates. The effects of enzalutamide on BCRP and MRP2 substrates have not been evaluated in vivo. Oral medicines with a narrow therapeutic range that are BCRP or MRP2 substrates (e.g. methotrexate) should be used with caution when administered concurrently with ENZUTIX and may require dose adjustments to maintain optimal plasma concentrations.

Medicinal products which prolong the QT interval
Since androgen deprivation treatment may prolong the QT interval, the concurrent use of ENZUTIX with medicines known to prolong the QT interval or medicines able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicines, 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. ENZUTIX can be taken without regard to food.

Women of childbearing potential
ENZUTIX is contraindicated for use by women. There is no human data on the use of enzalutamide during pregnancy and is not for use in women of childbearing potential. ENZUTIX may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant (see sections 4.3 and 6.6).

Contraception in males and females
It is unknown whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with ENZUTIX 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 documented reproductive toxicity.

Pregnancy
ENZUTIX is not for use in women and is contraindicated in women who are or may become pregnant (see sections 4.3 and 6.6). Considering the pharmacological consequences of androgen receptor signalling inhibition, maternal use of enzalutamide is expected to produce changes in hormone levels that could affect the development of the foetus.

Breastfeeding
ENZUTIX is not for use in women (see section 4.3). It is unknown if enzalutamide or its metabolites are excreted in human milk. Studies in animals have documented enzalutamide and/or its metabolites are secreted in rat milk.

Fertility
Studies in animals have documented that enzalutamide affected the reproductive system in male rats and dogs.

Enzalutamide may influence a patient's ability to drive and operate machinery as psychiatric and neurologic events including seizures 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.

a. Summary of the safety profile
The most frequent adverse reactions are asthenia/fatigue, hot flush, headache, fractures, and hypertension. Other important adverse reactions include fall, cognitive disorder, and neutropenia. Seizures have been reported. Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients (see section 4.4).

b. Tabulated summary of adverse reactions
System organ class Frequency Adverse reactions
Blood and lymphatic system Less frequent Leukopenia and neutropenia. Frequency unknown Thrombocytopenia
Immune system disorders Frequency unknown Face oedema, tongue oedema, lip oedema and pharyngeal oedema.
Psychiatric disorders Frequent Anxiety. Less frequent Visual hallucination.
Nervous system disorders Frequent Headache, memory impairment, amnesia, disturbance in attention and restless legs syndrome. Less frequent Cognitive disorder and seizure u00a5 . Frequency unknown Posterior reversible encephalopathy syndrome.
Cardiac disorders Frequent Ischemic heart disease u2020 . Frequency unknown QT-prolongation (see sections 4.4 and 4.5)
Vascular disorders Frequent Hot flushes and hypertension.
Gastrointestinal disorders Frequency unknown Nausea, vomiting and diarrhoea.
Skin and subcutaneous tissue disorders Frequent Dry skin and pruritus. Frequency unknown Rash.
Musculoskeletal and connective tissue disorders Frequent Fracturesu2021. Frequency unknown Myalgia, muscle spasms, muscular weakness, and back pain.
Reproductive System and breast disorders Frequent Gynaecomastia. General disorders and administration site disorders Frequent Asthenia and fatigue. Injury, poisoning and procedural complications Frequent Falls. u00a5 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. u2020 As evaluated by narrow SMQs of 'Myocardial Infarction' and 'Other Ischemic Heart Disease' including angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia, and arteriosclerosis coronary artery. u2021 Includes all preferred terms with the word 'fracture' in bones.

c. Description of selected adverse reactions
Seizure
Studies documented that 0,4 % of patients treated with a daily dose of 160 mg enzalutamide experienced a seizure. Dose appears to be an important predictor of the risk of seizure. Studies documented in patients with predisposing factors for seizure (of which 1,6 % had a history of seizures), 2,2 % patients treated with enzalutamide (with a median treatment duration of 9,3 months) experienced a seizure. The mechanism by which enzalutamide may lower the seizure threshold is unknown. However, based on data from in vitro studies it could be related to enzalutamide and its active metabolite that bind to and can inhibit the activity of the GABA-gated chloride channel.

Ischemic Heart Disease
Studies documented 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

There is no antidote for enzalutamide. In the event of an overdose, treatment with ENZUTIX 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 overdose.