Dizalet 40mg Capsules

DIZALET is indicated for the treatment of adult men with metastatic castration-resistant prostate cancer (CRPC)

Posology
The recommended dose of DIZALET is 160 mg (four 40 mg capsules) as a single oral daily dose.
SPECIAL POPULATIONS
Elderly patients
No dose adjustment is necessary for elderly patients (see section 5.2).
Patients with hepatic impairment
No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B; 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).
Patients with 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 this medicine in the paediatric population, as prostate cancer is not present in children and adolescents.
Method of administration
DIZALET should be swallowed whole with water, and can be taken with or without food. If a patient misses taking DIZALET 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.

Hypersensitivity to enzalutamide or to any of the excipients.
Not to be used in women.

Risk of Seizure
Caution should be used in administering DIZALET to patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours or brain metastases, or alcoholism. In addition, the risk of seizure may be increased in patients receiving concomitant medicines that lower the seizure threshold.
Posterior reversible encephalopathy syndrome
There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving DIZALET (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 DIZALET in patients who develop PRES is recommended.
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) medical practitioners should assess the risk including the potential for Torsade de pointes prior to initiating DIZALET.
Renal Impairment
Caution is required in patients with severe renal impairment as DIZALET has not been studied in this patient population.
Hepatic Impairment
Caution is required in patients with severe hepatic impairment as DIZALET has not been studied in this patient population.
Excipients
DIZALET contains sorbitol (E420). Patients with the rare hereditary condition of sorbitol intolerance should not take DIZALET.

Potential for other medicines to affect enzalutamide exposures:
CYP2C8 inhibitors and inducers
CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased 4,26-fold while the C max decreased by 18 %; the AUC and C max of the active metabolite decreased by 25 % and 44 %, respectively. Strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8 are to be avoided or used with caution during DIZALET treatment. 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.
CYP3A4 inhibitors and inducers
CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 1,41-fold while the C max was essentially unaffected (decreased by 2 %); the AUC of the active metabolite increased 1,21-fold while the C max decreased by 14 %. No dose adjustment is necessary when DIZALET is co-administered with inhibitors or inducers of CYP3A4.
Potential for DIZALET to affect exposures to other medicines:
Enzyme induction
DIZALET is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of DIZALET (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). Uridine 5'-diphospho-glucuronosyltransferase (UGT1A1) may have been induced as well. Taken together, these results suggest that enzalutamide causes enzyme induction via activation of the nuclear pregnane receptor (PXR). Medicines with a narrow therapeutic range that are substrates of CYP3A4, CYP2C9, CYP2C19, and UGT1A1 should be used with caution when administered concomitantly with DIZALET and may require dose adjustment to maintain therapeutic plasma concentrations. Such substrates include, but are not limited to:

• Macrolide antibiotics (e.g. clarithromycin)
• Benzodiazepines (e.g. diazepam, midazolam)
• Immune modulators (e.g. ciclosporin, tacrolimus)
• HIV antivirals (e.g. indinavir, ritonavir)
• Anti-epileptics (e.g. phenobarbitone, phenytoin)
• Coumarins (e.g. warfarin)
• Certain anticancer agents (e.g. cabazitaxel, irinotecan, sunitinib)

DIZALET is contraindicated for use by women.
Contraception in males and females
It is not known whether DIZALET or its metabolites are present in semen. A condom is required during and for 3-4 months after treatment with DIZALET 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 4 months after treatment. The recommended duration of contraception in female patients should be until the end of relevant systemic exposure to the genotoxic compound incl. potential genotoxic metabolites (i.e. five half-lives after the last dose) plus 6 months. The duration of folliculogenesis is described as 6 to 12 months. The 7-month contraception recommendation for genotoxic pharmaceuticals after cessation of therapy covers the growth and maturation phase of folliculogenesis and is expected to allow elimination of most damaged follicles and oocytes.
Pregnancy
Considering the pharmacological consequences of androgen receptor signalling inhibition, maternal use of DIZALET is expected to produce changes in hormone levels that could affect development of the foetus.
Lactation
DIZALET is not for use in women. It is unknown whether DIZALET or its metabolites are excreted in human milk.
Fertility
The recommended duration of contraception in male patients should be until the end of relevant systemic exposure to the genotoxic compound incl. potential genotoxic metabolites (i.e. five half-lives after the last dose) plus 90 days. Use of contraception for a period of 4 months after cessation of therapy will minimize the risk of adverse embryo-fetal effects from genotoxic pharmaceuticals. The 4 months cover the period of spermatogenesis and the epididymal maturation.

DIZALET may influence a patient's ability to drive and operate machinery. Patients should be warned to ascertain their individual side effect profile before driving or using machinery.

a. Summary of the safety profile
The most frequent adverse reactions seen are asthenia/fatigue, hot flushes, headache and hypertension. Other important adverse reactions include falls, non-pathologic fractures, cognitive disorder, and neutropenia. Seizure occurred in 0,4 % of DIZALET - treated patients and in 0,1 % of placebo-treated patients.
b. Adverse Reactions Identified in Clinical Trials
System organ class Frequency and adverse reaction
Blood and lymphatic system disorders Less frequent: leucopenia, neutropenia
General Disorders Frequent: asthenia/fatigue
Psychiatric Disorders Frequent: anxiety Less frequent: visual hallucinations
Nervous System Disorders Frequent: headache, memory impairment, amnesia, disturbance in attention, restless legs syndrome Less common: cognitive disorder, seizure
Reproductive system and breast disorder Frequent: gynaecomastia
Vascular Disorders Frequent: hot flushes, hypertension
Skin and Subcutaneous Tissue Disorders Frequent: dry skin, pruritus
Injury, Poisoning and Procedural Complications Frequent: falls
c. Description of selected adverse reactions
Seizure
Seizure In controlled clinical studies, 10 patients (0.5%) experienced a seizure out of 2051 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. The mechanism by which DIZALET 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.
d. Other special population
Elderly patients
No overall differences in safety or effectiveness were observed between the elderly patients and younger patients.
f. 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 to SAHPRA via The u20186.04 Adverse Drug Reactions Reporting Formu2019. Found 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 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.