Enzalutamide

Registered South African indications:

• Metastatic hormone-sensitive prostate cancer
• High risk non-metastatic castration-resistant prostate cancer
• Metastatic castration-resistant prostate cancer

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Porphyria

Cautions

• Males of reproductive potential
• Severe renal impairment
• Severe hepatic impairment 
• History of seizures or other predisposing factors
• Recent myocardial infarction (<6 months)
• Unstable angina (<3 months)
• New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥45%
• Bradycardia
• Uncontrolled hypertension
• History of or risk factors for QT prolongation
• May impair ability to drive or operate machinery

Forms avail. in SA and covered in this monograph: cap

Used for the treatment of

• Metastatic hormone-sensitive prostate cancer (additional agent required)
  - In combination with androgen deprivation therapy
• High-risk non-metastatic castration resistant prostate cancer
• Metastatic castration-resistant prostate cancer
  - Treatment in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated
  - Treatment where disease has progressed on or after docetaxel therapy

Consult specialist for dosages and regimens

Not indicated for use in children

Pregnancy

• Contraindicated
• Enzalutamide is  not indicated for use in women and is contraindicated in women who are or may become pregnant
• There is no human data on the use of enzalutamide 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
• 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

Breastfeeding

• Not indicated for use in women
• 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

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe or ESRD: Caution; no dose adjustment recommended
  Enzalutamide has not been studied in severe renal impairment

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  An increased half-life on enzalutamide has been observed in severe hepatic impairment, possibly due 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

Elderly            

• No dose adjustment recommended

Porphyria Information

• Probably porphyrinogenic (PRP)
  Enzalutamide is a strong inducer of CYP3A4 and also a moderate inducer of CYP2C9 and CYP2C19. It is suggested that the induction of CYP 3A4 may last as long as 8 weeks. This may complicate the management of a potential porphyrinogenic attack

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Memory impairment
• Amnesia
• Disturbance in attention
• Restless legs syndrome
• Cognitive disorder
• Seizure
  - Grand mal convulsion
  - Complex partial seizures
  - Partial seizures
  - Status epilepticus
• Posterior reversible encephalopathy syndrome
• Anxiety
• Visual hallucinations
• Fatigue

Cardiovascular Disorders

• QT-prolongation
• Ischaemic heart disease
  - Angina pectoris
  - Coronary artery disease
  - Myocardial infarctions
  - Acute coronary syndrome
  - Angina unstable
  - Myocardial ischaemia
  - Coronary artery arteriosclerosis
• Hot flush
• Hypertension

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea

Genitourinary Disorders

• Gynaecomastia

Musculoskeletal Disorders

• Fractures
• Myalgia
• Muscle spasms
• Muscular weakness
• Back pain

Skin and Subcutaneous Tissue Disorders

• Dry skin
• Pruritus
• Rash

Immune, Blood and Lymphatic System Disorders

• Face oedema
• Tongue oedema
• Lip oedema
• Pharyngeal oedema
• Leucopenia
• Neutropenia
• Thrombocytopenia

Other

• Falls

• Agents that lower the seizure threshold
• Anticoagulants
• Acenocoumarol
• Warfarin
• Clopidogrel
• QT-prolonging agents
• Class IA or III antiarrhythmic agents
• Quinidine
• Disopyramide
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Methadone
• Moxifloxacin
• Antipsychotics
• Haloperidol
• Cytotoxic chemotherapy
• CYP2C8 inhibitors
• Gemfibrozil
• CYP3A substrates
• CYP2B6 substrates
• CYP2C9 substrates
• CYP2C19 substrates
• Uridine 5'-diphospho-glucuronosyltransferase substrates
• P-glycoprotein substrates
• Colchicine
• Dabigatran etexilate
• Multidrug resistance-associated protein 2 (MRP2) substrates
• Breast cancer resistance protein (BCRP) substrates
• Organic anion transporting polypeptide 1B1 (OATP1B1) substrates
• Analgesics
• Fentanyl
• Tramadol
• Antibiotics
• Clarithromycin
• Doxycycline
• Anticancer agents
• Cabazitaxel
• Antiepileptics
• Carbamazepine
• Clonazepam
• Phenytoin
• Primidone
• Valproic acid
• Beta-blockers
• Bisoprolol
• Propranolol
• Calcium channel blockers
• Diltiazem
• Felodipine
• Nicardipine
• Nefedipine
• Verapamil
• Cardiac glycosides
• Digoxin
• Corticosteroids
• Dexamethasone
• Prednisolone
• HIV antivirals
• Indinavir
• Ritonavir
• Hypnotics
• Diazepam
• Midazolam
• Zolpidem
• Immunosuppressants
• Tacrolimus
• Proton pump inhibitors
• Omeprazole
• Statins metabolised by CYP3A4
• Atorvastatin
• Simvastatin
• Thyroid agents
• Levothyroxine
• Pioglitazone
• Caffeine
• Itraconazole
• Rifampicin

• Full blood count with differential
• Hepatic function
• Blood pressure

Specific cases may require

• International normalization ratio

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.

Capsule 40mg

• Xtandi (Astellas) originator