Apalutamide

Registered South African indications:

• Non-metastatic, castration-resistant prostate cancer
  - In men who had a bilateral orchiectomy or in combination with a gonadotrophin-releasing hormone (GnRH) analogue

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy (including women who may become pregnant)

Cautions

• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment (Child-Pugh Class C)
• History of seizures
• Predisposing factors for seizure
  - Underlying brain injury
  - Recent stroke (within one year)
  - Primary brain tumours
  - Brain metastases
• Fracture and fall risk
• Cardiovascular risk factors
  - Hypertension
  - Diabetes
  - Dyslipidaemia
• Significant cardiovascular disease in the past 6 months
  - Severe/unstable angina
  - Myocardial infarction
  - Symptomatic congestive heart failure
  - Arterial or venous thromboembolic events (e.g. pulmonary embolism, cerebrovascular accident including transient ischaemic attacks)
  - Clinically significant ventricular arrhythmias
• Cardiovascular disease
  - Hypercholesterolaemia
  - Hypertriglyceridaemia
  - Other cardio-metabolic disorders
• History of or risk factors for QT prolongation
• Coadministration with medicinal products that lower the seizure threshold
• May impair ability to drive and operate machinery

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

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
  - In men who are at high risk of developing metastatic disease
  - In men who had a bilateral orchiectomy or in combination with a gonadotrophin-releasing hormone (GnRH) analogue
• Metastatic hormone-sensitive prostate cancer (mHSPC)
  - In combination with androgen deprivation therapy

Consult specialist for dosages and regimens

Not indicated for use in children

Pregnancy

• Contraindicated
• There are no data available from the use of apalutamide in pregnant women. Animal reproductive studies have not been conducted with apalutamide
• Apalutamide is contraindicated in women who are or may become pregnant. Based on its mechanism of action, apalutamide may cause foetal harm when administered during pregnancy
• It is not known whether apalutamide or its metabolites are present in semen. Apalutamide may be harmful to a developing foetus
• For patients having sex with female partners of reproductive potential, a condom should be used along with another highly effective contraceptive method during treatment and for 3 months after the last dose of apalutamide

Breastfeeding

• Caution; not recommended
• It is unknown whether apalutamide/ metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Apalutamide should not be used during breastfeeding

Fertility

• Based on animal studies, apalutamide may decrease fertility in males of reproductive potential

Renal impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  If treatment is started, patients should be monitored for adverse reactions and dose reduction be considered as warranted

Hepatic impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available
  Apalutamide is not recommended in patients with severe hepatic impairment as there are no data in this patient population and apalutamide is primarily hepatically eliminated

Elderly 

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Seizure (including tongue biting)
• Fatigue

Cardiovascular Disorders

• Ischaemic heart disease
  - Angina pectoris
  - Angina unstable
  - Myocardial infarction
  - Acute myocardial infarction
  - Coronary artery occlusion
  - Coronary artery stenosis
  - Acute coronary syndrome
  - Arteriosclerosis coronary artery
  - Abnormal cardiac stress test
  - Increased troponin
  - Myocardial ischaemia
• QT prolongation
• Hot flush
• Hypertension

Gastrointestinal Disorders

• Diarrhoea

Endocrine and Metabolic Disorders

• Hypothyroidism
• Increased blood thyroid-stimulating hormone
• Decreased thyroxine
• Autoimmune thyroiditis
• Decreased free thyroxine
• Decreased tri-iodothyronine
• Hypercholesterolaemia
• Hypertriglyceridaemia
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Muscle spasm
• Fracture
  - Rib fracture
  - Lumbar vertebral fracture
  - Spinal compression fracture
  - Spinal fracture
  - Foot fracture
  - Hip fracture
  - Humerus fracture
  - Thoracic vertebral fracture
  - Upper limb fracture
  - Fractured sacrum
  - Hand fracture
  - Pubis fracture
  - Acetabulum fracture
  - Ankle fracture
  - Compression fracture
  - Costal cartilage fracture
  - Facial bones fracture
  - Lower limb fracture
  - Osteoporotic fracture
  - Wrist fracture
  - Avulsion fracture
  - Fibula fracture
  - Fractured coccyx
  - Pelvic fracture
  - Radius fracture
  - Sternal fracture
  - Stress fracture
  - Traumatic fracture
  - Cervical vertebral fracture
  - Femoral neck fracture
  - Tibia fracture

Skin and Subcutaneous Tissue Disorders

• Skin rash
  - Maculopapular rash
  - Generalised rash
  - Urticaria
  - Pruritic rash
  - Macular rash
  - Conjunctivitis
  - Erythema multiforme
  - Papular rash
  - Skin exfoliation
  - Genital rash
  - Erythematous rash
  - Stomatitis
  - Drug eruption
  - Mouth ulceration
  - Pustular rash
  - Blisters
  - Papule
  - Pemphigoid
  - Skin erosion
  - Dermatitis
  - Vesicular
• Pruritus

Sensory Disorders

• Dysgeusia

Others

• Fall

• Strong CYP2C8 inhibitors
• Gemfibrozil
• Clopidogrel
• Strong CYP3A4 inhibitor
• Itraconazole
• Ketoconazole
• Ritonavir
• Clarithromycin
• CYP2B6 substrates
• Efavirenz
• CYP3A4 substrates
• Midazolam
• Darunavir
• Felodipine
• Simvastatin
• CYP2C19 substrates
• Omeprazole
• Diazepam
• CYP2C9 substrates
• Warfarin
• Phenytoin
• UDP-glucuronosyl transferase (UGT) substrates
• Levothyroxine
• Valproic acid
• P-glycoprotein substrates
• Fexofenadine
• Colchicine
• Dabigatran etexilate
• Digoxin
• Breast cancer resistance protein (BCRP) substrates
• Organic anion transporting polypeptide 1B1 (OATP1B1) substrates
• Rosuvastatin
• Lapatinib
• Methotrexate
• Repaglinide
• Medicinal agents known to prolong the QT interval
• Medicinal agents able to induce Torsade de Pointes
• Class IA antiarrhythmics
• Quinidine
• Disopyramide
• Class III antiarrhythmics
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Methadone
• Moxifloxacin
• Antipsychotics
• Haloperidol

See additional prescribing points

• Thyroid function

None routine. Specific cases may require

• International Normalised Ratio

Additional observations

• Assess for falls and fracture risk
• Signs and symptoms of
  - Cardiovascular events
  - Seizure
  - Dermatologic toxicity

Additional precautions

• Co-administration of apalutamide with warfarin and coumarin-like anticoagulants should be avoided
• If apalutamide is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted

Potential for apalutamide to affect exposures to other medicinal products

• Apalutamide 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
• Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl metabolite cannot be excluded
• No in vitro inhibition of organic anion transporter 1 (OAT1) was observed

Apalutamide is an orally administered, selective androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide prevents AR nuclear translocation, inhibits DNA binding, impedes AR-mediated transcription and lacks androgen receptor agonist activity. Apalutamide treatment decreases tumor cell proliferation and increases apoptosis leading to potent antitumor activity. A major metabolite, N-desmethyl apalutamide, exhibited one-third the in vitro activity of apalutamide.

Tablet 60mg

• Erleada (Janssen Pharmaceutica) originator