Darolutamide

Registered South African indications:

• Non-metastatic castration resistant prostate cancer (nmCRPC)

Contraindications

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

Cautions

• Breastfeeding
• Males of reproductive potential
• Severe and end stage (receiving dialysis) renal impairment (eGFR≤29ml/min/1,73m²)
• Moderate to severe (Child-Pugh class B and C) hepatic impairment
• Clinically significant cardiovascular disease in the past 6 months
  - Stroke
  - Myocardial infarction
  - Severe/unstable angina pectoris
  - Coronary/peripheral artery bypass graft
  - Symptomatic congestive heart failure
• History of risk factors for QT prolongation
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

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

Treatment should be initiated and supervised by a specialist experienced in treatment of prostate cancer

Used for the treatment of
Non-metastatic castration resistant prostate cancer (nmCRPC)
- In those who are at high risk of developing metastatic disease

• Oral (tab): 600mg (two 300mg tabs), 12hrly; Max: 1200mg/24hrs

Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated

If a dose is missed, the dose should be taken as soon as the patient remembers prior to the next scheduled dose. Two doses should not be taken together to make up for a missed dose

 Darolutamide is for oral use

The tablets should be taken whole with food

Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

Not indicated for use in children

Pregnancy

• Contraindicated
• Darolutamide is not indicated in women of childbearing potential. It is not to be used in women who are, or may be, pregnant
• Based on its mechanism of action, darolutamide may cause foetal harm. No non-clinical reproductive toxicity studies have been conducted
• It is not known whether darolutamide or its metabolites are present in semen. If the patient is engaged in sexual activity with a pregnant woman, a condom should be used during and for 1 week after completion of treatment with darolutamide
• Exposure of the foetus to an androgen receptor inhibitor through seminal transfer to the pregnant woman has to be avoided, as this could affect development of the foetus
• If the patient is engaged in sexual activity with a woman of childbearing potential, a highly effective contraceptive method (<1% failure rate per year) should be used during and for 1 week after completion of treatment with darolutamide to prevent pregnancy

Breastfeeding

• Caution; not recommended 
• Darolutamide is not to be used in women who are breastfeeding
• It is unknown whether darolutamide or its metabolites are excreted in human milk. No studies in animals have been conducted to evaluate the excretion of darolutamide or its metabolites into milk. A risk to the breastfed child cannot be excluded

Fertility 

• There are no human data on the effect of darolutamide on fertility. Based on animal studies, darolutamide may impair fertility in males of reproductive potential

Renal Impairment 

• Mild to moderate (eGFR≥30ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR 15-29ml/min/1.73m²): Caution; dose adjustment recommended 
  Recommended dose if not receiving haemodialysis: Oral (fct): Initial: 300mg, 12hrly
• End-stage (receiving dialysis): eGFR<15ml/min/1.73m²: Caution; no information available 

Hepatic Impairment
South African manufacturer recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended 
  Oral (fct): Initial: 300mg, 12hrly
• Severe (Child-Pugh class C): Caution; no information available 

International manufacturer recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate to severe (Child-Pugh class B and C): Caution; dose adjustment recommended 
  Oral (fct): Initial: 300mg, 12hrly

Elderly 

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Fatigue

Cardiovascular Disorders 

• Ischaemic heart disease
  - Coronary artery arteriosclerosis
  - Coronary artery disease
  - Coronary artery occlusion
  - Coronary artery stenosis
  - Acute coronary syndrome
  - Acute myocardial infarction
  - Angina pectoris
  - Unstable angina
  - Myocardial infarction
  - Myocardial ischaemia
• Heart failure
  - Cardiac failure
  - Acute cardiac failure 
  - Chronic cardiac failure
  - Congestive cardiac failure 
  - Cardiogenic shock

Hepatobiliary Disorders 

• Increased bilirubin
• Increased aspartate aminotransferase

Musculoskeletal Disorders 

• Pain in extremity
• Musculoskeletal pain
• Fractures

Skin and Subcutaneous Tissue Disorders 

• Rash

Immune, Blood and Lymphatic System Disorders 

• Decreased neutrophil count 

• Strong and moderate CYP3A4 
• Strong and moderate P-gp inducers
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifampicin
• Breast cancer resistance protein (BCRP) substrates
• Organic anion transporting polypeptides (OATP) 1B1 and 1B3 substrates
• Rosuvastatin
• Methotrexate
• Sulfasalazine
• Fluvastatin
• Atorvastatin
• Pitavastatin
• Medicinal agents that prolong the QT interval
• Class I antiarrhythmics 
• Quinidine
• Disopyramide 
• Class III antiarrhythmics 
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Methadone
• Moxifloxacin
• Antipsychotics
• Haloperidol

Other interactions

• St John's wort

Specific cases may require

• Hepatic function
• Renal function 

Additional observations

• Adherence

Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand-binding domain. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide. Darolutamide treatment decreases prostate tumour cell proliferation leading to potent antitumour activity.

Tablet 300mg

• Nubeqa (Bayer) originator