Apalutamide is an androgen receptor inhibitor used for the treatment of patients with

• metastatic castration-sensitive prostate cancer
•  non-metastatic castration-resistant prostate cancer.

Apalutamide is an oral, selective androgen receptor (AR) inhibitor. It binds directly to the androgen receptor and blocks its activity. This prevents the receptor from moving to the cell nucleus, reduces DNA binding, and inhibits androgen-dependent gene transcription. As a result, cancer cell growth decreases and programmed cell death (apoptosis) increases, producing strong antitumor effects.

The recommended dose of Apalutamide is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. Apalutamide can be taken with or without food. Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral orchiectomy.

Effect of Other Drugs on Apalutamide: CYP2C8 Inhibitors: CYP2C8 helps eliminate Apalutamide and form its active metabolite. In a study, co-administration of a single 240 mg dose of Apalutamide with gemfibrozil (strong CYP2C8 inhibitor) decreased Cmax by 21% and increased AUC by 68%. For total active moieties (Apalutamide + active metabolite), Cmax decreased by 21% and AUC increased by 45%. No initial dose adjustment is required with strong CYP2C8 inhibitors (e.g., gemfibrozil, clopidogrel), but dose reduction based on tolerability can be considered. Mild or moderate CYP2C8 inhibitors are not expected to significantly affect Apalutamide exposure.

CYP3A4 Inhibitors: CYP3A4 also plays a role in Apalutamide elimination and metabolite formation. Co-administration with itraconazole (strong CYP3A4 inhibitor) decreased Cmax by 22%, while AUC remained similar. For total active moieties, Cmax decreased by 22% with little effect on AUC. No initial dose adjustment is required with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin), but dose reduction based on tolerability can be considered. Mild or moderate CYP3A4 inhibitors do not significantly affect Apalutamide exposure.

CYP3A4 or CYP2C8 Inducers: The effect of inducers on Apalutamide pharmacokinetics has not been studied in vivo. Based on inhibitor studies, CYP3A4 or CYP2C8 inducers are not expected to have clinically significant effects, so dose adjustment is not needed.

Effect of Apalutamide on Other Drugs: CYP and UGT Substrates: Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. Co-administration with drugs metabolized by these enzymes can reduce their exposure. Consider substituting the drug or monitor for loss of effect. Apalutamide may also reduce exposure of drugs metabolized by UGT enzymes. Use caution and monitor effectiveness.

Transporter Substrates (P-gp, BCRP, OATP1B1): Apalutamide is a weak inducer of P-gp, BCRP, and OATP1B1. At steady-state, it reduces plasma levels of fexofenadine (P-gp substrate) and rosuvastatin (BCRP/OATP1B1 substrate). Caution is advised when co-administering drugs that are substrates of these transporters; monitor for loss of activity.

• Hypersensitivity to the active substance
• Women who are pregnant or may become pregnant

The following clinically significant adverse reactions have been reported in clinical trials:

• Endocrine disorders: Hypothyroidism
• Metabolism and nutrition disorders: Hypercholesterolemia, hypertriglyceridemia
• Nervous system disorders: Dysgeusia, seizures
• Cardiac disorders: Ischemic heart disease
• Vascular disorders: Hot flush, hypertension
• Gastrointestinal disorders: Diarrhea
• Skin and subcutaneous tissue disorders: Skin rash, pruritus
• Musculoskeletal and connective tissue disorders: Fracture, arthralgia, muscle spasm
• General disorders and administration site conditions: Fatigue
• Investigations: Decreased body weight
• Injury, poisoning and procedural complications: Falls, fractures

Pregnancy: Apalutamide is contraindicated in women who are pregnant or may become pregnant. Based on its mechanism of action, Apalutamide may cause fetal harm if used during pregnancy. There are no available data on the use of Apalutamide in pregnant women. Animal reproductive studies with Apalutamide have not been conducted.

Breast-feeding: It is not known whether apalutamide or its metabolites are excreted in human milk. A potential risk to the breastfed infant cannot be ruled out. Apalutamide should not be used during breastfeeding.

Females and Males of Reproductive Potential: Contraception in males and females: It is unknown whether apalutamide or its metabolites are present in semen. Apalutamide may cause harm to a developing fetus. Male patients with female partners of reproductive potential should use a condom along with an additional highly effective contraceptive method during treatment and for 3 months after the last dose of Apalutamide.

Fertility: Based on animal studies, Apalutamide may impair fertility in males of reproductive potential.

Seizures: Apalutamide is not recommended for patients with a history of seizures or conditions that increase seizure risk, such as: Prior brain injury, Recent stroke (within one year), Primary brain tumors Brain metastases. If a seizure occurs during treatment, Apalutamide should be permanently discontinued. In the SPARTAN and TITAN studies, seizures occurred in 0.4% of patients receiving Apalutamide and 0.2% of patients receiving placebo. These studies excluded patients with prior seizure history or risk factors.

Falls and Fractures: Patients taking Apalutamide have experienced falls and fractures. Before starting treatment: Assess fracture and fall risk. During treatment: Continue monitoring and manage according to standard guidelines. Consider using bone-targeted therapies when appropriate.

Ischemic Heart Disease: Ischemic heart disease, including fatal events, has occurred in patients on Apalutamide, especially those with existing cardiac risk factors. Monitor patients for signs of heart disease. Optimize management of risk factors such as hypertension, diabetes, and dyslipidemia following standard care.

Concomitant Use with Other Drugs:  Apalutamide is a potent enzyme inducer, which may reduce the effectiveness of many drugs. Avoid co-administration with drugs that are sensitive substrates of metabolizing enzymes or transporters if their effect is critical and dose adjustment is difficult. Avoid using Apalutamide with warfarin or coumarin-like anticoagulants. If co-administered with CYP2C9-metabolized anticoagulants, additional INR monitoring is required.

Recent Cardiovascular Disease:  Patients with significant cardiovascular events in the past 6 months (e.g., severe/unstable angina, myocardial infarction, symptomatic heart failure, thromboembolic events, or serious arrhythmias) were excluded from clinical trials. Safety in these patients is not established. If prescribed, monitor cardiovascular risk factors (hypercholesterolemia, hypertriglyceridemia, cardio-metabolic disorders) and treat according to guidelines.

QT Interval Considerations:  Androgen deprivation therapy may prolong the QT interval. In patients with QT prolongation history or risk factors, or those taking drugs that prolong QT, assess benefit-risk, including risk of Torsade de pointes, before starting Apalutamide.

There is no specific antidote for Apalutamide overdose. In case of overdose, treatment should be stopped and supportive care provided until symptoms improve.

Cytotoxic Chemotherapy

Store below 30°C in a cool and dry place. Protect from light and moisture. Keep out of reach of children.