Abiraterone Acetate is a CYP17 inhibitor indicated for use in combination with prednisone for the treatment of:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Metastatic high-risk castration-sensitive prostate cancer (CSPC)

Abiraterone Acetate is converted in the body to Abiraterone, an androgen biosynthesis inhibitor that blocks 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is present in testicular, adrenal, and prostatic tumor tissues and is essential for androgen production. CYP17 catalyzes two sequential reactions:

1.Conversion of pregnenolone and progesterone into their 17α-hydroxy derivatives via 17α-hydroxylase activity.

2.Formation of dehydroepiandrosterone (DHEA) and androstenedione through C17,20-lyase activity. Both DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 by Abiraterone may also increase mineralocorticoid production in the adrenals. Androgen-sensitive prostate cancer responds to therapies that lower androgen levels. Treatments like GnRH agonists or orchiectomy reduce androgen production in the testes but do not affect adrenal or tumor androgen production.

Clinical trials showed that Abiraterone Acetate reduces serum testosterone and other androgens. Monitoring serum testosterone is not required, and changes in prostate-specific antigen (PSA) may be seen, though these changes do not necessarily correlate with clinical benefit in individual patients.

Recommended Dose For Metastatic CRPC: The recommended dose of Abiraterone Acetate is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with Prednisone 5 mg orally twice daily.

Recommended Dose For Metastatic High-Risk CSPC: The recommended dose of Abiraterone Acetate is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with Prednisone 5 mg administered orally once daily.

Patients receiving Abiraterone Acetate should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Abiraterone Acetate must be taken on an empty stomach, at least one hour before or at least two hours atier a meal. The tablets should be swallowed whole with water. Do not crush or chew tablets.

Dose Modification:

• For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the Abiraterone Acetate starting dose to 250 mg once daily.
• For patients who develop hepatotoxicity during treatment, hold Abiraterone Acetate until recovery. Retreatment may be initated at a reduced dose. Abiraterone Acetate should be discontinued if patients develop severe hepatotoxicity.
• Avoid concomitant strong CYP3A4 inducers (e.g., Phenytoin, Carbamazepine, Rifampin, Rifabutin, Rifapentine, Phenobarbital) during Abiraterone Acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone Acetate dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued. Or, as directed by the registered physician.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Drugs That Inhibit or Induce CYP3A4 Enzymes: According to in vitro findings, Abiraterone Acetate acts as a substrate of CYP3A4. In a specific drug interaction study, co-administration with Rifampin, a potent CYP3A4 inducer, reduced Abiraterone exposure by 55%. Concomitant use of strong CYP3A4 inducers should be avoided during treatment with Abiraterone Acetate. If co-administration with a strong CYP3A4 inducer is unavoidable, the dosing frequency of Abiraterone Acetate should be increased. In another dedicated interaction study, co-administration with ketoconazole, a strong CYP3A4 inhibitor, showed no clinically significant impact on the pharmacokinetics of Abiraterone.

Effects of Abiraterone on Drug Metabolizing Enzymes: Abiraterone Acetate inhibits hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug interaction study, when Dextromethorphan (a CYP2D6 substrate) was administered with Abiraterone Acetate 1,000 mg once daily along with Prednisone 5 mg twice daily, the Cmax and AUC of Dextromethorphan increased by 2.8-fold and 2.9-fold, respectively. Co-administration of Abiraterone Acetate with CYP2D6 substrates that have a narrow therapeutic index (such as Thioridazine) should be avoided. If alternative therapies are not feasible, dose reduction of the concomitant CYP2D6 substrate should be considered. In a CYP2C8 drug interaction study in healthy individuals, co-administration of Pioglitazone (a CYP2C8 substrate) with a single 1,000 mg dose of Abiraterone Acetate resulted in a 46% increase in Pioglitazone AUC. Therefore, patients receiving CYP2C8 substrates with a narrow therapeutic index alongside Abiraterone Acetate should be carefully monitored for signs of toxicity.

Abiraterone Acetate is contraindicated in patients with known hypersensitivity to Abiraterone Acetate or any of its excipients.

The most frequently reported adverse effects of Abiraterone Acetate include fatigue, joint pain (arthralgia), high blood pressure (hypertension), nausea, swelling (edema), low potassium levels (hypokalemia), hot flashes, diarrhea, vomiting, upper respiratory tract infections, cough, and headache.

The safety and effectiveness of Abiraterone Acetate have not been established in women. Animal studies and its mechanism of action suggest that Abiraterone may cause fetal harm and pregnancy loss. There are no data on its use in pregnant women. There is no information regarding the presence of Abiraterone Acetate in human breast milk, or its effects on the breastfed infant or milk production.

Abiraterone Acetate may lead to hypertension, hypokalemia, and fluid retention due to elevated mineralocorticoid levels resulting from CYP17 inhibition. Patients should be regularly monitored for these conditions at least once every month. Blood pressure and potassium levels must be properly controlled before starting treatment and maintained throughout therapy with Abiraterone. Patients should also be observed for any signs and symptoms of adrenocortical insufficiency. Liver function tests, including serum transaminases (ALT and AST) and bilirubin, should be assessed before initiating treatment, every two weeks during the first three months, and monthly thereafter.

There is no specific antidote for an Abiraterone Acetate overdose. In case of overdose: Stop Abiraterone Acetate immediately. Provide general supportive care, including monitoring for arrhythmias and heart failure. Assess liver function and manage any complications accordingly.

Cytotoxic Chemotherapy

Store below 25°C. Protect from light and moisture. Keep out of reach of children.