ABIRATERONE Drug Interactions: What You Need to Know

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Drug Interactions (FDA Label)

INTERACTIONS

CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency. ( 2.5 , 7.1 )
CYP2D6 Substrates: Avoid co-administration of abiraterone acetate tablets with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate. ( 7.2 )

7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes Based on in vitro data, abiraterone acetate tablets are a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) ] .

7.2 Effects of Abiraterone on Drug Metabolizing Enzymes Abiraterone acetate tablets are an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) ] . In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate tablets [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.6) ] .

Drug Interactions Studies Clinical Studies

Effect of Other Drugs on Abiraterone Acetate Tablets Strong CYP3A4 inducers: In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC ∞ of abiraterone was decreased by 55%. Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate Tablets on Other Drugs CYP2D6 substrates: The C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold. CYP1A2 substrates: When abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. CYP2C8 substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of 1,000 mg abiraterone acetate.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5.

Transporter

Systems In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.

Contraindications

Pregnancy Abiraterone acetate can cause fetal harm and potential loss of pregnancy [see Use in Specific Populations (8.1) ]. Pregnancy. (4, 8.1)

Related Warnings

AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) : MDS/AML, including a case with fatal outcome, has been observed in patients treated with AKEEGA. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 ) Myelosuppression: Test complete blood counts weekly for the first month, every two weeks for the next two months, monthly for the remainder of the first year, then every other month, and as clinically indicated. ( 2.3 , 5.2 ) Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions: Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. ( 5.3 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue treatment as recommended. ( 2.3 , 5.4 ) Adrenocortical insufficiency : Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.5 ) Hypoglycemia: Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and assess if antidiabetic agent dose modifications are required. ( 5.6 ) Increased fractures and mortality in combination with radium Ra 223 dichloride : Use of AKEEGA plus prednisone in combination with radium Ra 223 dichloride is not recommended. ( 5.7 )

Posterior Reversible Encephalopathy

Syndrome (PRES): PRES has been observed in patients treated with niraparib, a component of AKEEGA. Discontinue AKEEGA if PRES is confirmed. ( 5.8 ) Embryo-Fetal Toxicity: AKEEGA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). In the individual AMPLITUDE and MAGNITUDE studies, MDS or AML, including cases with fatal outcomes, were reported in 0.6% (2/347) and 0.5% (1/212) of patients treated with AKEEGA plus prednisone, respectively. All patients in other tumor types treated with niraparib, a component of AKEEGA, who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed.

5.2 Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In AMPLITUDE, Grade 3–4 anemia, neutropenia, and thrombocytopenia were reported, respectively in 29%, 10%, and 4.9% of patients receiving AKEEGA. Overall, 25% of patients with anemia required a red blood cell transfusion, including 15% who required more than one transfusion. Discontinuation due to anemia occurred in 1.2% of patients. In MAGNITUDE Cohort 1, Grade 3–4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients with anemia required a red blood cell transfusion, including 19.5% who required more than one transfusion. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3) ] .

5.3 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) ] . In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA. In AMPLITUDE, which used prednisone 5 mg daily in combination with AKEEGA, Grades 3–4 hypokalemia was detected in 9% of patients on the AKEEGA arm, and Grades 3–4 hypertension was observed in 30% of patients on the AKEEGA arm. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grade 3–4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grade 3–4 hypertension was observed in 14% of patients on the AKEEGA arm. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from AMPLITUDE and MAGNITUDE.

5.4 Hepatotoxicity AKEEGA may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In AMPLITUDE, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.9% and 1.3% of patients, respectively. In MAGNITUDE Cohort 1, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.8% and 0.9% of patients, respectively. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from AMPLITUDE and MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications [see Dosage and Administration (2.3) ]. Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 × ULN at any time after receiving AKEEGA.

5.5 Adrenocortical Insufficiency AKEEGA may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

5.6 Hypoglycemia AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2) ] . Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

5.7 Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA, in combination with prednisone.

5.8 Posterior Reversible Encephalopathy Syndrome AKEEGA may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA. Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known.

5.9 Embryo-Fetal Toxicity The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) ] . Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1) ] . In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA [see Use in Specific Populations (8.1 , 8.3) ] . Females who are or may become pregnant should handle AKEEGA with protection, e.g., gloves [see How Supplied/Storage and Handling (16) ].

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