Niraparib Tosylate Monohydrate And Abiraterone Acetate
FDA Drug Information • Also known as: Akeega
- Brand Names
- Akeega
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION AKEEGA ® (niraparib and abiraterone acetate) tablets contain niraparib tosylate (as the monohydrate) and abiraterone acetate. Niraparib Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}- 2H -indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C 26 H 30 N 4 O 5 S and it has a molecular weight of 510.61 g/mol. The molecular structure is shown below: Niraparib tosylate monohydrate is a white to off-white, non-hygroscopic crystalline solid. Niraparib tosylate monohydrate is highly soluble in aqueous media over the pH range 1.2 to 6.8 (1.65–1.77 mg/mL determined at 37 ± 1°C). Chemical Structure Abiraterone Acetate Abiraterone acetate is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Its molecular formula is C 26 H 33 N O 2 and it has a molecular weight of 391.55 g/mol. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. AKEEGA tablets are supplied as 50 mg/500 mg niraparib/abiraterone acetate and 100 mg/500 mg niraparib/abiraterone acetate film-coated tablets for oral administration. Each AKEEGA tablet (50 mg/500 mg) contains 50 mg of niraparib (equivalent to 76.9 mg niraparib tosylate) and 500 mg of abiraterone acetate. Each AKEEGA tablet (100 mg/500 mg) contains 100 mg of niraparib (equivalent to 153.7 mg niraparib tosylate) and 500 mg of abiraterone acetate. AKEEGA tablet core contains the following inactive ingredients: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified...
What Is Niraparib Tosylate Monohydrate And Abiraterone Acetate Used For?
1 INDICATIONS AND USAGE AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA [see Dosage and Administration (2.1) ] . AKEEGA is a combination of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor indicated with prednisone for the treatment of adult patients with: deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA. ( 1 , 2.1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION BRCA2 m mCSPC: The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) BRCA m mCRPC : The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) Take AKEEGA on an empty stomach at least one hour before or two hours after food. ( 2.2 ) For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of mCSPC with AKEEGA based on the presence of a BRCA2 gene alteration [see Clinical Studies (14.1) ] . Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration [see Clinical Studies (14.2) ] . Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage BRCA2- mutated ( BRCA2 m) Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone once daily until disease progression or unacceptable toxicity. BRCA -mutated ( BRCA m) Metastatic Castration-Resistant Prostate Cancer (mCRPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone once daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach at least one hour before or two hours after food. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day. 2.3 Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. If the toxicity is attributed to one component of AKEEGA, the other component of AKEEGA may be continued as a single agent at the current dose until the adverse reaction resolves and AKEEGA can be resumed (see Table 1 ). Table 1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Myelosuppression [see Warnings and Precautions (5.2) ] Hemoglobin <8 g/dL Withhold AKEEGA and monitor blood counts weekly. When hemoglobin returns to ≥9 g/dL, resume at the reduced dose of AKEEGA 100...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Myelodysplastic syndrome/acute myeloid leukemia [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Hypokalemia, fluid retention, and cardiovascular adverse reactions [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Adrenocortical insufficiency [see Warnings and Precautions (5.5) ] Hypoglycemia [see Warnings and Precautions (5.6) ] Increased fractures and mortality in combination with Radium 223 Dichloride [see Warnings and Precautions (5.7) ] Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥20%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, fluid retention/edema, increased bilirubin, respiratory tract infection and arrhythmia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg) in BRCA2 m patients (N=162) in the AMPLITUDE study and in BRCA m patients in Cohort 1 (N=113) in the MAGNITUDE study unless otherwise specified. BRCA2 -mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) The safety of AKEEGA in patients with BRCA2 m mCSPC was evaluated in AMPLITUDE [see Clinical Studies (14.1) ]. Patients were randomized to receive either AKEEGA (niraparib 200 mg and abiraterone acetate 1,000 mg once daily) (n=162), or placebo and abiraterone acetate (n=161) until unacceptable toxicity or progression. Patients in both arms also received prednisone 5 mg daily. The median duration of exposure for AKEEGA was 26 months (range: 0 to 48 months). Serious adverse reactions occurred in 36% of patients who received AKEEGA. Serious adverse reactions reported in >2% of patients included anemia (4.9%), and pneumonia (3.7%). Fatal adverse reactions occurred in 4.9% of patients who received AKEEGA, including sudden death (1.9%), COVID-19 pneumonia (1.2%), pneumocystis jirovecii pneumonia (0.6%), pneumonia (0.6%), and cardio-respiratory arrest (0.6%). Permanent discontinuation of any component of AKEEGA due to an adverse reaction occurred in 13% of patients. Dosage interruptions of any component of AKEEGA due to an adverse reaction occurred in 67% of patients. Adverse reactions which required dosage interruption in >2% of patients included anemia (30%), COVID-19 (10%), hypertension (9%), neutropenia (8%), thrombocytopenia (8%), hypokalemia (7%), vomiting (4.9%), fatigue (4.3%), diarrhea (2.5%), and pneumonia (2.5%). Dose reductions of any component of AKEEGA due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dose reductions in >2% of patients included anemia (17%). The most common adverse reactions (>20%), including laboratory abnormalities, in patients who received AKEEGA were decreased hemoglobin, decreased lymphocyte count, hypertension, decreased neutrophil count, musculoskeletal pain, decreased platelet count, constipation, fatigue, decreased potassium, increase creatinine, nausea, increased alkaline phosphate, increased aspartate aminotransferase, respiratory tract infection, arrhythmia, increased blood bilirubin, and fluid retention/edema. Table 2: Adverse...
Drug Interactions
7 DRUG INTERACTIONS Strong CYP3A4 Inducers: Avoid coadministration. ( 7.1 ) CYP2D6 Substrates: Avoid coadministration of AKEEGA with CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate. ( 7.2 ) 7.1 Effect of Other Drugs on AKEEGA Effect of CYP3A4 Inducers Avoid coadministration with strong CYP3A4 inducers [see Clinical Pharmacology (12.3) ] . Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of abiraterone. 7.2 Effects of AKEEGA on Other Drugs CYP2D6 Substrates Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug. Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA increases the concentration of CYP2D6 substrates [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions related to these substrates. CYP2C8 Substrates Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. Abiraterone is a CYP2C8 inhibitor. AKEEGA increases the concentration of CYP2C8 substrates [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions related to these substrates.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary The safety and efficacy of AKEEGA have not been established in females. Based on findings from animal studies and mechanism of action [see Clinical Pharmacology (12.1) ] , AKEEGA can cause fetal harm and potential loss of pregnancy. There are no human data on the use of AKEEGA in pregnant women. 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) ] . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. 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 (see Data ) . Data Animal Data Niraparib Niraparib is genotoxic and targets actively dividing cells. Animal developmental and reproductive toxicology studies were not conducted with niraparib. Abiraterone Acetate In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6–17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients receiving 1,000 mg daily...
Overdosage
10 OVERDOSAGE In the event of an overdose, administration of AKEEGA should be stopped and general supportive measures undertaken, including monitoring for arrhythmias and cardiac failure and assessing liver function. There is no specific treatment in the event of AKEEGA overdose.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING AKEEGA ® (niraparib and abiraterone acetate) tablets are available in the strengths and packages listed below: AKEEGA 50 mg/500 mg film-coated tablets Yellowish orange to yellowish brown, oval, film-coated tablets debossed with "N 50 A" on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-050-60 AKEEGA 100 mg/500 mg film-coated tablets Orange, oval, film-coated tablets debossed with "N 100 A" on one side and plain on the other side. They are available in bottles of 60 tablets. NDC 57894-100-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Based on its mechanism of action, AKEEGA may harm a developing fetus. Females who are or may become pregnant should handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1) ] .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.