Akeega: Package Insert / Prescribing Info

2.1 Patient Selection

Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCAgene alteration [see Clinical Studies (14)] .

Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

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.

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. Do not eat food two hours before and one hour after taking AKEEGA. 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).

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA.

All patients treated with niraparib 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 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 required a red blood cell transfusion, including 11% who required multiple transfusions. 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 MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grades 3–4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grades 3–4 hypertension were observed in 14% of patients on the AKEEGA arm.

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 MAGNITUDE.

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.

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 MAGNITUDE Cohort 1, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.8% of patients. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from 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)].

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 combination with prednisone 10 mg daily in BRCA-mutated patients in Cohort 1 (N=113) of MAGNITUDE.

7.1 Effect of Other Drugs on AKEEGA

7.2 Effects of AKEEGA on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness of AKEEGA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 113 patients with BRCAgene alteration(s) who received AKEEGA in MAGNITUDE, 34.5% of patients were less than 65 years, 38.9% of patients were 65 years to 74 years, and 26.5% were 75 years and over.

There was an insufficient number of patients with BRCAgene alteration(s) treated with AKEEGA in MAGNITUDE to accurately characterize efficacy or safety by age.

8.6 Hepatic Impairment

Avoid use of AKEEGA in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.4)and Clinical Pharmacology (12.3)] .

No dosage modification is necessary for patients with mild hepatic impairment.

8.7 Renal Impairment

Monitor patients with severe renal impairment for increased adverse reactions and modify dosage as recommended for adverse reactions [see Clinical Pharmacology (12.3)].

No dosage modification is recommended for patients with mild to moderate renal impairment.

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 26H 30N 4O 5S 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).

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 26H 33NO 2and 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 microcrystalline cellulose, sodium lauryl sulfate.

• The 50 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide.
• The 100 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide.

12.1 Mechanism of Action

Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitrostudies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2and in human patient‑derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2.

Abiraterone acetate is converted in vivoto abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals [see Warnings and Precautions (5.9)] .

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.

Abiraterone decreased serum testosterone and other androgens in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of abiraterone on serum testosterone levels.

Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.

In mouse xenograft models of prostate cancer, the combination of niraparib and abiraterone acetate increased anti-tumor activity when compared to either drug alone.

12.2 Pharmacodynamics

The exposure-response relationship and time-course of pharmacodynamic response for the safety and effectiveness of AKEEGA have not been fully characterized.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 BRCA-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC)

The efficacy of AKEEGA was investigated in Cohort 1 of MAGNITUDE (NCT03748641), a randomized double-blind, placebo-controlled, multi-cohort, multi-center study in which 423 patients with homologous recombination repair (HRR) gene-mutated (HRRm) mCRPC were randomized (1:1) to receive niraparib 200 mg and abiraterone 1,000 mg (N=212) or placebo and abiraterone (N=211) until unacceptable toxicity or progression. All patients received prednisone 10 mg daily and a GnRH analog or had prior bilateral orchiectomy. Patients with mCRPC who had not received prior systemic therapy in the mCRPC setting except for a short duration of prior abiraterone acetate plus prednisone (up to four months) and ongoing ADT, were eligible. Patients could have received prior docetaxel or androgen-receptor (AR) targeted therapies in either the metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) setting.

Randomization was stratified by prior docetaxel for mCSPC (yes or no), prior AR targeted therapy for mCSPC or nmCRPC (yes or no), prior abiraterone acetate for mCRPC (yes or no), and BRCA-status ( BRCAm vs. other).

Of the 423 patients enrolled, 225 (53%) had BRCAgene mutations ( BRCAm). Mutation status of BRCAgenes was determined prospectively using the Foundation One CDx tissue assay or other clinical trial assays.

Among the 225 patients with BRCAm, the median age was 68 years (range 43–100) and 66% were 65 years of age or older; 72% were White, 17% Asian, and 1% Black, and 10% other or not reported; 12% were Hispanic or Latino; and baseline ECOG performance status (PS) was 0 (66%) or 1 (34%). Twenty-four percent had received prior docetaxel, 5% received prior AR-targeted therapy for mCSPC or nmCRPC, and 26% received prior abiraterone acetate plus prednisone for up to 4 months for mCRPC. Thirty-seven percent had bone-only metastases and 21% had visceral metastases. Seven percent had BRCA1 mutations, 78% had BRCA2 mutations, and 15% had BRCAmutations in combination with mutations in other HRR genes.

The major efficacy outcome measure was radiographic progression free survival (rPFS) determined by blinded independent central radiology (BICR) review evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (soft tissue lesions) and Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Overall survival (OS) was an additional efficacy outcome measure.

A statistically significant improvement in rPFS for niraparib plus abiraterone compared to placebo plus abiraterone was observed in BRCAm patients, and the Cohort 1 intention to treat (ITT) population. In an exploratory analysis in the subgroup of 198 (47%) patients with non- BRCAmutations, the rPFS hazard ratio was 0.99 (95% CI: 0.67, 1.44) and the OS hazard ratio was 1.13 (95% CI: 0.77, 1.64), indicating that the improvement in the ITT population was primarily attributed to the results seen in the subgroup of patients with BRCAm.

The efficacy results are presented in Table 4 and Figures 1 and 2 for patients in Cohort 1 with BRCAmutations.

At the protocol pre-specified final OS analysis in Cohort 1, 60 (53%) deaths and 70 (63%) deaths were observed in the AKEEGA arm and placebo arm, respectively, for patients with BRCAm. In an exploratory OS analysis in the subgroup of patients with BRCAm, the median in the AKEEGA arm was 30.4 (95% CI: 27.6, NE) and 28.6 months (95% CI: 23.8, 33.0) in the placebo arm, with an OS hazard ratio of 0.79 (95% CI: 0.55, 1.12).

Figure 1: Kaplan-Meier Plot of BICR Assessed Radiographic Progression-Free Survival in the BRCAm Population (MAGNITUDE, primary analysis)

Figure 2: Kaplan-Meier Plot of Overall Survival in the BRCAm Population (MAGNITUDE, final analysis)

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)] .

Hematologic Adverse Reactions

• Advise patients that periodic monitoring of their blood counts is recommended. Advise patients to contact their healthcare provider for new onset of pallor, weakness, dyspnea, fatigue, bleeding, fever, or symptoms of infection [see Warnings and Precautions (5.1, 5.2)] .

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

• Inform patients that AKEEGA is associated with, hypokalemia that may lead to QT prolongation. Advise patients that hypertension, hypokalemia, and fluid retention will be monitored at least weekly for the first two months, then once a month. Advise patients to adhere to corticosteroids and to report symptoms of hypokalemia or edema to their healthcare provider [see Warnings and Precautions (5.3)] .

Hepatotoxicity and Hepatic Impairment

• Inform patients that AKEEGA is associated with severe hepatotoxicity. Inform patients that their liver function will be monitored using blood tests. Advise patients to immediately report symptoms of hepatotoxicity to their healthcare provider [see Warnings and Precautions (5.4)] .

Adrenocortical Insufficiency

• Inform patients that AKEEGA with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their healthcare provider [see Warnings and Precautions (5.5)] .

Hypoglycemia

• Inform patients that AKEEGA is associated with hypoglycemia. Advise patients with diabetes to monitor blood glucose during and after discontinuation of treatment with AKEEGA [see Warnings and Precautions (5.6)] .

Posterior Reversible Encephalopathy Syndrome

• Inform patients that they are at risk of developing posterior reversible encephalopathy syndrome (PRES) that can present with signs and symptoms including seizure, headaches, altered mental status, or vision changes. Advise patients to contact their healthcare provider if they develop any of these signs or symptoms [see Warnings and Precautions (5.8)] .

Dosage and Administration

• Inform patients that AKEEGA is taken orally once daily with prednisone daily (according to their healthcare provider's instructions) and to not interrupt or stop either of these medications without consulting their healthcare provider [see Dosage and Administration (2.2)] .
• Inform patients coadministered a gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with AKEEGA [see Dosage and Administration (2.2)] .
• Inform patients that in the event of a missed daily dose of AKEEGA, they should take their normal dose as soon as possible on the same day and resume their next dose at the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.2)] .
• Instruct patients to take AKEEGA tablets as a single dose once daily on an empty stomach. Instruct patients to not eat food 2 hours before and 1 hour after taking AKEEGA. AKEEGA taken with food causes increased exposure and may result in adverse reactions. Instruct patients to swallow tablets whole with water and not to break, crush, or chew the tablets [see Dosage and Administration (2.2)] .

Embryo-Fetal Toxicity

• Inform patients that AKEEGA may harm a developing fetus and can cause loss of pregnancy [see Warnings & Precautions (5.9)and Use in Specific Populations (8.1)] .
• 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 (8.3)] .
• Advise females who are pregnant or may become pregnant to handle AKEEGA tablets with protection, e.g., gloves [see Use in Specific Populations (8.1)and How Supplied/Storage and Handling (16)] .

Infertility

• Advise male patients that AKEEGA may impair fertility [see Use in Specific Populations (8.3)].