Niraparib Tosylate Monohydrate and Abiraterone Acetate (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

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Introduction

Antineoplastic agent; fixed-combination preparation containing a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor (niraparib) and a 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor (abiraterone acetate).

Uses for Niraparib Tosylate Monohydrate and Abiraterone Acetate

Metastatic Castration-resistant Prostate Cancer

Used in combination with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of therapy.

American Urological Association (AUA) guidelines recommend offering a PARP inhibitor to patients with confirmed or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated (includingBRCA–mutated) mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or taxane-based chemotherapy. For patients unable to take or obtain PARP inhibitors, platinum-based chemotherapy is an alternative. Use of PARP inhibitors in combination with abiraterone is not discussed in the guideline.

Niraparib Tosylate Monohydrate and Abiraterone Acetate Dosage and Administration

General

Pretreatment Screening

• Check CBC at baseline. Do not start niraparib/abiraterone until adequate recovery from hematologic toxicity caused by previous therapy.

• Control hypertension and correct hypokalemia prior to starting treatment with niraparib/abiraterone.

• Measure serum aminotransferases (ALT and AST) and bilirubin levels prior to starting treatment with niraparib/abiraterone.

• Confirm presence of BRCA gene alteration prior to initiation of niraparib/abiraterone. Consult FDA website for list of FDA-approved companion diagnostic tests ([Web]).

Patient Monitoring

• Monitor CBC weekly during the first month of treatment, every 2 weeks for the next 2 months, monthly for the remainder of the first year, and then every other month, and as clinically indicated.

• Monitor for hypertension, hypokalemia, and fluid retention at least weekly for the first 2 months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention (e.g., heart failure, recent MI, cardiovascular disease, ventricular arrhythmia). Control hypertension and correct hypokalemia during treatment with niraparib/abiraterone.

• Measure serum aminotransferases (ALT and AST) and bilirubin levels every 2 weeks for the first 3 months of treatment and monthly thereafter. Elevations from baseline should prompt more frequent monitoring. Promptly measure total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

• Monitor patients for signs and symptoms of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency.

• Monitor blood glucose in patients with diabetes during and after discontinuation of niraparib/abiraterone. Assess if antihyperglycemic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

• Monitor all patients treated with niraparib/abiraterone for signs and symptoms of Posterior Reversible Encephalopathy Syndrome (PRES).

• Monitor patients with severe renal impairment (creatinine clearance 15–30 mL/minute) for increased adverse reactions and modify dosage as recommended for adverse reactions.

Dispensing and Administration Precautions

• Handling and Disposal: Females who are or may become pregnant should handle niraparib/abiraterone with protection (e.g., gloves).

Administration

Take tablets orally on an empty stomach. Do not eat for 2 hours before and 1 hour after taking tablets. Swallow tablets whole with water; do not break, crush, or chew tablets.

If dose is missed, take as soon as possible on the same day and resume at the normal schedule the following day.

Dosage

Adults

Deleterious or Suspected Deleterious BRCA-mutated Metastatic Castration-resistant Prostate Cancer

Oral

200 mg niraparib/1,000 mg abiraterone orally once daily in combination with prednisone 10 mg once daily until disease progression or unacceptable toxicity. Use with a gonadotropin-releasing hormone (GnRH) analog if patient has not undergone bilateral orchiectomy.

Dosage Modifications for Toxicity

For adverse reactions, consider interruption of treatment, dosage reduction, or discontinuation. Treatment should not be reinitiated until toxicity has resolved to grade 1 or baseline. If toxicity is attributed to one component of niraparib/abiraterone, the other component may be continued as a single agent at current dose until adverse reaction resolves and combination therapy can be resumed.

Myelosuppression

For hemoglobin <8 g/dL, withhold niraparib/abiraterone and monitor blood counts weekly. When hemoglobin returns to ≥9 g/dL, resume at reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue niraparib/abiraterone if hemoglobin has not returned to acceptable levels within 28 days of dose interruption period or if already taking reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.

For platelet counts <100,000/mm³, withhold niraparib/abiraterone for a maximum of 28 days. Consider platelet transfusion for platelet count ≤10,000/mm³. If there are other risk factors (e.g., coadministration of anticoagulation or antiplatelet drugs), consider interrupting these drugs and/or transfusion at higher platelet count.

For first occurrence of platelet count <100,000/mm^3, monitor blood counts weekly until platelets return to ≥100,000/mm³. Resume niraparib/abiraterone at same or reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily. If platelet count is <75,000/mm³, resume at reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily. For second occurrence of platelets <100,000/mm³, monitor blood counts weekly until platelets return to ≥100,000/mm³. Resume at reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.

Permanently discontinue niraparib/abiraterone if the platelet count has not returned to acceptable levels within 28 days of dose interruption period or if patients already receiving a reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.

For neutrophils <1000/mm³, withhold niraparib/abiraterone and monitor blood counts weekly. When neutrophils return to ≥1,500/mm³, resume at the reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue if neutrophils have not returned to acceptable levels within 28 days or if patient is already receiving a reduced dose of niraparib 100 mg/abiraterone 1,000 mg once daily.

If myelodysplastic syndrome or acute myeloid leukemia is confirmed, discontinue niraparib/abiraterone.

Hepatotoxicity

If ALT and/or AST >5 times ULN or total bilirubin >3 times ULN, withhold niraparib/abiraterone and closely monitor liver function. When AST and ALT resolve to ≤2.5 times ULN and total bilirubin ≤1.5 times ULN, resume at the reduced dose of niraparib 100 mg/abiraterone 500 mg once daily. When resumed, monitor serum aminotransferases every 2 weeks for 3 months, monthly thereafter, and as clinically indicated.

Permanently discontinue niraparib/abiraterone if ALT or AST ≥20 times ULN or ALT >3 times ULN and total bilirubin is >2 times ULN in the absence of biliary obstruction or other causes for concurrent elevation or if hepatotoxicity recurs at reduced dose of niraparib 100 mg/abiraterone 500 mg once daily.

Other Non-hematologic Adverse Reactions that Persist Despite Medical Management

Withhold niraparib/abiraterone until resolution of grade 3 or 4 adverse reactions or for a maximum of 28 days. If adverse reaction resolves in 28 days or less, resume therapy at the reduced dose.

Discontinue niraparib/abiraterone in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

Permanently discontinue niraparib/abiraterone if adverse reaction(s) have not resolved after 28 days or a grade 3 or 4 adverse reaction reoccurs after dose reduction.

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Avoid concomitant use with strong CYP3A4 inducers.

Avoid concomitant use with CYP2D6 substrates for which minimal changes in concentrations may lead to serious toxicities. If concomitant use is unavoidable, consider dose reduction of CYP2D6 substrate.

Special Populations

Hepatic Impairment

No dosage modification necessary for mild hepatic impairment (Child-Pugh class A). Avoid use in moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

No dosage modifications necessary for mild to moderate renal impairment (Cl_cr 30-90 mL/minute). Monitor for increased adverse reactions and modify dosage as recommended for adverse reactions in severe renal impairment (Cl_cr 15-30 mL/minute).

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Niraparib Tosylate Monohydrate and Abiraterone Acetate

Contraindications

• None.

Warnings/Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML)

MDS/AML, including fatal cases, has been observed.

For suspected MDS/AML or prolonged hematologic toxicities, refer patient to a hematologist for further evaluation. Discontinue niraparib/abiraterone if MDS/AML is confirmed.

Myelosuppression

May cause myelosuppression, including anemia, thrombocytopenia, or neutropenia. Monitor CBC weekly during the first month, every 2 weeks for the next 2 months, monthly for the remainder of the first year and then every other month, and as clinically indicated.

Do not start niraparib/abiraterone until adequate recovery from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following therapy interruption, discontinue niraparib/abiraterone and refer patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics.

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

May cause hypokalemia and fluid retention. QT prolongation and torsades de pointes observed in abiraterone-treated patients. Hypertension and hypertensive crisis reported in niraparib-treated patients.

Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first 2 months, then once a month. Closely monitor underlying conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention (e.g., CHF, recent MI, cardiovascular disease, ventricular arrhythmia). Control hypertension and correct hypokalemia before and during treatment. Discontinue niraparib/abiraterone in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions.

Hepatotoxicity

Severe hepatotoxicity, including fulminant hepatitis, acute liver failure, and deaths, reported. Safety of niraparib/abiraterone in moderate or severe hepatic impairment not established. Measure ALT, AST, and bilirubin levels prior to starting treatment, every 2 weeks for the first 3 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 baseline should prompt more frequent monitoring and may require dosage modifications.

Permanently discontinue niraparib/abiraterone if patient develops concurrent elevation of ALT >3 times the ULN and total bilirubin >2 times the ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or if patient develops ALT or AST ≥20 times the ULN at any time.

Adrenocortical Insufficiency

Niraparib/abiraterone may cause adrenal insufficiency. Monitor for symptoms and signs of adrenocortical insufficiency, particularly if prednisone is withdrawn or after prednisone dose reductions, or if patient experiences unusual stress. Symptoms and signs may be masked by adverse events associated with mineralocorticoid excess. Perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency if clinically indicated. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

Hypoglycemia

Niraparib/abiraterone may cause hypoglycemia when used concomitantly with other medications for diabetes. Severe hypoglycemia reported when abiraterone acetate was administered in patients receiving thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and after discontinuation of niraparib/abiraterone. Assess if antihyperglycemic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

Increased Fractures and Mortality in Combination with Radium-223 Dichloride

Niraparib/abiraterone with prednisone not recommended for use in combination with radium-223 dichloride. Subsequent treatment with radium-223 should not be initiated for at least 5 days after the last administration of niraparib/abiraterone in combination with prednisone.

Posterior Reversible Encephalopathy Syndrome (PRES)

May cause PRES. Monitor for signs and symptoms of PRES. If PRES suspected, promptly discontinue niraparib/abiraterone and administer appropriate treatment. The safety of reinitiation in patients previously experiencing PRES is not known.

Embyro-fetal Toxicity

Safety and efficacy not established in females. Can cause fetal harm, including teratogenicity, and/or embryo-fetal death.

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of niraparib/abiraterone. Females who are or may become pregnant should handle tablets with protection (e.g., gloves).

Specific Populations

Pregnancy

Safety and efficacy not established in females. Based on animal studies and mechanism of action, can cause fetal harm and potential loss of pregnancy.

Lactation

No data available on the presence of niraparib or abiraterone in human milk, or on the effects on the breast-fed child or milk production.

Females and Males of Reproductive Potential

Based on animal studies, may impair fertility in males of reproductive potential. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Pediatric Use

Safety and effectiveness in pediatric patients not established.

Geriatric Use

The MAGNITUDE trial did not include a significant number of patients with BRCA gene alteration(s) treated with niraparib/abiraterone to accurately characterize efficacy or safety by age.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A) does not affect niraparib exposure but increases abiraterone AUC by 1.1-fold compared to individuals with normal hepatic function.

Moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST value) increases niraparib AUC by 56%. Moderate hepatic impairment (Child-Pugh class B) increases abiraterone AUC 3.6-fold.

Severe hepatic impairment (Child-Pugh class C) increases abiraterone AUC 7-fold and increases the fraction of free drug 2-fold compared to individuals with normal hepatic function.

No dosage modification necessary for mild hepatic impairment (Child-Pugh class A). Avoid use in moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

No clinically significant effects on the pharmacokinetics in mild to moderate renal impairment (Cl_cr30-90 mL/minute).

No dosage modification recommended for mild to moderate renal impairment (Cl_cr 30-90 mL/minute). Severe renal impairment (Cl_cr 15-30 mL/minute) not studied. Monitor for increased adverse reactions in severe renal impairment (Cl_cr15-30 mL/minute) and modify dosage as recommended for adverse reactions.

Common Adverse Effects

Most common adverse reactions (≥10%): Decreased hemoglobin, decreased lymphocytes, decreased WBC, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, pyrexia.

Drug Interactions

Niraparib: Metabolized by carboxylesterases. Not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; not an inducer of CYP3A4 but is an inducer of CYP1A2. Does not inhibit UGT1A1, 1A4, 1A9, or 2B7. Substrate of breast cancer resistance protein (BRCP) and P-glycoprotein (P-gp). Inhibits BRCP and multidrug and toxic compound extrusion (MATE) 1 and 2. Does not inhibit P-gp, bile salt export pump (BSEP), or multidrug resistance-associated protein (MRP) 2.

Abiraterone: Abiraterone acetate rapidly converted to abiraterone and subsequently metabolized by CYP3A4 and sulfotransferase family 2A member 1 (SULT2A1). Substrate of CYP3A4 and has potential to inhibit CYP1A2, 2D6, 2C8, and to lesser extent CYP2C9, 2C19, and 3A4/5. Not a P-gp substrate but is a P-gp inhibitor. Inhibitor of organic anion transporter polypeptide (OATP) 1B1.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Abiraterone increases concentration of CYP2D6 substrates, which increases risk of adverse events related to these substrates. Avoid coadministration with CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternate treatments cannot be used, consider dose reduction of concomitant CYP2D6 substrate.

CYP2C8 substrates: Abiraterone increases the concentration of CYP2C8 substrates, increasing risk of adverse events related to these substrates. Monitor 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.

Strong CYP3A4 inducers: May decrease abiraterone concentrations, reducing effectiveness. Avoid concomitant use of strong CYP3A4 inducers.

Specific Drugs

Niraparib Tosylate Monohydrate and Abiraterone Acetate Pharmacokinetics

Niraparib: Exhibits dose proportional increase in C_max and AUC in dose range of 30-400 mg.

Abiraterone: No major deviation for dose proportionality observed in dose range of 250-1,000 mg.

Absorption

Bioavailability

Niraparib: Approximately 73%; T_max 3 hours.

Abiraterone: T_max 1.5 hours.

Effect of Food

Abiraterone: Administration with food results in up to 10-fold increase in AUC and 17-fold increase in systemic exposure compared to fasted state depending on fat content; administration with food has potential to result in increased and highly variable exposures.

Distribution

Plasma Protein Binding

Niraparib: 83%.

Abiraterone: >99% bound to albumin and alpha-1 acid glycoprotein.

Elimination

Metabolism

Niraparib: Metabolized by carboxylesterases.

Abiraterone: Abiraterone acetate rapidly converted to abiraterone; metabolized by CYP3A4 and sulfotransferase family 2A member 1 (SULT2A1).

Elimination

Niraparib: About 48% (range: 33-60%) recovered in urine and 39% (range: 28-47%) in feces; unchanged niraparib accounts for 11% and 19% of administered dose recovered in urine and feces, respectively.

Abiraterone: Approximately 88% recovered in feces and 5% in urine; unchanged abiraterone acetate and abiraterone account for 55% and 22% of administered dose recovered in the feces, respectively.

Half-life

Niraparib: Approximately 62 hours.

Abiraterone: Approximately 20 hours.

Special Populations

No clinically significant pharmacokinetic effects observed based on body weight, age, race/ethnicity, and mild to moderate renal impairment (Cl_cr30-90 mL/minute). Severe renal impairment (Cl_cr 15-30 mL/minute) not studied.

Stability

Storage

Oral

Tablets, film-coated

Store at 20–25ºC; excursions permitted to 15–30ºC.

Actions

• Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1 and PARP-2. In vitro studies 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. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild-type BRCA 1/2.

• Androgen-sensitive prostate cancer responds to treatment that decreases androgen levels. Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits 17α-hydroxylase/C17,20-lyase (CYP17) in testicular, adrenal, and prostatic tumor tissues, ultimately inhibiting the formation of dehydroepiandrosterone (DHEA) and androstenedione and increasing mineralocorticoid production by the adrenals.

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

• Changes in serum PSA may be observed but have not been shown to correlate with clinical benefit.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).

• Advise patients that periodic monitoring of their blood counts is recommended. Advise patients to contact their clinician for new onset of pallor, weakness, dyspnea, fatigue, bleeding, fever, or symptoms of infection.

• Inform patients that niraparib/abiraterone 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 2 months, then once a month. Advise patients to adhere to corticosteroids and to report symptoms of hypokalemia or edema to their clinician.

• Inform patients that niraparib/abiraterone 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 clinician.

• Inform patients that niraparib/abiraterone in combination with prednisone is associated with adrenal insufficiency. Advise patients to report symptoms of adrenocortical insufficiency to their clinician.

• Inform patients that niraparib/abiraterone is associated with hypoglycemia. Advise patients with diabetes to monitor blood glucose during and after discontinuation of treatment with niraparib/abiraterone.

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

• Inform patients coadministered gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with niraparib/abiraterone.

• Inform patients that niraparib/abiraterone is taken orally once daily with prednisone daily (according to their clinician’s instructions) and to not interrupt or stop either of these medications without consulting their clinician.

• Instruct patients to take niraparib/abiraterone 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 niraparib/abiraterone. Niraparib/abiraterone 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.

• Inform patients that in the event of a missed daily dose of niraparib/abiraterone, 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.

• Inform patients that niraparib/abiraterone may harm a developing fetus and can cause loss of pregnancy. Advise females who are pregnant or may become pregnant to handle niraparib/abiraterone tablets with protection (e.g., gloves).

• Advise male patients that niraparib/abiraterone may impair fertility. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of niraparib/abiraterone.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Niraparib/abiraterone is obtained through designated specialty distributors. Contact manufacturer or consult the niraparib/abiraterone website ([Web]) for specific availability information.

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