ZEJULA

Small Molecule Antineoplastic Poly (ADP-ribose) Polymerase (PARP) Inhibitors

Emetic Risk
Moderate/High
Administer routine antiemetic prophylaxis prior to treatment.

Niraparib capsules may be taken with or without food.
Swallow the capsules whole; do not chew, crush, split, or dissolve.
Take capsules at the same time daily; bedtime administration may help alleviate nausea.
If a dose is missed or the patient vomits, the next dose should be taken at the regularly scheduled time; do not take an additional dose.

thrombocytopenia / Delayed / 21.0-39.0
anemia / Delayed / 23.0-33.0
hypertension / Early / 11.0-13.0
elevated hepatic enzymes / Delayed / 0-8.0
fatigue / Early / 3.0-8.0
asthenia / Delayed / 0-8.0
new primary malignancy / Delayed / 1.2-7.0
nausea / Early / 1.0-5.0
vomiting / Early / 0-4.0
hyperglycemia / Delayed / 0-3.0
GI obstruction / Delayed / 0-2.9
dyspnea / Early / 0.4-2.0
constipation / Delayed / 0.7-1.0
musculoskeletal pain / Early / 0-1.0
headache / Early / 0.3-1.0
insomnia / Early / 0-1.0
hypomagnesemia / Delayed / 0-1.0
anorexia / Delayed / 0-1.0
back pain / Delayed / 0-0.8
infection / Delayed / 0-0.8
anxiety / Delayed / 0-0.7
xerostomia / Early / 0-0.7
rash / Early / 0-0.5
stomatitis / Delayed / 0-0.5
leukemia / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
pleural effusion / Delayed / Incidence not known

palpitations / Early / 0-10.0
sinus tachycardia / Rapid / 0-10.0
depression / Delayed / 0-10.0
conjunctivitis / Delayed / 0-10.0
peripheral edema / Delayed / 0-10.0
hypokalemia / Delayed / 0-10.0
encephalopathy / Delayed / 0.1-0.1
pneumonitis / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
impaired cognition / Early / Incidence not known
hallucinations / Early / Incidence not known
confusion / Early / Incidence not known

pharyngitis / Delayed / 0-23.0
dizziness / Early / 14.0-19.0
dyspepsia / Early / 17.0-18.0
cough / Delayed / 16.0-18.0
dysgeusia / Early / 0-13.0
epistaxis / Delayed / 0-10.0
weight loss / Delayed / 0-10.0
lethargy / Early / Incidence not known
malaise / Early / Incidence not known
photosensitivity / Delayed / Incidence not known

Zejula

Rx

Oral poly (ADP-ribose) polymerase (PARP) inhibitor
Used as maintenance therapy for advanced or recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer
Hematologic toxicity has been commonly reported, as well as cases of myelodysplastic syndrome/acute myeloid leukemia; closely monitor complete blood counts

300 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 8 weeks after the last platinum-containing regimen. In a randomized, double-blind, placebo-controlled clinical trial (NOVA), patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized to maintenance therapy with niraparib or placebo within 8 weeks of the last platinum-based therapy. Median progression-free survival was significantly improved in in the cohort of patients with germline BRCA mutations (gBRCAmut) (21 months vs. 5.5 months). Median overall survival was also significantly improved in the gBRCAmut cohort treated with niraparib compared with placebo (40.9 months vs. 38.1 months).

Dosage not available.

Dosage not available.

200 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 12 weeks after the last platinum-containing regimen. In a double-blind, phase 3 clinical trial, patients with newly diagnosed, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with a response to first-line platinum-based chemotherapy were randomized to receive maintenance therapy with niraparib or placebo within 12 weeks after completion of chemotherapy. Patients receiving maintenance therapy with niraparib had significantly improved progression-free survival (PFS) compared with placebo (21.9 months vs. 10.4 months), irrespective of BRCA status. Overall survival was not significantly different at only 10.8% data maturity. Treatment had expected adverse reactions that were somewhat mitigated for lower dosing in patients with a baseline weight below 77 kg or platelet counts of less than 150,000 cells/mm3.

300 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 12 weeks after the last platinum-containing regimen. In a double-blind, phase 3 clinical trial, patients with newly diagnosed, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with a response to first-line platinum-based chemotherapy were randomized to receive maintenance therapy with niraparib or placebo within 12 weeks after completion of chemotherapy. Patients receiving maintenance therapy with niraparib had significantly improved progression-free survival (PFS) compared with placebo (21.9 months vs. 10.4 months), irrespective of BRCA status. Overall survival was not significantly different at only 10.8% data maturity. Treatment had expected adverse reactions that were somewhat mitigated for lower dosing in patients with a baseline weight below 77 kg or platelet counts of less than 150,000 cells/mm3.

Dosage Adjustments for Baseline Hepatic Impairment:
Mild hepatic impairment (total bilirubin less than 1.5 times upper level of normal (ULN) and any AST or bilirubin below the ULN and AST greater than ULN): No dosage adjustment is necessary.
Moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN and any AST): Reduce the starting dose of niraparib to 200 mg PO once daily; monitor patients for hematologic toxicity and reduce the dose further if needed.
Severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST): The recommended dose of niraparib has not been established.
 
Dosage Adjustments for Treatment-Related Hepatotoxicity:
Grade 3 or higher elevation in liver function tests (total bilirubin greater than 3 times the upper limit of normal (ULN) or ALT/AST greater than 5 times ULN) where treatment is not considered feasible or adverse reaction persists despite treatment: Hold niraparib treatment for a maximum of 28 days. If resolution occurs within 28 days, restart therapy at a reduced dose (i.e., 300 mg to 200 mg; 200 mg to 100 mg). If grade 3 or higher hepatic dysfunction persists beyond 28 days or occurs at a daily dose of 100 mg, discontinue niraparib treatment.

Dosage Adjustments for Baseline Renal Insufficiency:
Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustment necessary.
Severe renal impairment (CrCl less than 30 mL/min) or end-stage renal disease (ESRD) undergoing hemodialysis: The safety of niraparib treatment is unknown.
 
Dosage Adjustments for Treatment-Related Nephrotoxicity:
Grade 3 or higher nephrotoxicity (SCr greater than 3 times the upper limit of normal (ULN) or GFR less than 25% of the lower limit of normal (LLN)) where treatment is not considered feasible or adverse reaction persists despite treatment: Hold niraparib treatment for a maximum of 28 days. If resolution occurs within 28 days, restart therapy at a reduced dose (i.e., 300 mg to 200 mg; 200 mg to 100 mg). If grade 3 or higher renal dysfunction persists beyond 28 days or occurs at a daily dose of 100 mg, discontinue niraparib treatment.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

Niraparib/ZEJULA Oral Tab: 100mg, 200mg, 300mg
ZEJULA Oral Cap: 100mg

300 mg PO once daily.

300 mg PO once daily.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Niraparib inhibits poly (ADP-ribose) polymerase (PARP) enzyme 1 (PARP1) and PARP enzyme 2 (PARP2). PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. In vitro, niraparib-induced cytotoxicity resulted in DNA damage, apoptosis and cell death due to increased formation of PARP-DNA complexes; cytotoxicity was observed in tumor cell lines irrespective of BRCA1/2 deficiencies. Niraparib decreased tumor growth in mouse xenograft models of human cancer with BCRA1/2 deficiencies and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2. Additionally, niraparib inhibits the uptake of norepinephrine and dopamine by binding to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) in vitro in cells with IC50 values that were lower than the Cmin at steady state in patients receiving the recommended dose. Because of this, niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS).

Niraparib is administered orally. It is 83% bound to human plasma proteins, with an average apparent volume of distribution (Vd/F) of 1,220 +/- 1,114 L; in a population pharmacokinetic analysis, the Vd/F of niraparib in cancer patients was 1,074 L. After oral administration, niraparib crossed the blood-brain barrier in rats and monkeys; the CSF:plasma Cmax ratio was 0.1 and 0.52 when administered to two Rhesus monkeys at a dose of 10 mg/kg. Niraparib is metabolized by carboxylesterases to form a major inactive metabolite, which undergoes subsequent glucuronidation. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/hour in cancer patients; after multiple daily dosing, the mean half-life is 36 hours. The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg. An average of 47.5% (range, 33.4% to 60.2%) of a single radio-labeled dose of niraparib was recovered over 21 days in urine, and 38.8% (range, 28.3% to 47%) in feces; unchanged drug accounted for 11% and 19% of the dose recovered in urine and feces, respectively.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: carboxylesterases, P-glycoprotein (P-gp), BCRP, CYP1A2, MATE1, MATE2
Clinical drug interaction studies have not been conducted with niraparib. Niraparib is a substrate of carboxylesterases in vitro, and the resulting inactive metabolite is further metabolized through glucuronidation in vivo. Niraparib is also a substrate of P-gp and BCRP in vitro. In vitro, it is a weak BCRP inhibitor as well as a weak CYP1A2 inducer. Niraparib inhibits multidrug and toxin extrusion (MATE) 1 and 2 with IC50 of 0.18 microMolar and 0.14 microMolar or less, respectively; increased plasma concentrations of MATE1 or 2 substrates cannot be excluded.

The mean Cmax after administration of a single 300-mg dose of niraparib was 804 +/- 403 ng/mL, with a Tmax of 3 hours; both the Cmax and AUC increased in a dose proportional manner over a range of 30 mg to 400 mg. Absolute bioavailability (F) is approximately 73%. Administration with a high fat meal (800 to 1,000 calories with approximately 50% of caloric content from fat) did not significantly impact the pharmacokinetics of niraparib.

Pregnancy should be avoided by females of reproductive potential during niraparib treatment and for at least 6 months after the last dose. Based on its mechanism of action, niraparib can cause teratogenicity and/or embryo-fetal death when administered to pregnant women because it is genotoxic and targets actively dividing cells (e.g., bone marrow). Because of this potential risk, animal developmental and reproductive studies were not conducted.

Due to the potential for serious adverse reactions in nursing infants, advise women to discontinue breast-feeding during niraparib treatment and for 1 month after the final dose. It is not known whether niraparib is present in human milk or if it has negative effects on milk production.