Niraparib

L01X - Other antineoplastic agents ATC L01XK52 Small molecule approved 2017 Oral First-in-class Natural product Orphan

JFDA label: Akeega 50/500mg Film Coated Tablets

Mechanism of Action

Inhibitor of Poly [ADP-ribose] polymerase 2 — Poly [ADP-ribose] polymerase 2 inhibitor; Inhibitor of Poly [ADP-ribose] polymerase 1 — Poly [ADP-ribose] polymerase-1 inhibitor

Target	Action	Gene / class
Poly [ADP-ribose] polymerase 1 efficacy	INHIBITOR	PARP1
Poly [ADP-ribose] polymerase 2 efficacy	INHIBITOR	PARP2

Indications

Approved

Ovarian, fallopian tube, or primary peritoneal cancer

Contraindications

Source: Lexicomp

There are no contraindications listed in the manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Very Common Hypertension

Common Palpitations · peripheral edema · tachycardia

Nervous system disorders (6)

Very Common anxiety · dizziness · Fatigue · headache · insomnia

Common Depression

Hepatobiliary disorders (3)

Very Common increased serum ALT · Increased serum AST

Common Increased serum alkaline phosphatase

Renal and urinary disorders (2)

Very Common Urinary tract infection

Common Increased serum creatinine

Blood and lymphatic system disorders (4)

Very Common anemia · leukopenia · neutropenia · Thrombocytopenia

Metabolism and nutrition disorders (3)

Common Hypokalemia · increased gamma-glutamyl transferase · weight loss

Gastrointestinal disorders (9)

Very Common constipation · decreased appetite · dyspepsia · mucositis · Nausea · stomatitis · vomiting

Common Dysgeusia · xerostomia

Skin and subcutaneous tissue disorders (1)

Very Common Skin rash

Musculoskeletal and connective tissue disorders (2)

Very Common back pain · Weakness

Eye disorders (1)

Common Conjunctivitis

Respiratory, thoracic and mediastinal disorders (5)

Very Common cough · dyspnea · Nasopharyngitis

Common Bronchitis · epistaxis

Dosing

Source: Lexicomp

Ovarian, fallopian tube, or primary peritoneal cancer, recurrent (maintenance treatment): Oral: 300 mg once daily, continue until disease progression or unacceptable toxicity (Mirza 2016). Begin treatment no later than 8 weeks following the most recent platinum-containing regimen. Missed/vomited doses: If a dose is missed or vomited, an additional dose should not be taken that day. Resume dosing with the next scheduled daily dose.

Refer to adult dosing.

Renal function estimated using the Cockcroft-Gault formula. CrCl 30 to CrCl End stage renal disease (ESRD): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatic function estimated using the National Cancer Institute Organ Dysfunction Working Group Criteria. Mild impairment: No dosage adjustment necessary. Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Thrombocytopenia, anemia and neutropenia commonly occur, including grade 3 and 4 events (which rarely required discontinuation). Monitor blood counts weekly for the first month, then monthly for 11 months, then periodically thereafter. Do not initiate niraparib until hematologic toxicity due to previous chemotherapy has resolved to grade 1 or lower. Hematologic toxicity may require treatment interruption, dose reduction, or discontinuation. If hematologic toxicities do not resolve with 28 days following interruption, discontinue niraparib and obtain consult with hematology for further assessment, including marrow and cytogenetic analysis.

Cardiovascular effects

Hypertension and hypertensive crisis have been reported, including grade 3 and 4 hypertension (hypertension required discontinuation in rare cases). Monitor blood pressure and heart rate monthly during the first year and periodically thereafter. Patients with cardiac disorders (especially coronary insufficiency, arrhythmias and hypertension) should be monitored closely. If necessary, hypertension should be managed with antihypertensives and niraparib dose adjustment.

Gastrointestinal toxicity

Nausea, vomiting, constipation and mucositis/stomatitis have been reported. Consider administering niraparib at bedtime to diminish the potential for nausea and vomiting.

Secondary malignancy

Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been reported (rare), including fatal cases. The duration of niraparib treatment prior to the development of MDS/AML varied from Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

Animal reproduction studies have not been conducted, however based on the mechanism of action, niraparib may cause fetal harm if used during pregnancy. Pregnancy testing should be conducted prior to treatment and effective contraception should be used during therapy and for at least 6 months after the last dose in women of reproductive potential. Fertility may be impaired if administered to males.

Lactation

Avoid

It is not known if niraparib is present in breast milk. Due to the potential for adverse events, breastfeeding is not recommended during therapy and for 1 month after the last dose.

Monitoring

Clinical pearl	CBC with differential (weekly for the first month, then monthly for 11 months, then periodically); pregnancy test (prior to treatment; in females of reproductive potential). Monitor blood pressure and heart rate monthly during the first year and periodically thereafter.

Chemistry & Properties

Formula	C19H20N4O
Molecular weight	320.4 g/mol
IUPAC name	2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide
CAS	1038915-60-4
PubChem CID	24958200
InChIKey	`PCHKPVIQAHNQLW-CQSZACIVSA-N`
logP	2.59 (XLogP 2.2)
Polar surface area	72.94 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.78
Lipinski violations	0

SMILES

NC(=O)c1cccc2cn(-c3ccc([C@@H]4CCCNC4)cc3)nc12

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.197 h
Volume of distribution	3.047 L/kg
Protein binding	84.7%
BBB penetrant	Yes

Receptor binding (top 2)

Target	Action	Affinity
poly(ADP-ribose) polymerase 2 (PARP2)	Inhibitor	pIC50 8.7
poly(ADP-ribose) polymerase 1 (PARP1)	Inhibitor	pIC50 8.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Abciximab	moderate
Abemaciclib	moderate
Acalabrutinib	moderate
Acetylsalicylic acid	moderate
Aflibercept	moderate
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Alpelisib	moderate
Alteplase	moderate
Altretamine	moderate
Amiodarone	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Akeega 100/500mg Film Coated	Film-Coated Tablet Niraparib tosylate monohydrate 159.40 mg, Abiratrone acetate 500 mg	56 tab	Adatco Drug Store	—
Akeega 50/500mg Film Coated Tablets	Film-Coated Tablet Niraparib tosylate monohydrate 79.70 mg, Abiratrone acetate 500 mg	56 tab	Adatco Drug Store	—