Rucaparib (Monograph)

Brand name: Rubraca
Drug class: Antineoplastic Agents
- PARP Inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
Chemical name: 8-Fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one- compd. with 7,7-dimethyl-2-oxo-(1S,4R)-bicyclo[2.2.1]heptane-1-methanesulfonic acid (1:1)
Molecular formula: C₁₉H₁₈FN₃O•C₁₀H₁₆O₄S
CAS number: 1859053-21-6

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).

Uses for Rucaparib

Ovarian Cancer

Used as a single-agent therapy for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy (designated an orphan drug by FDA for this use).

Used as a single-agent therapy for the treatment of adults with deleterious germline and/or somatic BRCA-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer previously treated with 2 or more chemotherapy regimens (designated an orphan drug by FDA for this use). FDA-approved companion diagnostic test required to confirm BRCA-positive status prior to initiation of therapy.

Prostate Cancer

Used as a single-agent therapy for the treatment of adults with deleterious germline or somatic BRCA-mutated metastatic castration-resistant prostate cancer previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Accelerated approval based on objective response rate and duration of response. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies. FDA-approved companion diagnostic test required to confirm BRCA mutation status prior to initiation of therapy.

Rucaparib Dosage and Administration

General

Pretreatment Screening

Confirm presence of deleterious germline and/or somatic BRCA mutation prior to initiation of rucaparib therapy for previously treated advanced ovarian cancer and metastatic castration-resistant prostate cancer. Consult FDA website for list of FDA-approved companion diagnostic tests ([Web]).
Complete blood cell count (CBC).
Pregnancy testing for females of reproductive potential.

Patient Monitoring

CBC monthly during therapy.

Other General Considerations

Tachyphylaxis of nausea symptoms usually occurs during the first cycle of PARP inhibitor therapy, often without antiemetic therapy or dose reduction.
A light meal or snack prior to each dose of a PARP inhibitor may mitigate nausea.
If persistent nausea/vomiting, weight loss >5%, and/or reduction in performance status occurs in the absence of other etiology (e.g., bowel obstruction), ASCO recommends temporarily withholding therapy followed by dosage reduction.

Administration

Oral Administration

Administer orally twice daily without regard to meals.

If a dose is missed or vomited, the next dose should be taken at the regularly scheduled time. Do not replace vomited doses.

Dosage

Available as rucaparib camsylate; dosage expressed in terms of rucaparib.

Adults

Ovarian Cancer

Maintenance Treatment of Recurrent Ovarian Cancer

Oral

600 mg (two 300-mg tablets) twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Previously Treated Advanced BRCA-Mutated Ovarian Cancer

Oral

600 mg (two 300-mg tablets) twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Prostate Cancer

Oral

600 mg (two 300-mg tablets) twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Use with a gonadotropin-releasing hormone (GnRH) analog in patients who have not previously undergone bilateral orchiectomy.

Dosage Modification for Toxicity

If adverse reactions occur, consider interruption of therapy or dosage reduction.

If dosage reduction is necessary, reduce dosage to 500 mg twice daily.

If dosage reduction from 500 mg twice daily is necessary, reduce dosage to 400 mg twice daily.

If further reduction is necessary, reduce dosage to 300 mg twice daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration): Adjustment of initial dosage not necessary.

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN): No specific dosage recommendations at this time.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): Adjustment of initial dosage not necessary.

Severe renal impairment (Cl_cr <30 mL/minute) or dialysis: No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Rucaparib

Contraindications

Manufacturer states none known.

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported rarely in patients receiving rucaparib; some cases were fatal. All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents. The duration of rucaparib therapy in patients who developed MDS/AML ranged from 1–53 months. MDS/AML not observed in patients with metastatic castration-resistant prostate cancer regardless of HRD mutation.

Monitor CBC at baseline and monthly thereafter. Delay initiation of rucaparib until hematologic toxicity caused by previous chemotherapy resolves to grade 1 or less.

If prolonged hematologic toxicity (>4 weeks) occurs, interrupt therapy or administer at a reduced dosage, and monitor CBC counts weekly until recovery to grade 1 or less. If hematologic toxicity persists for >4 weeks following dosage modification or if MDS/AML is suspected, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample. If MDS/AML is confirmed, discontinue rucaparib.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryotoxicity demonstrated in animals.

Avoid pregnancy during therapy. Verify pregnancy status prior to initiating rucaparib therapy. Females of reproductive potential should use effective contraceptive methods while receiving rucaparib and for 6 months after the drug is discontinued. Males with such female partners or partners who are pregnant should use effective contraceptive methods while receiving rucaparib and for 3 months after the drug is discontinued. Males should be advised to refrain from donating sperm while receiving rucaparib and for 3 months after the drug is discontinued. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.

Specific Populations

Pregnancy

May cause fetal harm.

Avoid pregnancy during therapy. Verify pregnancy status prior to initiating rucaparib therapy.

Lactation

Not known whether rucaparib is distributed into milk. Discontinue breast-feeding during therapy and for 2 weeks after drug discontinuance.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety relative to younger patients, but increased sensitivity cannot be ruled out.

Hepatic Impairment

In population pharmacokinetic analyses, pharmacokinetics not altered by mild hepatic impairment; initial dosage adjustment not necessary in such patients.

Limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.

Renal Impairment

Systemic exposure not substantially altered by mild or moderate renal impairment; initial dosage adjustment not necessary in such patients.

Not studied in patients with severe renal impairment or in those receiving dialysis.

Common Adverse Effects

Ovarian cancer (≥20%): Nausea, fatigue/asthenia, vomiting, anemia, dysgeusia, AST/ALT elevation, constipation, decreased appetite, diarrhea, thrombocytopenia, neutropenia, stomatitis, nasopharyngitis/upper respiratory infection, rash, abdominal pain/distention, and dyspnea.

Metastatic castration-resistant prostate cancer (≥20%): Fatigue/asthenia, nausea, anemia, AST/ALT elevation, decreased appetite, rash, constipation, thrombocytopenia, vomiting, and diarrhea.

Drug Interactions

Metabolized principally by CYP2D6 and, to a lesser extent, by CYP isoenzymes 1A2 and 3A4.

Reversible inhibitor of CYP isoenzymes 1A2, 2C19, 2C9, and 3A and, to a lesser extent, CYP isoenzymes 2C8 and 2D6 and UGT1A1. At clinically relevant concentrations, induces CYP1A2 and downregulates CYP isoenzymes 2B6 and 3A4.

Inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, multidrug and toxic compound extrusion (MATE) 1, MATE2K, organic cation transporter (OCT) 1, OCT2, and multidrug resistance protein (MRP) 4. Does not inhibit MRP2, MRP3, or bile salt export pump (BSEP).

Substrate of P-gp and BCRP, but not a substrate of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, 3A, 2C9, or 2C19: Possible increased systemic exposure of substrate drugs and possible toxicity. Adjust dosage of CYP1A2, 3A, 2C9, and 2C19 substrate drugs, if clinically indicated.

Specific Drugs

Drug	Interaction	Comments
Caffeine	CYP1A2 substrate: Possible increased systemic exposure of substrate drug Caffeine: AUC of caffeine increased 2.55-fold	Adjust dosage of caffeine if clinically indicated
Digoxin	P-gp substrate: Possible increased substrate concentrations Digoxin: AUC of digoxin increased 1.20-fold	Adjust dosage of digoxin if clinically indicated
Midazolam	CYP3A4 substrate: Possible increased systemic exposure of substrate drug Midazolam: AUC of midazolam increased 1.38-fold	Adjust dosage of midazolam if clinically indicated
Omeprazole	CYP2C19 substrate: Possible increased systemic exposure of substrate drug Omeprazole: AUC of omeprazole increased 1.55-fold	Adjust dosage of omeprazole if clinically indicated
Proton-pump inhibitors	No clinically meaningful effect on rucaparib exposure
Warfarin	CYP2C9 substrate: Possible increased systemic exposure of substrate drug Warfarin: AUC of warfarin increased by 1.49-fold	Consider more frequent monitoring of INR Adjust dosage of warfarin if clinically indicated

Rucaparib Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are linear, time independent, and dose proportional over a dosage range of 240–840 mg twice daily; mean systemic accumulation is 3.5- to 6.2-fold following repeated administration.

Median time to peak plasma concentrations is 1.9 hours following oral administration.

Mean absolute oral bioavailability is 36%.

Food

Administration with a high-fat meal decreased rate and modestly increased extent of absorption; time to peak plasma concentration delayed by 2.5 hours, and peak plasma concentration and AUC increased by 20 and 38%, respectively.

Special Populations

Mild hepatic impairment does not affect pharmacokinetics of rucaparib.

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment increased AUC by approximately 15 or 32%, respectively.

Effects of severe renal impairment, dialysis, and moderate to severe hepatic impairment on rucaparib pharmacokinetics not established.

Age, body weight, sex, and race do not affect exposure to rucaparib.

Genetic polymorphisms of CYP2D6 (i.e., poor, intermediate, or ultrarapid metabolizer) or CYP1A2 (i.e., hyperinducers) do not substantially affect exposure to rucaparib.

Distribution

Extent

Not known whether rucaparib distributes into milk.

Plasma Protein Binding

70%.

Elimination

Metabolism

Metabolized principally by CYP2D6 and, to a lesser extent, by CYP isoenzymes 1A2 and 3A4.

Oxidation, N-demethylation, N-methylation, and glucuronidation are major metabolic pathways.

Elimination Route

Unchanged drug accounts for 64% of plasma radioactivity.

Eliminated in feces (94.9% of recovered dose) and urine (44.9%).

Half-life

Terminal half-life: 25.9 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

Inhibits mammalian PARP enzymes, including PARP-1, PARP-2, and PARP-3. PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.
Rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, which result in disruption of cellular homeostasis and apoptosis.
PARP inhibitors, including rucaparib, appear to be selective for tumors cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).
Reduces tumor growth of xenograft models of human cancer (with or without deficiencies in BRCA) in mice.

Advice to Patients

Importance of reading the manufacturer's patient information.
If a dose is missed or vomited, importance of taking the next dose at the regularly scheduled time; do not take an extra dose to replace the missed dose.
Risk of MDS and AML. Importance of informing clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), shortness of breath, abnormal CBC counts, or requirement for blood product transfusions occurs.
Importance of hematologic monitoring during rucaparib therapy.
Risk of photosensitivity reactions. Importance of limiting exposure to sunlight and wearing protective clothing and using sunscreen when exposure cannot be avoided.
Risk of fetal harm and pregnancy loss. Necessity of advising females of reproductive potential to avoid pregnancy and to use an effective method of contraception while receiving rucaparib and for 6 months following discontinuance of therapy. Importance of advising males with female partners of reproductive potential or partners who are pregnant to use an effective method of contraception while receiving rucaparib and for 3 months following discontinuance of therapy. Importance of advising males not to donate sperm while receiving rucaparib and for 3 months following discontinuance of therapy. Importance of women informing clinicians immediately if they are pregnant or become pregnant during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Importance of advising women to avoid breast-feeding while receiving rucaparib therapy and for 2 weeks following discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information.

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.

Distribution of rucaparib is restricted. Contact manufacturer or consult the Rubraca Connections website ([Web]) for specific availability information.

Rucaparib Camsylate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	200 mg (of rucaparib)	Rubraca	Clovis Oncology
		250 mg (of rucaparib)	Rubraca	Clovis Oncology
		300 mg (of rucaparib)	Rubraca	Clovis Oncology