Rubraca
(rucaparib)Dosage & Administration
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Rubraca Prescribing Information
Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer
Rubraca is indicated for the maintenance treatment of adult patients with a deleterious BRCAmutation (germline and/or somatic)- associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
BRCA-mutated Metastatic Castration-Resistant Prostate Cancer
Rubraca is indicated for the treatment of adult patients with a deleterious BRCAmutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration ( 2.1)].
This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies ( 14.2)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Patient Selection
Maintenance Treatment ofBRCA-mutated Recurrent Ovarian Cancer
Select patients for the maintenance treatment of recurrent ovarian cancer with Rubraca based on the presence of a deleterious BRCAmutation (germline and/or somatic) [ see Clinical Studies ( 14.1) ].
An FDA-approved test for the detection of deleterious germline and/or somatic BRCAmutations is not currently available.
Treatment ofBRCA-mutated mCRPC after Androgen Receptor-directed Therapy and Chemotherapy
Select patients for the treatment of mCRPC with Rubraca based on the presence of a deleterious BRCAmutation (germline and/or somatic) in plasma specimens [see Clinical Studies ( 14.2)]. A negative result from a plasma specimen does not mean that the patient's tumor is negative for BRCAmutations. Should the plasma specimen have a negative result, consider performing further genomic testing using tumor specimens as clinically indicated.
Information on the FDA-approved tests for the detection of a BRCAmutation in patients with ovarian cancer or with prostate cancer is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dose
The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for a total daily dose of 1,200 mg.
Continue treatment until disease progression or unacceptable toxicity.
If a patient misses a dose of Rubraca, instruct the patient to take the next dose at its scheduled time. Vomited doses should not be replaced.
Patients receiving Rubraca for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.
Dose Modifications for Adverse Reactions
To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended Rubraca dose modifications for adverse reactions are indicated in Table 1.
| Dose Reduction | Dose |
| Starting Dose | 600 mg twice daily (two 300 mg tablets) |
| First Dose Reduction | 500 mg twice daily (two 250 mg tablets) |
| Second Dose Reduction | 400 mg twice daily (two 200 mg tablets) |
| Third Dose Reduction | 300 mg twice daily (one 300 mg tablet) |
- Tablets (200 mg): blue, round, immediate-release, film-coated, debossed with “C2”.
- Tablets (250 mg): white, diamond, immediate-release, film-coated, debossed with “C25”.
- Tablets (300 mg): yellow, oval, immediate-release, film-coated, debossed with “C3”.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, Rubraca can cause fetal harm when administered to pregnant women. There are no available data in pregnant women to inform the drug-associated risk. In an animal reproduction study, administration of rucaparib to pregnant rats during organogenesis resulted in embryo-fetal death at maternal exposures that were 0.04 times the AUC 0-24hin patients receiving the recommended dose of 600 mg twice daily [see Data]. Apprise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In a dose range-finding embryo-fetal development study, pregnant rats received oral doses of 50, 150, 500, or 1000 mg/kg/day of rucaparib during the period of organogenesis. Post-implantation loss (100% early resorptions) was observed in all animals at doses greater than or equal to 50 mg/kg/day (with maternal systemic exposures approximately 0.04 times the human exposure at the recommended dose based on AUC 0-24h).
Lactation
Risk Summary
There is no information regarding the presence of rucaparib in human milk, or on its effects on milk production or the breast-fed child. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks following the last dose.
Females and Males of Reproductive Potential
Rubraca can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating Rubraca.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1)] .
Males
Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective methods of contraception during treatment and for 3 months following last dose of Rubraca. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1) and Nonclinical Toxicology ( 13.1)].
Pediatric Use
The safety and effectiveness of Rubraca in pediatric patients have not been established.
Geriatric Use
Of the 937 patients with ovarian cancer who received Rubraca in clinical trials including ARIEL3, 41% were age 65 or older and 10% were 75 years or older. No major differences in safety were observed between younger and older patients with ovarian cancer.
Of the 209 patients with mCRPC who received Rubraca in TRITON2, 77% were age 65 or older and 33% were 75 years or older. No major differences in safety were observed between younger and older patients with mCRPC.
Renal Impairment
No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method) [see Clinical Pharmacology ( 12.3)]. Rubraca has not been studied in patients with CLcr < 30 mL/min or patients on dialysis.
Hepatic Impairment
No dosage modification is recommended for patients with mild to moderate hepatic impairment (total bilirubin ≤ 3 x upper limit of normal [ULN] or AST > ULN) [see Clinical Pharmacology ( 12.3)] . Rubraca has not been studied in patients with severe hepatic impairment (total bilirubin > 3 x ULN and any AST).
None.
Myelodysplastic Syndrome/Acute Myeloid Leukemia
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1594 treated patients with ovarian cancer [see Adverse Reactions ( 6.1)] , MDS/AML occurred in 32 patients (2%), including those in long term follow-up. Of these, 14 occurred during treatment or during the 28-day safety follow-up (0.9%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from < 2 months to approximately 72 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents.
In ARIEL3, of patients with a germline and/or somatic BRCAmutation treated with Rubraca, MDS/AML occurred in 9 out of 129 (7%) patients treated with Rubraca and 4 out of 66 (6%) patients treated with placebo. The duration of therapy with Rubraca in patients who developed secondary MDS/cancer therapy-related AML varied from 1.2 to 4.7 years.
In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation [see Adverse Reactions ( 6.1)].
Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose according to Table 1[see Dosage and Administration ( 2.3)] and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.
Embryo-Fetal Toxicity
Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC 0-24hin patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)].
Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Rubraca [see Use in Specific Populations ( 8.1, 8.3)].