ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]. Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]. Most common adverse reactions (>= 20%) among patients with ovarian cancer were nausea, fatigue (including asthenia), vomiting, anemia, dysgeusia, AST/ALT elevation, constipation, decreased appetite, diarrhea, thrombocytopenia, neutropenia, stomatitis, nasopharyngitis/URI, rash, abdominal pain/distention, and dyspnea. (6.1)Most common adverse reactions (>= 20%) among patients with BRCA-mutated mCRPC were fatigue (including asthenia), nausea, anemia, ALT/AST increased, decreased appetite, rash, constipation, thrombocytopenia, vomiting, diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Clovis Oncology, Inc. at 1-844-258-7662 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (>= 20%) among patients with ovarian cancer were nausea, fatigue (including asthenia), vomiting, anemia, dysgeusia, AST/ALT elevation, constipation, decreased appetite, diarrhea, thrombocytopenia, neutropenia, stomatitis, nasopharyngitis/URI, rash, abdominal pain/distention, and dyspnea. (6.1). Most common adverse reactions (>= 20%) among patients with BRCA-mutated mCRPC were fatigue (including asthenia), nausea, anemia, ALT/AST increased, decreased appetite, rash, constipation, thrombocytopenia, vomiting, diarrhea. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population in the WARNINGS AND PRECAUTIONS section reflect exposure to Rubraca at 600 mg BID in 1146 patients in Study10 (CO-338-010), ARIEL2, ARIEL3, and TRITON2.. Maintenance Treatment of Recurrent Ovarian CancerThe safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, randomized (2:1), double-blind, placebo-controlled study in which 561 patients received either Rubraca 600 mg BID (n=372) or placebo (n=189) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.3 months (range: 1 month to 35 months) for patients who received Rubraca and 5.5 months for patients who received placebo.Dose interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving Rubraca and 10% of those receiving placebo; dose reductions due to an adverse reaction occurred in 55% of Rubraca patients and 4% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and fatigue/asthenia (13%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 2% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were anemia (3%), thrombocytopenia (3%) and nausea (3%). Table describes the adverse reactions occurring in >=20% of patients; while Table describes the laboratory abnormalities occurring in >=25% of patients occurring in ARIEL3.Table 2. Adverse Reactions in ARIEL3 Occurring in >= 20% of Patientsa National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)b Consists of grouped related terms that reflect the medical concept of the adverse reactionAdverse reactionsRubracaN=372PlaceboN=189Gradesa1-4%Grades 3-4%Gradesa1-4%Grades 3-4%Gastrointestinal DisordersNausea764360.5Abdominal pain/distentionb 463390.5Constipation372241Vomiting374151Diarrhea320.5221Stomatitisb 281140.5General Disorders and Administration Site ConditionsFatigue/asthenia737463Skin and Subcutaneous Tissue DisordersRashb 431230Nervous System DisordersDysgeusia40070InvestigationsAST/ALT elevation381140Blood and Lymphatic System DisordersAnemia392150.5Thrombocytopenia29530Neutropenia20851Respiratory, Thoracic, and Mediastinal DisordersNasopharyngitis/Upper respiratory tract infectionb 290.3181Metabolism and Nutrition DisordersDecreased appetite231140Adverse reactions occurring 20% of patients treated with Rubraca include headache (18%), dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%), peripheral edema (11%), and depression (11%).Table 3. Laboratory Abnormalities in ARIEL3 Occurring in >= 25% of Patientsa Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Laboratory ParameteraRubracaN=372PlaceboN=189Grade 1-4%Grade 3-4%Grade 1-4%Grade 3-4%ChemistryIncrease in creatinine980.3900Increase in cholesterol844780Increase in ALT73740Increase in AST61140Increase in Alkaline Phosphatase370.3100HematologyDecrease in hemoglobin8813561Decrease in platelets44290Decrease in leukocytes443290Decrease in neutrophils386223Decrease in lymphocytes295203. Treatment ofBRCA-mutated Recurrent Ovarian Cancer After or More ChemotherapiesRubraca 600 mg twice daily as monotherapy has also been studied in 377 patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have progressed after or more prior chemotherapies in two open-label, single arm trials. In these patients, the median age was 62 years (range: 31 to 86), 100% had an ECOG performance status of or 1, 38% had BRCA-mutated ovarian cancer, 45% had received or more prior lines of chemotherapy, and the median time since ovarian cancer diagnosis was 43 months (range: to 197). Table describes the adverse reactions occurring in >=20% of patients; while Table describes the laboratory abnormalities occurring in >=35% of patients occurring in ARIEL2.Table 4. Adverse Reactions Reported in >= 20% of Patients with Ovarian Cancer After >= Chemotherapies Treated with Rubraca in Study 10 and ARIEL2National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)Adverse ReactionAll Ovarian Cancer Patients(N 377)Gradesa1-4(%)Grades 3-4(%)Gastrointestinal DisordersNausea775Vomiting464Constipation402Diarrhea342Abdominal Pain323General DisordersAsthenia/Fatigue7711Blood and Lymphatic System DisordersAnemia4425Thrombocytopenia215Nervous System DisordersDysgeusia390.3Metabolism and Nutrition DisordersDecreased appetite393Respiratory, Thoracic, and Mediastinal DisordersDyspnea210.5The following adverse reactions have been identified in 20% of the 377 patients treated with Rubraca 600 mg twice daily: dizziness (17%), neutropenia (15%), rash (includes rash, rash erythematous, rash maculopapular and dermatitis) (13%), pyrexia (11%), photosensitivity reaction (10%), pruritus (includes pruritus and pruritus generalized) (9%), hypersensitivity (includes flushing, wheezing, eyelid edema, drug hypersensitivity, face edema, swelling face) (4%), palmar-plantar erythrodysaesthesia syndrome (2%), and febrile neutropenia (1%).Table 5. Laboratory Abnormalities Reported in >= 35% of Patients with Ovarian Cancer After >= Chemotherapies Treated with Rubraca in Study 10 and ARIEL2a At least one worsening shift in CTCAE grade and by maximum shift from baseline.b Increase in ALT/AST led to treatment discontinuation in 0.3% of patients (1/377).Laboratory ParameterAll Patients with Ovarian Cancer(N 377)Grade 1-4a(%)Grade 3-4(%)Clinical ChemistryIncrease in creatinine921Increase in ALTb 7413Increase in ASTb 735Increase in cholesterol402HematologicDecrease in hemoglobin6723Decrease in lymphocytes457Decrease in platelets396Decrease in absolute neutrophil count3510. Treatment ofBRCA-mutated mCRPC after Androgen Receptor-directed Therapy and ChemotherapyThe safety of Rubraca 600 mg twice daily was evaluated in single arm trial (TRITON2) [see Clinical Studies (14.2)]. TRITON2 enrolled 209 patients with HRD-positive mCRPC, including 115 with BRCA-mutated mCRPC. Among the patients with BRCA-mutated mCRPC, the median duration of Rubraca treatment was 6.5 months (range 0.5 to 26.7).There were (1.7%) patients with adverse reactions leading to death, one each attributed to acute respiratory distress syndrome and pneumonia.Dose interruptions due to an adverse reaction occurred in 57% of patients receiving Rubraca. Adverse reactions requiring dose interruption in >3% of patients included anemia, thrombocytopenia, asthenia/fatigue, nausea, vomiting, neutropenia, ALT/AST increased, creatinine increased, decreased appetite, acute kidney injury, and hypophosphatemia.Dose reductions due to an adverse reaction occurred in 41% of patients receiving Rubraca. Adverse reactions requiring dose reduction in >3% of patients were anemia (14%), asthenia/fatigue (10%), thrombocytopenia (7%), nausea (6%), decreased appetite (4%), and rash (3%).Discontinuation due to adverse reactions occurred in 8% of patients receiving Rubraca. None of the adverse reactions leading to discontinuation of Rubraca (ECG QT prolonged, acute respiratory distress syndrome, anemia, balance disorder, cardiac failure, decreased appetite/fatigue/weight decreased, leukopenia/neutropenia, ALT/AST increased, and pneumonia) occurred in more than one patient (<1%).Tables and summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA-mutated mCRPC in TRITON2.Table 6. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated mCRPC in TRITON2a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)b Includes platelet count decreasedc Includes blister, blood blister, dermatitis, dermatitis contact, eczema, genital rash, palmar-plantar erythrodysaesthesia syndrome, photosensitivity reaction, psoriasis, rash, rash maculo-papular, rash pruritic, skin exfoliation, skin lesion, urticariaAdverse ReactionRubracaN 115Gradesa1-4(%)Grades 3-4(%)General disorders and administration site conditions Asthenia/Fatigue629Gastrointestinal disorders Nausea523 Constipation271 Vomiting221 Diarrhea200Blood and lymphatic system disorders Anemia4325 Thrombocytopeniab 2510Metabolism and nutrition disorders Decreased appetite282Skin and subcutaneous tissue disorders Rashc 272Investigations ALT/AST increased335Other clinically relevant adverse reactions that occurred in less than 20% of patients included dyspnea, dizziness, bleeding, urinary tract infection, dysgeusia, dyspepsia, hypersensitivity (including flushing, asthma, choking sensation, periorbital swelling, swelling face, and wheezing), pneumonia, sepsis, ischemic cardiovascular events, renal failure, and venous thromboembolism.Table 7. Laboratory Abnormalities in >= 35% (Grades 1-4) and >= 2% (Grades 3-4) Worsening from Baseline in Patients with BRCA-mutated mCRPC in TRITON2a Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available for 111 to 115 patients.b NCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03c Grade 3-4 ALT or AST elevation led to drug interruption in patients, of which had dose reduction upon rechallenge.Laboratory ParameterRubraca = 115aGrade 1-4b(%)Grade 3-4(%)Clinical ChemistryIncrease in ALTc 695Decrease in phosphate6815Increase in alkaline phosphatase442Increase in creatinine432Increase in triglycerides425Decrease in sodium383 HematologicDecrease in leukocytes695Decrease in absolute neutrophil count6210Decrease in hemoglobin5925Decrease in lymphocytes4217Decrease in platelets4010.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with rucaparib.Rucaparib was clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. The clastogenic response in mitotically-stimulated cells was anticipated based on the mechanism of action of rucaparib and indicates potential genotoxicity in humans. Rucaparib was not mutagenic in bacterial reverse mutation (Ames) test.Fertility studies with rucaparib have not been conducted. In 3-month repeat-dose general toxicology studies, rucaparib had no effects on male and female reproductive organs at doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively. These dose levels resulted in systemic exposures of approximately 0.3 and 0.09 times the human exposure (AUC0-24h), respectively, at the recommended dose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced cytotoxicity and anti-tumor activity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.. 12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of rucaparib has not fully been characterized.. Cardiac ElectrophysiologyA positive concentration-QTc relationship was observed in patients who were administered continuous dosages of Rubraca ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean (90% confidence interval [CI]) QTcF increase from baseline at steady state of Rubraca 600 mg twice daily was 14.9 msec (11.1, 18.7 msec).. 12.3 Pharmacokinetics. The AUC and Cmax of rucaparib demonstrated linear pharmacokinetics over dose range from 240 mg to 840 mg twice daily (0.4 times to 1.4 times the approved recommended dosage). The mean (coefficient of variation [CV]) steady-state rucaparib Cmax is 1,940 ng/mL (54%) and AUC0-12h is 16,900 h.ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold.. AbsorptionThe median Tmax (min, max) at the steady state is 1.9 hours (0, 5.98) at the approved recommended dosage. The mean (min, max) absolute bioavailability is 36% (30%, 45%).. Effect of FoodFollowing high-fat meal (approximately 800-1000 calories, including approximately 250 calories from carbohydrates, approximately 500-600 calories from fat, approximately 150 calories from protein), the Cmax was increased by 20%, AUC0-24h was increased by 38%, and the Tmax was delayed by 2.5 hours, as compared to fasted conditions [see Dosage and Administration (2.2)].. DistributionThe mean apparent volume of distribution is 2300 (21%).Rucaparib is 70% bound to human plasma proteins in vitro. Rucaparib preferentially distributed to red blood cells with blood-to-plasma concentration ratio of 1.8.. EliminationThe mean apparent total clearance at steady state is 44.2 L/h (45%) and the mean terminal elimination half-life is 26 (39%) hours.. MetabolismIn vitro, rucaparib is primarily metabolized by CYP2D6 and to lesser extent by CYP1A2 and CYP3A4. In addition to CYP-based oxidation, rucaparib also undergoes N-demethylation, N-methylation, and glucuronidation.. ExcretionFollowing single oral dose of radiolabeled rucaparib, unchanged rucaparib accounted for 64% of the radioactivity. Rucaparib accounted for 45% and 95% of radioactivity in urine and feces, respectively.. Specific PopulationsAge (20 to 86 years), race (White, Black, and Asian), sex, body weight (41 to 171 kg), mild to moderate renal impairment (CLcr >= 30 mL/min), mild hepatic impairment (total bilirubin ULN and AST ULN or total bilirubin to 1.5 ULN and any AST), and CYP2D6 or CYP1A2 genotype polymorphisms did not have clinically meaningful effect on the pharmacokinetics of rucaparib. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr 15 mL/min), or severe hepatic impairment (total bilirubin 3 ULN and any AST) has not been studied.. Hepatic ImpairmentModerate hepatic impairment (total bilirubin 1.5 to x ULN and any AST) increased rucaparib AUC by 45%, but had no effect on Cmax compared to patients with normal hepatic function.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Other Drugs on RucaparibConcomitant administration of Rubraca with proton pump inhibitor had no clinically meaningful effect on steady-state concentrations of rucaparib.. Effect of Rucaparib on Other DrugsConcomitant administration of Rubraca with rosuvastatin (BCRP substrate) had no clinically meaningful effect on the concentrations of rosuvastatin.Coadministration of Rubraca with the following substrates increased the Cmax of each coadministered substrate by <= 1.1-fold and increased the AUC of each substrate as follows:Caffeine (CYP1A2): by 2.6-foldMidazolam (CYP3A4): by 1.4-foldWarfarin (CYP2C9): by 1.5-foldOmeprazole (CYP2C19): by 1.6-foldDigoxin (P-glycoprotein): by 1.2-foldConcomitant administration of Rubraca with an oral contraceptive containing ethinylestradiol and levonorgestrel (CYP3A substrates): increased ethinylestradiol AUC by 1.4-fold and lenovorgestrel AUC by 1.6-fold, but did not have clinically meaningful effect on their Cmax.. Caffeine (CYP1A2): by 2.6-fold. Midazolam (CYP3A4): by 1.4-fold. Warfarin (CYP2C9): by 1.5-fold. Omeprazole (CYP2C19): by 1.6-fold. Digoxin (P-glycoprotein): by 1.2-fold. In Vitro StudiesCytochrome P450 (CYP) Enzymes: Rucaparib inhibited CYP2C8 and CYP2D6 and induced CYP1A2.UDP-glucuronosyltransferase (UGT) Enzymes: Rucaparib inhibited UGT1A1.Transporter Systems: Rucaparib is substrate of P-gp and BCRP. Rucaparib is not substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.Rucaparib inhibited OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT1, OCT2, and MRP4. Rucaparib did not inhibit MRP2, MRP3, or BSEP.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ovarian Cancer. Maintenance Treatment of Recurrent Ovarian CancerThe efficacy of Rubraca was investigated in ARIEL3 (NCT01968213), double-blind, multicenter clinical trial in which 564 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were in response to platinum-based chemotherapy were randomized (2:1) to receive Rubraca tablets 600 mg orally twice daily (n=375) or placebo (n=189). Treatment was continued until disease progression or unacceptable toxicity. All patients had achieved response (complete or partial) to their most recent platinum-based chemotherapy. Randomization was stratified by best response to last platinum (complete or partial), time to progression following the penultimate platinum therapy (6 to <= 12 months and 12 months), and tumor biomarker status. The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1).The median age was 61 years (range: 39 to 84) for patients receiving Rubraca and 62 years (range: 36 to 85) for those on placebo; the majority were White (80%); and 100% had an ECOG performance status of or 1. All patients had received at least two prior platinum-based chemotherapies (range: to 7). total of 34% of patients were in complete response (CR) to their most recent therapy. The progression-free interval to penultimate platinum was 6-12 months in 40% of patients and 12 months in 60%. Prior bevacizumab therapy was reported for 22% of patients who received Rubraca and 23% of patients who received placebo. Measurable disease was present at baseline in 37% of patients.Tumor tissue samples were tested using clinical trial assay (CTA) (N=564), and the FoundationFocus(TM) CDx BRCA LOH test (n=518). Of the samples evaluated with both tests, homologous recombination deficiency (HRD) positive status (as defined by the presence of deleterious BRCA mutation or high genomic loss of heterozygosity) was confirmed by the FoundationFocus(TM) CDx BRCA LOH test for 94% (313/332) of HRD-positive patients determined by the CTA; and of these, tumor BRCA (tBRCA) mutant status was confirmed by the FoundationFocus(TM) CDx BRCA LOH test for 99% (177/178) of tBRCA-positive patients determined by the CTA. Blood samples for 94% (186/196) of the tBRCA patients were evaluated using central blood germline BRCA test. Based on these results, 70% (130/186) of the tBRCA patients had germline BRCA mutation and 30% (56/186) had somatic BRCA mutation.ARIEL3 demonstrated statistically significant improvement in PFS for patients randomized to Rubraca as compared with placebo in all patients, and in the HRD and tBRCA subgroups. Results from blinded independent radiology review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (with 22% of events).Efficacy results are summarized in Table and Figures 1, 2, and 3.Table 8. Efficacy Results ARIEL3 (Investigator Assessment)All randomized patients.HRD includes all patients with deleterious germline or somatic BRCA mutation or high genomic loss of heterozygosity, as determined by the CTA.tBRCA includes all patients with deleterious germline or somatic BRCA mutation, as determined by the CTA.RubracaPlaceboAll PatientsaPatients, N375189PFS events, (%)234 (62%)167 (88%)PFS, median in months10.85.4HR (95% CI)0.36 (0.30, 0.45)p-value< 0.0001HRD GroupbPatients, N236118PFS events, (%)134 (57%)101 (86%)PFS, median in months13.65.4HR (95% CI)0.32 (0.24, 0.42)p-value< 0.0001tBRCAGroupcPatients, N13066PFS events, (%)67 (52%)56 (85%)PFS, median in months16.65.4HR (95% CI)0.23 (0.16, 0.34)p-value< 0.0001Figure 1. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: All PatientsFigure 2. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: HRD GroupFigure 3. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: tBRCA Group. Figure 1. Figure 2. Figure 3. Treatment of BRCA-mutated Ovarian Cancer After or More ChemotherapiesThe efficacy of Rubraca was investigated in 106 patients in two multicenter, single-arm, open-label clinical trials, Study 10 (NCT01482715) and ARIEL2 (NCT01891344), in patients with advanced BRCA-mutant ovarian cancer who had progressed after or more prior chemotherapies. All 106 patients received Rubraca 600 mg orally twice daily as monotherapy until disease progression or unacceptable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator and IRR according to RECIST v1.1.The median age of the patients was 59 years (range: 33 to 84), the majority were White (78%), and 100% had an ECOG performance status of or 1. All patients had received at least two prior platinum-based chemotherapies and 43% had received or more prior lines of platinum-based chemotherapy. There were 18/106 patients (17%) who had deleterious BRCA mutations detected in tumor tissue and not in whole blood specimens. Tumor BRCA mutation status was verified retrospectively in 96% (64/67) of the patients for whom tumor tissue sample was available by the companion diagnostic FoundationFocus(TM) CDxBRCA test, which is FDA approved for selection of patients for Rubraca treatment.Efficacy results are summarized in Table 9.Table 9. Overall Response and Duration of Response in Patients with BRCA-mutant Ovarian Cancer Who Received or More Chemotherapies in Study 10 and ARIEL2Investigator-assessedN=106Objective Response Rate (95% CI)54% (44, 64)Complete Response9%Partial Response45%Median DOR in months (95% CI)9.2 (6.6, 11.6)Response assessment by independent radiology review was 42% (95% CI [32, 52]), with median DOR of 6.7 months (95% CI [5.5, 11.1]). Investigator-assessed ORR was 66% (52/79; 95% CI [54, 76]) in platinum-sensitive patients, 25% (5/20; 95% CI [9, 49]) in platinum-resistant patients, and 0% (0/7; 95% CI [0, 41]) in platinum-refractory patients. ORR was similar for patients with BRCA1 gene mutation or BRCA2 gene mutation.. 14.2 Metastatic Castration-Resistant Prostate Cancer with BRCA mutations. The efficacy of Rubraca was investigated in TRITON2 (NCT02952534), an ongoing multi-center, single arm clinical trial in patients with BRCA-mutated mCRPC who had been treated with androgen receptor-directed therapy and taxane-based chemotherapy. There were 115 patients with either germline or somatic BRCA mutations enrolled in TRITON2, of whom 62 patients had measurable disease at baseline by independent radiology review (IRR). Patients received Rubraca 600 mg orally twice daily until disease progression or unacceptable toxicity. Patients also received concomitant GnRH analog or had prior bilateral orchiectomy. Objective response rate (ORR) and duration of response (DOR) were assessed in patients with measurable disease by blinded IRR and by the investigator according to modified RECIST v1.1/ Prostate Cancer Working Group (PCWG3) criteria.For the 62 patients with measurable disease at baseline, the median age was 73 years (range 52 to 88); the majority were White (73%) and 10% were Black; and 98% of patients had an ECOG performance status of or 1. All patients had received at least one prior androgen receptor-directed therapy, 34% had received prior androgen receptor-directed therapies and 2% had received prior androgen receptor-directed therapies, and all patients also received prior taxane chemotherapy. Eighteen percent of patients had lung and 21% had liver metastases at baseline. Twenty-four percent had metastases to lymph nodes alone. Forty percent had 10 or more bone lesions at baseline.All 62 patients had deleterious somatic or germline BRCA mutation detected from either central plasma (26%), central tissue (32%), or local (42%) testing. Of the 62 patients, 66% had somatic BRCA mutation, 34% had germline BRCA mutation, 85% had BRCA2 mutation, and 15% had BRCA1 mutation.The major efficacy outcomes of the study were confirmed ORR by IRR using modified RECIST v1.1/PCWG3 criteria and DOR. Efficacy results of TRITON2 are provided in Table 10. The ORR by IRR was similar in patients with germline versus somatic BRCA mutation.Table 10. Efficacy Results in Patients with BRCA-mutated mCRPC TRITON2 (IRR-assessed)NE not evaluablea Defined per modified RECIST v1.1 criteria and with no confirmed bone progression per PCWG3.b The range for the DOR was 1.7-24+ months. Fifteen of the 27 (56%) patients with confirmed objective response had DOR of >= months.Rubraca(N 62)Confirmed Objective Response Rate (95% CI)a 44% (31, 57)Median DOR in months (95% CI)b NE (6.4, NE).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population in the WARNINGS AND PRECAUTIONS section reflect exposure to Rubraca at 600 mg BID in 1146 patients in Study10 (CO-338-010), ARIEL2, ARIEL3, and TRITON2.. Maintenance Treatment of Recurrent Ovarian CancerThe safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, randomized (2:1), double-blind, placebo-controlled study in which 561 patients received either Rubraca 600 mg BID (n=372) or placebo (n=189) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.3 months (range: 1 month to 35 months) for patients who received Rubraca and 5.5 months for patients who received placebo.Dose interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving Rubraca and 10% of those receiving placebo; dose reductions due to an adverse reaction occurred in 55% of Rubraca patients and 4% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (18%), anemia (17%), nausea (15%), and fatigue/asthenia (13%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 2% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were anemia (3%), thrombocytopenia (3%) and nausea (3%). Table describes the adverse reactions occurring in >=20% of patients; while Table describes the laboratory abnormalities occurring in >=25% of patients occurring in ARIEL3.Table 2. Adverse Reactions in ARIEL3 Occurring in >= 20% of Patientsa National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)b Consists of grouped related terms that reflect the medical concept of the adverse reactionAdverse reactionsRubracaN=372PlaceboN=189Gradesa1-4%Grades 3-4%Gradesa1-4%Grades 3-4%Gastrointestinal DisordersNausea764360.5Abdominal pain/distentionb 463390.5Constipation372241Vomiting374151Diarrhea320.5221Stomatitisb 281140.5General Disorders and Administration Site ConditionsFatigue/asthenia737463Skin and Subcutaneous Tissue DisordersRashb 431230Nervous System DisordersDysgeusia40070InvestigationsAST/ALT elevation381140Blood and Lymphatic System DisordersAnemia392150.5Thrombocytopenia29530Neutropenia20851Respiratory, Thoracic, and Mediastinal DisordersNasopharyngitis/Upper respiratory tract infectionb 290.3181Metabolism and Nutrition DisordersDecreased appetite231140Adverse reactions occurring 20% of patients treated with Rubraca include headache (18%), dizziness (19%), dyspepsia (19%), insomnia (15%), dyspnea (17%), pyrexia (13%), peripheral edema (11%), and depression (11%).Table 3. Laboratory Abnormalities in ARIEL3 Occurring in >= 25% of Patientsa Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.Laboratory ParameteraRubracaN=372PlaceboN=189Grade 1-4%Grade 3-4%Grade 1-4%Grade 3-4%ChemistryIncrease in creatinine980.3900Increase in cholesterol844780Increase in ALT73740Increase in AST61140Increase in Alkaline Phosphatase370.3100HematologyDecrease in hemoglobin8813561Decrease in platelets44290Decrease in leukocytes443290Decrease in neutrophils386223Decrease in lymphocytes295203. Treatment ofBRCA-mutated Recurrent Ovarian Cancer After or More ChemotherapiesRubraca 600 mg twice daily as monotherapy has also been studied in 377 patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have progressed after or more prior chemotherapies in two open-label, single arm trials. In these patients, the median age was 62 years (range: 31 to 86), 100% had an ECOG performance status of or 1, 38% had BRCA-mutated ovarian cancer, 45% had received or more prior lines of chemotherapy, and the median time since ovarian cancer diagnosis was 43 months (range: to 197). Table describes the adverse reactions occurring in >=20% of patients; while Table describes the laboratory abnormalities occurring in >=35% of patients occurring in ARIEL2.Table 4. Adverse Reactions Reported in >= 20% of Patients with Ovarian Cancer After >= Chemotherapies Treated with Rubraca in Study 10 and ARIEL2National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)Adverse ReactionAll Ovarian Cancer Patients(N 377)Gradesa1-4(%)Grades 3-4(%)Gastrointestinal DisordersNausea775Vomiting464Constipation402Diarrhea342Abdominal Pain323General DisordersAsthenia/Fatigue7711Blood and Lymphatic System DisordersAnemia4425Thrombocytopenia215Nervous System DisordersDysgeusia390.3Metabolism and Nutrition DisordersDecreased appetite393Respiratory, Thoracic, and Mediastinal DisordersDyspnea210.5The following adverse reactions have been identified in 20% of the 377 patients treated with Rubraca 600 mg twice daily: dizziness (17%), neutropenia (15%), rash (includes rash, rash erythematous, rash maculopapular and dermatitis) (13%), pyrexia (11%), photosensitivity reaction (10%), pruritus (includes pruritus and pruritus generalized) (9%), hypersensitivity (includes flushing, wheezing, eyelid edema, drug hypersensitivity, face edema, swelling face) (4%), palmar-plantar erythrodysaesthesia syndrome (2%), and febrile neutropenia (1%).Table 5. Laboratory Abnormalities Reported in >= 35% of Patients with Ovarian Cancer After >= Chemotherapies Treated with Rubraca in Study 10 and ARIEL2a At least one worsening shift in CTCAE grade and by maximum shift from baseline.b Increase in ALT/AST led to treatment discontinuation in 0.3% of patients (1/377).Laboratory ParameterAll Patients with Ovarian Cancer(N 377)Grade 1-4a(%)Grade 3-4(%)Clinical ChemistryIncrease in creatinine921Increase in ALTb 7413Increase in ASTb 735Increase in cholesterol402HematologicDecrease in hemoglobin6723Decrease in lymphocytes457Decrease in platelets396Decrease in absolute neutrophil count3510. Treatment ofBRCA-mutated mCRPC after Androgen Receptor-directed Therapy and ChemotherapyThe safety of Rubraca 600 mg twice daily was evaluated in single arm trial (TRITON2) [see Clinical Studies (14.2)]. TRITON2 enrolled 209 patients with HRD-positive mCRPC, including 115 with BRCA-mutated mCRPC. Among the patients with BRCA-mutated mCRPC, the median duration of Rubraca treatment was 6.5 months (range 0.5 to 26.7).There were (1.7%) patients with adverse reactions leading to death, one each attributed to acute respiratory distress syndrome and pneumonia.Dose interruptions due to an adverse reaction occurred in 57% of patients receiving Rubraca. Adverse reactions requiring dose interruption in >3% of patients included anemia, thrombocytopenia, asthenia/fatigue, nausea, vomiting, neutropenia, ALT/AST increased, creatinine increased, decreased appetite, acute kidney injury, and hypophosphatemia.Dose reductions due to an adverse reaction occurred in 41% of patients receiving Rubraca. Adverse reactions requiring dose reduction in >3% of patients were anemia (14%), asthenia/fatigue (10%), thrombocytopenia (7%), nausea (6%), decreased appetite (4%), and rash (3%).Discontinuation due to adverse reactions occurred in 8% of patients receiving Rubraca. None of the adverse reactions leading to discontinuation of Rubraca (ECG QT prolonged, acute respiratory distress syndrome, anemia, balance disorder, cardiac failure, decreased appetite/fatigue/weight decreased, leukopenia/neutropenia, ALT/AST increased, and pneumonia) occurred in more than one patient (<1%).Tables and summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA-mutated mCRPC in TRITON2.Table 6. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated mCRPC in TRITON2a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03)b Includes platelet count decreasedc Includes blister, blood blister, dermatitis, dermatitis contact, eczema, genital rash, palmar-plantar erythrodysaesthesia syndrome, photosensitivity reaction, psoriasis, rash, rash maculo-papular, rash pruritic, skin exfoliation, skin lesion, urticariaAdverse ReactionRubracaN 115Gradesa1-4(%)Grades 3-4(%)General disorders and administration site conditions Asthenia/Fatigue629Gastrointestinal disorders Nausea523 Constipation271 Vomiting221 Diarrhea200Blood and lymphatic system disorders Anemia4325 Thrombocytopeniab 2510Metabolism and nutrition disorders Decreased appetite282Skin and subcutaneous tissue disorders Rashc 272Investigations ALT/AST increased335Other clinically relevant adverse reactions that occurred in less than 20% of patients included dyspnea, dizziness, bleeding, urinary tract infection, dysgeusia, dyspepsia, hypersensitivity (including flushing, asthma, choking sensation, periorbital swelling, swelling face, and wheezing), pneumonia, sepsis, ischemic cardiovascular events, renal failure, and venous thromboembolism.Table 7. Laboratory Abnormalities in >= 35% (Grades 1-4) and >= 2% (Grades 3-4) Worsening from Baseline in Patients with BRCA-mutated mCRPC in TRITON2a Denominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available for 111 to 115 patients.b NCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03c Grade 3-4 ALT or AST elevation led to drug interruption in patients, of which had dose reduction upon rechallenge.Laboratory ParameterRubraca = 115aGrade 1-4b(%)Grade 3-4(%)Clinical ChemistryIncrease in ALTc 695Decrease in phosphate6815Increase in alkaline phosphatase442Increase in creatinine432Increase in triglycerides425Decrease in sodium383 HematologicDecrease in leukocytes695Decrease in absolute neutrophil count6210Decrease in hemoglobin5925Decrease in lymphocytes4217Decrease in platelets4010.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Rucaparib is an inhibitor of the mammalian polyadenosine 5-diphosphoribose polymerase (PARP) enzyme. The chemical name is 8-fluoro-2-4-[(methylamino)methyl]phenyl-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt. The chemical formula of rucaparib camsylate is C19H18FN3OoC10H16O4S and the relative molecular mass is 555.67 Daltons.The chemical structure of rucaparib camsylate is shown below:Rucaparib camsylate is white to pale yellow powder; formulated into tablet for oral use. Rucaparib shows pH-independent low solubility of approximately mg/mL across the physiological pH range.Rubraca (rucaparib) tablets contain rucaparib camsylate as the active ingredient. Each 200 mg tablet contains 344 mg rucaparib camsylate equivalent to 200 mg rucaparib free base. Each 250 mg tablet contains 430 mg rucaparib camsylate equivalent to 250 mg rucaparib free base. Each 300 mg tablet contains 516 mg rucaparib camsylate equivalent to 300 mg rucaparib free base.The inactive ingredients in Rubraca tablets include: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The cosmetic blue film coating for 200 mg tablets, cosmetic white film coating for 250 mg tablets, and cosmetic yellow film coating for 300 mg tablets is Opadry II containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc. The coating is colorized as blue using brilliant blue aluminum lake and indigo carmine aluminum lake, or yellow using yellow iron oxide.. Chemical Structure of Rucaparib Camsylate.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dose is 600 mg orally twice daily with or without food. (2.2)Continue treatment until disease progression or unacceptable toxicity. (2.2)For adverse reactions, consider interruption of treatment or dose reduction. (2.3)Patients receiving RUBRACA for mCRPC should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.2). Recommended dose is 600 mg orally twice daily with or without food. (2.2). Continue treatment until disease progression or unacceptable toxicity. (2.2). For adverse reactions, consider interruption of treatment or dose reduction. (2.3). Patients receiving RUBRACA for mCRPC should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.2). 2.1 Patient Selection. Treatment ofBRCA-mutated Ovarian Cancer after or More ChemotherapiesSelect patients for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer with Rubraca based on the presence of deleterious BRCA mutation (germline and/or somatic) [see Clinical Studies (14.1)].. Treatment ofBRCA-mutated mCRPC after Androgen Receptor-directed Therapy and ChemotherapySelect patients for the treatment of mCRPC with Rubraca based on the presence of deleterious BRCA mutation (germline and/or somatic) in plasma specimens [see Clinical Studies (14.2)]. negative result from plasma specimen does not mean that the patients tumor is negative for BRCA mutations. Should the plasma specimen have negative result, consider performing further genomic testing using tumor specimens as clinically indicated.Information on the FDA-approved tests for the detection of BRCA mutation in patients with ovarian cancer or with prostate cancer is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dose. The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food, for total daily dose of 1,200 mg.Continue treatment until disease progression or unacceptable toxicity.If patient misses 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 gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.. 2.3 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.Table 1. Recommended Dose Modifications for Adverse ReactionsDose ReductionDoseStarting Dose600 mg twice daily (two 300 mg tablets)First Dose Reduction500 mg twice daily (two 250 mg tablets)Second Dose Reduction400 mg twice daily (two 200 mg tablets)Third Dose Reduction300 mg twice daily (one 300 mg tablet).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 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.. 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.. Tablets: 200 mg, 250 mg, and 300 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Effect of Rubraca on Other Drugs. Certain CYP1A2, CYP3A, CYP2C9, or CYP2C19 SubstratesConcomitant administration of Rubraca with CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates can increase the systemic exposure of these substrates [see Clinical Pharmacology (12.3)], which may increase the frequency or severity of adverse reactions of these substrates. If concomitant administration is unavoidable between Rubraca and substrates of these enzymes where minimal concentration changes may lead to serious adverse reactions, decrease the substrate dosage in accordance with the approved prescribing information.If concomitant administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 937 patients with ovarian cancer who received Rubraca in ARIEL3, ARIEL2, and Study 10, 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedRubraca is available as 200 mg, 250 mg, and 300 mg tablets.200 mg Tablets:Blue, round, and debossed with C2 on one sideSupplied in bottles of 60 tablets (NDC: 69660-201-91)250 mg Tablets:White, diamond, and debossed with C25 on one sideSupplied in bottles of 60 tablets (NDC: 69660-202-91)300 mg Tablets:Yellow, oval, and debossed with C3 on one sideSupplied in bottles of 60 tablets (NDC: 69660-203-91). Blue, round, and debossed with C2 on one side. Supplied in bottles of 60 tablets (NDC: 69660-201-91). White, diamond, and debossed with C25 on one side. Supplied in bottles of 60 tablets (NDC: 69660-202-91). Yellow, oval, and debossed with C3 on one side. Supplied in bottles of 60 tablets (NDC: 69660-203-91). StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RUBRACA is poly (ADP-ribose) polymerase (PARP) inhibitor indicated:Ovarian cancerfor the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. (1.1)for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. (1.1, 2.1)Prostate cancerfor the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and taxane-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. (1.2, 2.1)This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.2). for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. (1.1). for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. (1.1, 2.1). for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and taxane-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. (1.2, 2.1)This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.2). 1.1 Ovarian Cancer. Rubraca is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)]. Rubraca is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.. Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)]. 1.2 Metastatic Castration-Resistant Prostate Cancer with BRCA Mutations. Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or need for blood transfusions. These may be signs of hematological toxicity or more serious uncommon bone marrow problem called myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) which have been reported in patients treated with Rubraca [see Warnings and Precautions (5.1)].. Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for months after receiving the last dose of Rubraca. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for months after receiving the last dose of Rubraca. Advise male patients not to donate sperm during therapy and for months following the last dose of Rubraca [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].. Photosensitivity: Advise patients to use appropriate sun protection due to the increased susceptibility to sunburn while taking Rubraca [see Adverse Drug Reactions (6.1)].. Lactation: Advise females not to breastfeed during treatment and for weeks after the last dose of Rubraca [see Use in Specific Populations (8.2)].. Dosing Instructions: Instruct patients to take Rubraca orally twice daily with or without food. Doses should be taken approximately 12 hours apart. Advise patients that if dose of Rubraca is missed or if the patient vomits after taking dose of Rubraca, patients should not take an extra dose, but take the next dose at the regular time [see Dosage and Administration (2.2)].Distributed by: Clovis Oncology, Inc.Boulder, CO 803011-844-258-7662Rubraca is registered trademark of Clovis Oncology, Inc.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 weeks following the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cancer cell death. Increased rucaparib-induced cytotoxicity and anti-tumor activity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with rucaparib.Rucaparib was clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. The clastogenic response in mitotically-stimulated cells was anticipated based on the mechanism of action of rucaparib and indicates potential genotoxicity in humans. Rucaparib was not mutagenic in bacterial reverse mutation (Ames) test.Fertility studies with rucaparib have not been conducted. In 3-month repeat-dose general toxicology studies, rucaparib had no effects on male and female reproductive organs at doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively. These dose levels resulted in systemic exposures of approximately 0.3 and 0.09 times the human exposure (AUC0-24h), respectively, at the recommended dose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel Rubraca tablets 200 mg Bottle LabelNDC 69660-201-91Rubraca(R)(rucaparib) tablets200 mg60 tabletsEach tablet contains 344 mg rucaparib camsylate equivalent to 200 mg rucaparibRx onlyKeep out of reach of children. Principal Display Panel Rubraca tablets 200 mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Rubraca in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of rucaparib has not fully been characterized.. Cardiac ElectrophysiologyA positive concentration-QTc relationship was observed in patients who were administered continuous dosages of Rubraca ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean (90% confidence interval [CI]) QTcF increase from baseline at steady state of Rubraca 600 mg twice daily was 14.9 msec (11.1, 18.7 msec).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The AUC and Cmax of rucaparib demonstrated linear pharmacokinetics over dose range from 240 mg to 840 mg twice daily (0.4 times to 1.4 times the approved recommended dosage). The mean (coefficient of variation [CV]) steady-state rucaparib Cmax is 1,940 ng/mL (54%) and AUC0-12h is 16,900 h.ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold.. AbsorptionThe median Tmax (min, max) at the steady state is 1.9 hours (0, 5.98) at the approved recommended dosage. The mean (min, max) absolute bioavailability is 36% (30%, 45%).. Effect of FoodFollowing high-fat meal (approximately 800-1000 calories, including approximately 250 calories from carbohydrates, approximately 500-600 calories from fat, approximately 150 calories from protein), the Cmax was increased by 20%, AUC0-24h was increased by 38%, and the Tmax was delayed by 2.5 hours, as compared to fasted conditions [see Dosage and Administration (2.2)].. DistributionThe mean apparent volume of distribution is 2300 (21%).Rucaparib is 70% bound to human plasma proteins in vitro. Rucaparib preferentially distributed to red blood cells with blood-to-plasma concentration ratio of 1.8.. EliminationThe mean apparent total clearance at steady state is 44.2 L/h (45%) and the mean terminal elimination half-life is 26 (39%) hours.. MetabolismIn vitro, rucaparib is primarily metabolized by CYP2D6 and to lesser extent by CYP1A2 and CYP3A4. In addition to CYP-based oxidation, rucaparib also undergoes N-demethylation, N-methylation, and glucuronidation.. ExcretionFollowing single oral dose of radiolabeled rucaparib, unchanged rucaparib accounted for 64% of the radioactivity. Rucaparib accounted for 45% and 95% of radioactivity in urine and feces, respectively.. Specific PopulationsAge (20 to 86 years), race (White, Black, and Asian), sex, body weight (41 to 171 kg), mild to moderate renal impairment (CLcr >= 30 mL/min), mild hepatic impairment (total bilirubin ULN and AST ULN or total bilirubin to 1.5 ULN and any AST), and CYP2D6 or CYP1A2 genotype polymorphisms did not have clinically meaningful effect on the pharmacokinetics of rucaparib. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr 15 mL/min), or severe hepatic impairment (total bilirubin 3 ULN and any AST) has not been studied.. Hepatic ImpairmentModerate hepatic impairment (total bilirubin 1.5 to x ULN and any AST) increased rucaparib AUC by 45%, but had no effect on Cmax compared to patients with normal hepatic function.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Other Drugs on RucaparibConcomitant administration of Rubraca with proton pump inhibitor had no clinically meaningful effect on steady-state concentrations of rucaparib.. Effect of Rucaparib on Other DrugsConcomitant administration of Rubraca with rosuvastatin (BCRP substrate) had no clinically meaningful effect on the concentrations of rosuvastatin.Coadministration of Rubraca with the following substrates increased the Cmax of each coadministered substrate by <= 1.1-fold and increased the AUC of each substrate as follows:Caffeine (CYP1A2): by 2.6-foldMidazolam (CYP3A4): by 1.4-foldWarfarin (CYP2C9): by 1.5-foldOmeprazole (CYP2C19): by 1.6-foldDigoxin (P-glycoprotein): by 1.2-foldConcomitant administration of Rubraca with an oral contraceptive containing ethinylestradiol and levonorgestrel (CYP3A substrates): increased ethinylestradiol AUC by 1.4-fold and lenovorgestrel AUC by 1.6-fold, but did not have clinically meaningful effect on their Cmax.. Caffeine (CYP1A2): by 2.6-fold. Midazolam (CYP3A4): by 1.4-fold. Warfarin (CYP2C9): by 1.5-fold. Omeprazole (CYP2C19): by 1.6-fold. Digoxin (P-glycoprotein): by 1.2-fold. In Vitro StudiesCytochrome P450 (CYP) Enzymes: Rucaparib inhibited CYP2C8 and CYP2D6 and induced CYP1A2.UDP-glucuronosyltransferase (UGT) Enzymes: Rucaparib inhibited UGT1A1.Transporter Systems: Rucaparib is substrate of P-gp and BCRP. Rucaparib is not substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.Rucaparib inhibited OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT1, OCT2, and MRP4. Rucaparib did not inhibit MRP2, MRP3, or BSEP.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased 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 AUC0-24h in patients receiving the recommended dose of 600 mg twice daily [see Data]. Apprise pregnant women of the potential risk to 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 DataIn 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 AUC0-24h).

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.2)10/2020Dosing and Administration (2.1)10/2020.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: May 2020PATIENT INFORMATIONRubraca(R)(roo-brah-kah)(rucaparib)tabletsWhat is the most important information should know about RubracaRubraca may cause serious side effects including:Bone marrow problems called Myelodysplastic Syndrome (MDS) or type of cancer of the blood called Acute Myeloid Leukemia (AML). Some people who have cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during or after treatment with Rubraca. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with Rubraca.Symptoms of low blood cell counts are common during treatment with Rubraca, but can be sign of serious problems, including MDS or AML. Tell your healthcare provider if you have any of the following symptoms during treatment with Rubraca:weaknessweight lossfeverfrequent infectionsblood in urine or stoolshortness of breathfeeling very tiredbruising or bleeding more easilyYour healthcare provider will do blood tests to check your blood cell counts: before treatment with Rubraca.every month during treatment with Rubraca.weekly if you have low blood cell counts for long time. Your healthcare provider may stop treatment with Rubraca until your blood cell counts improve. See What are possible side effects of Rubraca for more information about side effects.What is RubracaRubraca is prescription medicine used in adults for:the maintenance treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer when your cancer has come back and you are in response (complete or partial response) to platinum-based chemotherapy.the treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene, and you have been treated with or more chemotherapy medicines for your cancer.Your healthcare provider will perform test to make sure Rubraca is right for you.the treatment of castration-resistant prostate cancer (prostate cancer that no longer responds to medical or surgical treatment that lowers testosterone):that has spread to other parts of the body, and has certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene, and you have been treated with certain medicines for your cancer. Your healthcare provider will perform test to make sure Rubraca is right for you. It is not known if Rubraca is safe and effective in children.Before you take Rubraca, tell your healthcare provider about all of your medical conditions, including if you:are pregnant or plan to become pregnant. Rubraca can harm your unborn baby and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with Rubraca.If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Rubraca.Females who are able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant.Males with female partners who are pregnant or able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca.Males should not donate sperm during treatment and for months after the last dose of Rubraca. are breastfeeding or plan to breastfeed. It is not known if Rubraca passes into breast milk. Do not breastfeed during treatment and for weeks after the last dose of Rubraca. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take RubracaTake Rubraca exactly as your healthcare provider tells you.Your healthcare provider may temporarily stop treatment with Rubraca or change your dose of Rubraca if you have side effects. Do not change your dose or stop taking Rubraca unless your healthcare provider tells you to.Take Rubraca times day. Each dose should be taken about 12 hours apart.Take Rubraca with or without food.If you are taking Rubraca for prostate cancer and you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with Rubraca unless you have had surgery to lower the amount of testosterone in your body (surgical castration).If you miss dose of Rubraca, take your next dose at your usual scheduled time. Do not take an extra dose to make up for missed dose.If you vomit after taking dose of Rubraca, do not take an extra dose. Take your next dose at your usual time.If you take too much Rubraca, call your healthcare provider or go to the nearest emergency room right away.What should avoid while taking RubracaAvoid spending time in sunlight. Rubraca can make your skin sensitive to the sun (photosensitivity). You may sunburn more easily during treatment with Rubraca. You should wear hat and clothes that cover your skin and use sunscreen to help protect against sunburn if you have to be in the sunlight.What are the possible side effects of RubracaRubraca may cause serious side effects.See What is the most important information should know about RubracaThe most common side effects of Rubraca in people with ovarian cancer include:nauseatiredness or weaknessvomitingdecrease in hemoglobin (anemia)changes in how food tasteschanges in liver function testsconstipationdecreased appetitediarrhealow blood cell countsmouth soresupper respiratory tract infectionshortness of breathrashstomach (abdomen) pain or swellingThe most common side effects of Rubraca in people with prostate cancer include:tiredness or weaknessnauseadecrease in hemoglobin (anemia)changes in liver function testsdecreased appetiterashconstipationlow blood cell countsvomitingdiarrheaThese are not all of the possible side effects of Rubraca. For more information, ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store RubracaStore Rubraca at room temperature between 68F to 77F (20C to 25C).Keep Rubraca and all medicines out of the reach of children.General information about the safe and effective use of Rubraca.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Rubraca for condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about Rubraca.What are the ingredients in RubracaActive ingredient: rucaparib Inactive ingredients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc. The blue film coating contains brilliant blue aluminum lake and indigo carmine aluminum lake. The yellow film coating contains yellow iron oxide.Distributed by: Clovis Oncology, Inc. Boulder, Colorado 80301For more information, go to www.Rubraca.com or call 1-844-258-7662.. weakness. weight loss. fever. frequent infections. blood in urine or stool. shortness of breath. feeling very tired. bruising or bleeding more easily. before treatment with Rubraca.. every month during treatment with Rubraca.. weekly if you have low blood cell counts for long time. Your healthcare provider may stop treatment with Rubraca until your blood cell counts improve. the maintenance treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer when your cancer has come back and you are in response (complete or partial response) to platinum-based chemotherapy.. the treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene, and you have been treated with or more chemotherapy medicines for your cancer.. Your healthcare provider will perform test to make sure Rubraca is right for you.. the treatment of castration-resistant prostate cancer (prostate cancer that no longer responds to medical or surgical treatment that lowers testosterone):that has spread to other parts of the body, and has certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene, and you have been treated with certain medicines for your cancer. Your healthcare provider will perform test to make sure Rubraca is right for you. that has spread to other parts of the body, and has certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene, and you have been treated with certain medicines for your cancer. are pregnant or plan to become pregnant. Rubraca can harm your unborn baby and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with Rubraca.If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Rubraca.Females who are able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant.Males with female partners who are pregnant or able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca.Males should not donate sperm during treatment and for months after the last dose of Rubraca. If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with Rubraca.. Females who are able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant.. Males with female partners who are pregnant or able to become pregnant should use effective birth control during treatment and for months after the last dose of Rubraca.. Males should not donate sperm during treatment and for months after the last dose of Rubraca.. are breastfeeding or plan to breastfeed. It is not known if Rubraca passes into breast milk. Do not breastfeed during treatment and for weeks after the last dose of Rubraca. Talk to your healthcare provider about the best way to feed your baby during this time. Take Rubraca exactly as your healthcare provider tells you.. Your healthcare provider may temporarily stop treatment with Rubraca or change your dose of Rubraca if you have side effects. Do not change your dose or stop taking Rubraca unless your healthcare provider tells you to.. Take Rubraca times day. Each dose should be taken about 12 hours apart.. Take Rubraca with or without food.. If you are taking Rubraca for prostate cancer and you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with Rubraca unless you have had surgery to lower the amount of testosterone in your body (surgical castration).. If you miss dose of Rubraca, take your next dose at your usual scheduled time. Do not take an extra dose to make up for missed dose.. If you vomit after taking dose of Rubraca, do not take an extra dose. Take your next dose at your usual time.. If you take too much Rubraca, call your healthcare provider or go to the nearest emergency room right away.. See What is the most important information should know about Rubraca. nausea. tiredness or weakness. vomiting. decrease in hemoglobin (anemia). changes in how food tastes. changes in liver function tests. constipation. decreased appetite. diarrhea. low blood cell counts. mouth sores. upper respiratory tract infection. shortness of breath. rash. stomach (abdomen) pain or swelling. tiredness or weakness. nausea. decrease in hemoglobin (anemia). changes in liver function tests. decreased appetite. rash. constipation. low blood cell counts. vomiting. diarrhea. Store Rubraca at room temperature between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

1.1 Ovarian Cancer. Rubraca is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)]. Rubraca is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.. Rubraca is indicated for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca [see Dosage and Administration (2.1)].

STORAGE AND HANDLING SECTION.

StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2). Lactation: Advise women not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased 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 AUC0-24h in patients receiving the recommended dose of 600 mg twice daily [see Data]. Apprise pregnant women of the potential risk to 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 DataIn 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 AUC0-24h).. 8.2 Lactation. Risk SummaryThere 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 weeks following the last dose.. 8.3 Females and Males of Reproductive Potential. Rubraca can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating Rubraca.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months following the last dose of Rubraca [see Use in Specific Populations (8.1)].. MalesBased 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 months following last dose of Rubraca. Advise male patients not to donate sperm during therapy and for months following the last dose of Rubraca [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of Rubraca in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 937 patients with ovarian cancer who received Rubraca in ARIEL3, ARIEL2, and Study 10, 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.. 8.6 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.. 8.7 Hepatic Impairment. No dosage modification is recommended for patients with mild to moderate hepatic impairment (total bilirubin <= 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 ULN and any AST).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to RUBRACA, and some cases were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction. Discontinue if MDS/AML is confirmed. (2.3, 5.1)Embryo-Fetal Toxicity: RUBRACA can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to RUBRACA, and some cases were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction. Discontinue if MDS/AML is confirmed. (2.3, 5.1). Embryo-Fetal Toxicity: RUBRACA can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). 5.1 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 1146 treated patients [see Adverse Reactions (6.1)], MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from month to approximately 53 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 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 (> weeks), interrupt Rubraca or reduce dose according to Table [see Dosage and Administration (2.3)] and monitor blood counts weekly until recovery. If the levels have not recovered to Grade or less after weeks or if MDS/AML is suspected, refer the patient to hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.. 5.2 Embryo-Fetal Toxicity. Rubraca can cause fetal harm when administered to 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 AUC0-24h in patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for 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 months following the last dose of Rubraca [see Use in Specific Populations (8.1, 8.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dosage modification is recommended for patients with mild to moderate hepatic impairment (total bilirubin <= 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 ULN and any AST).

RENAL IMPAIRMENT SUBSECTION.

8.6 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.