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 (>= 10%) among patients with ovarian cancer were nausea, fatigue (including asthenia), anemia, AST/ALT increased, vomiting, diarrhea, decreased appetite, thrombocytopenia, dysgeusia, neutropenia, blood creatinine increased, dyspnea, dizziness, dyspepsia, photosensitivity reaction, and leukopenia. 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 ZR pharma& GmbH agent at 1-800-506-850 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch. Most common adverse reactions (>= 10%) among patients with ovarian cancer were nausea, fatigue (including asthenia), anemia, AST/ALT increased, vomiting, diarrhea, decreased appetite, thrombocytopenia, dysgeusia, neutropenia, blood creatinine increased, dyspnea, dizziness, dyspepsia, photosensitivity reaction, and leukopenia. 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 for patients with ovarian cancer in the WARNINGS AND PRECAUTIONS section reflect exposure to Rubraca at 600 mg orally twice daily in 1594 patients treated on clinical trials including ARIEL3. In this group, 57% of patients were exposed for months or longer and 33% were exposed for greater than one year.In the pooled safety population for patients with ovarian cancer, the most common adverse reactions in >= 10% of patients were nausea (68%), asthenia/fatigue (65%), anemia/hemoglobin decreased (45%), AST/ALT increased (39%), vomiting (36%), diarrhea (29%), decreased appetite (27%), thrombocytopenia/platelet count decreased (25%), dysgeusia (24%), neutropenia/neutrophil count decreased (21%), blood creatinine increased (17%), dyspnea (16%), dizziness (14%), dyspepsia(11%), photosensitivity reaction (10%), and leukopenia/white blood cell count decreased (10%).. Maintenance Treatment ofBRCA-mutated Recurrent Ovarian CancerThe safety of Rubraca for the maintenance treatment of patients with BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, randomized (2:1), double-blind, placebo-controlled study in which 195 patients with deleterious BRCAmutation received either Rubraca 600 mg orally twice daily (n=129) or placebo (n=66) until disease progression or unacceptable toxicity. The median duration of study treatment was 13.6 months (range: 1 month to 39 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 67% of patients receiving Rubraca and 14% of those receiving placebo; dose reductions due to an adverse reaction occurred in 57% of Rubraca patients and 6% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (25%), anemia (19%), AST/ALT increased (16%), fatigue/asthenia (14%), and nausea (10%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 5% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were thrombocytopenia (4%), nausea (3%), and anemia (2%). Table 2describes the adverse reactions occurring in >=20% of patients; while Table 3describes the laboratory abnormalities occurring in >=25% of patients occurring in ARIEL3. Table 2. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) bConsists of grouped related terms that reflect the medical concept of the adverse reaction Adverse reactionsRubracaN=129PlaceboN=66Grades 1-4a%Grades 3-4%Grades 1-4a%Grades 3-4%Gastrointestinal DisordersNausea792290Abdominal pain/distention 483492Constipation394362Vomiting374140Diarrhea342180Stomatitis 280.8120General Disorders and Administration Site ConditionsFatigue/asthenia749525Skin and Subcutaneous Tissue DisordersRash 450230Nervous System DisordersDysgeusia33060Headache220152InvestigationsAST/ALT elevation331630Blood and Lymphatic System DisordersAnemia412660Thrombocytopenia35630Neutropenia22860Respiratory, Thoracic, and Mediastinal DisordersNasopharyngitis/Upper respiratory tract infection 290202Metabolism and Nutrition DisordersDecreased appetite232140Adverse reactions occurring 20% of patients treated with Rubraca include insomnia (19%), dyspnea (17%), dizziness (15%), pyrexia (15%), dyspepsia (12%), peripheral edema (12%), and depression (11%).Table 3. Laboratory Abnormalities in >= 25% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3aPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. bNCI CTCAE version 4.03. Laboratory ParameteraRubracaN=129PlaceboN=66Grades 1-4b%Grades 3-4%Grades 1-4b%Grades 3-4%ChemistryIncrease in creatinine960890Increase in ALT671160Increase in AST59160Increase in cholesterol393200Increase in Alkaline Phosphatase39030HematologyDecrease in hemoglobin6118142Decrease in platelets47280Decrease in leukocytes393230Decrease in neutrophils386182Decrease in lymphocytes337142. 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 4and 5summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA--mutated mCRPC in TRITON2. Table 4. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated mCRPC in TRITON2Adverse ReactionRubraca = 115 Grades 1-4 (%) Grades 3-4 (%) aNCI CTCAE version 4.03. bIncludes platelet count decreased cIncludes 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, urticaria General disorders and administration site conditions Asthenia/Fatigue629Gastrointestinal disorders Nausea523 Constipation271 Vomiting221 Diarrhea200Blood and lymphatic system disorders Anemia4325 Thrombocytopenia 2510Metabolism and nutrition disorders Decreased appetite282Skin and subcutaneous tissue disorders Rash 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, venous thromboembolism, and stomatitis.Table 5. Laboratory Abnormalities in >= 35% (Grades 1-4) and >= 2% (Grades 3-4) Worsening from Baseline in Patients with BRCA-mutated mCRPC in TRITON2aDenominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available for 111 to 115 patients. bNCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03 cGrade 3-4 ALT or AST elevation led to drug interruption in patients, of which had dose reduction upon rechallenge. Laboratory ParameterRubraca = 115 Grades 1-4 (%) Grades 3-4 (%) Clinical ChemistryIncrease in ALT 695Decrease in phosphate6815Increase in alkaline phosphatase442Increase in creatinine432Increase in triglycerides425Decrease in sodium383HematologicDecrease in leukocytes695Decrease in absolute neutrophil count6210Decrease in hemoglobin5925Decrease in lymphocytes4217Decrease in platelets4010.

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 vitrostudies 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 BRCA1/2and 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 maxof 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 maxis 1,940 ng/mL (54%) and AUC 0-12his 16,900 hxng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold. AbsorptionThe median max(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 maxwas increased by 20%, AUC 0-24hwas increased by 38%, and the maxwas 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 maxcompared 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 maxof 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 levonorgestrel AUC by 1.6-fold, but did not have clinically meaningful effect on their max. 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 Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer. The 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.Tumor tissue samples were tested using clinical trial assay (CTA) (N=564) and an investigational Foundation Medicine tissue test (n=518). Of the samples evaluated with both tests, tumor BRCA(t BRCA) mutant status was confirmed for 99% (177/178) of BRCA-positive patients determined by the CTA. Blood samples for 94% (186/196) of the BRCApatients were evaluated using central blood germline BRCAtest. Based on these results, 70% (130/186) of the BRCApatients had germline BRCAmutation and 30% (56/186) had somatic BRCAmutation. The efficacy results are based on the BRCA(germline or somatic) subgroup. 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). Overall survival (OS) was an additional outcome measure.Of the 564 enrolled patients, 196 patients (35%) had t BRCAmutation. Among the patients who had tBRCAmutation, the median age was 58 years (range: 42 to 81) for patients receiving Rubraca and 59 years (range: 36 to 84) for those on placebo; the majority were White (84%); and 100% had an ECOG performance status of or 1. All patients had received at least two prior platinum-based chemotherapies (range: to 5). total of 33% of patients were in complete response (CR) to their most recent therapy. The progression-free interval to penultimate platinum was 6-12 months in 41% of patients and 12 months in 59%. Prior bevacizumab therapy was reported for 22% of patients who received Rubraca and 17% of patients who received placebo. Measurable disease was present at baseline in 32% of patients. ARIEL3 demonstrated statistically significant improvement in PFS for patients randomized to Rubraca as compared with placebo in patients who had t BRCAmutation. Results from blinded independent radiology review were consistent. Efficacy results for patients with t BRCAmutation are summarized in Table 6and Figure 1. Table 6. Efficacy Results in Patients with tBRCA-mutated Ovarian Cancer ARIEL3 (Investigator Assessment) at BRCAincludes all patients with deleterious germline or somatic BRCAmutation, as determined by the CTA. RubracaN=130PlaceboN=66Progression Free Survival Number of events, (%)67 (52%)56 (85%) Median in months (95% CI)16.6 (13.4-22.9)5.4 (3.4-6.7) HR (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: tBRCAGroupA final OS analysis was conducted after 130 events were observed. Exploratory OS results showed HR of 0.83 (95% CI: 0.58, 1.19) in the BRCAsubgroup with median OS of 45.9 months (95% CI: 37.7, 59.6) for patients treated with Rubraca and 47.8 months (95% CI: 43.2, 55.8) for patients on placebo. Figure 1. 14.2 BRCA-mutated Metastatic Castration-Resistant Prostate Cancer. 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 BRCAmutations 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 BRCAmutation detected from either central plasma (26%), central tissue (32%), or local (42%) testing. Of the 62 patients, 66% had somatic BRCAmutation, 34% had germline BRCAmutation, 85% had BRCA2mutation, and 15% had BRCA1mutation. 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 7. The ORR by IRR was similar in patients with germline versus somatic BRCAmutation. Table 7. Efficacy Results in Patients with BRCA-mutated mCRPC TRITON2 (IRR-assessed)NE not evaluableaDefined per modified RECIST v1.1 criteria and with no confirmed bone progression per PCWG3. bThe 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) 44% (31, 57)Median DOR in months (95% CI) 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 for patients with ovarian cancer in the WARNINGS AND PRECAUTIONS section reflect exposure to Rubraca at 600 mg orally twice daily in 1594 patients treated on clinical trials including ARIEL3. In this group, 57% of patients were exposed for months or longer and 33% were exposed for greater than one year.In the pooled safety population for patients with ovarian cancer, the most common adverse reactions in >= 10% of patients were nausea (68%), asthenia/fatigue (65%), anemia/hemoglobin decreased (45%), AST/ALT increased (39%), vomiting (36%), diarrhea (29%), decreased appetite (27%), thrombocytopenia/platelet count decreased (25%), dysgeusia (24%), neutropenia/neutrophil count decreased (21%), blood creatinine increased (17%), dyspnea (16%), dizziness (14%), dyspepsia(11%), photosensitivity reaction (10%), and leukopenia/white blood cell count decreased (10%).. Maintenance Treatment ofBRCA-mutated Recurrent Ovarian CancerThe safety of Rubraca for the maintenance treatment of patients with BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, randomized (2:1), double-blind, placebo-controlled study in which 195 patients with deleterious BRCAmutation received either Rubraca 600 mg orally twice daily (n=129) or placebo (n=66) until disease progression or unacceptable toxicity. The median duration of study treatment was 13.6 months (range: 1 month to 39 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 67% of patients receiving Rubraca and 14% of those receiving placebo; dose reductions due to an adverse reaction occurred in 57% of Rubraca patients and 6% of placebo patients. The most frequent adverse reactions leading to dose interruption or dose reduction of Rubraca were thrombocytopenia (25%), anemia (19%), AST/ALT increased (16%), fatigue/asthenia (14%), and nausea (10%). Discontinuation due to adverse reactions occurred in 15% of Rubraca patients and 5% of placebo patients. Specific adverse reactions that most frequently led to discontinuation in patients treated with Rubraca were thrombocytopenia (4%), nausea (3%), and anemia (2%). Table 2describes the adverse reactions occurring in >=20% of patients; while Table 3describes the laboratory abnormalities occurring in >=25% of patients occurring in ARIEL3. Table 2. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) bConsists of grouped related terms that reflect the medical concept of the adverse reaction Adverse reactionsRubracaN=129PlaceboN=66Grades 1-4a%Grades 3-4%Grades 1-4a%Grades 3-4%Gastrointestinal DisordersNausea792290Abdominal pain/distention 483492Constipation394362Vomiting374140Diarrhea342180Stomatitis 280.8120General Disorders and Administration Site ConditionsFatigue/asthenia749525Skin and Subcutaneous Tissue DisordersRash 450230Nervous System DisordersDysgeusia33060Headache220152InvestigationsAST/ALT elevation331630Blood and Lymphatic System DisordersAnemia412660Thrombocytopenia35630Neutropenia22860Respiratory, Thoracic, and Mediastinal DisordersNasopharyngitis/Upper respiratory tract infection 290202Metabolism and Nutrition DisordersDecreased appetite232140Adverse reactions occurring 20% of patients treated with Rubraca include insomnia (19%), dyspnea (17%), dizziness (15%), pyrexia (15%), dyspepsia (12%), peripheral edema (12%), and depression (11%).Table 3. Laboratory Abnormalities in >= 25% of Patients with BRCA-mutated Ovarian Cancer in ARIEL3aPatients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. bNCI CTCAE version 4.03. Laboratory ParameteraRubracaN=129PlaceboN=66Grades 1-4b%Grades 3-4%Grades 1-4b%Grades 3-4%ChemistryIncrease in creatinine960890Increase in ALT671160Increase in AST59160Increase in cholesterol393200Increase in Alkaline Phosphatase39030HematologyDecrease in hemoglobin6118142Decrease in platelets47280Decrease in leukocytes393230Decrease in neutrophils386182Decrease in lymphocytes337142. 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 4and 5summarize the adverse reactions and laboratory abnormalities, respectively, in patients with BRCA--mutated mCRPC in TRITON2. Table 4. Adverse Reactions Reported in >= 20% of Patients with BRCA-mutated mCRPC in TRITON2Adverse ReactionRubraca = 115 Grades 1-4 (%) Grades 3-4 (%) aNCI CTCAE version 4.03. bIncludes platelet count decreased cIncludes 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, urticaria General disorders and administration site conditions Asthenia/Fatigue629Gastrointestinal disorders Nausea523 Constipation271 Vomiting221 Diarrhea200Blood and lymphatic system disorders Anemia4325 Thrombocytopenia 2510Metabolism and nutrition disorders Decreased appetite282Skin and subcutaneous tissue disorders Rash 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, venous thromboembolism, and stomatitis.Table 5. Laboratory Abnormalities in >= 35% (Grades 1-4) and >= 2% (Grades 3-4) Worsening from Baseline in Patients with BRCA-mutated mCRPC in TRITON2aDenominator for each laboratory parameter is based on the number of patients with baseline and post-treatment laboratory value available for 111 to 115 patients. bNCI CTCAE version 5.0; decrease in phosphate is graded using NCI CTACE Version 4.03 cGrade 3-4 ALT or AST elevation led to drug interruption in patients, of which had dose reduction upon rechallenge. Laboratory ParameterRubraca = 115 Grades 1-4 (%) Grades 3-4 (%) Clinical ChemistryIncrease in ALT 695Decrease in phosphate6815Increase in alkaline phosphatase442Increase in creatinine432Increase in triglycerides425Decrease in sodium383HematologicDecrease in leukocytes695Decrease in absolute neutrophil count6210Decrease in hemoglobin5925Decrease in lymphocytes4217Decrease in platelets4010.

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. Maintenance Treatment ofBRCA-mutated Recurrent Ovarian CancerSelect patients for the maintenance treatment of recurrent ovarian cancer with Rubraca based on the presence of 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 ChemotherapySelect patients for the treatment of mCRPC with Rubraca based on the presence of deleterious BRCAmutation (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 BRCAmutations. 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 BRCAmutation 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).

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 deleterious BRCAmutation (germline and/or somatic)- associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. 1.1) Prostate cancerfor the treatment of adult patients with deleterious BRCAmutation (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 deleterious BRCAmutation (germline and/or somatic)- associated 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 BRCAmutation (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) 1.1 Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer. Rubraca is indicated for the maintenance treatment of adult patients with deleterious BRCAmutation (germline and/or somatic)- associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. 1.2 BRCA-mutated Metastatic Castration-Resistant Prostate Cancer. Rubraca is indicated for the treatment of adult patients with deleterious BRCAmutation (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)] Manfuactured for:zr pharma& GmbHTaborstrasse 11020 ViennaAustriaDistributed by:Summit SD, LLC255 Northwest Victoria Drive, Suite ALees Summit, MO 64086Rubraca is registered trademark of pharma&.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The AUC and maxof 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 maxis 1,940 ng/mL (54%) and AUC 0-12his 16,900 hxng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold. AbsorptionThe median max(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 maxwas increased by 20%, AUC 0-24hwas increased by 38%, and the maxwas 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 maxcompared 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 maxof 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 levonorgestrel AUC by 1.6-fold, but did not have clinically meaningful effect on their max. 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: June 2023PATIENT 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 Rubracafor 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 with certain type of inherited (germline) or acquired (somatic) abnormal BRCAgene when your cancer has come back and you are in response (complete or partial response) to platinum-based chemotherapy. 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 BRCAgene, 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.Femaleswho 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. Maleswith 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. Malesshould 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 Rubraca The most common side effects of Rubraca in people with ovarian cancer include: nauseatiredness or weaknessdecrease in hemoglobin (anemia)changes in liver and kidney function testsvomitingdiarrheadecreased appetitelow blood cell countschanges in how food tastesshortness of breathdizzinessindigestionreaction to sunlightThe 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. Manufactured for:zr pharma& GmbH, Taborstrasse 1, 1020 Vienna, AustriaDistributed by: Summit SD LLC, 255 Northwest Victoria Drive, Suite A, Lees Summit, MO 64086For more information call tel: 1-800-506-8501. 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 with certain type of inherited (germline) or acquired (somatic) abnormal BRCAgene when your cancer has come back and you are in response (complete or partial response) to platinum-based chemotherapy. 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 BRCAgene, 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 BRCAgene, 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.Femaleswho 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. Maleswith 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. Malesshould 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.. Femaleswho 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. Maleswith 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. Malesshould 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. decrease in hemoglobin (anemia). changes in liver and kidney function tests. vomiting. diarrhea. decreased appetite. low blood cell counts. changes in how food tastes. shortness of breath. dizziness. indigestion. reaction to sunlight. 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).

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 AUC 0-24hin 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 AUC 0-24h). 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 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.. 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 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 germline and/or somatic BRCAmutation treated with Rubraca, MDS/AML occurred in out of 129 (7%) patients treated with Rubraca and 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 (> 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 AUC 0-24hin 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)].