Data from FDA - Curated by EPG Health - Last updated 05 June 2018

Indication(s)

1 INDICATIONS AND USAGE RUBRACA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a 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. (1.2, 2.3) 1.1 Maintenance Treatment of Recurrent 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 a complete or partial response to platinum-based chemotherapy [see Dosage and Administration (2.1)]. 1.2 Treatment of BRCA-mutated Ovarian Cancer After 2 or More Chemotherapies 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)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
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)]. Most common adverse reactions (≥ 20%) 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 laboratory abnormalities (≥ 25%) were increase in creatinine, increase in ALT, increase in AST, increase in alkaline phosphatase, decrease in hemoglobin, increase in cholesterol, decrease in platelets, decrease in leukocytes, decrease in lymphocytes, and decrease in neutrophils. (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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Maintenance Treatment of Recurrent Ovarian Cancer The safety of Rubraca for the maintenance treatment of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer was investigated in ARIEL3, a 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 2. Adverse Reactions in ARIEL3 Occurring in ≥ 20% of Patients a 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 reaction Adverse reactions Rubraca N=372 Placebo N=189 Grades a 1-4 % Grades 3-4 % Grades a 1-4 % Grades 3-4 % Gastrointestinal Disorders Nausea 76 4 36 0.5 Abdominal pain/distentionb 46 3 39 0.5 Constipation 37 2 24 1 Vomiting 37 4 15 1 Diarrhea 32 0.5 22 1 Stomatitisb 28 1 14 0.5 General Disorders and Administration Site Conditions Fatigue/asthenia 73 7 46 3 Skin and Subcutaneous Tissue Disorders Rashb 43 1 23 0 Nervous System Disorders Dysgeusia 40 0 7 0 Investigations AST/ALT elevation 38 11 4 0 Blood and Lymphatic System Disorders Anemia 39 21 5 0.5 Thrombocytopenia 29 5 3 0 Neutropenia 20 8 5 1 Respiratory, Thoracic, and Mediastinal Disorders Nasopharyngitis/Upper respiratory tract infectionb 29 0.3 18 1 Metabolism and Nutrition Disorders Decreased appetite 23 1 14 0 Adverse 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 Patients a Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Laboratory Parameter a Rubraca N=372 Placebo N=189 Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Chemistry Increase in creatinine 98 0.3 90 0 Increase in cholesterol 84 4 78 0 Increase in ALT 73 7 4 0 Increase in AST 61 1 4 0 Increase in Alkaline Phosphatase 37 0.3 10 0 Hematology Decrease in hemoglobin 88 13 56 1 Decrease in platelets 44 2 9 0 Decrease in leukocytes 44 3 29 0 Decrease in neutrophils 38 6 22 3 Decrease in lymphocytes 29 5 20 3 Treatment of BRCA-mutated Recurrent Ovarian Cancer After 2 or More Chemotherapies Rubraca 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 2 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 0 or 1, 38% had BRCA-mutated ovarian cancer, 45% had received 3 or more prior lines of chemotherapy, and the median time since ovarian cancer diagnosis was 43 months (range: 6 to 197). Table 4. Adverse Reactions Reported in ≥ 20% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2 Adverse Reaction All Ovarian Cancer Patients (N = 377) % Grades a 1-4 Grades 3-4 a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) Gastrointestinal Disorders Nausea 77 5 Vomiting 46 4 Constipation 40 2 Diarrhea 34 2 Abdominal Pain 32 3 General Disorders Asthenia/Fatigue 77 11 Blood and Lymphatic System Disorders Anemia 44 25 Thrombocytopenia 21 5 Nervous System Disorders Dysgeusia 39 0.3 Metabolism and Nutrition Disorders Decreased appetite 39 3 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 21 0.5 The 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%), Palmar-plantar erythrodysaesthesia syndrome (2%), and febrile neutropenia (1%). Table 5. Laboratory Abnormalities Reported in ≥ 35% of Patients with Ovarian Cancer After ≥ 2 Chemotherapies Treated with Rubraca in Study 10 and ARIEL2 a 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 Parameter All Patients with Ovarian Cancer (N = 377) % Grade 1-4 a Grade 3-4 Clinical Chemistry Increase in creatinine 92 1 Increase in ALTb 74 13 Increase in ASTb 73 5 Increase in cholesterol 40 2 Hematologic Decrease in hemoglobin 67 23 Decrease in lymphocytes 45 7 Decrease in platelets 39 6 Decrease in absolute neutrophil count 35 10

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dose is 600 mg orally twice daily with or without food. (2.1) Continue treatment until disease progression or unacceptable toxicity. (2.1) For adverse reactions, consider interruption of treatment or dose reduction. (2.2) 2.1 Recommended Dose The recommended dose of Rubraca is 600 mg (two 300 mg tablets) taken orally twice daily with or without food. Continue treatment until disease progression or unacceptable toxicity. If a patient misses a dose of Rubraca, instruct the patient to take the next dose at its scheduled time. Vomited doses should not be replaced. 2.2 Dose Modifications for Adverse Reactions To manage adverse reactions, consider interruption of treatment or dose reduction. Recommended dose reductions are indicated in Table 1. Table 1. Recommended Dose Adjustments Dose Reduction Dose Starting Dose 600 mg twice daily (two 300 mg tablets) First Dose Reduction 500 mg twice daily (two 250 mg tablets) Second Dose Reduction 400 mg twice daily (two 200 mg tablets) Third Dose Reduction 300 mg twice daily (one 300 mg tablet) 2.3 Patient Selection for Treatment of BRCA-mutated Ovarian Cancer Select patients for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) [see Indications and Usage (1.2) and Clinical Studies (14.2)]. Information on the FDA-approved test for the detection of a tumor BRCA mutation in patients with ovarian cancer is available at: http://www.fda.gov/CompanionDiagnostics.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Rubraca can cause fetal harm when administered to pregnant women. There are no available data in pregnant women to inform the drug-associated risk. In an animal reproduction study, administration of rucaparib to pregnant rats during organogenesis resulted in embryo-fetal death at maternal exposures that were 0.04 times the AUC0-24h in patients receiving the recommended dose of 600 mg twice daily [see Data]. Apprise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a dose range-finding embryo-fetal development study, pregnant rats received oral doses of 50, 150, 500, or 1000 mg/kg/day of rucaparib during the period of organogenesis. Post-implantation loss (100% early resorptions) was observed in all animals at doses greater than or equal to 50 mg/kg/day (with maternal systemic exposures approximately 0.04 times the human exposure at the recommended dose based on AUC0-24h). 8.2 Lactation Risk Summary There is no information regarding the presence of rucaparib in human milk, or on its effects on milk production or the breast-fed child. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks following the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating Rubraca. Contraception Females Rubraca can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. 8.4 Pediatric Use The safety and effectiveness of Rubraca in pediatric patients have not been established. 8.5 Geriatric Use In clinical studies 40% (297/749) of patients with ovarian cancer treated with Rubraca were 65 years of age or older and 9% (65/749) were 75 years or older. Grade 3-4 adverse reactions occurred in 65% of patients 65 years or older and in 63% of patients 75 years or older. For patients 65 years or older, the most common Grade 3-4 adverse reactions were anemia, fatigue/asthenia, and ALT/AST increase. No major differences in safety were observed between these patients and younger patients for the maintenance treatment of recurrent ovarian cancer or for the treatment of BRCA-mutated ovarian cancer after two or more chemotherapies. 8.6 Hepatic Impairment No starting dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times ULN and any AST). No recommendation for starting dose adjustment is available for patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN) due to a lack of data [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No starting dose adjustment is recommended for patients with mild to moderate renal impairment (baseline creatinine clearance [CLcr] between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method). There is no recommended starting dose for patients with CLcr less than 30 mL/min or patients on dialysis due to a lack of data [See Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS CYP1A2, CYP3A, CYP2C9, and CYP2C19 substrates: Adjust dosage if clinically indicated. (7) 7.1 Effect of Rucaparib on Cytochrome p450 (CYP) Substrates Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing the frequency of international normalized ratio (INR) monitoring.

More information

Category Value
Authorisation number NDA209115
Agency product number 41AX9SJ8KO
Orphan designation No
Product NDC 69660-201,69660-203,69660-202
Date Last Revised 06-04-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder Clovis Oncology, Inc.