b'LYNPARZA (olaparib) tablets, for oral use After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Lynparza Initial U.S. Approval: 2014dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.2) and Clinical Brief Summary of Prescribing Information. For complete prescribing information consultPharmacology (12.3) in the full Prescribing Information].ofcial package insert.Dosage Modications for Renal ImpairmentINDIC ATIONS AND USAGE Moderate Renal ImpairmentIn patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer 200 mg orally twice daily [see Use in Specic Populations (8.6) and Clinical Pharmacology (12.3) Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleteriousin the full Prescribing Information].germlineorsomatichomologousrecombinationrepair(HRR)gene-mutatedmetastaticCONTRAINDICATIONScastration-resistant prostate cancer (mCRPC) who have progressed following prior treatment withNone.enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companionWARNINGS AND PRECAUTIONSdiagnostic for Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information].Myel odysplastic Syndrome/Acute Myeloid LeukemiaTreatment of BRCA-mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or PrednisoloneMyelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients Lynparza is indicated in combination with abiraterone and prednisone or prednisolone for thetreated with Lynparza and some cases were fatal.treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm)In clinical studies, among 2219 patients with various BRCAm, gBRCAm, HRR gene-mutated or metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on anHRD-positive cancers who received Lynparza as a single agent or as part of combination regimen, FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) in theconsistent with approved indications, the cumulative incidence of MDS/AML was approximately full Prescribing Information]. 1.2% (26/2219) [see Adverse Reactions (6.1) in the full Prescribing Information]. Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with Lynparza in patients who DOSAGE AND ADMINISTRATION developed MDS/AML was approximately 2 years (range: 6 months to 4 years). All of these Patient Selection patients had received previous chemotherapy with platinum agents and/or other DNA damaging Information on FDA-approved tests for the detection of genetic mutations is available atagents including radiotherapy.http://www.fda.gov/companiondiagnostics. Do not start Lynparza until patients have recovered from hematological toxicity caused by Select patients for treatment with Lynparza based on the presence of deleterious or suspectedprevious chemotherapy ( Grade 1). Monitor complete blood count for cytopenia at baseline and deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on themonthly thereafter for clinically signicant changes during treatment. For prolonged hematological indication, biomarker, and sample type (Table 1). toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further Table 1 Biomarker Testing for Patient Selection* investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is Indication Biomarker Sample type conrmed, discontinue Lynparza.Pneu monitisTumor Blood Plasma(ctDNA) In clinical studies enrolling 2901 patients with various cancers who received Lynparza as a single agent [see Adverse Reactions (6.1) in the full Prescribing Information], the incidence of ATMm, BRCA1m, BRCA2m, BARD1m,pneumonitis, including fatal cases, was 0.8% (24/2901). If patients present with new or worsening BRIP1m, CDK12m, CHEK1m, CHEK2m,X respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, Germline or somatic HRRFANCLm, PALB2m, RAD51Bm, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis gene-mutated metastatic RAD51Cm, RAD51Dm, is conrmed, discontinue Lynparza treatment and treat the patient appropriately.castration-resistant RAD54Lm Venous Thromboembolismprostate cancer gBRCA1m, gBRCA2m X Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1) in the full Prescribing Information]. ATMm, BRCA1m, BRCA2m X In the combined data of two randomized, placebo-controlled clinical studies (PROfound and BRCA-mutated metastaticPROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in castration-resistant 8% of patients who received Lynparza, including pulmonary embolism in 6%. In the control arms, prostate cancer in BRCA1m, BRCA2m X X X VTE occurred in 2.5% including pulmonary embolism in 1.5%.combination with Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary abiraterone and embolism and treat as medically appropriate, which may include long-term anticoagulation as prednisone or prednisolone clinically indicated.*Where testing fails or tissue sample is unavailable/insufcient, or when germline testing is negative, considerEmbryo-Fetal Toxicityusing an alternative test, if available. Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and ndings in animals. In an animal reproduction study, administration of olaparib Recommended Dosage to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food. toxicity at exposures below those in patients receiving the recommended human dose of If a patient misses a dose of Lynparza, instruct patient to take their next dose at its scheduled time.300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk Instruct patients to swallow tablets whole. Do not chew, crush, dissolve, or divide tablet. for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. Based on ndings from HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer genetic toxicity and animal reproduction studies, advise male patients with female partners of Continue treatment until disease progression or unacceptable toxicity for: reproductive potential or who are pregnant to use effective contraception during treatment and HRR gene-mutated metastatic castration-resistant prostate cancer. for 3 months following the last dose of Lynparza [see Use in Specic Populations (8.1, 8.3) in BRCA-mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abirateronethe full Prescribing Information].and Prednisone or Prednisolone ADVERSE REACTIONSContinue treatment until disease progression or unacceptable toxicity. The following adverse reactions are discussed elsewhere in the labeling:When used with Lynparza, the recommended dose of abiraterone is 1000 mg taken orally once Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the daily. Abiraterone should be given in combination with prednisone or prednisolone 5 mg orallyfull Prescribing Information]twice daily. Refer to the Prescribing Information for abiraterone for dosing information.Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]Patients with mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog Venous Thromboembolism [see Warnings and Precautions (5.3) in the full Prescribing concurrently or should have had bilateral orchiectomy. Information]Dosage Modications for Adverse ReactionsClin ical Trial ExperienceTomanageadversereactions,considerinterruptionoftreatmentordosereduction.TheBecause clinical trials are conducted under widely varying conditions, adverse reaction rates recommended dose reduction is 250 mg taken twice daily. observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reect the rates observed in practice.If a further dose reduction is required, then reduce to 200 mg taken twice daily. Unless otherwise specied, the data described in the WARNINGS AND PRECAUTIONS reect Dosage Modications for Concomitant Use with Strong or Moderate CYP3A Inhibitors exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza. twice daily tablet dose including ve controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, If concomitant use cannot be avoided, reduce Lynparza dosage to: POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that100 mg twice daily when used concomitantly with a strong CYP3A inhibitor. were pooled to conduct safety analyses. In addition to the 2901 patients, certain subsections in the WARNINGS AND PRECAUTIONS include adverse reactions observed with exposure to Lynparza150 mg twice daily when used concomitantly with a moderate CYP3A inhibitor. with abiraterone (n=398) in PROpel. All patients with metastatic castration resistant prostate cancer received concomitant ADT or previous bilateral orchiectomy.'