Olaparib

1 INDICATIONS AND USAGE Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer • for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.1 , 2.1 ) • in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: • a deleterious or suspected deleterious BRCA mutation, and/or • genomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.2 , 2.1 ) • for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.3 , 2.1 ) Breast cancer • for the adjuvant treatment of adult patients with deleterious or suspected deleterious g BRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.4 , 2.1 ) • for the treatment of adult patients with deleterious or suspected deleterious gBRCA m, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.5 , 2.1 ) Pancreatic cancer • for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.6 , 2.1 ) Prostate cancer • for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.7 , 2.1 ) • in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. ( 1.8 , 2.1 ) 1.1 First-Line Maintenance Treatment of BRCA -mutated Advanced Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] . 1.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: • a deleterious or suspected deleterious BRCA mutation, and/or • genomic instability. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 1.3 Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 1.4 Adjuvant Treatment of Germline BRCA -mutated HER2-negative High Risk Early Breast Cancer Lynparza is indicated for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA m human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [ see Dosage and Administration (2.1) ]. 1.5 Germline BRCA -mutated HER2-negative Metastatic Breast Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCA m, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] . 1.6 First-Line Maintenance Treatment of Germline BRCA -mutated Metastatic Pancreatic Adenocarcinoma Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] . 1.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ]. 1.8 Treatment of BRCA -mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone Lynparza is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.1) ] .

5 WARNINGS AND PRECAUTIONS • Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCA m, g BRCA m, HRR gene-mutated or HRD-positive cancers exposed to Lynparza and the majority of events had a fatal outcome. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. (5.1) • Pneumonitis: Occurred in 1.0% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. (5.2) • Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza. VTE occurred in 8% of patients with mCRPC. Monitor patients for signs and symptoms of VTE and PE and treat as medically appropriate. ( 5.3 ) • Hepatotoxicity, Including Drug-induced liver injury (DILI): Occurred in patients treated with Lynparza. If DILI is suspected, interrupt Lynparza. If DILI is confirmed, discontinue treatment. ( 5.4 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal. In clinical studies, among 2219 patients with various BRCA m, g BRCA m, HRR gene-mutated or HRD-positive cancers who received Lynparza as a single agent or as part of combination regimen, consistent with approved indications, the cumulative incidence of MDS/AML was approximately 1.2% (26/2219) [see Adverse Reactions (6.1) ]. Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was approximately 2 years (range: 4 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. In SOLO1, patients with newly diagnosed advanced BRCA m ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received Lynparza and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received Lynparza and 2.3% (3/131) in the control arm. In SOLO2, patients with BRCA m platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received Lynparza and 4% (4/99) in patients who received placebo. The duration of Lynparza treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological 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 investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. 5.2 Pneumonitis Pneumonitis, including severe and fatal cases, has occurred in patients treated with Lynparza. In clinical studies, among patients who received Lynparza as a single agent or as part of a combination regimen [see Error! Hyperlink reference not valid. ] , the incidence of pneumonitis, including fatal cases, was 1.0% (29/2851). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately . 5.3 Venous Thromboembolism Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1) ] . In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received Lynparza, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5% including pulmonary embolism in 1.5%. Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated. 5.4 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Lynparza [see Adverse Reactions (6.2) ] . Evaluate bilirubin and transaminases at baseline and throughout treatment with Lynparza. For patients who develop abnormal liver tests after Lynparza, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Lynparza. Upon confirmation of DILI, discontinue Lynparza. 5.5 Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk 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 findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza [see Use in Specific Populations ( 8.1 , 8.3 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) ] • Pneumonitis [see Warnings and Precautions (5.2) ] • Venous Thromboembolism [see Warnings and Precautions (5.3) ] • Hepatotoxicity, Including Drug-Induced Liver Injury [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥10%): • as a single agent were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia. (6.1) • in combination with bevacizumab were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache. ( 6.1 ) • in combination with abiraterone and prednisone or prednisolone were anemia, fatigue, nausea, diarrhea, decreased appetite, lymphopenia, dizziness, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Unless otherwise specified, the data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent or as part of a combination regimen (SOLO-1, SOLO-2, PAOLA-1, OlympiA, OlympiAD, POLO, PROfound, and PROpel) in 2851 patients that were pooled to conduct safety analyses. Additional data reflect exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In this pooled single agent safety population, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year in the Lynparza group. In this pooled single agent safety population, the most common adverse reactions in ≥10% of patients were nausea (60%), fatigue (55%), anemia (36%), vomiting (32%), diarrhea (24%), decreased appetite (22%), headache (16%), dysgeusia (15%), cough (15%), neutropenia (14%), dyspnea (14%), dizziness (12%), dyspepsia (12%), leukopenia (11%), and thrombocytopenia (10%). First-Line Maintenance Treatment of BRCA -mutated Advanced Ovarian Cancer SOLO-1 The safety of Lynparza for the maintenance treatment of patients with BRCA-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO- 1 [see Clinical Studies (14.1) ] . Patients received Lynparza tablets 300 mg orally twice daily (n=260) or placebo (n=130) until disease progression or unacceptable toxicity. The median duration of study treatment was 25 months for patients who received Lynparza and 14 months for patients who received placebo. Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to adverse reactions occurred in 12% of patients receiving Lynparza. The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%). Tables 2 and 3 summarize adverse reactions and laboratory abnormalities in SOLO-1. Table 2 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. in SOLO-1 (≥10% of Patients Who Received Lynparza) Adverse Reaction Lynparza tablets n=260 Placebo n=130 All Grades (%) Grades 3 – 4 (%) All Grades (%) Grades 3 – 4 (%) Gastrointestinal Disorders Nausea 77 1 38 0 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. 45 2 35 1 Vomiting 40 0 15 1 Diarrhea Includes colitis, diarrhea, and gastroenteritis. 37 3 26 0 Constipation 28 0 19 0 Dyspepsia 17 0 12 0 Stomatitis Includes stomatitis, aphthous ulcer, and mouth ulceration. 11 0 2 0 General Disorders and Administration Site Conditions Fatigue Includes asthenia, fatigue, lethargy, and malaise. 67 4 42 2 Blood and Lymphatic System Disorders Anemia 38 21 9 2 Neutropenia Includes neutropenia and febrile neutropenia. 17 6 7 3 Leukopenia Includes leukopenia and white blood cell count decreased. 13 3 8 0 Thrombocytopenia Includes platelet count decreased and thrombocytopenia. 11 1 4 2 Infections and Infestations Upper respiratory tract infection/ influenza/nasopharyngitis/bronchitis 28 0 23 0 UTI Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria. 13 1 7 0 Nervous System Disorders Dysgeusia 26 0 4 0 Dizziness 20 0 15 1 Metabolism and Nutrition Disorders Decreased appetite 20 0 10 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Includes dyspnea and dyspnea exertional. 15 0 6 0 Clinically relevant adverse reactions that occurred in 5% of patients included hypertension (19%) and anemia (17%). Dose interruptions due to an adverse reaction of any grade occurred in 54% of patients receiving Lynparza/bevacizumab and dose reductions due to an adverse reaction occurred in 41% of patients who received Lynparza/bevacizumab. The most frequent adverse reactions leading to dose interruption in the Lynparza/bevacizumab arm were anemia (21%), nausea (7%), vomiting (3%), and fatigue (3%), and the most frequent adverse reactions leading to reduction in the Lynparza/bevacizumab arm were anemia (19%), nausea (7%), and fatigue (4%). Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza/bevacizumab were anemia (4%) and nausea (3%). The most common adverse reactions (≥10%) for patients receiving Lynparza/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), diarrhea (18%), neutropenia (18%), leukopenia (18%), urinary tract infection (15%), and headache (14%). Tables 4 and 5 summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively. Table 4 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. Occurring in ≥10% of Patients Treated with Lynparza/bevacizumab in PAOLA-1 and at ≥5% Frequency Compared to the Placebo/bevacizumab Arm Adverse Reactions Lynparza/bevacizumab n=535 Placebo/bevacizumab n=267 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) General Disorders and Administration Site Conditions Fatigue (including asthenia) Includes asthenia and fatigue. 53 5 32 1.5 Gastrointestinal Disorders Nausea 53 2.4 22 0.7 Vomiting 22 1.7 11 1.9 Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 41 17 10 0.4 Lymphopenia Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased. 24 7 9 1.1 Leukopenia Includes leukopenia and white blood cell count decreased. 18 1.9 10 1.5 Clinically relevant adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), hypersensitivity (1.7%), pneumonitis (0.9%), and MDS/AML (0.7%). Venous thromboembolism occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%). Table 5 Laboratory Abnormalities Reported in ≥25% of Patients in PAOLA-1 Reported within 30 days of the last dose. Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. Lynparza/bevacizumab n =535 Placebo/bevacizumab n This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. =267 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 79 13 55 0.4 Decrease in lymphocytes 63 10 42 3 Increase in serum creatinine 61 0.4 36 0.4 Decrease in leukocytes 59 3.4 45 2.2 Decrease in absolute neutrophil count 35 7 30 3.7 Decrease in platelets 35 2.4 28 0.4 Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer SOLO-2 The safety of Lynparza for the maintenance treatment of patients with platinum sensitive g BRCA m ovarian cancer was investigated in SOLO-2 [see Clinical Studies (14.3) ] . Patients received Lynparza tablets 300 mg orally twice daily (n=195) or placebo (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Lynparza and 5.6 months for patients who received placebo. Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving Lynparza. Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in SOLO-2. Table 6 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. in SOLO-2 (≥20% of Patients Who Received Lynparza) Adverse Reaction Lynparza tablets n=195 Placebo n=99 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 76 3 33 0 Vomiting 37 3 19 1 Diarrhea 33 2 22 0 Stomatitis Represents grouped term consisting of abscess oral, aphthous ulcer, gingival abscess, gingival disorder, gingival pain, gingivitis, mouth ulceration, mucosal infection, mucosal inflammation, oral candidiasis, oral discomfort, oral herpes, oral infection, oral mucosal erythema, oral pain, oropharyngeal discomfort, and oropharyngeal pain. 20 1 16 0 General Disorders and Administration Site Conditions Fatigue including asthenia 66 4 39 2 Blood and Lymphatic Disorders Anemia Represents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell volume increased, and red blood cell count decreased. 44 20 9 2 Infections and Infestations Nasopharyngitis/URI/sinusitis/ rhinitis/influenza 36 0 29 0 Musculoskeletal and Connective Tissue Disorders Arthralgia/myalgia 30 0 28 0 Nervous System Disorders Dysgeusia 27 0 7 0 Headache 26 1 14 0 Metabolism and Nutrition Disorders Decreased appetite 22 0 11 0 Clinically relevant adverse reactions that occurred in upper limit of normal (ULN). 89 – 52 – Decrease in hemoglobin 83 17 69 0 Decrease in leukocytes 69 5 48 1 Decrease in lymphocytes 67 11 37 1 Decrease in absolute neutrophil count 51 7 34 3 Increase in serum creatinine 44 0 29 0 Decrease in platelets 42 2 22 1 Adjuvant Treatment of germline BRCA -mutated HER2-negative High Risk Early Breast Cancer OlympiA The safety of Lynparza as monotherapy for the adjuvant treatment of patients with gBRCA-mutated HER2-negative high risk early breast cancer was investigated in OlympiA [see Clinical Studies (14.4) ] . This study was a randomized, double-blind, multi-center study in which patients received either Lynparza tablets 300 mg orally twice daily (n=911) or placebo (n=904) for a total of 1 year, or until disease recurrence, or unacceptable toxicity. The median duration of treatment was 1 year in both arms. Dose interruptions due to an adverse reaction of any grade occurred in 31% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 23% of patients receiving Lynparza. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (11%), neutropenia (6%), nausea (5%), leukopenia (3.5%), fatigue (3%), and vomiting (2.9%) and the most frequent adverse reactions leading to dose reduction of Lynparza were anemia (8%), nausea (4.7%), neutropenia (4.2%), fatigue (3.3%), leukopenia (1.8%), and vomiting (1.5%). Discontinuation due to adverse reactions occurred in 10% of patients receiving Lynparza. The adverse reactions that most frequently led to discontinuation of Lynparza were nausea (2%), anemia (1.8%), and fatigue (1.3%). Tables 8 and 9 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in OlympiA. Table 8 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 in OlympiA (≥ 10% of Patients Who Received Lynparza) Adverse Reactions Lynparza tablets n=911 Placebo n=904 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 57 0.8 23 0 Vomiting 23 0.7 8 0 Diarrhea 18 0.3 14 0.3 Stomatitis Includes aphthous ulcer, mouth ulceration, and stomatitis. 10 0.1 4.5 0 General Disorders and Administration Site Conditions Fatigue (including asthenia) 42 1.8 28 0.7 Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, erythropenia, hematocrit decreased, hemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. 24 9 3.9 0.3 Leukopenia Includes leukopenia and white blood cell count decreased. 17 3 6 0.3 Neutropenia Includes agranulocytosis, febrile neutropenia, granulocyte count decreased, granulocytopenia, idiopathic neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased. 16 5 7 0.8 Nervous System Disorders Headache 20 0.2 17 0.1 Dysgeusia Includes dysgeusia and taste disorder. 12 0 4.8 0 Dizziness 11 0.1 7 0.1 Metabolism and Nutrition Disorders Decreased appetite 13 0.2 6 0 Clinically relevant adverse reactions that occurred in ULN. 67 0 4.8 0 Decrease in hemoglobin 65 8 31 0.9 Decrease in leukocytes 64 5 42 0.7 Decrease in absolute neutrophil count 39 7 27 1.1 Germline BRCA -mutated HER2-negative Metastatic Breast Cancer OlympiAD The safety of Lynparza was evaluated in g BRCA m patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD [see Clinical Studies (14.5) ] . Patients received either Lynparza tablets 300 mg orally twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy. Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 35% and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse reaction occurred in 5% of patients receiving Lynparza. Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities in OlympiAD. Table 10 Adverse Reactions Graded according to NCI CTCAE v4.0. in OlympiAD (≥20% of Patients Who Received Lynparza) Adverse Reaction Lynparza tablets n=205 Chemotherapy n=91 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Nausea 58 0 35 1 Vomiting 30 0 15 1 Diarrhea 21 1 22 0 Blood and Lymphatic Disorders Anemia Represents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased). 40 16 26 4 Neutropenia Represents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased). 27 9 50 26 Leukopenia Represents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased). 25 5 31 13 General Disorders and Administration Site Conditions Fatigue (including asthenia) 37 4 36 1 Infections and Infestations Respiratory tract infection Represents grouped terms consisting of bronchitis, influenza, lower respiratory tract infection, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 27 1 22 0 Nervous System Disorders Headache 20 1 15 2 Clinically relevant adverse reactions that occurred in ULN. 71 – 33 – Decrease in absolute neutrophil count 46 11 65 38 Decrease in platelets 33 3 28 0 First-line Maintenance Treatment of Germline BRCA -mutated Metastatic Pancreatic Adenocarcinoma POLO The safety of Lynparza as maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma following first-line treatment with platinum-based chemotherapy was evaluated in POLO [see Clinical Studies (14.6) ] . Patients received Lynparza tablets 300 mg orally twice daily (n=90) or placebo (n=61) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 34% were exposed for 6 months or longer and 25% were exposed for greater than one year. Among patients who received Lynparza, dosage interruptions due to an adverse reaction of any grade occurred in 35% and dosage reductions due to an adverse reaction occurred in 17%. The most frequent adverse reactions leading to dosage interruption or reduction in patients who received Lynparza were anemia (11%), vomiting (5%), abdominal pain (4%), asthenia (3%), and fatigue (2%). Discontinuation due to adverse reactions occurred in 6% of patients receiving Lynparza. The most frequent adverse reaction that led to discontinuation of Lynparza was fatigue (2.2%). Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities in patients in POLO. Table 12 Adverse Reactions Graded according to NCI CTCAE, version 4.0. in POLO (Occurring in ≥10% of Patients who Received Lynparza) Adverse Reaction Lynparza tablets (n=91) This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. Placebo (n=60) All Grades (%) Grades 3 – 4 (%) All Grades (%) Grades 3 – 4 (%) General Disorders and Administration Site Conditions Fatigue Includes asthenia and fatigue. 60 5 35 2 Gastrointestinal Disorders Nausea 45 0 23 2 Abdominal pain Includes abdominal pain, abdominal pain upper, and abdominal pain lower. 34 2 37 5 Diarrhea 29 0 15 0 Constipation 23 0 10 0 Vomiting 20 1 15 2 Stomatitis Includes stomatitis and mouth ulceration. 10 0 5 0 Blood and Lymphatic System Disorders Anemia 27 11 17 3 Thrombocytopenia Includes platelets count decreased and thrombocytopenia. 14 3 7 0 Neutropenia Includes neutropenia, febrile neutropenia, and neutrophil count decreased. 12 4 8 3 Metabolism and Nutrition Disorders Decreased appetite 25 3 7 0 Musculoskeletal and Connective Tissue Disorders Back pain 19 0 17 2 Arthralgia 15 1 10 0 Skin and Subcutaneous Tissue Disorder Rash Includes rash erythematous, rash macular, and rash maculo-papular. 15 0 5 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Includes dyspnea and dyspnea exertional. 13 0 5 2 Infections and Infestations Nasopharyngitis 12 0 3 0 Nervous System Disorders Dysgeusia 11 0 5 0 Clinically relevant adverse reactions that occurred in ULN. 71 – 30 – Decrease in lymphocytes 61 9 27 0 Decrease in platelets 56 2 39 0 Decrease in leukocytes 50 3 23 0 Decrease in absolute neutrophil count 25 3 10 0 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer PROfound The safety of Lynparza as monotherapy was evaluated in patients with mCRPC and HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone in PROfound [see Clinical Studies (14.7) ] . This study was a randomized, open-label, multi-center study in which 386 patients received either Lynparza tablets 300 mg orally twice daily (n=256) or investigator’s choice of enzalutamide or abiraterone acetate (n=130) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 62% were exposed for 6 months or longer and 20% were exposed for greater than one year. Fatal adverse reactions occurred in 4% of patients treated with Lynparza. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%). Serious adverse reactions occurred in 36% of patients receiving Lynparza. The most frequent serious adverse reactions (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%). Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 22% of Lynparza patients. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (25%) and thrombocytopenia (6%) and the most frequent adverse reaction leading to reduction of Lynparza was anemia (16%). Discontinuation due to adverse reactions occurred in 18% of Lynparza. The adverse reaction that most frequently led to discontinuation of Lynparza was anemia (7%). Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound. Table 14 Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Reported in ≥10% of Patients in PROfound Adverse Reactions Lynparza tablets n=256 Enzalutamide or abiraterone n=130 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Blood and lymphatic disorders Anemia Includes anemia and hemoglobin decreased. 46 21 15 5 Thrombocytopenia Includes platelet count decreased and thrombocytopenia. 12 4 3 0 Gastrointestinal disorders Nausea 41 1 19 0 Diarrhea 21 1 7 0 Vomiting 18 2 12 1 General disorders and administration site conditions Fatigue (including asthenia) 41 3 32 5 Metabolism and nutrition disorders Decreased appetite 30 1 18 1 Respiratory, thoracic, and mediastinal disorders Cough 11 0 2 0 Dyspnea 10 2 3 0 Clinically relevant adverse reactions that occurred in 2% of patients included anemia (6%), COVID-19 (6%), pneumonia (4.5%), pulmonary embolism (3.5%), and urinary tract infection (3%). Permanent discontinuation of Lynparza due to adverse reactions occurred in 16% of patients treated in the Lynparza with abiraterone arm. The most common adverse reactions which resulted in permanent discontinuation of Lynparza were anemia (4.3%) and pneumonia (1.5%). Dosage interruption of Lynparza due to adverse reactions occurred in 48% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage interruption of Lynparza were anemia (16%), COVID-19 (6%) fatigue (3.5%), nausea (2.8%), pulmonary embolism (2.3%), and diarrhea (2.3%). Dose reduction of Lynparza due to adverse reactions occurred in 21% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage reductions of Lynparza were anemia (11%) and fatigue (2.5%). The most common adverse reactions (≥10%) in patients who received Lynparza/abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities in PROpel, respectively. Table 16 Adverse Reactions (≥10%) in Patients Who Received Lynparza (with a Difference of ≥5% Compared to Placebo) in PROpel Adverse Reactions Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Lynparza/abiraterone n=398 Placebo/abiraterone n=396 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Blood and Lymphatic Disorders Anemia Includes anemia, anemia macrocytic, and red blood cell count decreased 48 16 18 3.3 Lymphopenia Includes lymphocyte count decreased and lymphopenia 14 5 6 1.8 General Disorders and Administration Site Conditions Fatigue (including asthenia) 38 2.3 30 1.5 Gastrointestinal Disorders Nausea 30 0.3 14 0.3 Diarrhea 19 1 10 0.3 Abdominal pain Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal pain lower 13 0 7 0.5 Metabolism and nutrition disorders Decreased appetite 16 1 7 0 Nervous System Disorders Dizziness Includes dizziness and vertigo. 14 0.3 7 0 Clinically relevant adverse reactions that occurred in <10% for patients receiving Lynparza plus abiraterone were headache (9%), VTE (8%), rash (7%), dysgeusia (6%), acute kidney injury (3%), stomatitis (2.5%), and pneumonitis (1%). Table 17 Selected Laboratory Abnormalities Reported in ≥20% of Patients in PROpel Laboratory Parameter Lynparza/abiraterone n=398 This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. Placebo/abiraterone n=396 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Decrease in hemoglobin 97 12 81 1.3 Decrease in lymphocytes 70 23 49 11 Decrease in platelets 23 1.2 20 0.3 Decrease in absolute neutrophil count 23 5 6 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders : Drug-induced liver injury. Immune System Disorders : Hypersensitivity including angioedema. Skin and Subcutaneous Tissue Disorders : Erythema nodosum, rash, dermatitis.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1) ] , Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily (see Data ). Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies. Data Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h ) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC 0-24h ) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery. Some findings noted above in the eyes, ribs, and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence. 8.2 Lactation Risk Summary No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose. 8.3 Females and Males of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating treatment with Lynparza. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months following the last dose. Males Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness of Lynparza have not been established in pediatric patients. 8.5 Geriatric Use Of the 2901 patients with advanced solid tumors who received Lynparza as a single agent, 680 (23%) patients were aged ≥65 years, and this included 206 (7%) patients who were aged ≥75 years. Thirteen (0.4%) patients were aged ≥85 years. Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (PAOLA-1), 204 (38%) patients were aged ≥65 years, and this included 31 (6%) patients who were aged ≥75 years. Of the 398 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with abiraterone and prednisone or prednisolone (PROpel), 268 (67%) patients were aged ≥65 years, and this included 95 (24%) patients who were aged ≥75 years. No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients. 8.6 Renal Impairment No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min) [see Dosage and Administration (2.5) ]. There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤30 mL/min) [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C) [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1) ] , Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily (see Data ). Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies. Data Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC 0-24h ) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC 0-24h ) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery. Some findings noted above in the eyes, ribs, and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.