PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0310-0679-60 Lynparza (olaparib) tablets 150mg Attention: Lynparza Tablets and Capsules are NOT substitutable. Do NOT take more than 4 Tablets a day. 60 Tablets Rx only AstraZeneca

ADVERSE REACTIONS SECTION.


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)] Most common adverse reactions (20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, neutropenia leukopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation and stomatitis. (6.1) Most common laboratory abnormalities (25%) were decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine and decrease in platelets. (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. Adverse reactions presented below were reported from clinical trials in 782 patients with ovarian cancer (555 received Lynparza, 227 received placebo). Maintenance Treatment of Recurrent Ovarian Cancer SOLO-2 The safety of Lynparza for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2. This study was a placebo-controlled, double-blind study in which 294 patients received either Lynparza 300 mg (2 x 150 mg tablets) twice daily (n=195) or placebo tablets twice daily (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. Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza and 18% of those receiving placebo; dose reductions due to an adverse reaction occurred in 27% of Lynparza patients and 3% of placebo patients. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation occurred in 11% of Lynparza patients and 2% in placebo patients. Table 1 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in SOLO-2. Table 2 presents the laboratory abnormalities that occurred in at least 25% of patients who received Lynparza in SOLO-2. Table 1 Adverse ReactionsGraded 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 Reactions Lynparza tablets n=195 Placebo n=99 Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Blood and lymphatic disorders AnemiaRepresents 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 Gastrointestinal disorders Nausea 76 3 33 0 Vomiting 37 3 19 1 Diarrhea 33 2 22 0 StomatitisRepresents 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 Infections and Infestations Nasopharyngitis/ URI/ sinusitis/ rhinitis/ influenza 36 0 29 0 General disorders and administration site conditions Fatigue including asthenia 66 4 39 2 Metabolism and nutrition disorders Decreased appetite 22 0 11 0 Musculoskeletal and connective tissue disorder Arthralgia/myalgia 30 0 28 0 Nervous system disorders Dysgeusia 27 0 7 0 Headache 26 1 14 0 In addition, the adverse reactions observed in SOLO-2 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 Study 19 The safety of Lynparza capsules as maintenance monotherapy was also evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19, a randomized, placebo-controlled, double-blind, multi-center study in which 264 patients received Lynparza 400 mg twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Lynparza and 4.6 months in patients who received placebo. Adverse reactions led to dose interruptions in 35% of those receiving Lynparza and 10% of those receiving placebo; dose reductions in 26% of Lynparza and 4% of placebo; and discontinuation in 6% of Lynparza and 2% in placebo. Table 3 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in Study 19. Table 4 presents the laboratory abnormalities that occurred in at least 25% of patients from Study 19. Table 3 Adverse ReactionsGraded according to NCI CTCAE 4.0. in Study 19 (20% of Patients who Received Lynparza) Adverse Reactions Lynparza capsules n=136 Placebo n=128 Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Blood and lymphatic disorders AnemiaRepresents grouped terms of related terms that reflect the medical concept of the adverse reaction. 23 7 7 1 Gastrointestinal disorders Nausea 71 2 36 0 Vomiting 35 2 14 1 Diarrhea 28 2 25 2 Constipation 22 1 12 0 General disorders and administration site conditions Fatigue (including asthenia) 63 9 46 3 Infections and infestations Respiratory tract infection 22 2 11 0 Metabolism and nutrition disorders Decreased appetite 21 0 13 0 Nervous system disorders Headache 21 0 13 1 In addition, the adverse reactions in Study 19 that occurred in ULN. 82 - 51 - Decrease in leukocytes 58 4 37 2 Decrease in lymphocytes 52 10 32 3 Decrease in absolute neutrophil count 47 7 40 2 Increase in serum creatinine 45 0 14 0 Decrease in platelets 36 4 18 0 Treatment of Advanced gBRCAm Ovarian Cancer After 3 or More Lines of Chemotherapy Pooled data Treatment with Lynparza (capsule formulation) as monotherapy was studied in 223 patients (pooled from 6 studies) with gBRCAm advanced ovarian cancer who had received 3 or more prior lines of chemotherapy. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4% of patients, and discontinuation in 7% of patients. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. The median exposure to Lynparza capsules in these patients was 5.2 months. Table 5 presents adverse reactions reported in 20% of patients and Table 6 presents laboratory abnormalities that occurred in at least 25% of patients from the pooled studies. Table 5 Adverse Reactions Reported in Pooled Data (20% of Patients who Received Lynparza) Adverse Reactions 3 or more lines of prior Chemotherapy Grades 1-4 n=223 (%) Grades 3-4 n=223 (%) Blood and Lymphatic disorders Anemia 34 18 Gastrointestinal disorders Decreased appetite 22 1 Nausea 64 3 Vomiting 43 4 Diarrhea 31 1 Dyspepsia 25 0 General disorders Fatigue/asthenia 66 8 Infections and infestations Nasopharyngitis/URI 26 0 Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain 21 0 Myalgia 22 0 Table 6 Laboratory Abnormalities Reported 25% of Patients in Pooled Data Laboratory Parameter Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. 3 or more lines of prior Chemotherapy Grades 1-4 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. =223 (%) Grades 3-4 n =223 (%) Decrease in hemoglobin 90 15 Decrease in absolute neutrophil count 25 7 Decrease in platelets 30 3 Decrease in lymphocytes 56 17 Mean corpuscular volume elevation 57 - Increase in creatinine 30 2 The following adverse reactions and laboratory abnormalities have been identified in 10 to ULN. 71 - 33 - Decrease in hemoglobin 82 17 66 3 Decrease in leukocytes 71 8 70 23 Decrease in lymphocytes 73 21 63 3 Decrease in absolute neutrophil count 46 11 65 38 Decrease in platelets 33 3 28 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Lynparza capsules. 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. Immune System Disorders: Hypersensitivity (rash/dermatitis).

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: Ovarian cancer 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 or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (1.2, 2.3) Breast cancer in patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (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. (1.3, 2.4) 1.1 Maintenance Treatment of Recurrent Ovarian Cancer Lynparza 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. 1.2 Advanced gBRCA-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza [see Dosage and Administration (2.3)]. 1.3 Germline BRCA-mutated HER2-negative Metastatic Breast Cancer Lynparza is indicated in patients with deleterious or suspected deleterious gBRCAm, 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 (2.4) ] .

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Tablets: 150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment OP150 on one side and plain on the reverse side. 100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment OP100 on one side and plain on the reverse side. Tablets: 150 mg, 100 mg (3)

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION To avoid substitution errors and overdose, do not substitute Lynparza tablets with Lynparza capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. (2.1) Recommended tablet dose is 300 mg taken orally twice daily with or without food. (2.2) Continue treatment until disease progression or unacceptable toxicity. (2.2) For adverse reactions, consider dose interruption or dose reduction. (2.5) For moderate renal impairment (CLcr 31-50 mL/min), reduce dose to 200 mg twice daily. (2.7) 2.1 Important Administration Instructions Lynparza is also available as a 50 mg capsule. DO NOT substitute Lynparza tablets (100 mg and 150 mg) with Lynparza capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation [see Clinical Pharmacology (12.3)]. Refer to the full prescribing information for Lynparza capsules for specific capsule dosing. 2.2 Recommended Dosing The recommended dose of Lynparza is 300 mg (two 150 mg tablets) taken orally twice daily, with or without food, for a total daily dose of 600 mg. The 100 mg tablet is available for dose reduction. Continue treatment until disease progression or unacceptable toxicity. If a patient misses a dose of Lynparza, instruct patient to take their next dose at its scheduled time. Swallow tablets whole. Do not chew, crush, dissolve, or divide tablet [see How Supplied/Storage and Handling (16.2) ]. 2.3 Patient Selection for gBRCAm Advanced Ovarian Cancer Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious BRCA-mutations [see Indications and Usage (1.2) and Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics. 2.4 Patient Selection for gBRCAm HER2-negative Metastatic Breast Cancer Select patients for the treatment of HER2-negative metastatic breast cancer with Lynparza based on the presence of deleterious or suspected deleterious gBRCA-mutation [see Indications and Usage (1.3) and Clinical Studies (14.3) ]. Information on FDA-approved tests for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics. 2.5 Dose Adjustments for Adverse Reactions To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg (one 150 mg tablet and one 100 mg tablet) taken twice daily, for a total daily dose of 500 mg. If a further dose reduction is required, then reduce to 200 mg (two 100 mg tablets) taken twice daily, for a total daily dose of 400 mg. 2.6 Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If a strong CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 100 mg (one 100 mg tablet) taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg) [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 2.7 Dose Modifications for Patients with Renal Impairment Patients with mild renal impairment (CLcr 51-80 mL/min as estimated by Cockcroft-Gault equation) do not require an adjustment in Lynparza dosing. In patients with moderate renal impairment (CLcr 31-50 ml/min) the recommended dose reduction is to 200 mg (two 100 mg tablets) twice daily, for a total daily dose of 400 mg. The pharmacokinetics of Lynparza have not been evaluated in patients with severe renal impairment or end-stage renal disease (CLcr 30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Lynparza is available as 150 mg and 100 mg tablets. 150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment OP150 on one side and plain on the reverse, are available in: Bottles of 60 tablets (NDC 0310-0679-60) and Bottles of 120 tablets (NDC 0310-0679-12). 100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment OP100 on one side and plain on the reverse, are available in: Bottles of 60 tablets (NDC 0310-0668-60) and Bottles of 120 tablets (NDC 0310-0668-12). 16.2 Storage Store at 20C to 25C (68F to 77F), excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store in original bottle to protect from moisture.

DESCRIPTION SECTION.


11 DESCRIPTION Olaparib is an inhibitor of the mammalian polyadenosine 5-diphosphoribose polymerase (PARP) enzyme. The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure: The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46. Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range. Lynparza tablets for oral administration contain 100 mg or 150 mg of olaparib. Inactive ingredients in the tablet core are copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate. The tablet coating consists of hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only).

OVERDOSAGE SECTION.


10 OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat the patient symptomatically.

SPL MEDGUIDE SECTION.


Lung problems (pneumonitis). Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis. Pneumonitis may lead to death. BRCA BRCAIt is not known if Lynparza is safe and effective in children. Females Males Tell your healthcare provider right away if you become pregnant. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects. notdo notDo not Keep Lynparza and all medicines out of the reach of children. Medication Guide Lynparza (Lin-par-zah) (olaparib) tablets What is the most important information I should know about Lynparza? Lynparza may cause serious side effects, including: Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have ovarian cancer or breast cancer and who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with Lynparza. Symptoms of low blood cell counts are common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms may include: weakness weight loss fever frequent infections blood in urine or stool shortness of breath feeling very tired bruising or bleeding more easily Your healthcare provider will do blood tests to check your blood cell counts: before treatment with Lynparza every month during treatment with Lynparza weekly if you have low blood cell counts that last a long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve. What is Lynparza? Lynparza is a prescription medicine used to treat adults with: Ovarian cancer owho have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy or owho have advanced ovarian cancer with a certain type of abnormal inherited gene, and have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you. Breast cancer owho have a certain type of abnormal inherited gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you. Before taking Lynparza, tell your healthcare provider about all of your medical conditions, including if you: have lung or breathing problems have kidney problems are pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage). If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with Lynparza. who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you. with female partners who are pregnant or able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 3 months after the last dose of Lynparza. Do not donate sperm during treatment with Lynparza and for 3 months after your final dose. are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time. How should I take Lynparza? Take Lynparza tablets exactly as your healthcare provider tells you. Your healthcare provider may temporarily stop treatment with Lynparza or change your dose of Lynparza if you experience side effects. Lynparza comes as tablets and capsules. Lynparza tablets and capsules are the same. If your healthcare provider prescribes Lynparza tablets for you, take Lynparza capsules. take more than 4 Lynparza tablets in 1 day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist. Take Lynparza by mouth 2 times a day. Each dose should be taken about 12 hours apart. Swallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets. Take Lynparza with or without food. If you miss a dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for a missed dose. If you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking Lynparza? Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during treatment with Lynparza since they may increase the level of Lynparza in your blood. What are the possible side effects of Lynparza? Lynparza may cause serious side effects. See What is the most important information I should know about Lynparza? The most common side effects of Lynparza are: nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms. low number of red or white blood cells tiredness or weakness sore throat or runny nose diarrhea joint, muscle, and back pain headache constipation changes in the way food tastes loss of appetite mouth sores respiratory tract infections changes in kidney function blood test low number of platelets indigestion or heartburn These are not all the possible side effects of Lynparza. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Lynparza? Store Lynparza at room temperature, between 68F to 77F (20C to 25C). Store Lynparza in the original bottle to protect it from moisture. General information about the safe and effective use of Lynparza Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lynparza for a condition for which it was not prescribed. Do not give Lynparza 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 information about Lynparza that is written for health professionals. What are the ingredients in Lynparza? Active ingredient: olaparib Inactive ingredients: Tablet contains: copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate Tablet coating contains: hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only) Lynparza is a registered trademark of the AstraZeneca group of companies. AstraZeneca 2018 Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 For more information, call 1-800-236-9933 or go to www.Lynparza.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 2/2018

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in 2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia. 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 fatal cases, occurred in < 1% of patients treated with Lynparza. 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 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. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza [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 3 months following the last dose of Lynparza [see Use in Specific Populations (8.1 , 8.3) ] .

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the olaparib dose. (2.6, 7.2, 12.3) CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers as decreased efficacy can occur. (7.3, 12.3) 7.1 Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. 7.2 Drugs That May Increase Olaparib Plasma Concentrations Olaparib is primarily metabolized by CYP3A. In patients (n=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 170%. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 121%. Avoid concomitant use of strong CYP3A inhibitors such as itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir or moderate CYPA inhibitors such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil. If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.5)]. Avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during Lynparza treatment since they are CYP3A inhibitors [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. 7.3 Drugs That May Decrease Olaparib Plasma Concentrations In patients (n=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by approximately 60%. Avoid concomitant use of strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. Johns Wort or moderate CYP3A4 inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin. If a moderate CYP3A inducer cannot be avoided, there is a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with olaparib. Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian Chinese hamster ovary (CHO) cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test. In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 7% of the human exposure (AUC0-24h) at the recommended dose). In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC0-24h) at the recommended dose).

USE IN SPECIFIC POPULATIONS SECTION.


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 (AUC0-24h) 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 (AUC0-24h) 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 Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Lynparza. Contraception Females Lynparza 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 with Lynparza and for at least 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 The safety and efficacy of Lynparza have not been established in pediatric patients. 8.5 Geriatric Use In clinical studies of Lynparza enrolling 687 patients with advanced solid tumors who received Lynparza tablets 300 mg twice daily as monotherapy, 146 (21%) patients were aged 65 years, and this included 29 (4%) patients who were aged 75 years. No patients were aged 85 years. No overall differences in the safety or effectiveness of Lynparza were observed between younger and older patients. 8.6 Hepatic Impairment No adjustment to the starting dose is required in patients with mild hepatic impairment. A 15% increase in mean exposure (AUC) was observed in patients with mild hepatic impairment (based on Child-Pugh classification A) compared to patients with normal hepatic function. There are no data in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. A 24% increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 51-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). A 44% increase in AUC was observed in patients with moderate renal impairment (CLcr = 31-50 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). For patients with moderate renal impairment, reduce the dose of Lynparza to 200 mg twice daily [see Dosage and Administration (2.6)]. There are no data in patients with severe renal impairment or end-stage disease (CLcr 30 mL/min) [see Clinical Pharmacology (12.3)].

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1.3) 1/2018 Dosage and Administration (2.4) 1/2018 Warnings and Precautions (5) 1/2018

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Instructions: Inform patients that Lynparza should be taken twice daily with or without food. Instruct patients that if they miss a dose of Lynparza, they should take their next normal dose at the usual time. Swallow each tablet whole. Do not chew, crush, dissolve, or divide tablet. Do not take more than 4 tablets daily [see Dosage and Administration (2.2)]. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza [see Drug Interactions (7.3)]. Inform patients not to substitute Lynparza tablets (100 mg and 150 mg) with Lynparza capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation [see Dosage and Administration (2.1)]. 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 a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1)]. Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2)]. Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a 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 with Lynparza and for 6 months after the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months after receiving 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 Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. Lactation: Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose [see Use in Specific Populations (8.2)]. Nausea/Vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Maintenance Treatment of Recurrent Ovarian Cancer The efficacy of Lynparza was investigated in two randomized, placebo-controlled, double-blind, multicenter studies in patients with recurrent ovarian cancers who were in response to platinum-based therapy. SOLO-2 SOLO-2 (NCT01874353) was a double-blind, placebo-controlled trial in which patients (n=295) with gBRCAm ovarian, fallopian tube, or primary peritoneal cancer were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 months versus > 12 months). All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. All patients had a deleterious or suspected deleterious germline BRCA-mutation as detected either by a local test (n= 236) or central Myriad CLIA test (n=59), subsequently confirmed by BRACAnalysis CDx (n= 286). The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional endpoints included overall survival (OS). The median age of patients treated with Lynparza was 56 years (range: 28 to 83) and 56 years (range: 39 to 78) among patients treated with placebo. The Eastern Cooperative Oncology Group (ECOG) performance score was 0 in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were White, 17% were enrolled in the U.S. or Canada, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment. SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo (Table 9 and Figure 1). Results from a blinded independent review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature with 24% of events. Table 9 Efficacy Results SOLO-2 (Investigator Assessment) Lynparza tablets (n=196) Placebo (n=99) Progression-Free Survival Number of events (%) 107 (54.6%) 80 (80.8%) Median, months 19.1 5.5 Hazard ratioHazard ratio from the stratified proportional hazards model, stratified by response to last platinum chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment. (95% CI) 0.30 (0.22, 0.41) p-valueThe p-value is derived from a stratified log-rank test. 12 months), and descent (Jewish versus non-Jewish). The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to RECIST, version 1.0. The median age of patients treated with Lynparza (n=136) was 58 years (range: 21 to 89) and 59 years (range 33 to 84) among patients treated with placebo (n=129). ECOG performance status was 0 in 81% of patients receiving Lynparza and 74% of patients receiving placebo. Of all patients, 97% were White, 19% were enrolled in the US or Canada, 45% were in complete response following their most recent platinum chemotherapy regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum. Prior bevacizumab therapy was reported for 13% of patients receiving Lynparza and 16% of patients receiving placebo. A retrospective analysis for germline BRCA mutation status, some performed using the Myriad test, indicated that 36% (n=96) of patients from the ITT population had deleterious gBRCA mutation, including 39% (n=53) of patients on Lynparza and 33% (n=43) of patients on placebo. Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with Lynparza versus placebo (Table 10 and Figure 2). Table 10 Efficacy Results - Study 19 (Investigator Assessment) Lynparza capsules (n=136) Placebo (n=129) Progression-Free Survival Number of events (%) 60 (44%) 94 (73%) Median, months 8.4 4.8 Hazard ratioHazard ratio is derived from a stratified proportional hazards model, stratified by response to last platinum chemotherapy, time to disease progression in the penultimate platinum-based chemotherapy and Jewish and non-Jewish descent. (95% CI) 0.35 (0.25, 0.49) p-valueThe p-value is derived from a stratified log-rank test. gBRCA-mutated Ovarian Cancer Treated with 3 or More Prior Lines of Chemotherapy The efficacy of Lynparza was also investigated in a single-arm study of patients with deleterious or suspected deleterious gBRCAm advanced cancers. A total of 137 patients with measurable, advanced gBRCAm ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza capsules at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator according to RECIST, version 1.0. The median age of the patients was 58 years, the majority were White (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious gBRCAm status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the BRACAnalysis CDx. Efficacy results are summarized in Table 11. Table 11 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received 3 or More Lines of Chemotherapy n=137 Objective Response Rate (95% CI) 34% (26, 42) Complete Response 2% Partial Response 32% Median DOR in months (95% CI) 7.9 (5.6, 9.6) 14.3 Treatment of gBRCAm HER2-negative Metastatic Breast Cancer OlympiAD OlympiAD (NCT02000622) was an open-label study in which patients (n=302) with gBRCAm HER2-negative metastatic breast cancer were randomized 2:1 to receive Lynparza 300 mg tablets or healthcare providers choice of chemotherapy (capecitabine, eribulin, or vinorelbine, at standard doses) until progression or unacceptable toxicity. Randomization was stratified by prior use of chemotherapy for metastatic disease (yes vs no), hormone receptor status (hormone receptor positive vs triple negative), and previous use of platinum-based chemotherapy (yes vs no). Patients were required to have received treatment with an anthracycline (unless contraindicated) and a taxane, in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor-positive disease must have progressed on at least 1 endocrine therapy (adjuvant or metastatic), or have disease that the treating healthcare provider believed to be inappropriate for endocrine therapy. Patients with prior platinum therapy were required to have no evidence of disease progress during platinum treatment. No prior treatment with a PARP inhibitor was permitted. Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDX and 297 were confirmed to have deleterious or suspected deleterious gBRCAm status; 202 were randomized to the Lynparza arm and 95 to the healthcare providers choice of chemotherapy arm. Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76), 65% were White, 4% were males and all the patients had an ECOG PS of 0 or 1. Approximately 50% of patients had triple-negative tumors and 50% had estrogen receptor and/or progesterone receptor positive tumors and the proportions were balanced across treatment arms. Patients in each treatment arm had received a median of 1 prior chemotherapy regimen for metastatic disease; approximately 30% had not received a prior chemotherapy regimen for metastatic breast cancer. Twenty-one percent of patients in the Lynparza arm and 14% in the chemotherapy arm had received platinum therapy for metastatic disease. Seven percent of patients in each treatment arm had received platinum therapy for localized disease. The major efficacy outcome measure was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1. A statistically significant improvement in PFS was demonstrated for the Lynparza arm compared to the chemotherapy arm. Efficacy data for OlympiAD are displayed in Table 12 and Figure 3. Consistent results were observed across patient subgroups defined by study stratification factors. An exploratory analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. The overall survival (OS) data were not mature at the time of the final PFS analysis (46% of patients had died). Table 12 Efficacy Results - OlympiAD (BICR-assessed) Lynparza tablets (n=205) Chemotherapy (n=97) Progression-Free Survival Number of events (%) 163 (80%) 71 (73%) Median, months 7.0 4.2 Hazard ratio (95% CI)Hazard ratio is derived from a stratified log-rank test, stratified by ER, PgR negative versus ER and or PgR positive and prior chemotherapy (yes versus no) 0.58 (0.43, 0.80) p-valueFor PFS, p-value (2-sided) was compared to 0.05 0.0009 Patients with Measurable Disease n=167 n=66 Objective Response Rate (95% CI)Response based on confirmed responses. The confirmed complete response rate was 7.8% for Lynparza compared to 1.5% for chemotherapy arm. 52% (44, 60) 23% (13, 35) Figure 3: Kaplan-Meier Curves of Progression-Free Survival OlympiAD

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA and non-BRCA proteins involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed. 12.3 Pharmacokinetics Lynparza is available as a tablet and capsule formulation. The oral bioavailability of the tablet formulation is higher than the capsule formulation. Population pharmacokinetic analyses have shown that the steady state exposure (AUC) following 300 mg tablet twice daily was 77% higher compared to that following 400 mg capsule twice daily. The olaparib geometric mean AUC and Cmax following a single 300 mg tablet dose were 42.0 g*h/mL (n = 204) and 5.8 g/mL (n = 204), respectively, and the steady state geometric mean AUC and Cmax following 300 mg tablet twice daily were 49.0 g*h/mL (n = 227) and 7.7 g/mL (n = 227), respectively. Olaparib showed time-dependent PK that the steady state clearance decreased by 15% after multiple dosing. Absorption Following oral administration of olaparib, absorption is rapid with median peak plasma concentrations typically achieved 1.5 hours after dosing. An AUC mean accumulation ratio of 1.8 is observed at steady state following multiple dosing of 300 mg tablets twice daily. Systemic exposure (single dose AUC) to olaparib increases approximately proportionally with doses over the dose range of 25 mg to 450 mg, Cmax increased slightly less than proportionally for the same dose range. Co-administration of a high fat meal with olaparib slowed the rate (tmax delayed by 2.5 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%). Distribution Olaparib had a mean ( standard deviation) apparent volume of distribution of 158 136 L after a single 300 mg dose of olaparib. The in vitro protein binding of olaparib is approximately 82%. Metabolism In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism of olaparib. Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation. Excretion A mean ( standard deviation) terminal plasma half-life of 14.9 8.2 hours and apparent plasma clearance of 7.4 3.9 L/h were observed after a single 300 mg dose of olaparib. Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites. Drug Interactions Based on the data from a drug-interaction trial (n=57), the AUC and Cmax of olaparib increased by 170% and 42%, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 121% and 14%, respectively. Based on the data from a drug-interaction trial (n=22), the AUC and Cmax of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by approximately 60% and 31%, respectively. In vitro studies have shown that olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be a weak CYP3A inhibitor in humans. In vitro studies also indicated that olaparib is an inhibitor of UGT1A1, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. In vitro, olaparib is a substrate of, and inhibits, the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated. Pharmacokinetics in Specific Populations Hepatic Impairment In a hepatic impairment trial, the mean AUC increased by 15% and the mean Cmax by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=9) compared with patients with normal hepatic function (n=13). Mild hepatic impairment had no effect on the protein binding of olaparib and therefore total plasma exposure was representative of free drug. There are no data in patients with moderate or severe hepatic impairment. Renal Impairment In a renal impairment trial, the mean AUC increased by 24% and Cmax by 15%, when olaparib was dosed in patients with mild renal impairment (CLcr = 51-80 mL/min defined by the Cockcroft-Gault equation; n=13) and by 44% and 26%, respectively, when olaparib was dosed in patients with moderate renal impairment (CLcr = 31-50 mL/min; n=13), compared to those with normal renal function (CLcr 81 mL/min; n=12). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr 30 mL/min).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS None. None. (4)