奥拉帕尼胶囊|LYNPARZA(olaparib) capsules-药品说明书与价格-中国新特药网第一医药站
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奥拉帕尼胶囊|LYNPARZA(olaparib) capsules
奥拉帕尼胶囊|LYNPARZA(olaparib) capsules
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日，美国FDA授予Lynparza（Olaparib，中文药名；奥拉帕尼）加速批准，这款新药用于治疗与BRCA基因缺陷相关的晚期卵巢癌妇女，该基因缺陷可通过一种FDA批准的诊断试剂进行检测。 卵巢癌形成 ...关键字：
日，美国FDA授予Lynparza（Olaparib，中文药名；奥拉帕尼）加速批准，这款新药用于治疗与BRCA基因缺陷相关的晚期卵巢癌妇女，该基因缺陷可通过一种FDA批准的诊断试剂进行检测。 卵巢癌形成于卵巢中，卵巢是女性生殖腺，共有一对，也是卵细胞（卵子）形成的地方。美国国家癌症研究所预测，2014年美国将有2.198万名妇女被确诊患有卵巢癌，有1.427万人会死于这种疾病。Lynparza（Olaparib）是一种多聚二磷酸腺苷核糖聚合酶（PARP）抑制剂，它可阻断参与修复受损DNA 的酶。这款药物适用于高度预处理的与 BRCA 基因缺陷相关的卵巢癌。“今天的批准是一种用于治疗卵巢癌的新类型药物的首次批准，”FDA药物评价与研究中心血液及肿瘤产品办公室主任、医学博士Pazdur称。“Lynparza（Olaparib）被批准用于有特定BRCA基因缺陷的患者，这是对疾病潜在机理的一个更好理解，也是开发靶向、更具个体化治疗药物的一个例证。FDA批准Lynparza（Olaparib）时伴随批准一款叫BRACAnalysis CDx的基因检测试剂，它将用来检测卵巢癌患者的血样中是否存在BRCA 基因突变 (gBRCAm)。BRCA基因参与修复受损DNA，正常工作可抑制肿瘤增长。因突变而导致 BRCA 基因缺陷的妇女更可能发生卵巢癌，据预测，所有卵巢癌中10-15% 的人与这些遗传性BRCA突变相关。FDA通过该机构用于高风险医疗器械的上市前批准通道评价了BRACAnalysis CDx的安全性及有效性。目前为止，该生产商（一家临床实验室）一直在销售这种检测试剂，但不具体用作一种伴随诊断试剂，未获FDA 批准作为一种实验室开发检测试剂 (LDT)，即一种被设计、生产及用于单一实验室的试剂。这款新的检测试剂被批准作为一种伴随诊断试剂，特别是用来识别可能成为Lynparza（Olaparib）治疗候选人的晚期卵巢癌患者。“安全有效伴随诊断试剂及药物的批准依然是肿瘤领域重要的发展，”FDA器械及放射卫生体外诊断及放射卫生办公室主任、哲学博士Gutierrez 称。“我们很高兴 BRACAnalysis CDx 成为 FDA首款以及市前批准申请的方式而批准的一种LDT，也是一款首次获批的LDT伴随诊断试剂。伴随诊断试剂的使用有助于销售安全有效的特定满足患者需求的治疗药物。FDA对BRACAnalysis CDx的批准基于支持 Lynparza（Olaparib）批准的临床研究数据。来自临床试验受试者的血样通过检测证实该试剂可用于检测这类人群的BRCA突变。Lynparza（Olaparib）的疗效在一项由137名接受该药物治疗的gBRCAm相关卵巢癌受试者参与的研究中得到检测。这项研究旨在检测客观缓解率(ORR)，亦即经历肿瘤部分缩小或完全消失的受试者的比例。结果显示，34% 的受试者经历了平均7.9个月的ORR。Lynparza(Olaparib)的常见副作用有恶心、疲劳、呕吐、腹泻、扭曲的味道 (味觉障碍)、消化不良、头痛、食欲下降、常见的类似感冒症状(鼻咽炎)、咳嗽、关节疼痛(关节痛)、肌肉骨骼疼痛、肌肉疼痛(肌痛)、背部疼痛、皮疹(皮炎) 和腹痛。严重副作用包括发生骨髓增生异常综合征，这是一种骨髓不能产生足够功能性血细胞的病症，还包括急性骨髓性白血病（一种骨骨髓癌）及肺炎。最常见的实验室异常情况有肌酐升高、平均红细胞容积增加、白细胞计数降低（淋巴细胞和中性粒细胞）及血小板水平降低。6月份，Lynparza（Olaparib）作为维持治疗药物（阻止癌症回转的药物）的潜在立用途受到 FDA 肿瘤药物顾问委员会的审查。该委员会以11比2的投票结果向FDA建议，数据不支持Lynparza（Olaparib）用于这一适应症的加速批准。在此会议之后，该公司提交了其它支持Lynparza（Olaparib）用于不同用途的信息，即用于已接受三种或更多种化疗治疗的 gBRCAm 相关卵巢癌患者。FDA是以加速批准计划批准Lynparza(Olaparib)的，这一批准计划可允许基于显示一款药物对合理可能预测患者临床收益的代理终点有效的数据来批准这款药物用于治疗一种严重或危及生命的疾病。该计划可以使患者更早地获取新药，同时申请该药物的公司要进行验证性临床试验。Lynparza（Olaparib）的申请审评是在优先审评计划下完成的，这一计划为旨在治疗一种严重疾病或病症的药物提供一个加快的审评，如果获得批准，该药物与已上市产品相比将对疾病提供明显的改善。BRACAnalysis CDx的上市申请是以FDA用于器械的优先审评计划而完成审评的，这一计划可为满足某种标准的器械提供优先审评，这包括旨在治疗或诊断一种危及生命或不可逆转的使人衰弱的疾病或病症，如果获得批准，该器械与已上市产品相比，将为疾病提供明显的、具有临床意义的优势。Lynparza（Olaparib）由位于特拉华州威尔明顿的阿斯利康上市销售。BRACAnalysis CDx 位于盐湖城的 Myriad Genetic Laboratories 公司生产。
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LYNPARZA safely and effectively. See full prescribing information for LYNPARZA. LYNPARZA™ (olaparib) capsules, for oral use Initial U.S. Approval: 2014 INDICATIONS AND USAGE Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. (1.1) The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.1, 14) DOSAGE AND ADMINISTRATION • Recommended dose is 400 mg taken twice daily. ( 2.2) • Continue treatment until disease progression or unacceptable toxicity. ( 2.2) • For adverse reactions, consider dose interruption of treatment or dose reduction. ( 2.3) DOSAGE FORMS AND STRENGTHS Capsules: 50 mg ( 3) CONTRAINDICATIONS None (4)WARNINGS AND PRECAUTIONS • Myelodysplastic syndrome/Acute Myeloid Leukemia: (MDS/AML) occurred in patients exposed to Lynparza, and some cases were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. ( 5.1) • Pneumonitis: occurred in patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. ( 5.2) • Embryo-Fetal toxicity: Lynparza can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy. ( 5.3, 8.1) ADVERSE REACTIONS • Most common adverse reactions (≥20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort. ( 6.1) • Most common laboratory abnormalities (≥25%) were increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in absolute neutrophil count, 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 . DRUG INTERACTIONS • CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the dose. ( 2.3, 7.2) • CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy. ( 7.3) USE IN SPECIFIC POPULATIONS • Nursing Mothers: Discontinue treatment or discontinue nursing. ( 8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.Revised: 12/2014
FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Treatment of gBRCA-mutated advanced ovarian cancerLynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response [seeClinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2 DOSAGE AND ADMINISTRATION 2.1 Patient SelectionSelect patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [seeIndications and Usage (1)andClinical Studies (14)]. Information on FDA-approved test for the detection of BRCA-mutations is available at . 2.2 Recommended DosingThe recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [seeHow Supplied/Storage and Handling (16.2)]. 2.3 Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction.The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.2.4 Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [seeDrug Interactions (7.2)].3 DOSAGE FORMS AND STRENGTHS Lynparza (olaparib) is supplied as a white, opaque, hard capsule (50 mg), marked in black ink with “OLAPARIB 50 mg” on the cap and the AstraZeneca logo on the body.4 CONTRAINDICATIONS(What is this?) None 5 WARNINGS AND PRECAUTIONS 5.1 Myelodysplastic syndrome/Acute Myeloid LeukemiaMyelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (&1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from &6 months to &2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE 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 PneumonitisPneumonitis, including fatal cases, occurred in &1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.5.3 Embryo-Fetal ToxicityLynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [seeUse in Specific Populations (8.1)].Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [seeUse in Specific Populations (8.6)].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) ] 6.1 Clinical Trial ExperienceBecause 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. Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [seeClinical Studies (14)], adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. 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. Table 1 presents the frequency of adverse reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days. Table 1 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza&
Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily. Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza&
The following adverse reactions and laboratory abnormalities have been identified in ≥10 to &20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in ≥1 to &10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA-mutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of tho dose reductions in 15% of Lynparza and 5% and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction. Table 3 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial&
Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial
Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. 7 DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A.7.1 Anticancer AgentsClinical 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 ConcentrationsIn patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold. Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., 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 [seeDosage and Administration (2.4)].Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].7.3 Drugs that may Decrease Olaparib Plasma ConcentrationsIn 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 50-60%.Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [seeClinical Pharmacology (12.3)].8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [seeWarnings and Precautions (5.3)] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.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 11% 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 0.3% 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 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.8.3 Nursing MothersIt is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and efficacy of Lynparza has not been established in pediatric patients.8.5 Geriatric UseIn clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more frequently in patients aged ≥65 years (53.4%) than those &65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.8.6 Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [seeUse in Specific Populations (8.1)]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.8.7 Hepatic ImpairmentThe effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin &1.5 X ULN and AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin &1.5 X ULN) [seeClinical Pharmacology (12.3)].8.8 Renal ImpairmentBased on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr &80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr &50 mL/min) or patients on dialysis [seeClinical Pharmacology (12.3)].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 symptomatically.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 of approximately 0.1 mg/mL across the physiological pH range.Lynparza is available in 50 mg capsules for oral administration. Each capsule contains olaparib as the active ingredient and the following inactive ingredients:• Capsule content: lauroyl polyoxylglycerides • Capsule shell: hypromellose, titanium dioxide, gellan gum, potassium acetate • Capsule printing ink: shellac, ferrosoferric oxide 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionLynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, 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. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.12.3 PharmacokineticsAbsorption Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days. Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials.Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 20%).Distribution Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%.Metabolism In vitro, CYP3A4 was shown to be the enzyme 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 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1L/h were observed after a single 400 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.Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of olaparib increased by 1.5- and 1.2-fold, respectively, when olaparib was dosed in patients with mild renal impairment (CLcr = 50-80 mL/ N=14) compared to those with normal renal function (CLcr &80 mL/ N=8). There are no data in patients with CLcr &50 mL/min or in patients on dialysis.Drug Interactions In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations than are clinically achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro studies have shown that olaparib is a substrate of CYP3A4.Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7-and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2-and 1.1-fold, 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 using PBPK models suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 60% and 20 - 30%, respectively.In vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been conducted with olaparib.Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian 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 11% 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 7% of the human exposure (AUC0-24h) at the recommended dose).14 CLINICAL STUDIES The efficacy of Lynparza was investigated in a single-arm study in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). A total of 137 patients with measurable, gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza 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 v1.1.The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the companion diagnostic BRACAnalysis CDx™, which is FDA approved for selection of patients for Lynparza treatment.Efficacy results from Study 1 are summarized in Table 5.Table 5 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received 3 or More Prior Lines of Chemotherapy in Study 1 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)Close 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Lynparza 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and AstraZen available in:Bottles of 112 capsules NDC 16.2 Storage Store at 25&C (77&F), excursions permitted to 15-30&C (59-86&F) [see USP Controlled Room Temperature]Lynparza should not be exposed to temperatures greater than 40&C or 104&F. Do not take Lynparza if it is suspected of having been exposed to temperatures greater than 40&C or 104&F.
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