LYNPARZA TM (olaparib) capsules Table 3 Adverse Reactions Reported in ≥ 20% of Patients with gBRCA -Mutated Ovarian Cancer in the Randomized Trial (continued) Adverse Reactions Lynparza Placebo N=53 N=43 Grades Grades Grades Grades 1-4 3-4 1-4 3-4 % % % % Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in ≥ 25% of Patients with gBRCA -Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza N=53 Grades Grades 1-4 3-4 % % 85 8 32 8 26 6 85 -26 0 Placebo N=43 Grades Grades 1-4 3-4 % % 58 2 23 0 19 0 44 -5 0 2 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 11% 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 0.3% 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. 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. 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) in the full Prescribing Information] . Advise females of reproductive potential to use highly effective contraception during treatment with Lynparza and for at least 6 months following the last dose. Pediatric Use The safety and efﬁcacy of Lynparza have not been established in pediatric patients. Geriatric Use In 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 ≥ 65 years. 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. Hepatic Impairment No adjustment to the starting dose is required in patients with mild hepatic impairment. A 1.2-fold 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) in the full Prescribing Information] . Renal Impairment A 1.2-fold 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). No dose adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. A 1.4-fold 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 300 mg twice daily [see Dosage and Administration (2.5) in the full Prescribing Information] . There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤ 30 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information] . 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. Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 3313518 1/17 01/2017 Decrease in hemoglobin Decrease in absolute neutrophil count Decrease in platelets Mean corpuscular volume elevation Increase in creatinine* * Patients were allowed to enter clinical studies with laboratory values of Grade 1. DRUG INTERACTIONS 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. 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 2.7-fold. A moderate CYP3A inhibitor, ﬂuconazole, is predicted to increase the AUC of olaparib by 2.2-fold. Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, 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 [see Dosage and Administration (2.4) in the full Prescribing Information] . Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information] . 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 50%. 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 [see Clinical Pharmacology (12.3) in the full Prescribing Information] . USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on ﬁndings in animals and its mechanism of action [see Clinical Pharmacology (12.1) in the full Prescribing Information] , 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 400 mg twice daily [see Data in the full Prescribing Information] . Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.