1.1 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.

2.1 Important Administration Instructions

Lynparza is also available as 100 mg and 150 mg tablets. DO NOT substitute Lynparza capsules (50 mg) with Lynparza tablets (100 mg and 150 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 tablets for specific tablet dosing.

2.2 Patient Selection

Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.

2.3 Recommended Dosing

The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken orally twice daily with or without food, 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 [see How Supplied/Storage and Handling (16.2)].

2.4 Dose Adjustments for Adverse Reactions

To manage adverse reactions, consider interruption of treatment or dose reduction.

The recommended dose reduction is 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.

If a further dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.

2.5 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 [see Drug Interactions (7.2)].

2.6 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 300 mg (six 50 mg capsules) twice daily, for a total daily dose of 600 mg. The pharmacokinetics of olaparib 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)].

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Lynparza monotherapy in clinical trials, including long-term follow up, was <1.5% (21/1680) and the majority of events had a fatal outcome. Of these, 19/21 patients had a documented BRCA mutation, 1 patient had gBRCA wildtype and in 1 patient the BRCA mutation status was unknown. Additional cases of MDS/AML have been documented in patients treated with Lynparza in combination studies. The duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from < 6 months to > 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 previous cancer or 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 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 400 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)].

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.

Treatment of Advanced gBRCAm Ovarian Cancer after 3 or More Lines of Chemotherapy

Pooled data

Treatment with Lynparza capsules 400 mg twice daily 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 in these patients was 5.2 months.

Table 1 presents adverse reactions reported in ≥20% of patients and Table 2 presents laboratory abnormalities that occurred in at least 25% of patients from the pooled studies.

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, and venous thrombosis (including pulmonary embolism).

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 patients and 4% of placebo patients; and discontinuation in 6% of Lynparza patients and 2% in placebo patients.

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.

In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dyspepsia, stomatitis, dysgeusia, dizziness, increase in creatinine, neutropenia, thrombocytopenia, leukopenia, lymphopenia, dyspnea, pyrexia and edema.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity (rash/dermatitis)

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, and telaprevir. Avoid use of moderate CYP3A inhibitors such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, and 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 (2.4) 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 50%.

Avoid concomitant use of strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. John’s Wort. Avoid concomitant use of moderate CYP3A4 inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 400 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 0.3% 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 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 highly effective contraception during treatment with Lynparza and for at least 6 months following the last dose.

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 482 patients with advanced solid tumors who received Lynparza tablets 300 mg twice daily as monotherapy, 135 (28%) patients were aged ≥65 years. There appeared to be no major difference in the safety profile of patients treated with olaparib aged <65 years versus ≥65 years, nor within the age categories of 65 to 74 years, 75 to 84 years. No patients were aged ≥85 years.

8.6 Hepatic Impairment

No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment. A 15% increase and an 8% increase in mean exposure (AUC), respectively, were observed in patients with mild and moderate hepatic impairment (Child-Pugh classification A and B), compared to patients with normal hepatic function. There are no data in patients with severe hepatic impairment (Child-Pugh classification C) [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 capsules to 300 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)].

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 complex, resulting in disruption of cellular homeostasis and 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 tablets and in 109 patients following multiple dosing of 300 mg tablets 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 400 mg capsule dose were 37.2 μg*h/mL (N=48) and 4.02 μg/mL (N=48), respectively, and the steady state geometric mean AUC and Cmax following 400 mg capsule twice daily were 43.5 μg*h/mL (N=48) and 6.18 μg/mL (N=48), respectively. Olaparib showed time-dependent PK that the steady state clearance decreased by 15% after multiple dosing.

Absorption

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 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 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1 L/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.

Drug Interactions

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 suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2.2- and 1.2-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 suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by approximately 50% and 30%, 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 substrate 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 increased by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=10) and the mean AUC increased by 8% and the mean Cmax decreased by 13% when olaparib was dosed in patients with moderate hepatic impairment, compared to patients with normal hepatic function (n=13). 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 severe hepatic impairment (Child-Pugh classification C).

Renal Impairment

In a renal impairment trial, the mean AUC increased by 24% and the Cmax increased 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).

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 (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).

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 AstraZeneca logo on the body; available in:

Bottles of 112 capsules                    NDC 0310-0657-58

16.2 Storage

Refrigerate at 2ºC to 8ºC (36ºF to 46ºF). Protect from freezing.

If needed, Lynparza may be kept at room temperature not to exceed 30ºC (86ºF) for no more than 3 months. Lynparza should not be exposed to temperatures greater than 40ºC (104ºF). Do not take Lynparza if it is suspected of having been exposed to temperatures greater than 40ºC (104ºF) or has been frozen.

Refer to full prescribing information for storage conditions for Lynparza tablets.