DRUG INTERACTIONS

­ • CYP3A Inhibitors:                                                                                                         Avoid concomitant use of strong or moderate CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the olaparib dose. 

• CYP3A Inducers:                                                                                                            Avoid concomitant use of strong or moderate CYP3A inducers as decreased efficacy can occur. 

 ADVERSE REACTIONS

­ • Most common adverse reactions (=20%) in clinical trials were

anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis/upper respiratory tract infection/influenza, diarrhea, arthralgia/myal

 • 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.

 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

Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza 

• 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 

 • 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  

• 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.

 • 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 

Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months after receiving the last dose.

• Lactation: Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose.

 • 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

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 Ad

 CLINICAL PHARMACOLOGY

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 platinumbased chemotherapy.

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.

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 µg*h/mL (n=204) and 5.8 µg/mL (n=204), respectively, and the steady state geometric mean AUC and Cmax following 300 mg tablet twice daily were 49.0 µg*h/mL (n=227) and 7.7 µg/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.

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).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                       Based on findings in animals and its mechanism of action, 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 

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.

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. 

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. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least 6 months following the last dose.

4.Pediatric Use                                                                                                                The safety and efficacy of Lynparza have not been established in pediatric patients.

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.

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 .

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 12 Reference ID: 4140621 >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.. There are no data in patients with severe renal impairment or end-stage disease (CLcr =30 mL/min) 

 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.