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Lynparza

Generic Name: Olaparib
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 4-[[3-[[4-(Cyclopropylcarbonyl)-1- piperazinyl]carbonyl]-4- fluorophenyl]methyl]-1(2H)-phthalazinone
Molecular Formula: C24H23FN4O3
CAS Number: 763113-22-0

Introduction

Antineoplastic agent; an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).1

Uses for Lynparza

Ovarian Cancer

Single-agent therapy for the treatment of confirmed or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved companion diagnostic test [BRACAnalysis CDx]) advanced ovarian cancer previously treated with ≥3 chemotherapy regimens1 2 8 (designated an orphan drug by FDA for this use).3

Accelerated approval based on objective response rate and duration of response.1 6 7 9 14 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1 6 9

Women with mutations that result in defective BRCA genes are more likely to develop ovarian cancer.14 Approximately 10–15% of all cases of ovarian cancer appear to be associated with these hereditary BRCA mutations.14

Lynparza Dosage and Administration

General

  • Obtain CBC prior to initiation of therapy and monthly during therapy.1 5 (See Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) under Cautions.)

Restricted Distribution Program

  • Must obtain olaparib through a specialty pharmacy.13

  • Contact specialty pharmacy at 844-275-2360 or consult the Lynparza website () for specific availability and ordering information.13

Administration

Oral Administration

Administer orally twice daily.1 Prescribing information in the US does not provide specific instructions concerning administration with regard to food;1 manufacturer in European Union recommends taking olaparib ≥1 hour after meals and avoiding eating preferably for ≤2 hours after taking the drug.12 (See Food under Pharmacokinetics.)

Swallow capsules whole; do not chew, dissolve, or open.1

Do not take capsules if exposure to temperatures >40°C is suspected or if capsules appear deformed or show evidence of leakage.1 (See Storage under Stability.)

Dosage

Adults

Ovarian Cancer
Oral

400 mg (eight 50-mg capsules) twice daily (total daily dosage of 800 mg).1 Continue therapy until disease progression or unacceptable toxicity occurs.1

If a dose is missed, the next dose should be taken at the regularly scheduled time.1 Do not take an extra dose.1

Dosage Modification for Toxicity
Oral

If adverse reactions occur, consider interruption of therapy or dosage reduction.1

If dosage reduction is necessary, reduce dosage to 200 mg (four 50-mg capsules) twice daily (total daily dosage of 400 mg).1

If further reduction is necessary, reduce dosage to 100 mg (two 50-mg capsules) twice daily (total daily dosage of 200 mg).1

Dosages <100 mg twice daily not recommended.1

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Oral

Avoid concomitant use of moderate or potent inhibitors of CYP3A.1 (See Specific Drugs and Foods under Interactions.)

If concomitant use of a potent CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 150 mg (three 50-mg capsules) twice daily.1

If concomitant use of a moderate CYP3A inhibitor cannot be avoided, reduce olaparib dosage to 200 mg (four 50-mg capsules) twice daily.1

Prescribing Limits

Adults

Ovarian Cancer
Oral

Dosages <100 mg twice daily not recommended.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild renal impairment: Adjustment of initial dosage not necessary, but closely monitor for toxicity.1

Moderate or severe renal impairment or hemodialysis: Not studied; no specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Lynparza

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported in <1% of olaparib-treated patients; most cases (77%) were fatal.1 5 All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents.1 The duration of olaparib therapy in patients who developed MDS/AML ranged from <6 months to >2 years.1

Monitor CBC at baseline and monthly thereafter.1 Delay initiation of olaparib until patients have recovered from hematologic toxicity caused by previous chemotherapy (≤grade 1).1

If prolonged hematologic toxicity occurs during therapy, interrupt therapy and monitor CBC weekly until recovery to ≤grade 1.1

If myelosuppression persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 If MDS/AML is confirmed, discontinue olaparib.1

Pneumonitis

Pneumonitis, sometimes fatal, reported in <1% of patients.1 12

If patient develops new or worsening pulmonary symptoms (see Advice to Patients) or a radiologic abnormality occurs, interrupt therapy and initiate prompt diagnostic evaluation.1 12 If pneumonitis is confirmed, discontinue olaparib and treat appropriately.1 12

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; teratogenicity, embryotoxicity, fetotoxicity, and embryolethality demonstrated in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use highly effective contraceptive methods while receiving olaparib and for ≥1 month after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether olaparib is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety, efficacy, and pharmacokinetics not established in pediatric patients.1 12

Geriatric Use

In clinical studies in patients with advanced solid tumors (the majority [69%] had ovarian cancer), 20% of patients were ≥65 years of age.1 Safety profile was similar regardless of patient age, except for an increased incidence of ≥grade 3 adverse reactions in geriatric patients relative to younger adults.1

Hepatic Impairment

Safety, efficacy, and pharmacokinetics not studied in patients with hepatic impairment.1

Patients with serum bilirubin concentrations >1.5 times ULN and ALT and/or AST concentrations ≥2.5 times ULN in the absence of liver metastases or ALT and/or AST concentrations >5 times ULN in the presence of liver metastases were excluded from clinical trials.1

Renal Impairment

Increased exposure observed in patients with mild renal impairment (Clcr of 50–80 mL/minute).1 (See Absorption under Pharmacokinetics.)

Not studied in patients with moderate or severe renal impairment (Clcr <50 mL/minute) or in those receiving dialysis.1

Common Adverse Effects

Adverse effects: Fatigue (including asthenia),1 2 nausea,1 2 abdominal pain or discomfort,1 2 vomiting,1 2 diarrhea,1 2 nasopharyngitis or pharyngitis,1 dyspepsia,1 back pain,1 headache,1 dermatitis or rash,1 decreased appetite,1 myalgia,1 arthralgia or musculoskeletal pain,1 cough,1 dysgeusia.1 2

Laboratory abnormalities: Anemia,1 2 elevated mean corpuscular volume (MCV),1 lymphopenia,1 thrombocytopenia,1 elevated Scr concentrations,1 neutropenia.1

Interactions for Lynparza

Metabolized principally by CYP3A4.1 Substrate of CYP3A4 and P-glycoprotein (P-gp) in vitro.1

Inhibits CYP3A and induces CYP2B6 at higher concentrations than are achieved clinically.1

Inhibitor of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, organic cation transporter (OCT) 1 and OCT2, organic anion transporter (OAT) 3, and multidrug and toxic compound extrusion (MATE) 1 and MATE2K; clinical relevance of these findings not known.1

Drugs Affecting Hepatic Microsomal Enzymes

Moderate and potent CYP3A inhibitors: Potential increased plasma concentrations and AUC of olaparib.1 Avoid concomitant use; consider choosing an alternative agent with less CYP3A inhibition potential.1 If concomitant therapy cannot be avoided, reduce olaparib dosage.1 (See Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration and also see Specific Drugs and Foods under Interactions.)

CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma concentrations and AUC of olaparib).1 Avoid concomitant use of moderate or potent CYP3A inducers.1 If concomitant use of a moderate CYP3A inducer cannot be avoided, consider potential for reduced efficacy of olaparib.1 (See Specific Drugs and Foods under Interactions.)

Antineoplastic Agents

Possible potentiation or prolongation of myelosuppression during concomitant use with other antineoplastic agents known to cause myelosuppression.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticonvulsants (carbamazepine, phenytoin)

Possible decreased olaparib concentrations1

Avoid concomitant use1

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Moderate or potent CYP3A inhibitors: Possible increased olaparib concentrations1

Fluconazole: May increase peak concentrations and AUC of olaparib by 1.1- and 2-fold, respectively1

Itraconazole: Increased olaparib peak concentrations and AUC by 1.4- and 2.7-fold, respectively1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

Fluconazole: If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Itraconazole, ketoconazole, posaconazole, voriconazole: If concomitant use cannot be avoided, reduce olaparib dosage to 150 mg twice daily1

Antiretroviral agents, HIV protease inhibitors (e.g., atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, ritonavir-boosted darunavir, ritonavir-boosted lopinavir, saquinavir)

Possible increased olaparib concentrations1

Moderate or potent CYP3A inhibitors: Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

Atazanavir, fosamprenavir, ritonavir-boosted darunavir: If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Indinavir, lopinavir, nelfinavir, ritonavir, ritonavir-boosted lopinavir, saquinavir: If concomitant use cannot be avoided, reduce olaparib dosage to 150 mg twice daily1

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (efavirenz, etravirine)

Possible decreased olaparib concentrations1

Efavirenz: May decrease peak concentrations and AUC of olaparib by 20–30 and 50–60%, respectively, based on pharmacokinetic models1

Avoid concomitant use1

If concomitant use cannot be avoided, consider potential for reduced efficacy of olaparib1

Aprepitant

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Bosentan

Possible decreased olaparib concentrations1

Avoid concomitant use1

If concomitant use cannot be avoided, consider potential for reduced efficacy of olaparib1

Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil)

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Ciprofloxacin

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Crizotinib

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Grapefruit or grapefruit juice

Possible increased olaparib concentrations1

Avoid concomitant use1

HCV protease inhibitors (e.g., boceprevir)

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 150 mg twice daily1

Imatinib

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Macrolides (clarithromycin, erythromycin, telithromycin)

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

Erythromycin: If concomitant use cannot be avoided, reduce olaparib dosage to 200 mg twice daily1

Clarithromycin, telithromycin: If concomitant use cannot be avoided, reduce olaparib dosage to 150 mg twice daily1

Modafinil

Possible decreased olaparib concentrations1

Avoid concomitant use1

If concomitant use cannot be avoided, consider potential for reduced efficacy of olaparib1

Nafcillin

Possible decreased olaparib concentrations1

Avoid concomitant use1

If concomitant use cannot be avoided, consider potential for reduced efficacy of olaparib1

Nefazodone

Possible increased olaparib concentrations1

Avoid concomitant use; consider choosing alternative agent with less CYP3A inhibition potential1

If concomitant use cannot be avoided, reduce olaparib dosage to 150 mg twice daily1

Rifampin

Rifampin decreased peak concentrations and AUC of olaparib by 71 and 87%, respectively1

Avoid concomitant use1

Seville oranges

Possible increased olaparib concentrations1

Avoid concomitant use1

St. John’s wort (Hypericum perforatum)

Possible decreased olaparib concentrations1

Avoid concomitant use1

Lynparza Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in about 1–3 hours.1

Systemic exposure appears to increase in a less than proportional manner following administration of olaparib 100–400 mg.1

Steady-state concentrations are achieved within 3–4 days.1

Systemic accumulation not observed following repeated doses.1

Food

Administration with a high-fat meal decreased the rate (time to peak concentration delayed by 2 hours) but did not substantially affect extent of absorption (mean AUC increased by approximately 20%).1

Special Populations

Mild (Clcr 50–80 mL/minute) renal impairment: Mean peak plasma concentrations and AUC increased by 1.2- and 1.5-fold, respectively, relative to individuals with normal renal function.1

Moderate or severe (Clcr <50 mL/minute) renal impairment or dialysis: Pharmacokinetics not studied.1

Distribution

Extent

Not known whether olaparib is distributed into milk.1

Plasma Protein Binding

Approximately 82% (at recommended dosage).1

Elimination

Metabolism

Primarily metabolized by CYP3A4.1

Elimination Route

Eliminated in urine (44%) and feces (42%).1

Half-life

Mean terminal plasma half-life: 11.9 hours.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C); avoid exposure to temperatures >40°C (see Administration under Dosage and Administration).1

Actions

  • Inhibits mammalian poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3.1 PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.1

  • Olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, which results in disruption of cellular homeostasis and apoptosis.1

  • PARP inhibitors, including olaparib, appear to be selective for tumors cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).2 10 In vitro, olaparib inhibited growth of such select tumor cell lines.1

  • Reduces tumor growth of xenograft models of human cancer in mice as a single agent or following platinum-based chemotherapy.1

  • Increases cytotoxicity and anti-tumor activity in BRCA-deficient cell lines and mouse tumor models.1

Advice to Patients

  • Importance of providing a copy of written patient information (medication guide) each time olaparib is dispensed.1 Importance of advising patients to read the patient information before taking olaparib and each time the prescription is refilled.1

  • Importance of advising patients to swallow olaparib capsules intact and not to chew, dissolve, or open capsules.1 Importance of also advising patients to avoid grapefruit, grapefruit juice, and Seville oranges while taking the drug.1

  • If a dose is missed, importance of advising patients not to take an extra dose and to take the next normal dose at the regularly scheduled time.1

  • Importance of informing patients to store olaparib capsules at room temperature (20–25°C) and to avoid exposing the capsules to temperatures >40°C.1 Importance of also advising patients that olaparib capsules should not be taken if they are suspected of having been exposed to temperatures >40°C or if they appear deformed or show evidence of leakage.1

  • Risk of MDS and AML.1 Importance of informing clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), or shortness of breath occurs.1

  • Importance of hematologic monitoring during olaparib therapy.1

  • Risk of pneumonitis.1 Importance of informing clinician if new or worsening respiratory symptoms, including shortness of breath, fever, cough, or wheezing, occur.1

  • Importance of advising patients that mild or moderate nausea and/or vomiting commonly occurs with olaparib therapy; patients experiencing these symptoms should contact their clinician for advice on available antiemetic treatment options.1

  • Risk of fetal harm and pregnancy loss.1 Necessity of advising women of childbearing potential to avoid pregnancy and to use a highly effective method of contraception while receiving olaparib and for ≥1 month following discontinuance of therapy.1 Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving olaparib therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., respiratory disorders, liver or kidney damage).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of olaparib is restricted.13 (See Restricted Distribution Program under Dosage and Administration.)

Olaparib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Lynparza

AstraZeneca

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. AstraZeneca Pharmaceuticals LP. Lynparza (olaparib) capsules prescribing information. Wilmington, DE: 2014 Dec.

2. Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015; 33:244-50. [PubMed 25366685]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2015 Feb 18.

4. US Food and Drug Administration. FDA briefing document: Oncologic drugs advisory committee meeting. Silver Spring, MD; June 2014. From FDA web site.

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206162Orig1s000: Medical review(s). From FDA website.

6. Moore KN, DiSilvestro P, Lowe ES et al. SOLO1 and SOLO2: Randomized phase III trials of olaparib in patients (pts) with ovarian cancer and a BRCA1/2 mutation (BRCAm). Abstract TPS5616 (presented at the 2014 ASCO meeting). Chicago, IL.

7. US Department of Health and Human Services, US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry. Expedited programs for serious conditions- drugs and biologics. 2014 May. From FDA website.

8. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014; 15:852-61. [PubMed 24882434]

9. US Food and Drug Administration. Center for Drug Evaluation and Research. Summary minutes of the oncologic drugs advisory committee meeting. Silver Spring, MD; June 2014. From FDA web site.

10. Reinbolt RE, Hays JL. The role of PARP inhibitors in the treatment of gynecologic malignancies. Front Oncol. 2013; 3:237. [PubMed 24098868]

11. US Food and Drug Administration. Summary review for regulatory action: NDA/BLA 206162. From FDA website.

12. AstraZeneca UK Limited. Lynparza (olaparib) 50 mg hard capsules summary of product characteristics. 2014 Jan.

13. AstraZeneca. How to order Lynparza: service request form and instructions. From the Lynparza website. Undated. Accessed 2015 Apr 3.

14. US Food and Drug Administration. Summary review for regulatory action: NDA/BLA 206162. From FDA website.

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