Dosing and uses of Lynparza (olaparib)
Adult dosage forms and strengths
capsule
- 50mg
Ovarian Cancer
Indicated as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with ≥3 prior lines of chemotherapy
400 mg (eight 50-mg capsules) PO BId
Continue treatment until disease progression or unacceptable toxicity
Dosage modifications
Management of adverse reactions
- Consider dose interruption or dose reduction to manage adverse reactions
- Recommended dose reduction: 200 mg (four 50-mg capsules) PO BID
- If a further final dose reduction is required, then reduce to 100 mg (two 50-mg capsules) PO BID
Coadministration with CYP3A inhibitors
- Strong and moderate CYP3A inhibitors: Avoid use and consider other agents
- If strong CYP3A inhibitors cannot be avoided: Reduce olaparib dose to 150 mg (three 50-mg capsules) PO BID
- If moderate CYP3A inhibitors cannot be avoided: Reduce olaparib dose to 200 mg (four 50-mg capsules) PO BID
Hepatic impairment
- Not studied
- No data in patients with baseline hepatic impairment (serum bilirubin >1.5 xULN)
Renal impairment
- Preliminary data show a 1.5-fold increase in mean exposure (AUC) with mild renal impairment (CrCl 50-80 mL/min) compared with normal renal function (CrCl >80 mL/min)
- CrCl 50-80 mL/min: No dose adjustment to the starting dose is required, but patients should be monitored closely for toxicity
- CrCl <50 mL/min or patients on dialysis: Data are not available
Dosing Considerations
The indication is approved under accelerated approval based on objective response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
Information on FDA-approved test for the detection of BRCA mutations is available at https://www.fda.gov/companiondiagnostics
Administration
Swallow capsule whole; do not chew, dissolve, or open capsule
Do not take capsules that appear deformed or show evidence of leakage
Missed dose: Instruct patient to take their next dose at its scheduled time
Pediatric dosage forms and strengths
Not indicated
Lynparza (olaparib) adverse (side) effects
>10%
Adverse effects listed are for grades 1-4 and data compiled from patients who received ≥3 lines of prior chemotherapy (n=223)
Decreased hemoglobin (90%)
Fatigue/asthenia (66%)
Nausea (64%)
Mean corpuscular volume elevation (57%)
Decreased lymphocytes (56%)
Abdominal pain/discomfort (43%)
Vomiting (43%)
Anemia (34%)
Diarrhea (31%)
Increased serum creatinine (30%)
Decreased platelets (30%)
Nasopharyngitis/URTI (26%)
Dyspepsia (25%)
Decrease ANC (25%)
Decreased appetite (22%)
Myalgia (22%)
Arthralgia/musculoskeletal pain (21%)
Warnings
Contraindications
None
Cautions
Pneumonitis, including fatal cases, occurred in <1%
Can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals; in women of childbearing potential, avoid pregnancy by using effective contraception during treatment and for at least 1 month after receiving the last dose
CYP3A substrate; avoid coadministration with CYP3A inhibitors and inducers
MDS/AML
- Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) has been confirmed in 6 (2%) of 298 patients enrolled in a single-arm trial of olaparib monotherapy
- Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated
- The majority of MDS/AML cases (17 of 22 cases) were fatal
- Monitor complete blood cell count testing at baseline and monthly thereafter
- Do not start olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE grade 1)
- For prolonged hematological toxicities, interrupt dosing and monitor blood counts weekly until recovery
- If the levels have not recovered to CTCAE grade ≤1 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 olaparib
- Clinical studies of olaparib in combination with other myelosuppressive anticancer agents observed potentiation and prolongation of myelosuppression
Pregnancy and lactation
Pregnancy category: D; 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 BId
Lactation: Unknown if distributed in human breast milk; 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
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Lynparza (olaparib)
Mechanism of action
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
Absorption
Peak plasma time: 1-3 hr
Steady-state achieved: 3-4 days
Coadministration with a high-fat meal slowed the rate (Tmax delayed by 2 hr) of absorption, but did not significantly alter the extent of absorption (mean AUC increased by approximately 20%)
Distribution
Protein bound: 82%
Vd: 167 L
Metabolism
Metabolized primarily by CYP3A4
Elimination
Half-life: 11.9 hr
Plasma clearance: 8.6 L/hr
Excretion: 44% urine; 42% feces
Excreted mostly as metabolites
Pharmacogenomics
Indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer
Information on FDA-approved test for the detection of BRCA mutations is available at https://www.fda.gov/companiondiagnostics
