olaparib (Rx)

All grades of severity are listed unless otherwise indicated

>10% (Maintenance Treatment for BRCA-mutated Advanced Ovarian)

Decreased hemoglobin (87%)

Increased mean corpuscular volume (87%)

Nausea (77%)

Decrease leukocytes (70%)

Fatigue (67%)

Decreased lymphocytes (67%)

Decreased ANC (51%)

Abdominal pain (45%)

Vomiting (40%)

Anemia (38%)

Diarrhea (37%)

Decreased platelets (35%)

Increased serum creatinine (34%)

Constipation (28%)

Upper respiratory tract infection (eg, influenza, nasopharyngitis, bronchitis) (28%)

Dysgeusia (26%)

Anemia, Grade 3 or 4 (21%)

Dizziness (20%)

Decreased appetite (20%)

Decreased hemoglobin, Grade 3 or 4 (19%)

Neutropenia (17%)

Dyspepsia (17%)

Dyspnea (15%)

Decreased lymphocytes, Grade 3 or 4 (14%)

Urinary tract infection (13%)

Thrombocytopenia (11%)

Stomatitis (11%)

>10% (Maintenance Treatment for Recurrent Advanced Ovarian)

Increased mean corpuscular volume (89%)

Decreased hemoglobin (83%)

Nausea (76%)

Decreased leukocytes (69%)

Decreased lymphocytes (67%)

Fatigue (66%)

Decreased ANC (51%)

Anemia (44%)

Increased serum creatinine (44%)

Decreased platelets (42%)

Vomiting (37%)

Upper respiratory tract infection (36%)

Diarrhea (33%)

Arthralgia/myalgia (30%)

Dysgeusia (27%)

Headache (26%)

Decreased appetite (22%)

Stomatitis (20%)

Neutropenia (19%)

Cough (18%)

Leukopenia (16%)

Hypomagnesemia (14%)

Thrombocytopenia (14%)

Dizziness (13%)

Dyspepsia (11%)

Increased creatinine (11%)

1-10% (BRCA-mutated Advanced Ovarian)

Maintenance treatment

• Neutropenia, Grade 3 or 4 (6%)
• Fatigue, Grade 3 or 4 (4%)
• Leukopenia, Grade 3 or 4 (3%)
• Diarrhea, Grade 3 or 4 (3%)
• Abdominal pain, Grade 3 or 4 (2%)
• Thrombocytopenia, Grade 3 or 4 (1%)
• Nausea, Grade 3 or 4 (1%)

1-10% (Maintenance Treatment for Recurrent Advanced Ovarian)

Edema (8%)

Rash (6%)

Fatigue, Grade 3 or 4 (4%)

Nausea, Grade 3 or 4 (3%)

Vomiting, Grade 3 or 4 (3%)

Diarrhea, Grade 3 or 4 (2%)

Lymphopenia (1%)

Headache, Grade 3 or 4 (1%)

Stomatitis, Grade 3 or 4 (1%)

Postmarketing Reports

Hypersensitivity (rash, dermatitis)

Cough

Thrombocytopenia

Dysgeusia

Lymphopenia

Dizziness

Stomatitis

Upper abdominal pain

Contraindications

None

Cautions

Pneumonitis, including fatal cases, occurred in <1%; interrupt treatment if pneumonitis is suspected; discontinue if pneumonitis is confirmed

Can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals; (see Pregnancy)

Myelodysplastic syndrome/ acute myeloid leukemia

• Incidence of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in clinical trials, including long-term follow up, was <1.5% (21/1680)
• Majority of MDS/AML cases had a fatal outcome; of these, 19/21 patients had a documented BRCA mutation, 1 patient had gBRCA wild-type and in 1 patient the BRCA mutation status was unknown
• Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment
• Do not initiate treatment until hematological toxicity caused by previous chemotherapy (CTCAE Grade ≤1) resolves
• For prolonged hematological toxicities, interrupt treatment and promptly assess source of symptoms; monitor blood counts weekly until recovery
• If levels have not recovered to CTCAE Grade ≤1 after 4 weeks, refer to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics
• All patients with myelodysplastic syndrome reported to have received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy; some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia
• If MDS/AML is confirmed, discontinue olaparib

Drug interactions overview

• Clinical studies of olaparib in combination with other myelosuppressive anticancer agents (eg, DNA damaging agents) indicate a potentiation and prolongation of myelosuppressive toxicity

• CYP3A4 inhibitors

  • Olaparib is a CYP3A4 substrate; coadministration of strong or moderate CYP3A4 inhibitors may increase olaparib plasma concentrations
  • Avoid concomitant use of strong or moderate CYP3A inhibitors (see Dosage Modifications)
  • If strong or moderate CYP3A inhibitors must be coadministered, reduce dose of olaparib (see Dosage Modifications)
  • Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during olarparib treatment since they are CYP3A inhibitors

• CYP3A4 inducers

  • Coadministration of strong or moderate CYP3A4 inducers may decrease olaparib plasma concentrations
  • Avoid concomitant use of strong or moderate CYP3A inducers
  • If a strong or moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of olaparib (see Dosage Modifications)

Pregnancy

Based on findings in animals and mechanism of action, fetal harm may occur when administered to a pregnant woman; there are no available data on use in pregnant women to inform of drug associated risk

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

Contraception

• In women of childbearing potential, avoid pregnancy by using effective contraception during treatment and for at least 6 month after receiving the last dose; pregnancy testing is recommended for females of reproductive potential prior to initiating treatment
• Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of olaparib
• Advise male patients not to donate sperm during therapy and for 3 months following the last dose of olaparib

Lactation

No data are available regarding presence of olaparib in human milk, or on effects on breastfed infant or on milk production; because of potential for serious adverse reactions in breastfed infants from therapy, advise lactating women not to breastfeed during treatment and for 1 month after receiving last dose

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.

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

Bioavailability of tablet formulation is higher than the capsule formulation (AUC at steady-state 77% higher with tablet)

Peak plasma time: 1.5 hr (tablet); 1-3 hr (capsule)

Peak plasma concentration: 7.7 mcg/mL (tablet at steady-state)

AUC: 49 mcg·hr/mL (tablet at steady-state)

Steady-state achieved: 3-4 days

Coadministration with a high-fat meal slowed the rate (Peak plasma time delayed by 2.5 hr [tablet] or 2 hr [capsule]) of absorption, but did not significantly alter the extent of absorption (mean AUC increased by ~8% [tablet] or ~20% [capsule])

Distribution

Protein bound: 82%

Vd: 158 L (tablet); 167 L (capsule)

Metabolism

Metabolized primarily by CYP3A4/5

Elimination

Half-life: 14.9 hr (tablet); 11.9 hr (capsule)

Plasma clearance: 7.4 L/hr (tablet); 8.6 L/hr (capsule)

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 or breast cancer

Information on FDA-approved test for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics

Oral Administration

To avoid substitution errors and overdose, do not substitute olaparib tablets with olaparib capsules on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation

Tablets or capsules: May take with or without food

Swallow tablets whole; do not chew, crush, dissolve or divide

Missed dose: Instruct patient to take their next dose at its scheduled time

Storage

Tablets: Store at 20-25ºC (68-77°F), excursions permitted to 15-30ºC (59-86°F)