Breast Cancer: Olaparib is indicated as monotherapy for adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer who have previously received chemotherapy in neoadjuvant, adjuvant, or metastatic settings. In hormone receptor (HR)-positive cases, patients should have disease progression on endocrine therapy or be unsuitable for it. Confirmation of germline BRCA mutation is required before treatment initiation.

Ovarian Cancer: Olaparib is indicated as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed (PSR) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have achieved complete or partial response to platinum-based chemotherapy.

Olaparib is a selective inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. These enzymes play an important role in cellular functions such as DNA repair, gene transcription, and cell cycle regulation.

Olaparib has demonstrated inhibition of tumor cell growth in vitro and reduction of tumor progression in mouse xenograft models, both as monotherapy and after platinum-based chemotherapy. Increased cytotoxic and antitumor effects have been observed particularly in BRCA-deficient cancer models. Mechanistically, olaparib inhibits PARP activity and promotes formation of PARP-DNA complexes, leading to disruption of DNA repair, loss of cellular homeostasis, and ultimately cell death.

Absorption: After oral administration of olaparib capsules, absorption is rapid with peak plasma concentrations reached within 1–3 hours. With repeated dosing, there is minimal accumulation (accumulation ratio 1.4–1.5 twice daily), and steady state is achieved within 3–4 days. Systemic exposure (AUC) increases less than proportionally over the dose range of 100–400 mg, with variability across studies. A high-fat meal delays absorption (Tmax delayed by ~2 hours) but has minimal effect on total exposure (AUC increases ~20%).

Distribution: The mean (± SD) apparent volume of distribution at steady state is 167 ± 196 L following a single 400 mg dose. In vitro protein binding is approximately 82%.

Metabolism: Olaparib is primarily metabolized by CYP3A4/5 enzymes. Following oral administration of 14C-olaparib, unchanged drug accounts for about 70% of circulating radioactivity in plasma. Metabolism is extensive, with unchanged drug representing 15% and 6% of radioactivity in urine and feces, respectively. Metabolism occurs mainly through oxidation, followed by glucuronide or sulfate conjugation of metabolites.

Excretion: The mean (± SD) terminal plasma half-life is 11.9 ± 4.8 hours, with an apparent plasma clearance of 8.6 ± 7.1 L/h after a single 400 mg dose. After administration of 14C-olaparib, 86% of radioactivity is recovered within 7 days, with 44% in urine and 42% in feces. Most of the eliminated material is in the form of metabolites.

Important Dosage Information: DO NOT substitute Olaparib capsules (50 mg) with Olaparib tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation.

Recommended Dosing: The recommended dose of Olaparib 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 Olaparib, 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.

Dosage Modifications 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.

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 Olaparib 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.

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 Olaparib 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). Or as directed by the registered physician.

Pediatric Use: The safety and efficacy of Olaparib has not been established in pediatric patients.

Anticancer Agents: Clinical studies show that olaparib used with other myelosuppressive anticancer drugs, including DNA-damaging agents, may increase and prolong bone marrow suppression toxicity.

Drugs That May Increase Olaparib Plasma Concentrations: Olaparib is mainly metabolized by CYP3A. Co-administration with itraconazole (a strong CYP3A inhibitor) increased olaparib AUC by 170%. Fluconazole (a moderate CYP3A inhibitor) is expected to increase AUC by about 121%. Strong CYP3A inhibitors such as itraconazole, ketoconazole, clarithromycin, telithromycin, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, and telaprevir should be avoided. Moderate CYP3A inhibitors such as ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil, imatinib, and others should also be avoided if possible. If unavoidable, olaparib dose reduction is required. Grapefruit, grapefruit juice, Seville oranges, and their juice should be avoided as they inhibit CYP3A.

Drugs That May Decrease Olaparib Plasma Concentrations: Rifampicin (strong CYP3A inducer) reduced olaparib AUC by 87%. Efavirenz (moderate CYP3A inducer) is expected to reduce AUC by about 50%. Strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. John’s Wort should be avoided. Moderate inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin should also be avoided. If unavoidable, reduced efficacy of olaparib should be expected.

Olaparib is contraindicated in patients with known hypersensitivity to olaparib or any component of the formulation.

The most common serious adverse effect is anemia (2.4% with olaparib vs 2.2% with chemotherapy). Other serious adverse reactions reported in single cases include allergic dermatitis, decreased neutrophil count, and decreased platelet count. Treatment discontinuation due to adverse events occurred in 4.9% of patients receiving olaparib compared with 7.7% in the chemotherapy group. Anemia and thrombocytopenia were the main causes of discontinuation in more than one patient.

Pregnancy: Olaparib may cause fetal harm based on its mechanism of action and animal studies. It has shown teratogenic and embryo-fetal toxic effects in rats at exposures below the recommended human dose. If used during pregnancy, patients should be informed about the potential risk to the fetus and possible pregnancy loss.

Nursing Mothers: It is unknown whether olaparib is excreted in human breast milk. Because many drugs are excreted in breast milk and due to the risk of serious adverse effects in nursing infants, a decision should be made either to discontinue breastfeeding or discontinue the drug, considering the importance of treatment to the mother.

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): In clinical trials of olaparib monotherapy, including long-term follow-up, the overall incidence of MDS/AML was less than 1.5% (21/1680 patients), with most cases resulting in death. Among these, 19 patients had confirmed BRCA mutations, 1 patient had BRCA wildtype, and in 1 patient the mutation status was unknown. Additional cases have been reported in combination therapy studies. The duration of olaparib treatment before development of secondary MDS/AML ranged from less than 6 months to more than 2 years. Most affected patients had prior exposure to platinum-based chemotherapy and/or other DNA-damaging agents such as radiotherapy. Some also had previous cancer history or bone marrow disorders.

Do not initiate olaparib until patients have recovered from hematological toxicity of prior chemotherapy (≤ Grade 1). Complete blood counts should be monitored at baseline and monthly thereafter for clinically significant changes. In case of prolonged cytopenia, olaparib should be interrupted and blood counts monitored weekly until recovery. If blood parameters do not recover to Grade 1 or below within 4 weeks, hematology consultation is recommended, including bone marrow examination and cytogenetic testing. If MDS/AML is confirmed, olaparib must be permanently discontinued.

Pneumonitis: Pneumonitis, including fatal cases, has been reported in less than 1% of patients receiving olaparib. If patients develop new or worsening respiratory symptoms such as shortness of breath, cough, or fever, or show radiological abnormalities, treatment should be interrupted and evaluated immediately. If pneumonitis is confirmed, olaparib should be permanently discontinued and appropriate treatment started.

No specific antidote exists for olaparib overdose, and symptoms are not well defined. In case of overdose, general supportive and symptomatic treatment should be provided.

Targeted cancer therapy

Store in a dry place below 30°C, protect from light. Keep out of reach of children.