Olarigen Capsule

Olaparib is an 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. 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 platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

Absorption: Following oral administration of Olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation ratio of 1.4-1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days. Limited data suggest that the systemic exposure (AUC) of Olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials. Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of Olaparib absorption (mean AUC increased by approximately 20%).

Distribution: Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 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 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1 L/h were observed after a single 400 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.

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 of Olarigen in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs That May Increase Olarigen Plasma Concentrations: Olarigen is primarily metabolized by CYP3A. In patients (n=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of Olarigen by 170%. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of Olarigen by 121%. Avoid concomitant use of strong CYP3A inhibitors such as itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, and telaprevir. Avoid use of moderate CYP3A inhibitors such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, and verapamil. If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Olarigen. Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during Olarigen treatment since they are CYP3A inhibitors.

Drugs That May Decrease Olarigen Plasma Concentrations: In patients (n=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of Olarigen by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of Olarigen by approximately 50%. Avoid concomitant use of strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. John’s Wort. Avoid concomitant use of moderate CYP3A4 inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Olarigen.

Olaparib is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation.

The most common serious adverse reaction reported was anemia (2.4% Olarigen vs 2.2% chemotherapy). The following serious ADRs were reported in one patient each: dermatitis allergic, neutrophil count decreased and platelet count decreased. The proportion of patients who permanently discontinued Olarigen due to adverse events was 4.9% in the Olarigen arm compared with 7.7% in the chemotherapy arm. Anemia and platelet count decrease were the only adverse reactions leading to discontinuation of Olarigen in more than one patient.

Pregnancy: Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib wasteratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Nursing Mothers: It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, 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.

Myelodysplastic Syndrome/Acute Myeloid Leukemia: Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Olarigen monotherapy in clinical trials, including long-term follow up, was <1.5% (21/1680) and the majority of events had a fatal outcome. Of these, 19/21 patients had a documented BRCA mutation, 1 patient had gBRCA wildtype and in 1 patient the BRCA mutation status was unknown. Additional cases of MDS/AML have been documented in patients treated with Olarigen in combination studies. The duration of therapy with Olarigen in patients who developed secondary MDS/cancer-therapy related AML varied from < 6 months to > 2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of previous cancer or bone marrow dysplasia. Do not start Olarigen until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Olarigen and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less 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 Olarigen.

Pneumonitis: Pneumonitis, including fatal cases, occurred in <1% of patients treated with Olarigen. If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Olarigen treatment and promptly assess the source of symptoms. If pneumonitis is confirmed, discontinue Olarigen treatment and treat the patient appropriately.

There is no specific treatment in the event of Olarigen overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

Targeted Cancer Therapy

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