Lynparza Drug Interactions

Clinical studies of olaparib in combination with other anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with myelosuppressive anticancer agents.
Effect of other drugs on olaparib: Strong and moderate CYP3A inhibitors: CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. Co-administration of olaparib with a strong CYP3A inhibitor (itraconazole) increased olaparib C_max by 42% and increased AUC by 170%. Therefore, concomitant use of itraconazole as well as other strong CYP3A inhibitors such as, but not limited to telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir and telaprevir is not recommended with Lynparza (see Precautions).
Physiologically-based pharmacokinetic (PBPK) modelling has shown that moderate inhibitors will alter the clearance of olaparib and therefore concomitant use of moderate CYP3A inhibitors such as, but not limited to ciprofloxacin, erythromycin, diltiazem, fluconazole and verapamil is not recommended with Lynparza (see Precautions).
If strong or moderate CYP3A inhibitors must be co-administered, the dose of Lynparza should be reduced (see Dosage & Administration).
Avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during Lynparza treatment since they are CYP3A inhibitors.
Strong and moderate CYP3A inducers: Co-administration of olaparib with a strong CYP3A inducer (rifampicin) decreased olaparib C_max by 71% and AUC by 87%. It is therefore possible that CYP3A inducers could substantially diminish the clinical efficacy of Lynparza and as such concomitant use of strong inducers such as, but not limited to phenytoin, rifabutin, rifampin (rifampicin), rifapentine, carbamazepine, nevirapine, phenobarbital and St. John's Wort (Hypericum perforatum) is not recommended with Lynparza (see Precautions).
PBPK modelling has shown that moderate CYP3A inducers will decrease olaparib AUC by approximately 60% and therefore concomitant use of moderate CYP3A inducers such as, but not limited to bosentan, efavirenz, etravirine, modafinil and nafcillin is not recommended with Lynparza. If a moderate CYP3A inducer must be co-administered, the prescriber should be aware of a potential for decreased efficacy of Lynparza (see Precautions).
Effect of olaparib on other drugs: CYP Interactions: Both induction and inhibition of CYP3A4 has been shown in vitro, however, PBPK simulations and clinical data suggest that the net effect of olaparib in vivo is weak inhibition of CYP3A. Therefore, caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeutic margin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) are combined with Lynparza. Appropriate clinical monitoring is recommended for patients receiving CYP3A substrates with a narrow therapeutic margin concomitantly with Lynparza.
Induction of CYP1A2 and 2B6 has been shown in vitro with CYP2B6 being most likely to be induced to a clinically relevant extent. Therefore, Lynparza upon co-administration may reduce the exposure to substrates of these metabolic enzymes.
Drug transporter interactions: Olaparib has also been shown to be an in vitro inhibitor of OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown, however, it cannot be excluded that Lynparza may increase the exposure to substrates of OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statins and valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide and methotrexate), MATE1 (e.g. metformin and cisplatin) and MATE2K (e.g. metformin). In particular, caution should be exercised if Lynparza is administered in combination with any statin.