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Pharmacokinetic interactions: Strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may increase the exposure of breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) substrates.
Active substances that may increase osimertinib plasma concentrations: In vitro studies have demonstrated that the Phase I metabolism of osimertinib is predominantly via CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients, TAGRISSO co-administered with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib [area under the curve (AUC) increased by 24% (90% CI 15, 35) and Cmax decreased -20% (90% CI -27, -13)]. Therefore, CYP3A4 inhibitors are not likely to affect the exposure of osimertinib.
Active substances that may decrease osimertinib plasma concentrations: In a clinical pharmacokinetic study in patients, the steady-state AUC of osimertinib was reduced, -78% (90% CI -81, -76), when co-administered with rifampicin (600 mg daily for 21 days). It is recommended that concomitant use of strong CYP3A inducers (e.g. Phenytoin, rifampicin, carbamazepine, St. John's Wort) with TAGRISSO should be avoided. If not possible, then increase TAGRISSO dose to 160 mg during the treatment with strong CYP3A inducer and resume at 80 mg, 3 weeks after discontinuation of the strong CYP3A inducer. Based on physiologically-based pharmacokinetic (PBPK) model simulations, no dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers.
Effect of gastric acid reducing active substances on osimertinib: In a clinical pharmacokinetic study, co-administration of omeprazole did not result in clinically relevant changes in osimertinib exposures. Gastric pH modifying agents can be concomitantly used with TAGRISSO without any restrictions.
Active substances whose plasma concentrations may be altered by TAGRISSO: Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporter.
In a clinical PK study, co-administration of TAGRISSO with rosuvastatin (sensitive BCRP substrate) increased the AUC and Cmax of rosuvastatin by 35% (90% CI 15, 57) and 72% (90% CI 46, 103), respectively. Patients taking concomitant medications with disposition dependent upon BCRP and with narrow therapeutic index should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving TAGRISSO.
In a clinical PK study, co-administration of TAGRISSO with simvastatin (sensitive CYP3A4 substrate) decreased the AUC and Cmax of simvastatin, -9% (90% CI -23, 8) and -23% (90% CI -37, -6), respectively. These changes are small and not likely to be of clinical significance. Clinical PK interactions with CYP3A4 substrates are unlikely.
In a clinical PK study, co-administration of TAGRISSO with fexofenadine (PXR/P-gp substrate) increased the AUC and Cmax of fexofenadine by 56% (90% CI 35, 79) and 76% (90% CI 49, 108) after a single dose and 27% (90% CI 11, 46) and 25% (90% CI 6, 48) at steady state, respectively. Patients taking concomitant medications with disposition dependent upon P-gp and with narrow therapeutic index (e.g. digoxin, dabigatran, aliskiren) should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving TAGRISSO (see Pharmacology: Pharmacokinetics under Actions).
