Erlotinib - Drug-Drug Interactions

The main drug-drug interactions associated with erlotinib include

CYP3A4 Inhibitors/ inducers

CYP3A4 Inhibitors

Potent CYP3A4 inhibitors increase erlotinib plasma concentrations and may lead to increased toxicity.^1,2 Co-administration of ketoconazole increased erlotinib C_max by 69% and AUC by 86%.²

CYP3A4 Inducers

CYP3A4 inducers decrease erlotinib plasma concentrations and may reduce efficacy.^1,2 Pre-treatment with rifampicin for 7-11 days prior to erlotinib decreased erlotinib AUC by 58-80%.¹ Concomitant erlotinib and rifampicin (600 mg once daily for 7 days) decreased the erlotinib AUC by 69%.²

QT prolongators

Non reported.

Other Drug-drug Interactions

Medicines that Alter Gastric pH

As the solubility of erlotinib decreases above pH 5, drugs affecting gastric pH can lower erlotinib plasma concentrations.^1,2 Co-administration of erlotinib with omeprazole, a proton pump inhibitor, decreased the erlotinib C_max and AUC by 61% and 46%, respectively.^1,2 Co-administration of erlotinib with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib C_max and AUC by 54% and 33%, respectively; this effect was substantially reduced when erlotinib was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg bid.^1,2

Cigarette Smoking

Cigarette smoking decreases erlotinib plasma concentrations and dose modifications are recommended.¹ A pharmacokinetic interaction study identified a significant 2.8-, 1.5- and 9-fold reduction in AUC_inf, C_max and plasma concentration at 24 hours, respectively, after erlotinib administration in smokers vs. non-smokers; this is likely to represent a clinically significant effect.² Smokers had a 24% higher rate of erlotinib clearance.^1,2

Anticoagulants

Interaction between erlotinib and coumarin-derived anticoagulants (including warfarin) can lead to increased INR and bleeding; severe and fatal haemorrhage has been reported.^1,2

Additional Interactions

Ciprofloxacin: co-administration of ciprofloxacin (a moderate CYP1A2 inhibitor) increased the erlotinib AUC by 39% and that of the active metabolite by 60%; the clinical relevance of this increase is unknown.²

Statins: erlotinib may increase the potential for statin-induced myopathy (rare).² As this is likely due to competition for CYP3A4, pravastatin (eliminated by the kidneys) may be considered.³

P-glycoprotein inhibitors: as erlotinib is a P-gp substrate, co-administration of P-gp inhibitors may lead to altered distribution and/or elimination of erlotinib.²

Capecitabine: capecitabine may increase erlotinib concentrations.²

Proteasome inhibitors: studies have shown EGFR degradation through the proteasome, indicating a potential for interaction.²

References

1. Food and Drug Administration. Erlotinib (TARCEVA) Prescribing information. 2015.
2. European Medicines Agency. Erlotinib (TARCEVA). Summary of Product Characteristics. 2015.
3. Pajares B, Torres E, Trigo JM et al. Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations. Clin Transl Oncol 2012; 14: 94-101.