Drug Interactions between erlotinib and Phenytoin Sodium, Extended Release

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of erlotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor that increased erlotinib systemic exposure (AUC) by 67%. In general, the effects of grapefruit products are concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

GENERALLY AVOID: Cigarette smoking reduces erlotinib exposure due to induction of hepatic CYP450 1A2, one of the isoenzymes responsible for the metabolic clearance of erlotinib. Induction of CYP450 1A1 in the lungs may also contribute. In one pharmacokinetic study of healthy subjects given a single 150 mg dose of erlotinib, mean erlotinib peak plasma concentration (Cmax), systemic exposure (AUC) and plasma concentration at 24 hours were decreased by 35%, 64% and 88%, respectively, in current smokers compared to former/never smokers. Likewise, in a phase 3 non-small cell lung cancer (NSCLC) trial, the steady-state trough plasma concentrations of erlotinib in current smokers were approximately 2-fold less than in former/never smokers, accompanied by a 24% increase in apparent erlotinib plasma clearance. In a phase 1 dose-escalation study that analyzed the steady-state pharmacokinetics of erlotinib in current smokers with NSCLC, there was a dose-proportional increase in erlotinib exposure when the dose was increased from 150 mg to 300 mg, the maximum tolerated dose in the study population. Median steady-state trough plasma concentration at the 300 mg dose was approximately 3-fold higher than at the 150 mg dose. The clinical impact of smoking on erlotinib efficacy has not been studied.

ADJUST DOSING INTERVAL: Food enhances the oral absorption of erlotinib. According to the product labeling, administration with food increased the oral bioavailability of erlotinib from approximately 60% to almost 100% compared to administration in the fasting state.

MANAGEMENT: Consumption of grapefruit and grapefruit juice should be avoided or limited during treatment with erlotinib. Patients who currently smoke cigarettes are advised to stop smoking as soon as possible. If cigarette smoking is continued while taking erlotinib, the manufacturer recommends increasing the dosage of erlotinib by 50 mg increments at 2-week intervals up to a maximum of 300 mg as tolerated. However, the efficacy and long-term safety of dosages higher than 150 mg daily have not been established. Data from a double-blind, randomized phase 3 study (MO22162, CURRENTS) demonstrated no benefit in progression free survival or overall survival with an erlotinib dosage of 300 mg daily relative to the recommended dosage of 150 mg daily in active smokers (average of 38 pack years) with locally advanced or metastatic NSCLC who have failed chemotherapy, although patients in the study were not selected based on epidermal growth factor receptor (EGFR) mutation status. Safety data were comparable between the two dosages, but a numerical increase in the incidence of rash, interstitial lung disease and diarrhea was observed with the higher dosage. Patients who have received a dosage increase should immediately revert to the recommended dosage of 150 mg or 100 mg once daily (depending on indication) upon cessation of smoking. Erlotinib should be administered on an empty stomach at least one hour before or two hours after the ingestion of food.