Drug Interactions between erlotinib and Sprycel

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of dasatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Because dasatinib prolongs the QT interval, high plasma levels of dasatinib may increase the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with dasatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Some authorities recommend close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention, bradycardia or other conduction disturbances) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with a potent CYP450 3A4 inhibitor is necessary.

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.