Interactions between Lidocan Patch and Lonafarnib

Monitor

Coadministration of potent CYP450 1A2 and/or 3A4 inhibitors with topical lidocaine formulations may significantly reduce lidocaine clearance and increase lidocaine plasma concentrations. Lidocaine is primarily metabolized by CYP450 1A2 and 3A4 into its two major, active metabolites, monoethylglycinexylidine (MEGX) and glycinexylidine (GX). In a drug study when a single dose of intravenous lidocaine was given with fluvoxamine, a potent CYP450 1A2 inhibitor, the plasma clearance of lidocaine was reduced by 41 to 60% in healthy subjects. When coadministered with potent CYP450 3A4 inhibitors, erythromycin and itraconazole, lidocaine plasma clearance was reduced by 9 to 18% in healthy subjects following a single intravenous lidocaine dose. When coadministered with both fluvoxamine and erythromycin, lidocaine plasma clearance was reduced by 53%. However, drug interaction studies evaluating potent CYP450 3A4 inhibitors with topical lidocaine formulations are unavailable. The degree of systemic absorption of topical lidocaine is dependent on the duration of application, the applied surface area, and the integrity of the application site. The risk of systemic lidocaine absorption may be greater when topical lidocaine is applied to areas of high systemic absorption (e.g., mucous membranes) with repeated doses over a long period of time. Increased lidocaine plasma concentrations may increase the risk and/or severity of adverse effects including central nervous system toxicity (e.g., dizziness, tremor, convulsions, drowsiness, mental status changes) and cardiovascular toxicity (e.g., bradycardia, hypotension, cardiac conduction abnormalities, cardiac arrest).

Management

Concomitant use of topical lidocaine with potent inhibitors of CYP450 1A2 and/or 3A4 should be done with caution and clinical monitoring. If coadministration is required, patients should be monitored for signs and symptoms of lidocaine toxicity including drowsiness, dizziness, mental status changes, tremor, bradycardia, and hypotension. Monitoring of pharmacologic response and plasma lidocaine levels may be advised whenever a potent CYP450 1A2 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the lidocaine dosage adjusted as necessary. If toxicity is suspected, the topical formulation of lidocaine should be discontinued. Additional consultation with individual product labeling may be advisable for further guidance.

Generally avoid

Grapefruit, grapefruit juice, grapefruit hybrids, starfruit, and Seville oranges may increase the plasma concentrations of lonafarnib. 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 other CYP450 3A4 inhibitors. When a single oral dose of lonafarnib (50 mg) was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. 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. Increased exposure to lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension. Lonafarnib alone prolongs the QTc interval, and increased exposure to lonafarnib may potentiate the risk of ventricular arrhythmias such as torsades de pointes, and sudden death.

Adjust dosing interval

Food does not have clinically relevant effects on the oral bioavailability of lonafarnib. When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions. When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting. However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

Management

Patients should avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, starfruit, and Seville oranges during treatment with lonafarnib. Additionally, lonafarnib should be administered with the morning and evening meals and an adequate amount of water. Consultation with product labeling may be advisable for further guidance.

Theoretically, grapefruit, grapefruit juice, grapefruit hybrids, starfruit, and Seville oranges may increase the plasma concentrations of topical lidocaine. 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. In a drug study when a single dose of intravenous lidocaine was coadministered with potent CYP450 3A4 inhibitors, erythromycin and itraconazole, lidocaine plasma clearance was reduced by 9 to 18% in healthy subjects. The degree of systemic absorption of topical lidocaine is dependent on the duration of application, the applied surface area, and the integrity of the application site. The risk of systemic lidocaine absorption may be greater when topical lidocaine is applied to areas of high systemic absorption (e.g., mucous membranes) with repeated doses over a long period of time. However, the clinical significance of this potential interaction is unknown.