Drug Interaction Report

MONITOR: There is clinical evidence that eslicarbazepine acetate can prolong the PR interval of the electrocardiogram (ECG) in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, calcium channel blockers, atazanavir, lopinavir, digoxin, lacosamide, mefloquine) may result in additive effects and increased risk of conduction disturbances and atrioventricular (AV) block. In phase III adult adjunctive epilepsy studies in patients who received eslicarbazepine acetate 400 mg, 800 mg, or 1200 mg per day, mean increases in the PR interval at the end of 12 weeks of maintenance treatment were 2.4 msec, 1.3 msec, and 2.6 msec, respectively, compared to 0.6 msec in the placebo group. PR interval values greater than 200 msec at study end that were not present at baseline were observed in 0.8% and 0.2% of patients treated with eslicarbazepine acetate and placebo, respectively. In a clinical pharmacology ECG trial of healthy subjects who received either the maximum recommended daily dose of eslicarbazepine acetate (1200 mg), two times the maximum recommended daily dose of eslicarbazepine acetate (2400 mg) or placebo for five days, the maximum mean placebo-adjusted increase in the PR interval on day 5 was 4.4 msec at 5 hours post-dose for the 1200 mg group, and 8.2 msec at 3 hours post-dose for the 2400 mg group. Excessive PR interval prolongation can result in AV block. Cases of AV block have been reported in post-marketing experience.

MANAGEMENT: Caution is advised if eslicarbazepine is used concomitantly with other agents that prolong the PR interval, especially in the elderly and patients with known conduction problems (e.g., marked first-degree AV block; second-degree or higher AV block; sick sinus syndrome without pacemaker), or a history of syncope, arrhythmia or severe cardiac disease such as myocardial ischemia or heart failure. Patients should be advised to notify their doctor if they experience dizziness, lightheadedness, fainting, or irregular heartbeat.

ADJUST DOSING INTERVAL: The bioavailability of metoprolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take metoprolol at the same time each day, preferably with or immediately following meals.

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.