Drug Interactions between chlorthalidone / clonidine and eslicarbazepine

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.

MONITOR: Coadministration with other medications that can lower serum sodium levels such as diuretics, selective serotonin reuptake inhibitors (SSRIs), and serotonin-noradrenaline reuptake inhibitors (SNRIs) may potentiate the risk of hyponatremia associated with eslicarbazepine. In controlled clinical trials, 1% and 1.5% of patients treated with eslicarbazepine acetate 800 mg/day and 1200 mg/day, respectively, had at least one serum sodium value less than 125 mEq/L, compared to none of the patients receiving placebo. Additionally, 5.1% of eslicarbazepine-treated patients experienced decreases greater than 10 mEq/L, versus 0.7% of placebo-treated patients. These effects were dose-related and generally appeared within the first 8 weeks of treatment, with onset as early as after 3 days. Serious, life-threatening complications have included seizures, dehydration from severe nausea and vomiting, severe gait instability, and injury. Hospitalization and discontinuation of eslicarbazepine therapy were required in some cases. Concurrent hypochloremia was also present in patients with hyponatremia.

MANAGEMENT: Routine monitoring of serum sodium and chloride levels should be considered during maintenance treatment with eslicarbazepine acetate and concomitant use of other medications known to decrease serum sodium levels. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hyponatremia such as nausea, vomiting, headache, malaise, lethargy, irritability, difficulty concentrating, memory impairment, confusion, weakness, muscle spasm, and unsteadiness (which may lead to falls). More severe and/or acute cases may include hallucination, syncope, seizure, coma, respiratory arrest, and death. Depending on the severity of hyponatremia, dosage reduction or discontinuation of eslicarbazepine acetate and other medications may be required, and appropriate medical intervention instituted as necessary.