Drug Interactions between carbamazepine and Lamictal

ADJUST DOSE: Coadministration with carbamazepine may decrease the serum concentrations of lamotrigine. The mechanism is carbamazepine induction of the hepatic glucuronidation of lamotrigine. Studies have found that carbamazepine can reduce lamotrigine serum concentrations by approximately 40%, and there have been case reports of patients who developed significantly increased lamotrigine levels and/or lamotrigine toxicity following withdrawal of carbamazepine.

MONITOR: Concomitant use of lamotrigine and carbamazepine in some patients has shown enhanced carbamazepine toxicity and in vitro data suggests concomitant use of lamotrigine with other sodium channel blockers, such as carbamazepine may increase the risk of proarrhythmias in patients with structural heart disease or myocardial ischemia. Data for enhanced carbamazepine toxicity, which is thought to be due to increased plasma concentrations of the pharmacologically active epoxide metabolite, is conflicting. In one report (n=9), mean serum carbamazepine-10,11-epoxide concentration increased by 45% and the carbamazepine-10,11-epoxide to carbamazepine ratio increased by 19% following introduction of lamotrigine; four patients experienced symptoms of clinical toxicity. Other investigators have failed to find evidence of a pharmacokinetic interaction in either children or adults. However, toxicity has occurred in the absence of significant alterations in carbamazepine or carbamazepine-10,11-epoxide pharmacokinetics, suggesting the possibility of a pharmacodynamic interaction. One study found that toxicity is more likely to occur if the initial carbamazepine level is high (above 8 mg/L in study patients) upon lamotrigine introduction. Data for increased risk of proarrhythmias is based on in vitro studies which have shown lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations. In healthy individuals, a thorough QT study did not show slowed ventricular conduction (widen QRS) with lamotrigine; however, the risk of slow ventricular conduction and proarrhythmias, including sudden death, may be increased in patients with structural heart disease or myocardial ischemia. Based on this data, there is a concern that concomitant use of other sodium channel blockers may increase the risk of proarrhythmias.

MANAGEMENT: When lamotrigine is added to existing therapy containing carbamazepine without valproate, the initial dosage of lamotrigine should be 0.6 mg/kg/day in two divided doses (2 to 12 years of age) or 50 mg/day (older than 12 years of age) for the first 2 weeks. The initial dosage should be doubled for the next 2 weeks, then increased by 1.2 mg/kg/day or 100 mg/day every 1 to 2 weeks as needed and as tolerated. The usual maintenance dosage is 5 to 15 mg/kg/day (up to 400 mg/day) in children up to 12 years of age and 300 to 500 mg/day (400 mg/day for the treatment of bipolar disorder) in older patients. Patients should be advised to promptly notify their physician if they experience worsening of seizure control, increased adverse effects, or signs of carbamazepine toxicity such as dizziness, drowsiness, vertigo, diplopia, nystagmus, ataxia, and nausea. A reduction in carbamazepine dosage generally will resolve the toxicity without the need to discontinue either drug. If carbamazepine is discontinued, lamotrigine half-life will be prolonged, and a dosage adjustment may be necessary. Prescribers should refer to the lamotrigine product labeling for complete dosing information. In addition, due to the potential for increased risk of proarrhythmias, the manufacturer recommends lamotrigine be avoided in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome or other sodium channelopathies). A joint task force of the International League Against Epilepsy and the American Epilepsy Society issued an advisory on Feb 25, 2021, for healthcare professionals in response to the FDA safety warning on the cardiac effects of lamotrigine. For patients under 60 years with no cardiac risk factors, they advise that clinicians should prescribe lamotrigine as usual. For patients with cardiac risk (over 60 years and under 60 years with known cardiac disease or significant risk factors), they advise clinicians to consider obtaining an ECG prior to initiating lamotrigine and repeating ECG as the serum lamotrigine level approaches the upper limit of the therapeutic range and/or with concomitant use of other sodium channel blockers or substances known to impair atrioventricular and/or intra-ventricular cardiac conduction. They also advise clinicians consider obtaining an ECG and/or cardiology consult in patients with sudden onset syncope or pre-syncope with loss of muscular tone without a clear vasovagal or orthostatic cause. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate an irregular heart rhythm such as dizziness, lightheadedness, fainting, palpitation, shortness of breath, or syncope.

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