Lamotrigine: Pharmacology, Clinical Utility, and New Safety Concerns

Lamotrigine was originally developed as an antiseizure drug because of its ability to reduce folate levels (1). At the time of the drug's development, it was thought that folate depletion would treat epileptic activity. Although this is now known to be incorrect, the drug did serendipitously treat seizures effectively (1). Currently, pharmacologists understand that lamotrigine reduces neuronal activity via a variety of mechanisms. The most commonly accepted mechanisms of action are enhancement of sodium channel inactivation and possible inhibition of synaptic glutamate release (2). In early studies, patients with epilepsy who were taking lamotrigine reported increases in a subjective sense of well-being, and this led to its exploration as a psychotropic drug (3). From a neuropsychiatric standpoint, lamotrigine appears to inhibit uptake of serotonin, dopamine, and noradrenaline (4).

Lamotrigine is absorbed continuously along the entire length of the gastrointestinal tract and is metabolized primarily by glucuronidation (2, 5). Both the immediate-release and extended-release formulations have half-lives of approximately 24–30 hours, but the enteric-coated extended-release form is absorbed more slowly (5). The extended-release formulation was created for the purpose of once-daily dosing for seizure disorders. When lamotrigine is used concurrently with carbamazepine, phenytoin, or phenobarbital, its plasma levels decrease by one-half (1, 2). When it is used with valproic acid, the valproic acid levels are reduced by about 25%, and the lamotrigine levels double (1, 2). The mechanisms of these drug interactions are not completely understood but thought to be due to competition for hepatic glucuronide metabolism (6).

The most common side effects of lamotrigine are dizziness, visual disturbances, ataxia, nausea or vomiting, and nonserious rash. The drug's manufacturer states that when used as monotherapy, the most common adverse reactions with the extended-release and immediate-release formulations are similar (7). Additionally, the rate of serious rash is usually not different between the two formulations (7). Serious rash (Stevens-Johnson syndrome), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are more common in pediatric populations compared with adult patients (0.3% in adults and 1% in children) (8). It is noteworthy that the distinction between the above serious conditions can be unclear and likely represents a spectrum of disease states. The vast majority of rashes that occur as a result of lamotrigine use are mild (8). Nonserious rashes can present as morbilliform, erythema multiforme, or urticaria (8). Unfortunately, simple morbilliform or urticarial rash can represent the initial stage of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (8). Consequently, when a rash occurs, patients must be referred for medical evaluation within 24 hours with possible referral to dermatology (8). Unless it is clear that the rash is not a result of lamotrigine use, lamotrigine should be discontinued immediately (6). The greatest risk of rash occurs within the first 6 weeks of treatment, although eruptions occurring beyond this time frame have been reported (6). Factors thought to increase the risk of rash are as follows: exceeding the maximum recommended dosage, titrating upward more rapidly than recommended in the guidelines, and coadministration of valproate (6). However, a rash can occur when none of these features are present (6).

There is an association between lamotrigine and aseptic meningitis as well as possible oral cleft abnormalities in newborns exposed to the drug in utero (2). The Food and Drug Administration (FDA) issued a controversial safety alert reporting an increase in suicidal thinking or behavior with all antiseizure medications, including lamotrigine; however, concerns have been raised regarding the methodology used in identifying this risk (9).

Lamotrigine is rated as a class C drug in pregnancy, and it is found in plasma levels of up to 50% in nursing infants (8). Dose reductions may be effective for patients with chronic kidney disease as a result of the prolongation of half-life, and caution is advised for patients with severe renal failure because of the paucity of studies (8). Reductions in dosage are also recommended for patients with moderate to severe hepatic insufficiency (8).