Lamotrigine

Lamotrigine is an antiepileptic agent that blocks use-dependent voltage-sensitive sodium channels, thereby preventing excitatory neurotransmitter release. However, this mechanism does not explain the broad range of clinical efficacy of this agent.

In noncomparative trials, adjunctive lamotrigine (≤15 mg/kg/day) improved seizure control in children and adolescents with various refractory seizure types, with about 29 to 90% of patients showing a ≦50% reduction in seizure frequency after ≥3 months’ treatment. Lamotrigine was particularly effective in generalised seizures, especially absence seizures and those related to the Lennox-Gastaut syndrome. In one placebo-controlled study, 33% of children and young adults (aged 3 to 25 years) with refractory Lennox-Gastaut syndrome had a reduction in seizure frequency of ≥50% after 16 weeks of adjunctive lamotrigine treatment, compared with 16% of placebo recipients (p = 0.01). Significant reductions in seizure frequency when compared with placebo were also observed in patients with refractory generalised and partial seizures. The use of lamotrigine has also been associated with beneficial effects on cognition and behaviour.

Adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological and are typically mild or moderate and transient with the exception of a potentially serious rash. Maculopapular or erythematous skin rash occurred in ≈12% of paediatric patients (aged <16 years) treated with lamotrigine and was the most common reason for treatment discontinuation. More severe forms of rash, including Stevens-Johnson syndrome, occasionally occurred, with a 3-fold higher incidence in children (≈1%) than adults (≈0.3%). However, lamotrigine treatment in paediatric trials was generally given at higher initial doses and faster dose escalations than recently revised recommendations. These factors, as well as concomitant use of valproic acid (valproate sodium), are associated with an increased risk of rash.

Lamotrigine is thought to act principally by inhibiting use-dependent voltage-sensitive sodium channels, thus stabilising the presynaptic membrane and preventing the release of excitatory neurotransmitters, predominantly glutamate. However, this mechanism cannot explain the observed clinical efficacy of lamotrigine against absence seizures, and other mechanisms, as yet unidentified, may be involved.

Lamotrigine suppresses burst firing in cultured rat cortical neurons and sustained repetitive firing in the mammalian spinal cord while leaving normal synaptic conduction unaffected, evidently through a preferential interaction with the slow inactivated sodium channel. The drug potently inhibits sodium-dependent glutamate and aspartate release as well as γ-aminobutyric acid (GABA) release from cortical slices.

In animal models, lamotrigine is effective against generalised tonic-clonic, absence and partial seizures. It selectively increases the threshold for localised seizure activity, suggesting a suppressant effect on seizure initiation rather than propagation. Lamotrigine reduces interictal spike activity, photosensitivity and paroxysmal slow spike-and-wave activity on EEG recordings in epileptic patients, but has no observed effect on background EEG activity.

In healthy volunteers, lamotrigine causes less impairment of psychomotor function than diazepam, carbamazepine and phenytoin, and is relatively free of sedative effects. It is also associated with improvements in mood and motor skills in children with epilepsy.

Oral absorption of lamotrigine is rapid and virtually complete. Its kinetics are linear over the dose range 30 to 450mg and are therefore not saturable at doses used clinically. In children aged ≤12 years, peak plasma lamotrigine concentrations occur 1 to 6 hours after administration. Plasma protein binding of lamotrigine in vitro is ≈55% and is constant over the plasma concentration range of 1 to 4 mg/L. Lamotrigine displays a moderate volume of distribution and shows good penetration into the brain, with a brain/serum concentration ratio of 2.8 in adult volunteers. Lamotrigine undergoes biotransformation by glucuronidation mainly to an inactive 2-N-glucuronide derivative, which accounts for approximately 80 to 90% of the amount recoverable in the urine after a single oral dose. Approximately 70% of a single oral dose of lamotrigine is recovered in the urine during the first 6 days postdose. Autoinduction of lamotrigine metabolism has been demonstrated in adults. The clearance of lamotrigine in children under 5 years old is 2 to 3 times higher than in adults, but elimination half-life (t1/2) values are comparable because of a larger volume of distribution in children. The mean t1/2, is ≈32 hours in children aged <12 years receiving single oral doses of lamotrigine in the absence of other medications; plasma clearance shows interindividual variation and is markedly affected by concomitant treatment with other antiepileptic agents (see Drug Interactions section). There is no clear correlation between plasma lamotrigine concentration and therapeutic efficacy or tolerability, but further data are required.

Although lamotrigine has little influence on the kinetics of other antiepileptic drugs, it can itself be influenced by concomitant medications via a number of pharmacokinetic and pharmacodynamic drug interactions. In children under 12 years, coadministration with enzyme-inducing agents such as carbamazepine or phenytoin significantly increases lamotrigine clearance, resulting in a reduction in mean t1/2 from ≈32 hours with monotherapy to ≈7 hours. In contrast, co-administration with valproic acid significantly increases the mean t1/2 of lamotrigine to between 45 and 65 hours; this pharmacokinetic interaction has been associated with increased susceptibility to rash.

There are age-related differences in lamotrigine clearance during polytherapy: the t1/2, of lamotrigine in the presence of enzyme inducers is shorter in children (≈7 hours) than in adults (≈14 hours).

A pharmacodynamic interaction between valproic acid and lamotrigine has been associated with increased therapeutic efficacy as well as some increased toxic effects. Signs of carbamazepine toxicity (dizziness, diplopia, nausea, ataxia and nystagmus) noted upon addition of lamotrigine to a carbamazepine regimen has also been attributed to a pharmacodynamic interaction.

The use of lamotrigine in paediatric clinical trials has largely been limited to patients with refractory epilepsies receiving lamotrigine as an adjunctive therapy. Initial data show lamotrigine has an efficacy profile in paediatric epilepsy similar to that in adults, displaying broad antiepileptic efficacy in a wide range of partial and generalised paediatric syndromes, and also demonstrating a number of non-seizure-related benefits.

In noncomparative trials, the percentage of paediatric patients with refractory epilepsy achieving at least a 50% reduction in seizure frequency during adjunctive lamotrigine therapy (≤15 mg/kg/day) ranged from about 29 to 90%, the large variability reflecting the heterogeneity of the population (interindividual differences in seizure type, concomitant medication, seizure frequency and neurological function). In these studies, patients with generalised syndromes displayed the best response to lamotrigine, especially those with absence epilepsy or seizures associated with the Lennox-Gastaut syndrome; patients with severe myoclonic epilepsy of infancy may not respond to lamotrigine therapy or may even have worse seizure control.

The efficacy of adjunctive lamotrigine therapy was confirmed in 3 placebo-controlled studies in patients with either refractory Lennox-Gastaut syndrome, partial seizures, or generalised seizures. In patients with Lennox-Gastaut syndrome, 33% of patients aged 3 to 25 years treated with lamotrigine (n = 78) had a reduction in seizure frequency of at least 50% compared with only 16% of patients in the placebo group (n = 89) after 16 weeks of treatment (p = 0.01). In patients (≤16 years) with partial seizures, 42% of those receiving lamotrigine (n = 98) achieved a ≥50% reduction in seizure frequency compared with 16% of patients receiving placebo (n = 101) after 18 weeks of treatment (p < 0.001). Lamotrigine was also significantly more effective than placebo in reducing seizure frequency in patients with generalised epilepsy syndromes in a small double-blind crossover trial.

Detailed longer term data are scarce; in one study (n = 155) the physicians’ global assessment of seizure control indicated that seizure control was generally maintained compared with the 3-month baseline period before lamotrigine treatment during long term lamotrigine treatment for up to 4 years.

In addition to its antiepileptic effect, lamotrigine has been shown to have positive effects on cognition and behaviour in a number of noncomparative trials; improvements in motor skills have also been observed. Seizure control does not always accompany these improvements, indicating that there could be a direct psychotropic effect of lamotrigine, that is yet to be determined.

Adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological but these are usually mild or moderate, infrequent and, with the exception of a rare but serious rash (see below), typically resolve promptly upon dose adjustment of lamotrigine or concomitant medications. Pooled tolerability data from clinical trials in children (≤16 years) [n = 544] revealed somnolence (17.8%), infection (17.6%), rash (16.9%), vomiting (15.8%), increased seizures (14.2%), pharyngitis (12.1%) and fever (12.1%) to be the most frequently occurring adverse events with adjunctive lamotrigine therapy.

In controlled trials, there were no significant differences in the frequency of adverse events between the lamotrigine (n = 168) and placebo (n = 171) treatment groups with the exception of dizziness, ataxia, tremor, nausea, diplopia and urinary tract infection.

Maculopapular or erythematous skin rash occurred in ≈12% of paediatric patients (aged <16 years) treated with lamotrigine and was the most common reason for treatment discontinuation. More severe forms of rash (requiring hospitalisation or possible Stevens-Johnson syndrome) occasionally occurred, with a 3-fold higher incidence in children (≈1 %) compared with adults (≈0.3%). Rash typically occurs within the first 2 to 8 weeks of treatment and may be accompanied by a flu-like syndrome. The risk of lamotrigine-associated rash may be increased with concomitant use of valproic acid, exceeding the recommended initial dosage of lamotrigine, or exceeding recommended dosage escalation rates. The disparity in the incidence of rash between adults and children could be attributable to the over-representation of these risk factors in paediatric trials and may be minimised by the recent changes made to the paediatric dosage guidelines.

Idiosyncratic haematological and other reactions have been reported during lamotrigine therapy but causality to the drug is not established. Instances of overdose in children are rare; overdose should be treated with supportive measures.

Current indications for lamotrigine therapy in children are limited to adjunctive use only. In the US, lamotrigine is indicated for paediatric patients aged 2 to 16 years with Lennox-Gastaut syndrome only; it has a broader indication in other countries, including the UK, for use in children aged 2 to 12 years with simple/complex partial or secondary/primary generalised seizures, or seizures related to the Lennox-Gastaut syndrome.

Dosage guidelines for lamotrigine treatment in children vary according to concomitant medication and have recently been revised by the manufacturer. For children receiving lamotrigine in combination with valproic acid (with or without other antiepileptic drugs), treatment is initiated at 0.15 mg/kg/day in 1 or 2 divided doses for 2 weeks followed by 0.3 mg/kg/day over weeks 3 to 4. Subsequent dosage increases of 0.3 mg/kg/day over 1 to 2 weeks are given until a maintenance dose is achieved (1 to 5 mg/kg/day; maximum of 200 mg/day). Patients receiving concomitant enzyme-inducing agents have a higher initiation dose (0.6 mg/kg/day) increasing to 1.2 mg/kg/day over weeks 3 to 4, with dosage increments of 1.2 mg/kg/day every 1 to 2 weeks until maintenance dosages of 5 to 15 mg/kg/day (maximum of 400 mg/day) are reached.

Adjustment of pre-existing antiepileptic drug dosages is not generally required during add-on therapy. However, if the adverse effects of carbamazepine appear when lamotrigine is added to treatment with this drug it may be appropriate to reduce the carbamazepine dose.

Lamotrigine is at present not indicated as a monotherapy in children. It is contraindicated in those patients who have shown a previous allergy/reaction to lamotrigine, and it is not recommended for patients with hepatic impairment. Unless safety concerns necessitate fast withdrawal, discontinuation of lamotrigine therapy should be performed gradually over a period of ≤2 weeks.