What is the role of lamotrigine (LTG) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Lamotrigine (LTG) is a triazine compound that is chemically unrelated to any of the other AEDs. It was developed as an antifolate agent on the basis of a theory that the mechanism of some AEDs is related to their antifolate property. LTG was approved in the United States in 1994. [13, 14, 15]

LTG’s major mechanism of action is blocking voltage-dependent sodium-channel conductance. It has been found to inhibit depolarization of the glutaminergic presynaptic membrane, thus inhibiting release of glutamate. It has a weak antifolate effect that is unrelated to its antiseizure efficacy.

On oral administration, LTG has a bioavailability close to 100%, reaching peak levels within 1-3 hours and achieving a volume of distribution of 0.9-1.3 L/kg. Its solubility is poor in both ethanol and water; therefore, it is not available in parenteral form. Protein binding is 55% and the elimination half-life is 24-41 hours. It is metabolized by the liver and excreted through the kidneys. It produces auto-induction at higher doses and has no active metabolites.

LTG levels increase with concomitant use of valproate (VPA) to 70 hours. Combination therapy with VPA enhances the antiepileptic effect; however, it also increases the chances of developing allergic skin reactions. LTG does not induce or inhibit hepatic enzymes; therefore, it does not affect the metabolism of lipid-soluble drugs such as warfarin and oral contraceptives. Conversely, drugs that induce hepatic enzymes may reduce the half-life of LTG from 23 hours to 14-16 hours. LTG levels must be adjusted accordingly.

LTG’s significant effect on seizures was demonstrated in 9 of 10 placebo-controlled trials in which LTG was administered as add-on therapy. LTG resulted in a 17-59% reduction in seizures, with most trials showing 25-30% median reduction in seizures.

LTG is effective in partial onset and secondarily generalized tonic-clonic seizures, primary generalized seizures (ie, absence seizures and primary generalized tonic-clonic seizures), atypical absence seizures, tonic/atonic seizures, and Lennox-Gastaut syndrome. It is sometimes effective for myoclonic seizures but can cause worsening of myoclonic seizures in some patients with juvenile myoclonic epilepsy or myoclonic epilepsy of infancy.

LTG currently is approved in the United States for adjunctive therapy for partial onset and secondarily generalized tonic-clonic seizures, crossover to monotherapy, and Lennox-Gastaut syndrome.

The dose regimen and titration schedule depends on coadministration of other AEDs, the titration rate being slower with enzyme-inhibiting AEDs such as valproate than with enzyme-inhibiting AEDs such as PHT and CBZ.

Preset packages are available with the recommended doses of LTG, with and without VPA. In children on VPA, the starting dose of LTG is 0.15 mg/kg, with increments every 1-2 weeks up to a maximum of 1-5 mg/kg. In patients taking concomitant enzyme inducers, the starting dose is 0.6 mg/kg, up to a maximum of 5-15 mg/kg. LTG is available in tablets (25 mg, 50 mg, 100 mg, 150 mg, and 200 mg) and chewable tablets (5 mg, 25 mg, and 100 mg); it is administered twice a day.

Unlike most AEDs, LTG produces few CNS side effects. Rash is the main concern associated with this drug; it occurs in 5% of patients and is associated with rapid titration. Severe rash (more common in children taking VPA) may develop and lead to Stevens-Johnson syndrome, which may be fatal (though this is rare, with an incidence of only 0.1%). Other commonly reported adverse reactions are headache, blood dyscrasias, ataxia, diplopia, GI disturbance, psychosis, tremor, hypersensitivity reactions, somnolence, and insomnia.

LTG is the only AED with more than 500 documented pregnancy exposures. The International Lamotrigine Pregnancy Registry Update reported 414 monotherapy exposures, giving a risk of 2.9%. The North American AED Pregnancy Registry found no overall risk of major malformations in 684 infants exposed to LTG monotherapy but noted an increased risk of orofacial clefts. In contrast, the EUROCAT congenital anomaly registers did not find an increased risk of orofacial clefts for 40 children exposed to LTG monotherapy. [16]

The excellent side-effect profile and lack of significant CNS toxicity make this drug one of the preferred choices in treating elderly patients. The reported low incidence of congenital malformations when exposed to pregnant patients makes this drug one of the preferred treatments during pregnancy.

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