Singapore Drugs Database

Indication

Indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age: partial seizures/primary generalized tonic-clonic seizures/generalized seizures of Lennox-Gastaut syndrome [FDA Label]. Indicated for conversion to monotherapy in adults (≥16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED)[FDA Label]. Indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (≥18 years of age) treated for acute mood episodes with standard therapy [FDA Label].

Mechanism of Action

Although chemically unrelated, lamotrigine resembles the actions of phenytoin and carbamazepine in inhibiting voltage-sensitive sodium channes thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids such as glutamate and aspartate [FDA Label]. Studies on lamotrigine show binding to sodium channels similar to local anesthetics, which could explain potential clinical benefit of lamotrigine in some neuropathic pain states [T28]. Lamotrigine displays binding properties to several different receptors. It mediates a weak inhibitory effect on serotonin 5-HT3 receptor with IC50 of 18 µM [FDA Label]. It also weakly binds to Adenosine A1/A2 receptors, α1/α2/β adrenergic receptors, dopamine D1/D2 receptors, GABA A/B receptors, histamine H1 receptors, κ-opioid receptor (KOR), mACh receptors and serotonin 5-HT2 receptors with an IC50>100 µM [FDA Label]. Lamotrigine had weak effects at sigma opioid receptors (IC50 = 145 µM) [FDA Label]. A study demonstrated an evidence _in vivo_ that lamotrigine inhibits Cav2.3 (R-type) calcium currents that could also contribute to its anticonvulsant activity [A31737]. This inhibition of calcium currents is also observed in topiramate.

Pharmacokinetics

Absorption

Lamotrigine is rapidly and completely absorbed with negligible first-pass metabolism. Its oral absolute bioavailability is 98% which is not affected by food intake. Peak plasma concentrations is reached anywhere from 1.4 to 4.8 hours following drug administration, which varies depending on the dosing regimen of lamotrigine, concomitant medications, and epileptic states [FDA Label].

Distribution

The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg and is independent of dose administered [FDA Label]. Lamotrigine accumulated in the kidney of the male rat, which is atttributable to α-2 microglobulin [FDA Label].

Metabolism

Lamotrigine predominantly undergoes glucuronidation to form 2-N-glucuronide conjugate, which is pharmacologically inactive. Of total radioactivity detected in urine following oral administration of 240 mg lamotrigine, the components recovered consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%) [FDA Label].

Elimination

Clearance

The mean apparent plasma clearance (Cl/F) ranges from 0.18 to 1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual [FDA Label].

Toxicity

Some fatal cases of overdose involving quantities up to 15 g have been reported. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay. While there is no known antidote for lamotrigine, hospitalization and general supportive care is recommended in case of suspected overdose. If indicated, gastric lavage and emesis may be required with appropriate precautions made to protect the airway. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood [FDA Label]. Oral TDLO in man is 19 mg/kg and oral TDLO (intermittent) in woman is 2 mg/kg/30H [MSDS]. Oral LD50 in mouse and rat is 205 mg/kg and 245 mg/kg, respectively [MSDS]. In animal studies, lamotrigine was not found to be teratogenic. However it decreased fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans [FDA Label]. There is no evidence of carcinogenic or mutagenic potential for lamotrigine and effect of lamotrigine on human fertility is unknown [FDA Label].

Active Ingredient/Synonyms

3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine | Lamotrigina | Lamotrigine | Lamotriginum | Lamotrigine |