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Pharmacology: It is suggested that Lamotrigine is a use- and voltage-dependent blocker of voltage gated sodium channels. It inhibits sustained repetitive firing of neurons and inhibits release of glutamate (the neurotransmitter which plays a key role in the generation of epileptic seizures). These effects are likely to contribute to the anticonvulsant properties of Lamotrigine.
In contrast, the mechanisms by which Lamotrigine exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.
Pharmacokinetics: Absorption: Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral administration of Lamotrigine. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. There is considerable inter-individual variation in steady state maximum concentrations but within an individual, concentrations rarely vary.
Distribution: Binding to plasma proteins is about 55%; it is very unlikely that displacement from plasma proteins would result in toxicity.
The volume of distribution is 0.92 to 1.22 L/Kg.
Biotransformation: UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of Lamotrigine.
Lamotrigine induces its own metabolism to a modest extent depending on dose. However, there is no evidence that Lamotrigine affects the pharmacokinetics of other AEDs and data suggest that interactions between Lamotrigine and medicinal products metabolized by cytochrome P450 enzymes are unlikely to occur.
Elimination: The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of Lamotrigine is primarily metabolic with subsequent elimination of glucuronide-conjugated material in urine. Less than
10% is excreted unchanged in the urine. Only about 2% of Lamotrigine-related material is excreted in feces. Clearance and half-life are independent of dose. The apparent plasma half-life in healthy subjects is estimated to be approximately 33 hours (range 14 to 103 hours).
The half-life of Lamotrigine is greatly affected by concomitant medicinal products. Mean half-life is reduced to approximately 14 hours when given with glucuronidation-inducing medicinal products such as Carbamazepine and Phenytoin and is increased to a mean of approximately 70 hours when co-administered with Valproate alone (see Dosage & Administration).
Linearity: The pharmacokinetics of Lamotrigine are linear up to 450 mg, the highest single dose tested.
Special patient populations: Children: Clearance adjusted for body weight is higher in children than in adults with the highest values in children under five years. The half-life of Lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme-inducing medicinal products such as Carbamazepine and Phenytoin and increasing to mean values of 45 to 50 hours when co-administered with Valproate alone (see Dosage & Administration).
Infants aged 2 to 26 months: The predicted serum concentration levels in children of 2 to 26 months were in general in the same range as those in older children, though higher Cmax levels are likely to be observed in some children with a body weight below 10 Kg.
Elderly: Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of Lamotrigine did not change to a clinically relevant extent. After single doses apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, pharmacokinetics of Lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/min/Kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/min/Kg) obtained in nine studies with non-elderly adults after single doses of 30 to 450 mg.
Renal impairment: For this patient population, initial doses of Lamotrigine should be based on the patient's concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see Dosage & Administration and Precaution).
Hepatic impairment: Initial, escalation and maintenance doses should generally be reduced in patients with moderate or severe hepatic impairment (see Dosage & Administration).
