Lamotrix Mechanism of Action

ATC Code: N03AX09.
Pharmacology: Pharmacodynamics: Mechanism of action: The results of pharmacological studies suggest that lamotrigine is a use-dependent blocker of voltage gated sodium channels. It produces a use-and voltage-dependent block of sustained repetitive firing in cultured neurons and inhibits pathological release of glutamate, the amino acid which plays a key role in the generation of epileptic seizures as well as inhibiting glutamate evoke bursts of action potentials.
Pharmacodynamic effects: In tests designed to evaluate the central nervous system effects of drug, the results obtained using doses of 240 mg lamotrigine administered to healthy volunteers did not differ from placebo, whereas both 1000 mg phenytoin and 10mg diazepam each significantly impaired fine visual motor co-ordination and eye movements, increased body sway and produced subjective sedative effects.
In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visual motor co-ordination and eye movements, while increasing both body sway and heart rate, whereas results with lamotrigine at doses of 150 mg and 300 mg did not differ from placebo.
Melanin binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.
Clinical Studies: Clinical efficacy and safety of adjunctive therapy in patients aged 1 to 24 months with partial seizures: The effectiveness of lamotrigine as adjunctive therapy in patients aged 1 to 24 months with partial seizures wasevaluated in a multi-centre, double-blind, placebo controlled add-on trial (Study LAM20006). Lamotrigine was added to 1 or 2 AEDs during an open-label phase (n=177).
Lamotrigine was given on alternate days or once daily if an initial total dose or dose titration step of less than 2 mg was required. Serum levels were measured at the end of week 2 of titration and the subsequent dose either reduced or not increased if the concentration exceeded 0.41 μg/mL, the expected concentration in adults at this time point. Dose reductions of up to 90% were required in some patients at the end of week 2. If valproate was used as an AED, lamotrigine was added only after an infant had been on valproate for 6 months without liver function test abnormalities.
The safety and efficacy of lamotrigine in patients weighing less than 6.7 kg, and taking valproate or AEDs other than carbamazepine, phenytoin, phenobarbital or primidone has not been evaluated. Patients achieving a 40% or greater reduction in partial seizure frequency (n=38) were randomised to either gradual withdrawal to placebo (n=19) or continued lamotrigine (n=19) for up to 8 weeks. The primary efficacy endpoint was based on the difference in the proportion of subjects receiving lamotrigine or placebo who met defined escape criteria. The escape criteria allowed the withdrawal of subjects from the study if their epilepsy conditions showed any signs of clinical deterioration. Statistical significance on the primary endpoint was not achieved; however, fewer patients met escape criteria on lamotrigine (58%) compared with placebo (84%) and took a longer time to meet escape criteria (42 versus 22 days).
A total of 256 subjects between 1 to 24 months of age have been exposed to lamotrigine in the dose range 1 to 15 mg/kg/day for up to 72 weeks. The safety profile of lamotrigine in children aged 1 month to 2 years was similar to that in older children except that clinically significant worsening of seizures (>=50%) was reported more often in children under 2 years of age (26%) as compared to older children (14%).
Clinical efficacy in the prevention of depressive episodes in patients with bipolar disorder: Adults (18 years of age and over): Two pivotal studies have demonstrated efficacy in the prevention of depressive episodes in patients with bipolar disorder.
Clinical study SCAB20003 was a multicenter, double-blind, double-dummy, placebo and lithium-controlled, randomized fixed dose evaluation of the long-term prevention of relapse and recurrence of depression and/or mania in patients with bipolar I disorder who had recently or were currently experiencing a major depressive episode. Once stabilized using lamotrigine monotherapy or lamotrigine plus psychotropic medication, patients were randomly assigned into one of five treatment groups: lamotrigine (50, 200, 400 mg/day), lithium (serum levels of 0.8 to 1.1 mMOL/L) or placebo for a maximum of 76 weeks (18 months). Treatment regimens were maintained until an emerging mood episode (depressive or manic) deemed it necessary to intervene with additional pharmacotherapy or electroconvulsive therapy (ECT).
The primary endpoint was "Time to Intervention for a Mood Episode (TIME)", where the interventions were either additional pharmacotherapy or ECT. This endpoint was analyzed using three methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003 to 0.029. In supportive analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode, the lamotrigine patients had longer times to first depressive episode than placebo patients (p=0.047), and the treatment difference with respect to time to manic/hypomanic or mixed episodes was not statistically significant. Clinical study SCAB2006 was a multicenter, double-blind, double-dummy, placebo and lithium-controlled, randomized, flexible dose evaluation of lamotrigine in the long-term prevention of relapse and recurrence of mania and/or depression in patients with bipolar I disorder who had recently or were currently experiencing a manic or hypomanic episode. Once stabilized using lamotrigine monotherapy or lamotrigine plus psychotropic medication, patients were randomly assigned into one of three treatment groups: lamotrigine (100 to 400 mg/day), lithium (serum levels of 0.8 to 1.1 mMOL/L) or placebo for a maximum of 76 weeks (18 months). Treatment regimens were maintained until an emerging mood episode (depressive or manic) deemed it necessary to intervene with additional pharmacotherapy or electroconvulsive therapy (ECT).
The primary endpoint was "Time to Intervention for a Mood Episode (TIME)", where the interventions were either additional pharmacotherapy or ECT. This endpoint was analyzed using three methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003 to 0.023. In supportive analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode, the lamotrigine patients had longer times to first depressive episode than placebo patients (p=0.015), and the treatment difference with respect to time to manic or hypomanic or mixed episodes was not statistically significant.
In clinical trials, propensity to induce destabilization, mania or hypomania whilst on lamotrigine therapy was not significantly different to placebo.
Pharmacokinetics: Absorption: Lamotrigine is rapidly and completely absorbed from the gut with no significant first pass metabolism. Peak plasma concentration occurs approximately 2.5 hours after oral drug administration. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. The pharmacokinetics are linear up to 450 mg, the highest single dose tested. There is considerable inter- individual variation in steady state maximum concentrations but within an individual concentrations rarely vary.
Distribution: Binding to plasma protein is about 55%; it is very unlikely that displacement from plasma protein would result in toxicity.
The volume of distribution (Vd) is 0.92 to 1.22 l/kg.
Metabolism: UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine. Lamotrigine induces its own metabolism to a modest extend depending on dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other AEDs and data suggest that interactions between lamotrigine and drugs metabolised by cytochrome P450 enzymes are unlikely to occur.
Elimination: The mean steady state clearance in healthy adults is 39 ± 14 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 drug-related material is excreted in faeces. Clearance and half life are independent of dose. The mean elimination half-life in healthy adults is 24 to 35 hours. In a study of subjects with Gilbert's Syndrome, mean apparent clearance was reduced by 32% compared with normal controls but the values are within the range for the general population.
The half-life of lamotrigine is greatly affected by concomitant medication. Mean half life is reduced to approximately 14 hours when given with glucuronidation-inducing drugs such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when co- administered with valproate alone. (See Dosage & Administration.)
Special Population: Children: Clearance adjusted for bodyweight 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 drugs such as carbamazepine and phenytoin and increasing to mean values of 45 to 50 hours when co-administered with valproate alone. (See Dosage & Administration.)
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 the 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 9 studies with non-elderly adults after single doses of 30 to 450 mg.
Patients with renal impairment: Twelve volunteers with chronic renal failure, and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of lamotrigine. Mean CL/F were 0.42 ml/min/kg (chronic renal failure), 0.33 ml/min/kg (between hemodialysis), and 1.57 ml/min/kg (during hemodialysis) compared to 0.58 ml/min/kg in healthy volunteers. Mean plasma half-lives were 42.9 h (chronic renal failure), 57.4h (between hemodialysis) and 13.0h (during hemodialysis), compared to 26.2h in healthy volunteers. On average, approximately 20% (range=5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated during a 4h hemodialysis session. For this patient population, initial doses of lamotrigine should be based on patients' AED regimen; reduced maintenance doses may be effective for patients with significant renal functional impairment.
Patients with hepatic impairment: A single-dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamotrigine was 0.31, 0.24 or 0.10 ml/min/kg in patients with grade A, B or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 ml/min/kg in the healthy controls. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh Grade B) and 75% in patients with severe (Child-Pugh Grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response.
Toxicology: Preclinical Safety Data: Reproductive toxicology studies with lamotrigine in animals at doses in excess of the human therapeutic dosage showed no teratogenic effects. However, as lamotrigine is a weak inhibitor of dihydrofolate reductase, there is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy. The results of a wide range of mutagenicity tests indicate that lamotrigine does not present a genetic risk to man. Lamotrigine was not carcinogenic in long-term studies in the rat and the mouse.