Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: GlaxoSmithKline NZ Limited, Private Bag 106600, Downtown, Auckland, NEW ZEALAND, Phone: (09) 367 2900, Facsimile: (09) 367 2910
Pharmacotherapeutic group: other antiepileptics
ATC code: N03AX09
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 neurones 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-evoked bursts of action potentials.
In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents. At therapeutic doses, lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, in patients with clinically important structural or functional heart disease lamotrigine could potentially slow ventricular conduction (widen QRS) and induce proarrhythmia.
In tests designed to evaluate the central nervous system effects of medicines, the results obtained using doses of 240 mg lamotrigine administered to healthy volunteers did not differ from placebo, whereas both 1000 mg phenytoin and 10 mg diazepam each significantly impaired fine visual motor coordination 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.
The effectiveness of lamotrigine as adjunctive therapy in patients aged 1 to 24 months with partial seizures was evaluated in a multi-centre, double-blind, placebocontrolled add-on trial (Study LAM20006). Lamotrigine was added to 1 or 2 AEMs 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 ug/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 AEM, 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 AEMs 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).
The adverse event profile was similar to that seen in older children.
Two pivotal studies have demonstrated efficacy in the prevention of depressive episodes in patients with bipolar I disorder.
Clinical study SCAB20003 was a multi-centre, double-blind, double-dummy, placebo and lithium-controlled, randomised 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 stabilised 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 mEq/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 analysed 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 multi-centre, double-blind, double dummy, placebo and lithium-controlled, randomised, flexible dose evaluation of lamotrigine in the longterm prevention of relapse and recurrence of manic and/or depression in patients with bipolar I disorder who had recently or were currently experiencing a manic or hypomanic episode. Once stabilised 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 mEq/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 analysed 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/hypomanic or mixed episodes was not statistically significant.
In clinical trials, propensity to induce destabilisation, mania or hypomania whilst on lamotrigine therapy was not significantly different to placebo.
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. 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.
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.
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 AEMs and data suggest that interactions between lamotrigine and medicines metabolised by cytochrome P450 enzymes are unlikely to occur.
The mean steady state clearance in healthy adults is 39 ± 14 mL/min. Clearance of lamotrigine is primarily metabolic with subsequent elimination of glucuronideconjugated 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 glucuronidationinducing medicines such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when co-administered with valproate alone (see section 4.2 Dose and method of administration and section 4.5 Interaction with other medicines and other forms of interaction).
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 medicines such as carbamazepine and phenytoin and increasing to mean values of 45 to 50 hours when co-administered with valproate alone (see section 4.2 Dose and method of administration).
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 9 studies with non-elderly adults after single doses of 30 to 450 mg.
Twelve volunteers with chronic renal failure, and another 6 individuals undergoing haemodialysis 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 haemodialysis), and 1.57 mL/min/kg (during haemodialysis) compared to 0.58 mL/min/kg in healthy volunteers. Mean plasma half-lives were 42.9 hours (chronic renal failure), 57.4 hours (between haemodialysis) and 13.0 hours (during haemodialysis), compared to 26.2 hours 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 4 hour haemodialysis 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.
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.
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.
Reproductive toxicology studies with lamotrigine in animals at doses less than the human dose of 400 mg/day [on a body surface area (mg/m²) basis] showed developmental toxicity (increased mortality, decreased body weight, increased structural variations, neurobehavioral abnormalities), but 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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
