Symla

Pharmacotherapeutic group: other antiepileptics, ATC code: N03AX09. Mechanism of action The results of pharmacological studies suggest that lamotrigine is a use- and voltage-dependent blocker of voltage gated sodium channels.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ It inhibits sustained repetitive firing of neurones 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. Pharmacodynamic effects In tests designed to evaluate the central nervous system effects of medicinal products, 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 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. Study of the effect of lamotrigine on cardiac conduction A study in healthy adult volunteers evaluated the effect of repeat doses of lamotrigine (up to 400 mg/day) on cardiac conduction, as assessed by 12-lead ECG. There was no clinically significant effect of lamotrigine on QT interval compared to placebo. Clinical efficacy and safety Prevention of mood episodes in patients with bipolar disorder The efficacy of lamotrigine in the prevention of mood episodes in patients with bipolar I disorder has been evaluated in two studies. Study SCAB2003 was a multicentre, 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 adjunctive therapy, 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). The primary endpoint was "Time to Intervention for a Mood Episode (TIME)", where the interventions were additional pharmacotherapy or electroconvulsive therapy (ECT). Study SCAB2006 had a similar design as study SCAB2003, but differed from study SCAB2003 in evaluating a flexible dose of lamotrigine (100 to 400 mg/day) and including patients with bipolar I disorder who had recently or were currently experiencing a manic episode. The results are shown in Table 7. Table 7: Summary of results from studies investigating the efficacy of lamotrigine in the prevention of mood episodes in patients with bipolar I disorder 'Proportion' of patients being event free at week 76 Study SCAB2003 Bipolar I Study SCAB2006 Bipolar I Inclusion criterion Major depressive episode Major manic episode Lamotrigine Lithium Placebo Lamotrigine Lithium Placebo Intervention free 0.22 0.21 0.12 0.17 0.24 0.04 p-value Log rank test 0.004 0.006 - 0.023 0.006 - Depression free 0.51 0.46 0.41 0.82 0.71 0.40 p-value Log rank test 0.047 0.209 - 0.015 0.167 - Free of mania 0.70 0.86 0.67 0.53 0.64 0.37 p-value Log rank test 0.339 0.026 - 0.280 0.006 - In supportive analyses of time to first depressive episode and time to first manic/hypomanic or mixed episode, the lamotrigine-treated patients had significantly longer times to first depressive episode than placebo patients, and the treatment difference with respect to time to manic/hypomanic or mixed episodes was not statistically significant. The efficacy of lamotrigine in combination with mood stabilisers has not been adequately studied. Paediatric population Children aged 1 to 24 months The efficacy and safety of adjunctive therapy in partial seizures in patients aged 1 to 24 months has been evaluated in a small double-blind placebo-controlled withdrawal study. Treatment was initiated in 177 subjects, with a dose titration schedule similar to that of children aged 2 to 12 years. Lamotrigine 2 mg tablets are the lowest strength available, therefore the standard dosing schedule was adapted in some cases during the titration phase (for example, by administering a 2 mg tablet on alternate days when the calculated dose was less than 2 mg). 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. Thirty-eight responders (> 40% decrease in seizure frequency) were randomised to placebo or continuation of lamotrigine. The proportion of subjects with treatment failure was 84% (16/19 subjects) in the placebo arm and 58% (11/19 subjects) in the lamotrigine arm. The difference was not statistically significant: 26.3%, CI95% -2.6%, 50.2%, p=0.07. 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%). Lennox-Gastaut syndrome There are no data for monotherapy in seizures associated with Lennox-Gastaut syndrome. Prevention of mood episodes in children (10-12 years of age) and adolescents (13-17 years of age) A multicentre, parallel group, placebo-controlled, double-blind, randomised withdrawal study, evaluated the efficacy and safety of lamotrigine IR as add-on maintenance therapy to delay mood episodes in male and female children and adolescents (age 10-17 years) who had been diagnosed with bipolar I disorder and who had remitted or improved from a bipolar episode while treated with lamotrigine in combinations with concomitant antipsychotic or other mood-stabilising drugs. The result of the primary efficacy analysis (time to occurrence of a bipolar event – TOBE) did not reach statistical significance (p=0.0717), thus efficacy was not shown. In addition, safety results showed increased reporting of suicidal behaviours in lamotrigine treated patients: 5% (4 patients) in the lamotrigine arm compared to 0 in placebo (see section 4.2).