Apo-Lamotrigine

Apo-Lamotrigine Mechanism of Action

lamotrigine

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Action
ATC Code: N 03 AX 09.
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 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.
Pharmacodynamic Effects: In tests designed to evaluate the central nervous system effects of drugs, the results obtained using doses of lamotrigine 240 mg administered to healthy volunteers did not differ from placebo, whereas both phenytoin 1000 mg and diazepam 10 mg, 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 carbamazepine 600 mg significantly impaired fine visual motor coordination and eye movements, while increasing both body sway and heart rate, whereas results with lamotrigine at doses of 150 and 300 mg did not differ from placebo.
Melanin Binding: Lamotrigine binds to melanin-containing tissues eg, 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 in the Prevention of Depressive Episodes in Patients with Bipolar Disorder: Two pivotal studies have demonstrated efficacy in the prevention of depressive episodes in patients with bipolar I disorder.
Clinical study SCAB20003 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 Apo-Lamotrigine monotherapy or Apo-Lamotrigine plus psychotropic medication, patients were randomly assigned into 1 of 5 treatment groups: Apo-Lamotrigine (50, 200, 400 mg/day), lithium (serum levels of 0.8-1.1 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 3 methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003-0.029. In supportive analyses of time to 1st depressive episode and time to 1st manic/hypomanic or mixed episode, the Apo-Lamotrigine patients had longer times to 1st 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 multicentre, double-blind, double dummy, placebo and lithium-controlled, randomised, flexible dose evaluation of Apo-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 stabilised using Apo-Lamotrigine monotherapy or Apo-Lamotrigine plus psychotropic medication, patients were randomly assigned into 1 of 3 treatment groups: Apo-Lamotrigine (100-400 mg/day), lithium (serum levels of 0.8-1.1 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 ECT.
The primary endpoint was "TIME", where the interventions were either additional pharmacotherapy or ECT. This endpoint was analyzed using 3 methods of handling data from patients who were withdrawn prior to having an intervention. The p-values for these analyses ranged from 0.003-0.023. In supportive analyses of time to 1st depressive episode and time to 1st manic/hypomanic or mixed episode, the Apo-Lamotrigine patients had longer times to 1st 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 Apo-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 concentrations occur approximately 2.5 hrs after oral drug administration. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. The pharmacokinetics is linear up to 450 mg, the highest single dose tested. There is considerable interindividual 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 0.92-1.22 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 extent depending on dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other antiepileptic drugs (AEDs) and data suggest that interactions between lamotrigine and drugs metabolised by cytochrome P-450 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 24-35 hrs. 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 hrs when given with glucuronidation-inducing drugs eg, carbamazepine and phenytoin and is increased to a mean of approximately 70 hrs when co-administered with valproate alone (see Dosage & Administration and Interactions).
Special Patient Populations: Children: Clearance adjusted for body weight is higher in children than in adults with the highest values in children <5 years. The half-life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hrs when given with enzyme-inducing drugs eg, carbamazepine and phenytoin and increasing to mean values of 45-50 hrs 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 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 (0.31-0.65 mL/min/kg) obtained in 9 studies with non-elderly adults after single doses of 30-450 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 hrs (chronic renal failure), 57.4 hrs (between hemodialysis) and 13 hrs (during hemodialysis), compared to 26.2 hrs in healthy volunteers. On average, approximately 20% (range = 5.6-35.1) of the amount of lamotrigine present in the body was eliminated during a 4-hr hemodialysis session. For this patient population, initial doses of Apo-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 0.1 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 mouse.
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