Lamotrigine (Page 10 of 12)

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in one mouse study or two rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg/day for mice and 10 to 15 mg/kg/day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2 , respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.

Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in two gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In two cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.

No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg/day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.

14. CLINICAL STUDIES

14.1 Epilepsy

Monotherapy With Lamotrigine in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single AED: The effectiveness of monotherapy with lamotrigine was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least four simple partial, complex partial, and/or secondarily generalized seizures during each of two consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.

Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic (GTC) seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentages of patients who met escape criteria were 42% (32/76) in the group receiving lamotrigine and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (p= 0.0012) in favor of lamotrigine. No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of valproate.

Adjunctive Therapy With Lamotrigine in Adults With Partial Seizures: The effectiveness of lamotrigine as adjunctive therapy (added to other AEDs) was established in three multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least four partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in two of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least four seizures per month during the baseline, lamotrigine or placebo was then added to the existing therapy. In all three studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than two other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of lamotrigine, or a target dose of 500 mg/day of lamotrigine. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.

A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than two other anticonvulsants and valproate was not allowed. The target dose of lamotrigine was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on lamotrigine compared with placebo (p<0.001).

The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than two other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of lamotrigine. The 28 other patients had a target dose of 300 mg/day of lamotrigine. The median change in seizure frequency was a 26% reduction on lamotrigine compared with placebo (p<0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.

Adjunctive Therapy With Lamotrigine in Pediatric Patients With Partial Seizures: The effectiveness of lamotrigine as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients 2 to 16 years of age (n = 98 on lamotrigine, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to two drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with lamotrigine and 7% on placebo, a difference that was statistically significant (p<0.01).

Adjunctive Therapy With Lamotrigine in Pediatric and Adult Patients With Lennox-Gastaut Syndrome: The effectiveness of lamotrigine as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients 3 to 25 years of age (n = 79 on lamotrigine, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to three drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with lamotrigine and 9% on placebo, a difference that was statistically significant (p<0.05). Drop attacks were significantly reduced by lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for lamotrigine and placebo, respectively).

Adjunctive Therapy With Lamotrigine in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures: The effectiveness of lamotrigine as adjunctive therapy in patients with primary generalized tonic-clonic seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients ≥ 2 years (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least three primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 mg/kg/day to 12 mg/kg/day for pediatric patients and from 200 mg/day to 400 mg/day for adult patients based on concomitant AED.

The primary efficacy endpoint was percentage change from baseline in primary generalized tonic-clonic seizures. For the intent-to-treat population, the median percent reduction of primary generalized tonic-clonic seizures was 66% in patients treated with lamotrigine and 34% on placebo, a difference that was statistically significant (p = 0.006).

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