Lamotrigine (Page 10 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in mice or rats following oral administration of lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m2) basis.

Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays.

No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2 basis.

14 CLINICAL STUDIES

14.1 Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures

The effectiveness of lamotrigine extended-release as adjunctive therapy in subjects with PGTC seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled trial in 143 patients aged 13 years and older (n = 70 on lamotrigine extended-release, n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with lamotrigine extended-release 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 200 to 500 mg/day of lamotrigine extended-release based on concomitant AEDs (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).

The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with lamotrigine extended-release and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05. Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with lamotrigine extended-release compared with the placebo group. For example, 70% of patients randomized to lamotrigine extended-release experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as ≥-100%.

Figure 1

Proportion of Patients by Responder Rate for Lamotrigine Extended-Release and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)

Lamotrigine extended-release tablets
(click image for full-size original)

14.2 Adjunctive Therapy for Partial-Onset Seizures

The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures.

The effectiveness of lamotrigine extended-release as adjunctive therapy in partial-onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with lamotrigine extended-release (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of lamotrigine extended-release based on concomitant AED (target dose =200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for lamotrigine extended-release and 2.1 for placebo.

The primary endpoint was the median percent change from baseline in partial-onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset seizures were 47% in patients treated with lamotrigine extended-release and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05.

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial-onset seizure frequency was consistently higher for the group treated with lamotrigine extended-release compared with the placebo group. For example, 44% of patients randomized to lamotrigine extended-release experienced a 50% or greater reduction in partial-onset seizure frequency compared with 21% of patients randomized to placebo.

Figure 2

Proportion of Patients by Responder Rate for Lamotrigine Extended-Release and Placebo Group (PartialOnset Seizure Study)

Lamotrigine extended-release tablets
(click image for full-size original)

14.3 Conversion to Monotherapy for Partial-Onset Seizures

The effectiveness of lamotrigine extended-release as monotherapy for partial-onset seizures was established in a historical control trial in 223 adults with partial-onset seizures. The historical control methodology is described in a publication by French, et al. [see References (15)]. Briefly, in this study, patients were randomized to ultimately receive either lamotrigine extended-release 300 mg or 250 mg once a day, and their responses were compared with those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving lamotrigine extended-release remained below the lower 95% prediction interval of 65.3% derived from the historical control data.

In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8-week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods while receiving valproate or a non–enzyme-inducing AED. Lamotrigine extended-release was added to either valproate or a non-enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with lamotrigine extended-release for 12 weeks. The escape criteria were 1 or more of the following:

(1) doubling of average monthly seizure count during any 28 consecutive days,

(2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase,

(3) emergence of a new seizure type compared with baseline

(4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.

The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.

Although the study population was not fully comparable with the historical control population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.

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