Lamotrigine 25 mg Tablet, 90-count — NDC 63187-487-90 (Billing 63187-0487-90)

12. CLINICAL PHARMACOLOGY

12.1Mechanism of Action The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state.

The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT 3 receptor (IC 50 = 18 µM). It does not exhibit high affinity binding (IC 50 >100 µM) to the following neurotransmitter receptors: adenosine A 1 and A 2 ; adrenergic α 1 , α 2 , and β; dopamine D 1 and D 2 ; γ-aminobutyric acid (GABA) A and B; histamine H 1 ; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT 2 .

Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC 50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC 50 >200 µM) when tested in rat synaptosomes and/or human platelets in vitro.

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC 50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

12.2Pharmacodynamics Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced.

Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1) ]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species. Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin.

It has been found in the uveal tract up to 52 weeks after a single dose in rodents. Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at hi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state.

The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT 3 receptor (IC 50 = 18 µM). It does not exhibit high affinity binding (IC 50 >100 µM) to the following neurotransmitter receptors: adenosine A 1 and A 2 ; adrenergic α 1 , α 2 , and β; dopamine D 1 and D 2 ; γ-aminobutyric acid (GABA) A and B; histamine H 1 ; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT 2 .

Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC 50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC 50 >200 µM) when tested in rat synaptosomes and/or human platelets in vitro.

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC 50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

12.3Pharmacokinetics The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 14 and 16. Table 14.

Mean a Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients With Epilepsy Adult Study Population Number of Subjects T max : Time of Maximum Plasma Concentration (hr) t ½ : Elimination Half-life (hr) Cl/F: Apparent Plasma Clearance (mL/min/kg) a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for T max . The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study.

The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies. b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7) ]. Healthy volunteers taking no other medications: Single-dose lamotrigine 179 2.2 (0.25-12.0) 32.8 (14.0-103.0) 0.44 (0.12-1.10) Multiple-dose lamotrigine 36 1.7 (0.5-4.0) 25.4 (11.6-61.6) 0.58 (0.24-1.15) Healthy volunteers taking valproate: Single-dose lamotrigine 6 1.8 (1.0-4.0) 48.3 (31.5-88.6) 0.30 (0.14-0.42) Multiple-dose lamotrigine 18 1.9 (0.5-3.5) 70.3 (41.9-113.5) 0.18 (0.12-0.33) Patients with epilepsy taking valproate only: Single-dose lamotrigine 4 4.8 (1.8-8.4) 58.8 (30.5-88.8) 0.28 (0.16-0.40) Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone b plus valproate: Single-dose lamotrigine 25 3.8 (1.0-10.0) 27.2 (11.2-51.6) 0.53 (0.27-1.04) Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone b : Single-dose lamotrigine 24 2.3 (0.5-5.0) 14.4 (6.4-30.4) 1.10 (0.51-2.22) Multiple-dose lamotrigine 17 2.0 (0.75-5.93) 12.6 (7.5-23.1) 1.21 (0.66-1.82) Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%).

The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets whether disintegrated in the mouth or swallowed whole with water were equivalent to the lamotrigine compressed tablets swallowed with water. Dose Proportionality: In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.

Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to

1.3L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers. Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations f… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Folate Metabolism: In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced.

Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1) ]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys: Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species. Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin.

It has been found in the uveal tract up to 52 weeks after a single dose in rodents. Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block.

Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology (12.3) ]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).

14. CLINICAL STUDIES

14.1Epilepsy 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 seiz… [Excerpted — this section continues on DailyMed.]

13. NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/m 2 and 60 to 90 mg/m 2 , 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/m 2 basis.

The effect of lamotrigine on human fertility is unknown.