Lamictal

Generic Name: lamotrigine
Dosage Form: tablets, chewable dispersible tablets

Lamictal Description

Lamictal (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as -triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Lamictal Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach), 150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).

Lamictal Chewable Dispersible Tablets are supplied for oral administration. The tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium starch glycolate.

Lamictal - Clinical Pharmacology

Mechanism 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. Lamictal 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 Lamictal, 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).

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

Pharmacological Properties

Although the relevance for human use is unknown, the following data characterize the performance of Lamictal in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>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 IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

Folate Metabolism

In vitro, lamotrigine was shown to be an inhibitor of 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 PRECAUTIONS: Pregnancy). 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 was found to accumulate 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 Drug Disposition). 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).

Pharmacokinetics and Drug Metabolism

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 1 and 2.

Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients With Epilepsy

Adult Study Population	Number of Subjects	Tmax: Time of Maximum Plasma Concentration (h)	t½: Elimination Half-life (h)	Cl/F: Apparent Plasma Clearance (mL/min/kg)
Healthy volunteers taking no other medications:
Single-dose Lamictal	179	2.2 (0.25-12.0)	32.8 (14.0-103.0)	0.44 (0.12-1.10)
Multiple-dose Lamictal	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 Lamictal	6	1.8 (1.0-4.0)	48.3 (31.5-88.6)	0.30 (0.14-0.42)
Multiple-dose Lamictal	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 Lamictal	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† plus valproate:
Single-dose Lamictal	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†:
Single-dose Lamictal	24	2.3 (0.5-5.0)	14.4 (6.4-30.4)	1.10 (0.51-2.22)
Multiple-dose Lamictal	17	2.0 (0.75-5.93)	12.6 (7.5-23.1)	1.21 (0.66-1.82)

*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 Tmax. 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.

†Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).

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.

Distribution

Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/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 from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.

Drug Disposition

Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Drug Interactions

The apparent clearance of lamotrigine is affected by the coadministration of certain medications. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.

Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking these AEDs.

Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the elimination half-life of lamotrigine), whether given with or without carbamazepine, phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half the dose used in patients not receiving valproate, even in the presence of drugs that increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions).

The following drugs were shown not to increase the apparent clearance of lamotrigine: felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS: Drug Interactions).

In vitro inhibition experiments indicated that the formation of the primary metabolite of lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

Lamictal has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug Interactions).

The pharmacokinetics of Lamictal were not changed by coadministration of bupropion (see PRECAUTIONS: Drug Interactions).

Coadministration of olanzapine did not have a clinically relevant effect on Lamictal pharmacokinetics (see PRECAUTIONS: Drug Interactions).

Enzyme Induction

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by Lamictal may not occur when Lamictal is given as adjunctive therapy in patients receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

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.

Elimination

(see Table 1).

Special Populations

Patients With Renal Insufficiency

Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of Lamictal. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session.

Hepatic Disease

The pharmacokinetics of lamotrigine following a single 100-mg dose of Lamictal were evaluated in 24 subjects with mild, moderate, and severe hepatic dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment was 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared to 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites liver impairment was 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared to 33 ± 7 hours in healthy controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION: Patients With Hepatic Impairment).

Age

Pediatric Patients

The pharmacokinetics of Lamictal following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged 10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received concomitant therapy with other AEDs and 12 patients received Lamictal as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.

Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearanceof lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.

Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy

Pediatric Study Population	Number of Subjects	Tmax (h)	t½ (h)	Cl/F (mL/min/kg)
Ages 10 months-5.3 years
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone*	10	3.0 (1.0-5.9)	7.7 (5.7-11.4)	3.62 (2.44-5.28)
Patients taking antiepileptic drugs (AEDs) with no known effect on the apparent clearance of lamotrigine	7	5.2 (2.9-6.1)	19.0 (12.9-27.1)	1.2 (0.75-2.42)
Patients taking valproate only	8	2.9 (1.0-6.0)	44.9 (29.5-52.5)	0.47 (0.23-0.77)
Ages 5-11 years
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone*	7	1.6 (1.0-3.0)	7.0 (3.8-9.8)	2.54 (1.35-5.58)
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate	8	3.3 (1.0-6.4)	19.1 (7.0-31.2)	0.89 (0.39-1.93)
Patients taking valproate only†	3	4.5 (3.0-6.0)	65.8 (50.7-73.7)	0.24 (0.21-0.26)
Ages 13-18 years
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone*	11	‡	‡	1.3
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate	8	‡	‡	0.5
Patients taking valproate only	4	‡	‡	0.3

*Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).

†Two subjects were included in the calculation for mean Tmax.

‡Parameter not estimated.

Elderly

The pharmacokinetics of lamotrigine following a single 150-mg dose of Lamictal were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).

Gender

The clearance of lamotrigine is not affected by gender. However, during dose escalation of Lamictal in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Race

The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

Clinical Studies

Epilepsy

The results of controlled clinical trials established the efficacy of Lamictal as monotherapy in adults with partial onset seizures already receiving treatment with carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug (AED), as adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult patients.

Monotherapy With Lamictal in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single AED

The effectiveness of monotherapy with Lamictal was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamictal (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 Lamictal 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 percentage of patients who met escape criteria was 42% (32/76) in the Lamictal group 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 Lamictal. 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 Lamictal, and cannot be interpreted to imply the superiority of Lamictal to an adequate dose of valproate.

Adjunctive Therapy With Lamictal in Adults With Partial Seizures

The effectiveness of Lamictal as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 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 4 seizures per month during the baseline, Lamictal or placebo was then added to the existing therapy. In all 3 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 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of Lamictal, or a target dose of 500 mg/day of Lamictal. 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 Lamictal, and 36% in patients receiving 500 mg/day of Lamictal. The seizure frequency reduction was statistically significant in the 500-mg/day group compared to 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 2 other anticonvulsants and valproate was not allowed. The target dose of Lamictal 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 Lamictal compared to 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 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of Lamictal. The 28 other patients had a target dose of 300 mg/day of Lamictal. The median change in seizure frequency was a 26% reduction on Lamictal compared to 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 Lamictal in Pediatric Patients With Partial Seizures

The effectiveness of Lamictal as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on Lamictal, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with Lamictal or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate (maximum dose, 750 mg per 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 Lamictal and 7% on placebo, a difference that was statistically significant (p<0.01).

Adjunctive Therapy With Lamictal in Pediatric and Adult Patients With Lennox-Gastaut Syndrome

The effectiveness of Lamictal as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on Lamictal, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with Lamictal or placebo added to their current AED regimen of up to 3 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 per day for patients taking valproate (maximum dose, 200 mg/day) and 15 mg/kg per 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 Lamictal and 9% on placebo, a difference that was statistically significant (p<0.05). Drop attacks were significantly reduced by Lamictal (34%) compared to placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for Lamictal and placebo, respectively).

Adjunctive Therapy With Lamictal in Pediatric and Adult Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of Lamictal 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 Lamictal, n = 59 on placebo). Patients with at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with Lamictal 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 Lamictal and 34% on placebo, a difference that was statistically significant (p=0.006).

Bipolar Disorder

The effectiveness of Lamictal in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of Lamictal, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of Lamictal. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with Lamictal, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with Lamictal, 50 mg/day (n = 50), Lamictal 200 mg/day (n = 124), Lamictal 400 mg/day (n = 47), or placebo (n = 121). Lamictal (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with Lamictal (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamictal was superior to placebo in delaying time to occurrence of a mood episode. The mean Lamictal dose was about 211 mg/day.

Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for Lamictal over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.

Indications and Usage for Lamictal

Epilepsy

Adjunctive Use

Lamictal is indicated as adjunctive therapy for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in adults and pediatric patients (≥2 years of age).

Monotherapy Use

Lamictal is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.

Safety and effectiveness of Lamictal have not been established (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).

Bipolar Disorder

Lamictal is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of Lamictal in the acute treatment of mood episodes has not been established.

The effectiveness of Lamictal as maintenance treatment was established in 2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined by DSM-IV (see CLINICAL STUDIES: Bipolar Disorder). The physician who elects to use Lamictal for periods extending beyond 18 months should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Lamictal is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings

SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF Lamictal.

ALTHOUGH BENIGN RASHES ALSO OCCUR WITH Lamictal, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, Lamictal SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Serious Rash

Pediatric Population

The incidence of serious rash associated with hospitalization and discontinuation of Lamictal in a prospectively followed cohort of pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of 952) patients not taking valproate.

Adult Population

Serious rash associated with hospitalization and discontinuation of Lamictal occurred in 0.3% (11 of 3,348) of adult patients who received Lamictal in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received Lamictal as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received Lamictal as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic abnormalities.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered Lamictal with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered Lamictal in the absence of valproate were hospitalized.

Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, 1 case was reported to be Stevens-Johnson−like.

Hypersensitivity Reactions

Hypersensitivity reactions, some fatal or life threatening, have also occurred. Some of these reactions have included clinical features of multiorgan failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamictal should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with Lamictal, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Acute Multiorgan Failure

Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving Lamictal. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received Lamictal in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause.

Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after Lamictal was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with Lamictal was discontinued.

Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

Withdrawal Seizures

As with other AEDs, Lamictal should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamictal. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of Lamictal should be tapered over a period of at least 2 weeks (see DOSAGE AND ADMINISTRATION).

Precautions

Concomitant Use with Oral Contraceptives

Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine (see PRECAUTIONS: Drug Interactions). Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking Lamictal (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of Lamictal). During the week of inactive hormone preparation (“pill-free” week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse events consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

Dermatological Events (see BOX WARNING, WARNINGS)

Serious rashes associated with hospitalization and discontinuation of Lamictal have been reported. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of Lamictal with valproate, (2) exceeding the recommended initial dose of Lamictal, or (3) exceeding the recommended dose escalation for Lamictal. However, cases have been reported in the absence of these factors.

In epilepsy clinical trials, approximately 10% of all patients exposed to Lamictal developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to Lamictal developed a rash. Rashes associated with Lamictal do not appear to have unique identifying features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

Although most rashes resolved even with continuation of treatment with Lamictal, it is not possible to predict reliably which rashes will prove to be serious or life threatening. ACCORDINGLY, Lamictal SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

It is recommended that Lamictal not be restarted in patients who discontinued due to rash associated with prior treatment with Lamictal unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued Lamictal, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued Lamictal for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of Lamictal is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND ADMINISTRATION).

Use in Patients With Epilepsy

Sudden Unexplained Death in Epilepsy (SUDEP)

During the premarketing development of Lamictal, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Lamictal (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for Lamictal, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving Lamictal and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving Lamictal and those receiving another antiepileptic drug that underwent clinical testing in a similar population at about the same time. Importantly, that drug is chemically unrelated to Lamictal. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

Status Epilepticus

Valid estimates of the incidence of treatment emergent status epilepticus among patients treated with Lamictal are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.

Use in Patients With Bipolar Disorder

Acute Treatment of Mood Episodes

Safety and effectiveness of Lamictal in the acute treatment of mood episodes has not been established.

Children and Adolescents (less than 18 years of age)

Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. It is not known whether Lamictal is associated with a similar risk in this population (see PRECAUTIONS: Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).

Safety and effectiveness of Lamictal in patients below the age of 18 years with mood disorders have not been established.

Clinical Worsening and Suicide Risk Associated With Bipolar Disorder

Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and /or the emergence of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Prescriptions for Lamictal should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Overdoses have been reported for Lamictal, some of which have been fatal (see OVERDOSAGE).

Addition of Lamictal to a Multidrug Regimen That Includes Valproate (Dosage Reduction)

Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence (see DOSAGE AND ADMINISTRATION).

Use in Patients With Concomitant Illness

Clinical experience with Lamictal in patients with concomitant illness is limited. Caution is advised when using Lamictal in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment.

Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of elimination of lamotrigine (see CLINICAL PHARMACOLOGY).

A study in individuals with severe chronic renal failure (mean creatinine clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Lamictal, it should be used with caution in these patients, generally using a reduced maintenance dose for patients with significant impairment.

Because there is limited experience with the use of Lamictal in patients with impaired liver function, the use in such patients may be associated with as yet unrecognized risks (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Binding in the Eye and Other Melanin-Containing Tissues

Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown.

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Information for Patients

Prior to initiation of treatment with Lamictal, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs.

Patients should be advised that Lamictal may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on Lamictal to gauge whether or not it adversely affects their mental and/or motor performance.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant.

Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the “pill free” week) may significantly increase lamotrigine plasma levels (see PRECAUTIONS: Drug Interactions). Women should also be advised to promptly notify their physician if they experience adverse events or changes in menstrual pattern (e.g., break-through bleeding) while receiving Lamictal in combination with these medications.

Patients should be advised to notify their physician if they stop taking Lamictal for any reason and not to resume Lamictal without consulting their physician.

Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking Lamictal. See PATIENT INFORMATION at the end of this labeling for the text of the leaflet provided for patients.

Laboratory Tests

The value of monitoring plasma concentrations of Lamictal has not been established. Because of the possible pharmacokinetic interactions between Lamictal and other drugs including AEDs (see Table 3), monitoring of the plasma levels of Lamictal and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of Lamictal and other drugs and whether or not dosage adjustments are necessary.

Drug Interactions

The net effects of drug interactions with Lamictal are summarized in Table 3 (see also DOSAGE AND ADMINISTRATION).

Oral Contraceptives

In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with a mean decrease in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (“pill-free” week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine plasma levels will be greater if the dose of Lamictal is increased in the few days before or during the “pill-free” week. Increases in lamotrigine plasma levels could result in dose-dependent adverse effects (see PRECAUTIONS: Concomitant Use With Oral Contraceptives).

In the same study, coadministration of Lamictal (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of Lamictal other than 300 mg/day have not been systematically evaluated in controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Dosage adjustments will be necessary for most women receiving estrogen-containing oral contraceptive preparations (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives).

Other Hormonal Contraceptives or Hormone Replacement Therapy

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2–fold, and the progestin only pills had no effect on lamotrigine plasma levels. Therefore, adjusments to the dosage of Lamictal in the presence of progestogens alone will likely not be needed.

Bupropion

The pharmacokinetics of a 100-mg single dose of Lamictal in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice a day) starting 11 days before Lamictal.

Carbamazepine

Lamictal has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with Lamictal than in patients receiving other AEDs with Lamictal (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of Lamictal on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, Lamictal had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.

The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.

Felbamate

In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with Lamictal (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

Folate Inhibitors

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Gabapentin

Based on a retrospective analysis of plasma levels in 34 patients who received Lamictal both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Levetiracetam

Potential drug interactions between levetiracetam and Lamictal were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that Lamictal does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of Lamictal.

Lithium

The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of Lamictal (100 mg/day) for 6 days.

Olanzapine

The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to Lamictal (200 mg once daily) in healthy male volunteers (n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).

In the same study, the AUC and Cmax of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine to Lamictal in healthy male volunteers compared to those receiving Lamictal alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

Oxcarbazepine

The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to Lamictal (200 mg once daily) in healthy male volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13).

In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to Lamictal in healthy male volunteers compared to those receiving Lamictal alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of Lamictal and oxcarbazepine compared to Lamictal alone or oxcarbazepine alone.

Phenobarbital, Primidone

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.

Phenytoin

Lamictal has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.

Pregabalin

Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between Lamictal and pregabalin

Rifampin

In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of Lamictal by approximately 2-fold (AUC decreased by approximately 40%).

Topiramate

Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of Lamictal resulted in a 15% increase in topiramate concentrations.

Valproate

When Lamictal was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding Lamictal to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.

Zonisamide

In a study of 18 patients with epilepsy, co-administration of zonisamide (200 to 400 mg/day) with Lamictal (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.

Known Inducers or Inhibitors of Glucuronidation

Drugs other than those listed above have not been systematically evaluated in combination with Lamictal. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of Lamictal may require adjustment based on clinical response.

Other

Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).

Table 3. Summary of Drug Interactions With Lamictal

Drug	Drug Plasma Concentration With Adjunctive Lamictal*	Lamotrigine Plasma Concentration With Adjunctive Drugs†
Oral contraceptives (e.g. ethinylestradiol/levonorgestrel‡	↔§	↓
Bupropion	Not assessed	↔
Carbamazepine (CBZ)	↔	↓
CBZ epoxide║	?
Felbamate	Not assessed	↔
Gabapentin	Not assessed	↔
Levetiracetam	↔	↔
Lithium	↔	Not assessed
Olanzapine	↔	↔¶
Oxcarbazepine	↔	↔
10-monohydroxy oxcarbazepine metabolite#	↔
Phenobarbital/primidone	↔	↓
Phenytoin (PHT)	↔	↓
Pregabalin	↔	↔
Rifampin	Not assessed	↓
Topiramate	↔**	↔
Valproate	↓	↑
Valproate + PHT and/or CBZ	Not assessed	↔
Zonisamide	Not assessed	↔

* From adjunctive clinical trials and volunteer studies.

†Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteers studies.

‡The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, and the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel combinations.

§Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Oral Contraceptives).

║Not administered, but an active metabolite of carbamazepine.

¶Slight decrease, not expected to be clinically relevant.

#Not administered, but an active metabolite of oxcarbazepine.

** Slight increase not expected to be clinically relevant.

↔ = No significant effect.

? = Conflicting data.

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per 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 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 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 per day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy

Teratogenic Effects

Pregnancy Category C. No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.

A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively.

Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.

When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.

Although Lamictal was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects

As with other antiepileptic drugs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Exposure Registry

To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll-free).

Labor and Delivery

The effect of Lamictal on labor and delivery in humans is unknown.

Use in Nursing Mothers

Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to Lamictal by this route are unknown, breastfeeding while taking Lamictal is not recommended.

Pediatric Use

Lamictal is indicated as adjunctive therapy for partial seizures, the generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in patients above 2 years of age.

Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.

Geriatric Use

Clinical studies of Lamictal for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF Lamictal, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH THERAPY WITH Lamictal. RARE DEATHS HAVE BEEN REPORTED, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE (see BOX WARNING).

Epilepsy

Most Common Adverse Events in All Clinical Studies

Adjunctive Therapy in Adults With Epilepsy

The most commonly observed (≥5%) adverse experiences seen in association with Lamictal during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with Lamictal than in patients receiving other AEDs with Lamictal. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate (see WARNINGS).

Approximately 11% of the 3,378 adult patients who received Lamictal as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).

In a dose response study in adults, the rate of discontinuation of Lamictal for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults With Epilepsy

The most commonly observed (≥5%) adverse experiences seen in association with the use of Lamictal during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5%) adverse experiences associated with the use of Lamictal during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received Lamictal as monotherapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients With Epilepsy

The most commonly observed (≥5%) adverse experiences seen in association with the use of Lamictal as adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients age 2 to 16 years with partial seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on Lamictal and 2.9% of patients on placebo discontinued due to adverse experiences. The most commonly reported adverse experiences that led to discontinuation were rash for patients treated with Lamictal and deterioration of seizure control for patients treated with placebo.

Approximately 11.5% of the 1,081 pediatric patients who received Lamictal as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Incidence in Controlled Clinical Studies of Epilepsy

The prescriber should be aware that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy

Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with Lamictal in placebo-controlled trials and were numerically more common in the patients treated with Lamictal. In these studies, either Lamictal or placebo was added to the patient's current AED therapy. Adverse events were usually mild to moderate in intensity.

Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients treated with Lamictal and numerically more frequent than in the placebo group.)

Body System/ Adverse Experience†	Percent of Patients Receiving Adjunctive Lamictal (n = 711)	Percent of Patients Receiving Adjunctive Placebo (n = 419)
Body as a whole
Headache	29	19
Flu syndrome	7	6
Fever	6	4
Abdominal pain	5	4
Neck pain	2	1
Reaction aggravated (seizure exacerbation)	2	1
Digestive
Nausea	19	10
Vomiting	9	4
Diarrhea	6	4
Dyspepsia	5	2
Constipation	4	3
Tooth disorder	3	2
Anorexia	2	1
Musculoskeletal
Arthralgia	2	0
Nervous
Dizziness	38	13
Ataxia	22	6
Somnolence	14	7
Incoordination	6	2
Insomnia	6	2
Tremor	4	1
Depression	4	3
Anxiety	4	3
Convulsion	3	1
Irritability	3	2
Speech disorder	3	0
Concentration disturbance	2	1
Respiratory
Rhinitis	14	9
Pharyngitis	10	9
Cough increased	8	6
Skin and appendages
Rash	10	5
Pruritus	3	2
Special senses
Diplopia	28	7
Blurred vision	16	5
Vision abnormality	3	1
Urogenital
Female patients only	(n = 365)	(n = 207)
Dysmenorrhea	7	6
Vaginitis	4	1
Amenorrhea	2	1

*Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to Lamictal or placebo. Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.

†Adverse experiences reported by at least 2% of patients treated with Lamictal are included.

In a randomized, parallel study comparing placebo and 300 and 500 mg/day of Lamictal, some of the more common drug-related adverse events were dose related (see Table 5).

Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial in Adults With Epilepsy

	Percent of Patients Experiencing Adverse Experiences
Adverse Experience	Placebo (n = 73)	Lamictal 300 mg (n = 71)	Lamictal 500 mg (n = 72)
Ataxia	10	10	28*†
Blurred vision	10	11	25*†
Diplopia	8	24*	49*†
Dizziness	27	31	54*†
Nausea	11	18	25*
Vomiting	4	11	18*

*Significantly greater than placebo group (p<0.05).

†Significantly greater than group receiving Lamictal 300 mg (p<0.05).

Other events that occurred in more than 1% of patients but equally or more frequently in the placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia, paresthesia, respiratory disorder, and urinary tract infection.

The overall adverse experience profile for Lamictal was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to Lamictal in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Generally, females receiving either adjunctive Lamictal or placebo were more likely to report adverse experiences than males. The only adverse experience for which the reports on Lamictal were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of Lamictal for individual adverse experiences.

Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures

Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with epilepsy treated with monotherapy with Lamictal in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with Lamictal and numerically more frequent than in the valproate group.)

Body System/ Adverse Experience†	Percent of Patients Receiving Lamictal Monotherapy‡ (n = 43)	Percent of Patients Receiving Low-Dose Valproate§Monotherapy (n = 44)
Body as a whole
Pain	5	0
Infection	5	2
Chest pain	5	2
Digestive
Vomiting	9	0
Dyspepsia	7	2
Nausea	7	2
Metabolic and nutritional
Weight decrease	5	2
Nervous
Coordination abnormality	7	0
Dizziness	7	0
Anxiety	5	0
Insomnia	5	2
Respiratory
Rhinitis	7	2
Urogenital (female patients only)	(n = 21)	(n = 28)
Dysmenorrhea	5	0

*Patients in these studies were converted to Lamictal or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category.

†Adverse experiences reported by at least 5% of patients are included.

‡Up to 500 mg/day.

§1,000 mg/day.

Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients receiving Lamictal and numerically more frequent than placebo were:

Body as a Whole

Asthenia, fever.

Digestive

Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional

Peripheral edema.

Nervous System

Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory

Epistaxis, bronchitis, dyspnea.

Skin and Appendages

Contact dermatitis, dry skin, sweating.

Special Senses

Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy

Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received Lamictal up to 15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified using COSTART terminology.

Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with Lamictal and numerically more frequent than in the placebo group.)

Body System/ Adverse Experience	Percent of Patients Receiving Lamictal (n = 168)	Percent of Patients Receiving Placebo (n = 171)
Body as a whole
Infection	20	17
Fever	15	14
Accidental injury	14	12
Abdominal pain	10	5
Asthenia	8	4
Flu syndrome	7	6
Pain	5	4
Facial edema	2	1
Photosensitivity	2	0
Cardiovascular
Hemorrhage	2	1
Digestive
Vomiting	20	16
Diarrhea	11	9
Nausea	10	2
Constipation	4	2
Dyspepsia	2	1
Tooth disorder	2	1
Hemic and lymphatic
Lymphadenopathy	2	1
Metabolic and nutritional
Edema	2	0
Nervous system
Somnolence	17	15
Dizziness	14	4
Ataxia	11	3
Tremor	10	1
Emotional lability	4	2
Gait abnormality	4	2
Thinking abnormality	3	2
Convulsions	2	1
Nervousness	2	1
Vertigo	2	1
Respiratory
Pharyngitis	14	11
Bronchitis	7	5
Increased cough	7	6
Sinusitis	2	1
Bronchospasm	2	1
Skin
Rash	14	12
Eczema	2	1
Pruritus	2	1
Special senses
Diplopia	5	1
Blurred vision	4	1
Ear disorder	2	1
Visual abnormality	2	0
Urogenital
Male and female patients
Urinary tract infection	3	0
Male patients only	n = 93	n = 92
Penis disorder	2	0

Bipolar Disorder: The most commonly observed (≥5%) adverse experiences seen in association with the use of Lamictal as monotherapy (100 to 400 mg/day) in Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated patients are included in Table 8. Adverse events that occurred in at least 5% of patients and were numerically more common during the dose escalation phase of Lamictal in these trials (when patients may have been receiving con