Lamictal Chewable Dispersible Tablets, Lamictal Tablets (Glaxosmithkline)

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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 C ₉ H ₇ N ₅ Cl ₂ , and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pK _a 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).

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.

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. 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).

LAMICTAL also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of this animal model to specific types of human epilepsy is unclear.

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-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 (alpha) ₁ , (alpha) ₂ , and (beta); dopamine D ₁ and D ₂ ; (gamma)-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.

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 (alpha)-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.

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 ¹⁴ C-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. Since 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.

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 ).

Oxcarbazepine and levetiracetam do not affect the apparent clearance 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 co-administration of bupropion (see PRECAUTIONS : Drug Interactions ).

Co-administration 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 t _1/2 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 moderate to severe hepatic dysfunction and compared with 12 subjects without hepatic impairment. The median apparent clearance of lamotrigine was 0.31, 0.24, or 0.10 mL/kg/min in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/kg/min in the healthy controls. Median half-life of lamotrigine was 36, 60, or 110 hours in patients with Grade A, B, or C hepatic impairment, respectively, versus 32 hours in healthy controls.

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 clearance of 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.

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).

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

Epilepsy:

Adjunctive Use:    LAMICTAL is indicated as adjunctive therapy for partial seizures in adults and pediatric patients (>/=2 years of age).

LAMICTAL is also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult 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 ).

Safety and effectiveness in patients below the age of 16 other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome have not been established (see BOX WARNING ).

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. It bears emphasis, accordingly, that LAMICTAL is only approved for use in those patients below the age of 16 who have partial seizures or generalized seizures associated with the Lennox-Gastaut syndrome (see INDICATIONS ).

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 pa-tient 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

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.

Suicide:    The possibility of a suicide attempt is inherent in Bipolar Disorder, and close supervision of high-risk patients should accompany drug therapy. 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 breast-feed or are breast-feeding 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. They should also be advised to promptly notify their physician if they experience 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:

Effects of Lamotrigine on the Pharmacokinetics of Other Drugs:   (see Table 3).

LAMICTAL Added to 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 lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels were seen to increase.

LAMICTAL Added to Oxcarbazepine:    The AUC and C _max 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). 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.

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

LAMICTAL Added to Valproate:    When LAMICTAL was administered to 18 healthy volunteers receiving valproate in a pharmacokinetic study, the trough steady-state valproate concentrations in plasma 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 plasma valproate concentrations in either adult or pediatric patients in controlled clinical trials.

LAMICTAL Added to Lithium:    The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by co-administration of 100 mg/day lamotrigine for 6 days.

LAMICTAL Added to Phenytoin:    LAMICTAL has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy.

LAMICTAL Added to Olanzapine:    The AUC and C _max 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 C _max in healthy male volunteers receiving olanzapine alone (n = 16).

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

Effects of Other Drugs on the Pharmacokinetics of Lamotrigine:   (see Table 3).

Valproate Added to LAMICTAL:    The addition of valproate increases 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.

Carbamazepine, Phenytoin, Phenobarbital, or Primidone Added to LAMICTAL:    The addition of these AEDs decreases lamotrigine steady-state concentrations by approximately 40%.

Oxcarbazepine Added to LAMICTAL:    The AUC and C _max of lamotrigine were similar 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 LAMICTAL alone (n = 13). 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.

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

Bupropion Added to LAMICTAL:    The pharmacokinetics of a 100-mg single dose of lamotrigine in 12 healthy volunteers were not changed by co-administration of bupropion at 300 mg/day starting 11 days before the lamotrigine dose.

Olanzapine Added to LAMICTAL:    The AUC and C _max of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n = 16) compared to healthy male volunteers receiving LAMICTAL alone (n = 12). This reduction in amotrigine plasma concentrations is not expected to be clinically relevant.

Other Psychotropic Drugs Added to LAMICTAL:    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 ).

Rifampin Added to LAMICTAL:    In a study in 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).

Interactions With Folate Inhibitors:    Lamotrigine is an inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Interactions With Oral Contraceptives:    Effect of Oral Contraceptives on LAMICTAL: In a study 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 two fold with a mean decrease in AUC of 52% and in C _max 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 preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week) for women not also taking a drug that increases the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine levels will be greater if the dose of LAMICTAL is increased in the few days before or during the pill-free week.

Dosage adjustments may be necessary for women receiving oral contraceptive preparations (see DOSAGE AND ADMINISTRATION : Women and Oral Contraceptives ).

Effect of LAMICTAL on Oral Contraceptives:    Co-administration of LAMICTAL (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel. There was a mean decrease in the AUC and C _max 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 studied.

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).

Interactions With 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 evaluated, although the effect may be similar to oral contraceptive preparations. Therefore, as for oral contraceptives, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION : Women and Oral Contraceptives ).

The net effects of drug interactions with LAMICTAL are summarized in Table 3.

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/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 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/m ² 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/m ² 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/m ² 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/m ² basis.

When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m ² 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, breast-feeding while taking LAMICTAL is not recommended.

Pediatric Use:    LAMICTAL is indicated as adjunctive therapy for partial seizures in patients above 2 years of age and for the generalized seizures of Lennox-Gastaut syndrome. Safety and effectiveness for other uses in patients with epilepsy below the age of 16 years have not been established (see BOX WARNING ).

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, 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.

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).

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.

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 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.

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 concomitant medications) compared to the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).

During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months' duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse experience. The adverse events which most commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood adverse events (2%).

Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance Treatment of Bipolar I Disorder:    Table 8 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy (100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in 2 double-blind, placebo-controlled trials of 18 months' duration and were numerically more frequent than in the placebo group.

These adverse events were usually mild to moderate in intensity.

Other events that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.

Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients receiving LAMICTAL and numerically more frequent than placebo were:

General:    Fever, neck pain.

Cardiovascular:    Migraine.

Digestive:    Flatulence.

Metabolic and Nutritional:    Weight gain, edema.

Musculoskeletal:    Arthralgia, myalgia.

Nervous System:    Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.

Respiratory:    Sinusitis.

Urogenital:    Urinary frequency.

Adverse Events Following Abrupt Discontinuation:    In the 2 maintenance trials, there was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients after abruptly terminating LAMICTAL therapy. 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 (see DOSAGE AND ADMINISTRATION ).

Mania/Hypomania/Mixed Episodes:    During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100 to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months, the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse events of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

The overall adverse event profile for LAMICTAL was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders:    LAMICTAL has been administered to 6,694 individuals for whom complete adverse event data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least one occasion while receiving LAMICTAL. All reported events are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.

Body as a Whole:    Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare: Abdomen enlarged, abscess, and suicide/suicide attempt.

Cardiovascular System:    Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.

Dermatological:    Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.

Digestive System:    Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.

Endocrine System:    Rare: Goiter and hypothyroidism.

Hematologic and Lymphatic System:    Infrequent: Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.

Metabolic and Nutritional Disorders:    Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.

Musculoskeletal System:    Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.

Nervous System:    Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident, cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.

Respiratory System:    Infrequent: Yawn. Rare: Hiccup and hyperventilation.

Special Senses:    Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.

Urogenital System:    Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence, menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and vaginal moniliasis.

Postmarketing and Other Experience:    In addition to the adverse experiences reported during clinical testing of LAMICTAL, the following adverse experiences have been reported in patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

Blood and Lymphatic:    Agranulocytosis, aplastic anemia, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.

Gastrointestinal:    Esophagitis.

Hepatobiliary Tract and Pancreas:    Pancreatitis.

Immunologic:    Lupus-like reaction, vasculitis.

Lower Respiratory:    Apnea.

Musculoskeletal:    Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Neurology:    Exacerbation of parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics.

Non-site Specific:    Hypersensitivity reaction, multiorgan failure, progressive immunosuppression.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of LAMICTAL have not been evaluated in human studies.

OVERDOSAGE

Human Overdose Experience:    Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

Management of Overdose:    There are no specific antidotes for LAMICTAL. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced or gastric lavage should be performed; usual precautions should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly absorbed (see CLINICAL PHARMACOLOGY ). It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMICTAL.

DOSAGE AND ADMINISTRATION

Epilepsy:

Adjunctive Use:    LAMICTAL is indicated as adjunctive therapy for partial seizures in adults and pediatric patients (>/=2 years of age). LAMICTAL is also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult 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.

Safety and effectiveness in pediatric patients below the age of 16 years other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome have not been established (see BOX WARNING ).

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.

General Dosing Considerations for Epilepsy and Bipolar Disorder Patients:    The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may 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 (see BOX WARNING ). Therefore, it is important that the dosing recommendations be followed closely.

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 ).

Women and Oral Contraceptives: Starting LAMICTAL in Women Taking Oral Contraceptives:    Although oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS : Drug Interactions ), no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of oral contraceptives. Therefore, dose escalation should follow the recommended guidelines based on whether LAMICTAL is added to valproate, whether LAMICTAL is added to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, or whether LAMICTAL is added in the absence of valproate, carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

Adjustments to the Maintenance Dose of LAMICTAL: (1) Taking or Starting Oral Contraceptives:    For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be increased, by as much as 2 fold over the recommended target maintenance dose, according to clinical response (see PRECAUTIONS : Drug Interactions ). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary. (2) Stopping Oral Contraceptives:    For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be decreased by as much as 50% of the maintenance dose with concurrent oral contraceptives, according to clinical response (see PRECAUTIONS : Drug Interactions ). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone or rifampin, no adjustment should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:    Although the effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, the effect may be similar to oral contraceptives (see PRECAUTIONS : Drug Interactions ). Therefore, similar adjustments to the dosage of LAMICTAL may be needed, based on clinical response.

Patients With Hepatic Impairment:    Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with moderate to severe liver dysfunction (see CLINICAL PHARMACOLOGY ), the following general recommendations can be made. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh Grade B) and 75% in patients with severe (Child-Pugh Grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response.

Patients With Renal Functional Impairment:    Initial doses of LAMICTAL should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY ). Few patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be used with caution in these patients.

Epilepsy:

Adjunctive Therapy With LAMICTAL for Epilepsy:    This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon whether or not the patient is receiving valproate (Tables 9 and 10 for patients 2 to 12 years of age, Tables 11 and 12 for patients greater than 12 years of age). In addition, the section provides a discussion of dosing for those patients receiving concomitant AEDs that have not been systematically evaluated in combination with LAMICTAL.

Patients 2 to 12 Years of Age: LAMICTAL Added to an Antiepileptic Drug Regimen Containing Valproate:    Recommended dosing guidelines are summarized in Table 9.

LAMICTAL Added to Carbamazepine, Phenytoin, Phenobarbital, or Primidone:    Recommended dosing guidelines are summarized in Table 10.

LAMICTAL Added to Oxcarbazepine or Levetiracetam, or to Antiepileptic Drugs for Which the Interaction With Lamotrigine is Not Known:    Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine. Specific dosing guidelines for the addition of LAMICTAL to oxcarbazepine or levetiracetam have not been studied in clinical trials. The effect of AEDs other than those already specified on the metabolism of LAMICTAL is not currently known. Therefore, no specific dosing guidelines can be provided. Conservative starting doses and dose escalations (as with concomitant valproate) would be prudent; maintenance dosing would be expected to fall between the maintenance dose with valproate, which decreases the apparent clearance of lamotrigine, and the maintenance dose without valproate, but with carbamazepine, phenytoin, phenobarbital, or primidone, which increase the apparent clearance of lamotrigine.

Note that the starting doses and dose escalations listed in Tables 9 and 10 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet (see HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes of LAMICTAL Chewable Dispersible Tablets).

Patients Over 12 Years of Age: LAMICTAL Added to an Antiepileptic Drug Regimen Containing Valproate:    Recommended dosing guidelines are summarized in Table 11.

LAMICTAL Added to Carbamazepine, Phenytoin, Phenobarbital, or Primidone:    Recommended dosing guidelines are summarized in Table 12.

LAMICTAL Added to Oxcarbazepine or Levetiracetam, or to Antiepileptic Drugs for Which the Interaction With Lamotrigine is Not Known:    Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine. Specific dosing guidelines for the addition of LAMICTAL to oxcarbazepine or levetiracetam have not been studied in clinical trials. The effect of AEDs other than those already specified on the metabolism of LAMICTAL is not currently known. Therefore, no specific dosing guidelines can be provided. Conservative starting doses and dose escalations (as with concomitant valproate) would be prudent; maintenance dosing would be expected to fall between the maintenance dose with valproate, which decreases the apparent clearance of lamotrigine, and the maintenance dose without valproate, but with carbamazepine, phenytoin, phenobarbital, or primidone, which increase the apparent clearance of lamotrigine.

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With LAMICTAL in Patients >/= 16 Years of Age With Epilepsy:    The goal of the transition regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of LAMICTAL.

The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in 2 divided doses.

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMICTAL should not be exceeded (see BOX WARNING ).

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With LAMICTAL:    After achieving a dose of 500 mg/day of LAMICTAL according to the guidelines in Table 12, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

Conversion from Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL:    The conversion regimen involves 4 steps. First, achieve a dose of 200 mg/day of LAMICTAL according to the guidelines in Table 11. Second, while keeping the LAMICTAL dose at 200 mg/day, valproate should be gradually decreased to a dose of 500 mg/day by decrements no greater than 500 mg/day per week. This dosage regimen is then maintained for 1 week. Third, LAMICTAL should then be increased to 300 mg/day while valproate is simultaneously decreased to 250 mg/day. This regimen should be maintained for 1 week. Fourth, valproate should then be discontinued completely and LAMICTAL increased by 100 mg/day every week until the recommended monotherapy dose of 500 mg/day is reached (see Table 13).

Conversion From Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL:    No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

Usual Maintenance Dose for Epilepsy:    The usual maintenance doses identified in Tables 9-12 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 9-13 has not been established in controlled trials.

Discontinuation Strategy for Patients With Epilepsy:    For patients receiving LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS ).

Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Target Plasma Levels for Patients With Epilepsy:    A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL should be based on therapeutic response.

Bipolar Disorder:    The goal of maintenance treatment with LAMICTAL is 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 target dose of LAMICTAL is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES : Bipolar Disorder ). Accordingly, doses above 200 mg/day are not recommended. Treatment with LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined in Table 14. If other psychotropic medications are withdrawn following stabilization, the dose of LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL should be doubled over a 2-week period in equal weekly increments (see Table 15). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of LAMICTAL should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 15). The dose of LAMICTAL may then be further adjusted to the target dose (200 mg) as clinically indicated.

If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see CLINICAL PHARMACOLOGY : Drug Interactions ).

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMICTAL should not be exceeded (see BOX WARNING ).

There is no body of evidence available to answer the question of how long the patient should remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES : Bipolar Disorder ). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Discontinuation Strategy in Bipolar Disorder:    As with other AEDs, LAMICTAL should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL. 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. Discontinuation of LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.

Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

HOW SUPPLIED

LAMICTAL Tablets, 25-mg

White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" bottles of 100 (NDC 0173-0633-02).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Tablets, 100-mg

Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", bottles of 100 (NDC 0173-0642-55).

LAMICTAL Tablets, 150-mg

Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150", bottles of 60 (NDC 0173-0643-60).

LAMICTAL Tablets, 200-mg

Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200", bottles of 60 (NDC 0173-0644-60).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.

LAMICTAL Chewable Dispersible Tablets, 2-mg

White to off-white, round tablets debossed with "LTG" over "2", bottles of 30 (NDC 0173-0699-00). ORDER DIRECTLY FROM Glaxosmithkline 1-800-334-4153.

LAMICTAL Chewable Dispersible Tablets, 5-mg

White to off-white, caplet-shaped tablets debossed with "GX CL2", bottles of 100 (NDC 0173-0526-00).

LAMICTAL Chewable Dispersible Tablets, 25-mg

White, super elliptical-shaped tablets debossed with "GX CL5", bottles of 100 (NDC 0173-0527-00).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Starter Kit for Patients Taking Valproate

25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25", blisterpack of 35 tablets (NDC 0173-0633-10).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin and Not Taking Valproate

25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and 100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", blisterpack of 84, 25-mg tablets and 14, 100-mg tablets (NDC 0173-0594-01)

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.

LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin, or Valproate

[FOR USE IN BIPOLAR PATIENTS ONLY]

25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25" and 100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100", blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] in a dry place and protect from light.

PATIENT INFORMATION

The following wording is contained in a separate leaflet provided for patients.

Information for the Patient

LAMICTAL® (lamotrigine) Tablets

LAMICTAL® (lamotrigine) Chewable Dispersible Tablets

ALWAYS CHECK THAT YOU RECEIVE LAMICTAL

Patients prescribed LAMICTAL (lah- MICK -tall) have sometimes been given the wrong medicine in error because many medicines have names similar to LAMICTAL. Taking the wrong medication can cause serious health problems. When your healthcare provider gives you a prescription for LAMICTAL

• make sure you can read it clearly.
• talk to your pharmacist to check that you are given the correct medicine.
• check the tablets you receive against the pictures of the tablets below. The pictures show actual tablet shape and size and the wording describes the color and printing that is on each strength of LAMICTAL Tablets and Chewable Dispersible Tablets.

Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided with any refill, in case any information has changed. This leaflet provides a summary of the information about your medicine. Please do not throw away this leaflet until you have finished your medicine. This leaflet does not contain all the information about LAMICTAL and is not meant to take the place of talking with your doctor. If you have any questions about LAMICTAL, ask your doctor or pharmacist.

Information About Your Medicine:

The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is one that you and your doctor should make together. When taking lamotrigine, it is important to follow your doctor's instructions.

1. The Purpose of Your Medicine:
   For Patients With Epilepsy:    LAMICTAL is intended to be used either alone or in combination with other medicines to treat seizures in people aged 2 years or older.
   For Patients With Bipolar Disorder:    LAMICTAL is used as maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or older treated for acute mood episodes with standard therapy.
2. Who Should Not Take LAMICTAL:
   You should not take LAMICTAL if you had an allergic reaction to it in the past.
3. Side Effects to Watch for:
   
   • Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in this leaflet. If you develop any side effects or symptoms you are concerned about or need more information, call your doctor.
   • Although most patients who develop rash while receiving LAMICTAL have mild to moderate symptoms, some individuals may develop a serious skin reaction that requires hospitalization. Rarely, deaths have been reported. These serious skin reactions are most likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin reactions occur more often in children than in adults.
   • Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of LAMICTAL faster than prescribed.
   • It is not possible to predict whether a mild rash will develop into a more serious reaction. Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor immediately, since these symptoms may be the first signs of a serious reaction. A doctor should evaluate your condition and decide if you should continue taking LAMICTAL.
4. The Use of LAMICTAL During Pregnancy and Breast-feeding:
   The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you should discuss this with your doctor to determine if you should continue to take LAMICTAL.
5. Use of Birth Control Pills or Other Female Hormonal Products:
   
   • Do not start or stop using birth control pills or other female hormonal products until you have consulted your doctor.
   • Tell your doctor as soon as possible if you experience changes in your menstrual pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or other female hormonal products.
6. How to Use LAMICTAL:
   
   • It is important to take LAMICTAL exactly as instructed by your doctor. The dose of LAMICTAL must be increased slowly. It may take several weeks or months before your final dosage can be determined by your doctor, based on your response.
   • Do not increase your dose of LAMICTAL or take more frequent doses than those indicated by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not restart without consulting your doctor.
   • If you miss a dose of LAMICTAL, do not double your next dose.
   • Always tell your doctor and pharmacist if you are taking any other prescription or over-the-counter medicines. Tell your doctor before you start any other medicines.
   • Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your doctor.
   • Use caution before driving a car or operating complex, hazardous machinery until you know if LAMICTAL affects your ability to perform these tasks.
   • If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types of seizures.
7. How to Take LAMICTAL:
   LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.
   LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.
   To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately 1 minute later, when the tablets are completely dispersed, mix the solution and take the entire amount immediately.
8. Storing Your Medicine:
   Store LAMICTAL at room temperature away from heat and light. Always keep your medicines out of the reach of children.
   This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder. Do not give the drug to others.
   If your doctor decides to stop your treatment, do not keep any leftover medicine unless your doctor tells you to. Throw away your medicine as instructed.

Manufactured for Glaxosmithkline

Research Triangle Park, NC 27709

by DSM Pharmaceuticals, Inc., Greenville, NC 27834 or

Glaxosmithkline, Research Triangle Park, NC 27709

DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.

©2004, Glaxosmithkline. All rights reserved.

August 2004/RL-2119

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