SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION

OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE

OF LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE

INCLUDED STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY

% (8 PER 1000). IN PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING

LAMICTAL AS ADJUNCTIVE THERAPY AND 0.3% (3 PER 1000) IN ADULTS. IN

A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS

TAKING ADJUNCTIVE LAMICTAL, THERE WAS 1 RASH-RELATED DEATH.

IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC

EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN

REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS

ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

BECAUSE THE RATE OF SERIOUS RASH IS GREATER IN PEDIATRIC

PATIENTS THAN IN ADULTS, IT BEARS EMPHASIS THAT LAMICTAL IS

APPROVED ONLY FOR USE IN PEDIATRIC PATIENTS BELOW THE AGE OF

YEARS WHO HAVE SEIZURES ASSOCIATED WITH THE

LENNOX-GASTAUT SYNDROME OR IN PATIENTS WITH PARTIAL SEIZURES

(SEE INDICATIONS).

OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT

ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY

OF RASH ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET

TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY 1)

COADMINISTRATION OF LAMICTAL WITH VALPROIC ACID (VPA), 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.

NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED

WITH LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF

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 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.

DESCRIPTION:

LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the

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

1. LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg

2. (peach), 150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled

3. amount of lamotrigine and the following inactive ingredients: lactose; magnesium stearate;

4. microcrystalline cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake

5. (100-mg tablet only); ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake

6. (200-mg tablet only).

7. LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The

8. tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the

9. following inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted

10. hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone,

11. 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). Pharmacological Properties: Although the relevance for human use is unknown, the following data characterize the performance of LAMICTAL in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 uM). It does not exhibit high affinity binding (IC50>100 uM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic a1, a2, and b; dopamine D1 and D2; g- aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 uM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, serotonin, or aspartic acid (IC50>100 uM). Effect of Lamotrigine on N-Methyl d-Aspartate (NMDA)-Mediated Activity: Lamotrigine did not inhibit NMDA-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 uM of glycine) in cultured hippocampal neurons exceeded 100 uM.

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 a-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 below). However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).

Pharmacokinetics and Drug Metabolism:

The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 1 and 2.

Table 1: Mean * Pharmacokinetic Parameters

in Adult Patients With Epilepsy or Healthy Volunteers

*The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.

+

Examples of EIAEDs are carbamazepine, phenobarbital, phenytoin, and primidone.

The apparent clearance of lamotrigine is affected by the coadministration of AEDs.

Lamotrigine is eliminated more rapidly in patients who have been taking hepatic EIAEDs, including carbamazepine, phenytoin, phenobarbital, and primidone. Most clinical experience is derived from this population.

VPA, however, actually decreases the apparent clearance of lamotrigine (i.e., more than doubles the elimination half-life of lamotrigine)

. Accordingly, if lamotrigine is to be administered to a patient receiving VPA, lamotrigine must be given at a reduced dosage, less than half the dose used in patients not receiving VPA (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions).

Absorption:

Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

Distribution:

Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding:

Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to

10 mcg/mL (10 mcg/mL is four to six 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 VPA. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites. Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 uCi) to six 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%).

Enzyme Induction:

The effects of lamotrigine on 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 T1/2 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 EIAEDs.

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 two 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 six 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 pharmacokinetic parameters of lamotrigine in patients with

impaired liver function have not been studied.

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 to11 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.

Table 2: Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy

*m

Two subjects were included in the calculation for mean t

ax.

+

Parameter not estimated.

Elderly:

In a single-dose study (150 mg of LAMICTAL), the pharmacokinetics of lamotrigine in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108) were similar to those of young, healthy volunteers in other studies.

Gender:

The clearance of lamotrigine is not affected by gender.

Race:

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

CLINICAL STUDIES:

The results of controlled clinical trials established the efficacy of LAMICTAL as monotherapy in adults with partial onset seizures already receiving treatment with a single enzyme-inducing antiepileptic drug (EIAED), 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 a Single EIAED:

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 four simple partial, complex partial, and/or secondarily generalized seizures during each of two consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or VPA (1000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or VPA 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 VPA 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 three 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 three studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than two other anticonvulsants and VPA 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 two other anticonvulsants and VPA 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 two other anticonvulsants. Thirteen patients were on concomitant VPA; 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 two drugs. Patients were dosed based on body weight and VPA use. Target doses were designed to approximate 5 mg/kg per day for patients taking VPA (maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking VPA (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 three drugs. Patients were dosed on a fixed-dose regimen based on body weight and VPA use. Target doses were designed to approximate 5 mg/kg per day for patients taking VPA (maximum dose, 200 mg/day) and 15 mg/kg per day for patients not taking VPA (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).

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

Adult Population:

Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in 0.3% (11 of 3348) of patients who received LAMICTAL in premarketing clinical trials. 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 VPA in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered LAMICTAL with VPA in clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2398 clinical trial patients and volunteers administered LAMICTAL in the absence of VPA were hospitalized. Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, one case was reported to be Stevens-Johnson-like.

Hypersensitivity Reactions:

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

established.

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

Acute Multiorgan Failure:

Multiorgan failure, which in some cases has been fatal or

irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3796 adult patients and 4 of 2435 pediatric patients who received LAMICTAL 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, three 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 two patients. Both pediatric patients were receiving concomitant therapy with VPA, 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 Dycrasias:

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 a rule, AEDs should not be abruptly discontinued because of the possibility of increasing seizure frequency. 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 VPA, 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 clinical trials, approximately 10% of all 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.

Sudden Unexplained Death in Epilepsy (SUDEP):

During the premarketing development

of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4700 patients with epilepsy (5747 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 2343 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.

Addition of LAMICTAL to a Multidrug Regimen That Includes VPA (Dosage Reduction):

Because VPA reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of VPA 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 no 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 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. 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 AEDs being taken concomitantly (see Table 3), monitoring of the plasma levels of LAMICTAL and concomitant AEDs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and other anti-seizure drugs and whether or not dosage adjustments are necessary.

Drug Interactions: Antiepileptic Drugs:

The use of AEDs in combination is complicated by the potential for pharmacokinetic interactions.

The interaction of lamotrigine with phenytoin, carbamazepine, and VPA has been studied. The net effects of these various AED combinations on individual AED plasma concentrations are summarized in Table 3.

Table 3: Summary of AED Interactions With LAMICTAL

* From adjunctive clinical trials and volunteer studies.

+

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

++

Not administered, but an active metabolite of carbamazepine.

-

= No significant effect.

? = Conflicting data. NE = Not evaluated.

Specific Effects of Lamotrigine on the Pharmacokinetics of Other AED Products: LAMICTAL Added to Phenytoin:

LAMICTAL has no appreciable effect on steady-state phenytoin plasma concentration.

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 EIAEDs 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 VPA:

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

Specific Effects of Other AED Products on the Pharmacokinetics of Lamotrigine: Phenytoin Added to LAMICTAL:

The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 45% to 54% depending upon the total daily dose of phenytoin (i.e., from 100 to 400 mg).

Carbamazepine Added to LAMICTAL:

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

Phenobarbital or Primidone Added to LAMICTAL:

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

VPA Added to LAMICTAL:

The addition of VPA increases lamotrigine steady-state concentrations in normal volunteers by slightly more than twofold.

Interactions With Drug Products Other Than AEDs: Folate Inhibitors:

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

Drug/Laboratory Test Interactions:

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No evidence of carcinogenicity was seen in one mouse study or two rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to

15 mg/kg per day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded. Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in two gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In two cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities. No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy:

Pregnancy Category C. No evidence of teratogenicity was found in mice, rats,

or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased. A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively. Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis. When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all three drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the two 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.

Pregnancy Exposure Registry: before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known,

To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients,

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 below the age of 16 years have not been established. (see BOX WARNING).

Geriatric Use:

Because few patients over the age of 65 (approximately 20) were exposed to LAMICTAL during its premarket evaluation, no specific statements about the safety or effectiveness of LAMICTAL in this age-group can be made.

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 six 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:

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 a single EIAED (e.g., carbamazepine, phenytoin, phenobarbital, etc. ).

Safety and effectiveness of LAMICTAL have not been established 1) as initial monotherapy, 2) for conversion to monotherapy from non-enzyme-inducing AEDs (e.g., valproate), or 3) for simultaneous conversion to monotherapy from two 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).

General Dosing Considerations:

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 valproic acid (VPA), 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.

Adjunctive Therapy With LAMICTAL:

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 VPA (Tables 8 and 9 for patients 2 to 12 years of age, Tables 10 and 11 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.

For dosing guidelines for LAMICTAL below, enzyme-inducing antiepileptic drugs (EIAEDs) include phenytoin, carbamazepine, phenobarbital, and primidone.

Patients 2 to 12 Years of Age:

Recommended dosing guidelines for LAMICTAL added to an antiepileptic drug (AED) regimen containing VPA are summarized in Table 8

Recommended dosing guidelines for LAMICTAL added to EIAEDs are summarized in Table 9.

LAMICTAL Added to AEDs Other Than EIAEDs and VPA:

The effect of AEDs other than EIAEDs and VPA on the metabolism of LAMICTAL is not currently known. Therefore, no specific dosing guidelines can be provided in that situation. Conservative starting doses and dose escalations (as with concomitant VPA) would be prudent; maintenance dosing would be expected to fall between the maintenance dose with VPA and the maintenance dose without VPA, but with an EIAED.

Note that the starting doses and dose escalations listed in Tables 8 and 9 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