Adjunctive Therapy:Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older:

• partial-onset seizures.
• primary generalized tonic-clonic (PGTC) seizures.
• generalized seizures of Lennox-Gastaut syndrome.

Monotherapy:Lamotrigine is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).

Safety and effectiveness of lamotrigine 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.

Limitations of Use:Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine in the acute treatment of mood episodes has not been established.

Rash:There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine with valproate, (2) exceeding the recommended initial dose of lamotrigine, or (3) exceeding the recommended dose escalation for lamotrigine. However, cases have occurred in the absence of these factors [see Boxed Warning] . Therefore, it is important that the dosing recommendations be followed closely.

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

It is recommended that lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, 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 lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)].

Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation:Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder:A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine should be based on therapeutic response [see Clinical Pharmacology (12.3)] .

Women Taking Estrogen-Containing Oral Contraceptives:Starting Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives:Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)] , no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy:The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine in the presence of progestogens alone will likely not be needed.

Patients Taking Atazanavir/Ritonavir:While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the dose of lamotrigine may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)] .

Patients with Hepatic Impairment:Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] , the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response.

Patients with Renal Impairment:Initial doses of lamotrigine should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] . Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients.

Discontinuation Strategy:Epilepsy:For patients receiving lamotrigine in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed.

If a decision is made to discontinue therapy with lamotrigine, 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 Warnings and Precautions (5.10)].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Patients Older than 12 Years:Recommended dosing guidelines are summarized in Table 1.

Patients Aged 2 to 12 Years:Recommended dosing guidelines are summarized in Table 2.

Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower 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 <30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

Usual Adjunctive Maintenance Dose for Epilepsy:The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1-4 has not been established in controlled trials.

Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine:After achieving a dose of 500 mg/day of lamotrigine using the guidelines in Table 1, the concomitant enzyme-inducing 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 Lamotrigine:The conversion regimen involves the 4 steps outlined in Table 4.

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

Adults

The target dose of lamotrigine 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 other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that 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 with 200 mg/day [see Clinical Studies (14.2)] . Accordingly, doses above 200 mg/day are not recommended.

Treatment with lamotrigine is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine should be adjusted. In patients discontinuing valproate, the dose of lamotrigine should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine 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 6). The dose of lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.

If other drugs are subsequently introduced, the dose of lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)].

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine should not be exceeded [see Boxed Warning] .

Pediatric Population:The incidence of serious rash associated with hospitalization and discontinuation of lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience.

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

Adult Population:Serious rash associated with hospitalization and discontinuation of lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received lamotrigine 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 lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine 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 those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.3)] .

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 lamotrigine 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 lamotrigine in the absence of valproate were hospitalized.

Patients with History of Allergy or Rash to Other Antiepileptic Drugs:The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

False-Positive Drug Test Results

Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result.

Plasma Concentrations of Lamotrigine

The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 13), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary.

Epilepsy:Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults with Epilepsy:The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine 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 lamotrigine than in patients receiving other AEDs with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions (5.1)].

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

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

Bipolar Disorder in Adults:The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind, placebo-controlled trials of 18 months' duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with 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 lamotrigine (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 reaction. The adverse reactions that most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).

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

Other reactions 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 reactions that occurred with a frequency of <5% and >1% of patients receiving lamotrigine 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.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including lamotrigine, during pregnancy. Encourage women who are taking lamotrigine tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary

Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population (see Data) . The majority of lamotrigine pregnancy exposure data are from women with epilepsy. In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.

Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see Data) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

As with other AEDs, 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-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response.

Data

Risk Summary

Lamotrigine is present in milk from lactating women taking lamotrigine tablets (see Data) . Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but is not reduced after delivery to the pre-pregnancy dosage. Glucuronidation is required for drug clearance. Glucuronidation capacity is immature in the infant and this may also contribute to the level of lamotrigine exposure. Events including rash, apnea, drowsiness, poor sucking, and poor weight gain (requiring hospitalization in some cases) have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. No data are available on the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lamotrigine tablets and any potential adverse effects on the breastfed infant from lamotrigine or from the underlying maternal condition.

Clinical Considerations

Human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity.

Data

Data from multiple small studies indicate that lamotrigine plasma levels in nursing infants have been reported to be as high as 50% of maternal plasma concentrations.

Epilepsy

Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months). Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.

Bipolar Disorder

Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR. In the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%).

Juvenile Animal Data

In a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats from postnatal day 7 to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m 2basis.

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 50for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established.

Folate Metabolism:In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)] . Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Cardiac Electrophysiology:Effect of Lamotrigine:In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents. At therapeutic doses, lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease), lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death. Elevated heart rates could also increase the risk of ventricular conduction slowing with lamotrigine.

Accumulation in Kidneys:Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.

Melanin Binding:Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.

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 tablets for oral suspension were found to be equivalent, whether administered as dispersed in water, chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets, whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine compressed tablets swallowed with water.

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

Distribution:Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 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.

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

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 ½and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7)] .

Elimination:The elimination half-life and apparent clearance of lamotrigine following oral administration of lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs.

Drug Interactions:The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions (5.9, 5.13), Drug Interactions (7)].

The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15, followed by details of the drug interaction studies below.

Specific Populations

Monotherapy with Lamotrigine in Adults with Partial-Onset Seizures Already Receiving Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug:The effectiveness of monotherapy with lamotrigine was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.

Trial endpoints were completion of all weeks of trial 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 seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentages of patients who met escape criteria were 42% (32/76) in the group receiving lamotrigine and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant ( P=0.0012) in favor of lamotrigine. No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this trial was to demonstrate the effectiveness and safety of monotherapy with lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of valproate.

Adjunctive Therapy with Lamotrigine in Adults with Partial-Onset Seizures:The effectiveness of lamotrigine as adjunctive therapy (added to other AEDs) was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, lamotrigine or placebo was then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial, 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 trials.

One trial (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 lamotrigine, or a target dose of 500 mg/day of lamotrigine. The median reductions in the frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group.

A second trial (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 lamotrigine 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 lamotrigine compared with placebo ( P<0.001).

The third trial (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 lamotrigine. The 28 other patients had a target dose of 300 mg/day of lamotrigine. The median change in seizure frequency was a 26% reduction on lamotrigine compared with 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 Lamotrigine in Pediatric Patients with Partial-Onset Seizures:The effectiveness of lamotrigine as adjunctive therapy in pediatric patients with partial-onset seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on lamotrigine, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with lamotrigine 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/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of all partial-onset seizures was 36% in patients treated with lamotrigine and 7% on placebo, a difference that was statistically significant ( P<0.01).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Lennox-Gastaut Syndrome:The effectiveness of lamotrigine 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 lamotrigine, n = 90 on placebo). Following a 4-week, single-blind, placebo phase, patients were randomized to 16 weeks of treatment with lamotrigine 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/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/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 lamotrigine and 9% on placebo, a difference that was statistically significant ( P<0.05). Drop attacks were significantly reduced by lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for lamotrigine and placebo, respectively).

Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-Clonic Seizures:The effectiveness of lamotrigine as adjunctive therapy in patients with PGTC seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years and older (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs.

The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with lamotrigine and 34% on placebo, a difference that was statistically significant ( P= 0.006).

Adults

The effectiveness of lamotrigine in the maintenance treatment of bipolar I disorder was established in 2 multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar disorder (4 to 6 episodes per year).

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

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

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

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 1)

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 2)