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 pK_a of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25° C). The structural formula is:

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

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

Epilepsy

Adjunctive Use

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

Monotherapy Use

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

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

Bipolar Disorder

LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy.

The effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established. The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-controlled trials of 18 months' duration in patients with Bipolar I Disorder as defined by DSM-IV (see CLINICAL STUDIES: Bipolar Disorder). The physician who elects to use LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Epilepsy

Adjunctive Use

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

Monotherapy Use

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

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

Bipolar Disorder

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

General Dosing Considerations for Epilepsy and Bipolar Disorder Patients

The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.

LAMICTAL Added to Drugs Known to Induce or Inhibit Glucuronidation

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

Target Plasma Levels for Patients With Epilepsy or Bipolar Disorder

A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL should be based on therapeutic response. The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism). See also DOSAGE AND ADMINISTRATION: Special Populations.

Special Populations

Women and Oral Contraceptives

Starting LAMICTAL in Women Taking Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: DRUG INTERACTIONS), no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with LAMICTAL based on the concomitant AED (see Table 11). See below for adjustments to maintenance doses of LAMICTAL in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of LAMICTAL

(1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases need to be increased, by as much as 2-fold over the recommended target maintenance dose, in order to maintain a consistent lamotrigine plasma level (see PRECAUTIONS: DRUG INTERACTIONS). (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of LAMICTAL and not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose will in most cases need to be increased by as much as 2-fold, in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases (see Table 11, column 2). Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (“pill-free” week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse events, such as dizziness, ataxia, and diplopia (see PRECAUTIONS: DRUG INTERACTIONS). If adverse events attributable to LAMICTAL consistently occur during the “pill-free” week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the “pill-free” week are not recommended. For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of LAMICTAL. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL will in most cases need to be decreased by as much as 50%, in order to maintain a consistent lamotrigine plasma level. The decrease in dose of LAMICTAL should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise (see PRECAUTIONS: DRUG INTERACTIONS). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of LAMICTAL should be necessary.

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 LAMICTAL in the presence of progestogens alone will likely not be needed.

Patients With Hepatic Impairment

Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver dysfunction (see CLINICAL PHARMACOLOGY), 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 Functional Impairment

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

Epilepsy

Adjunctive Therapy With LAMICTAL for Epilepsy

This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AED (Table 9 for patients 2 to 12 years of age and Table 11 for patients greater than 12 years of age). A weight-based dosing guide for pediatric patients on concomitant valproate is provided in Table 10.

Patients 2 to 12 Years of Age

Recommended dosing guidelines are summarized in Table 9.

Note that some of the starting doses and dose escalations listed in Table 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 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet (see HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes of LAMICTAL Chewable Dispersible Tablets).

Table 9. Escalation Regimen for LAMICTAL in Patients 2 to 12 Years of Age With
Epilepsy

	For Patients Taking Valproate (see Table 10 for weight-based dosing guide)	For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate*	For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone* and Not Taking Valproate
Weeks 1 and 2	0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).	0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.	0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.
Weeks 3 and 4	0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 10 for weight-based dosing guide).	0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.	1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.
Weeks 5 onwards to maintenance	The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.	The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose	The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose
Usual Maintenance Dose	1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone	4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses)	5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses)
Maintenance dose in patients less than 30 kg	May need to be increased by as much as 50%, based on clinical response	May need to be increased by as much as 50%, based on clinical response	May need to be increased by as much as 50%, based on clinical response
Note: Only whole tablets should be used for dosing * Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: DRUG INTERACTIONS).

Table 10. The Initial Weight-Based Dosing Guide for Patients 2 to 12 Years Taking
Valproate (Weeks 1 to 4) With Epilepsy

If the patient's weight is		Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets
Greater than	And less than	Weeks 1 and 2	Weeks 3 and 4
6.7 kg	14 kg	2 mg every other day	2 mg every day
14.1 kg	27 kg	2 mg every day	4 mg every day
27.1 kg	34 kg	4 mg every day	8 mg every day
34.1 kg	40 kg	5 mg every day	10 mg every day

Patients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 11.

Table 11. Escalation Regimen for LAMICTAL in Patients Over 12 Years of Age With
Epilepsy

	For Patients Taking Valproate	For Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate*	For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone* and Not Taking Valproate
Weeks 1 and 2	25 mg every other day	25 mg every day	50 mg/day
Weeks 3 and 4	25 mg every day	50 mg/day	100 mg/day (in 2 divided doses)
Weeks 5 onwards to maintenance	Increase by 25 to 50 mg/day every 1 to 2 weeks	Increase by 50 mg/day every 1 to 2 weeks	Increase by 100 mg/day every 1 to 2 weeks.
Usual Maintenance Dose	100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with valproate alone	225 to 375 mg/day (in 2 divided doses).	300 to 500 mg/day (in 2 divided doses).
* Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: DRUG INTERACTIONS).

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With LAMICTAL in Patients ≥16 Years of Age With Epilepsy

The goal of the transition regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of LAMICTAL.

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

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

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With LAMICTAL

After achieving a dose of 500 mg/day of LAMICTAL according to the guidelines in Table 11, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL

The conversion regimen involves 4 steps (see Table 12).

Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With
LAMICTAL in Patients ≥16 Years of Age With Epilepsy

	LAMICTAL	Valproate
Step 1	Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/day).	Maintain previous stable dose.
Step 2	Maintain at 200 mg/day.	Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week.
Step 3	Increase to 300 mg/day and maintain for 1 week.	Simultaneously decrease to 250 mg/day and maintain for 1 week.
Step 4	Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day.	Discontinue.

Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL

No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

Usual Maintenance Dose for Epilepsy

The usual maintenance doses identified in Tables 9-11 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials.

Discontinuation Strategy for Patients With Epilepsy

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

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

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

Bipolar Disorder

The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined in Table 13. If other psychotropic medications are withdrawn following stabilization, the dose of LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL should be doubled over a 2-week period in equal weekly increments (see Table 14). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of LAMICTAL should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 14). The dose of LAMICTAL may then be further adjusted to the target dose (200 mg) as clinically indicated.

Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking LAMICTAL (see DOSAGE AND ADMINISTRATION: Special Populations: Women and Oral Contraceptives: Adjustments to the Maintenance Dose of LAMICTAL).

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

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

Table 13. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder*

	For Patients Taking Valproate‡	For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† and Not Taking Valproate‡	For Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin† and Not Taking Valproate‡
Weeks 1 and 2	25 mg every other day	25 mg daily	50 mg daily
Weeks 3 and 4	25 mg daily	50 mg daily	100 mg daily, in divided doses
Week 5	50 mg daily	100 mg daily	200 mg daily, in divided doses
Week 6	100 mg daily	200 mg daily	300 mg daily, in divided doses
Week 7	100 mg daily	200 mg daily	up to 400 mg daily, in divided doses
* See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

Table 14. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder
Following Discontinuation of Psychotropic Medications*

	Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin† , or Valproate‡)	After Discontinuation of Valproate‡	After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin†
		Current LAMICTAL dose (mg/day) 100	Current LAMICTAL dose (mg/day) 400
Week 1	Maintain current LAMICTAL dose	150	400
Week 2	Maintain current LAMICTAL dose	200	300
Week 3 onward	Maintain current LAMICTAL dose	200	200
* See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS for a description of known drug interactions. † Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine. ‡ Valproate has been shown to decrease the apparent clearance of lamotrigine.

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

Discontinuation Strategy in Bipolar Disorder

As with other AEDs, LAMICTAL should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.

Administration of LAMICTAL Chewable Dispersible Tablets

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

To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately.

No attempt should be made to administer partial quantities of the dispersed tablets.

LAMICTAL Tablets, 25-mg

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

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

LAMICTAL Tablets, 100-mg

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

LAMICTAL Tablets, 150-mg

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

LAMICTAL Tablets, 200-mg

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

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

LAMICTAL Chewable Dispersible Tablets, 2-mg

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

LAMICTAL Chewable Dispersible Tablets, 5-mg

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

LAMICTAL Chewable Dispersible Tablets, 25-mg

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

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

LAMICTAL Starter Kit for Patients Taking Valproate

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

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

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

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

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

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

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

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

Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709 by DSM Pharmaceuticals, Inc.
Greenville, NC 27834 or GlaxoSmithKline
Research Triangle Park, NC 27709
DEPAKENE and DEPAKOTE are registered trademarks of Abbott Laboratories.
© 2006, GlaxoSmithKline. All rights reserved.
September 2006 RL-2329
FDA rev date: 9/25/2006

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

Epilepsy

Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in Adults With Epilepsy

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

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

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

Monotherapy in Adults With Epilepsy

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

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

Adjunctive Therapy in Pediatric Patients With Epilepsy

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

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

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

Incidence in Controlled Clinical Studies of Epilepsy

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

Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy

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

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

Body System/ Adverse Experience†	Percent of Patients Receiving Adjunctive LAMICTAL (n = 711)	Percent of Patients Receiving Adjunctive Placebo (n = 419)
Body as a whole
Headache	29	19
Flu syndrome	7	6
Fever	6	4
Abdominal pain	5	4
Neck pain	2	1
Reaction aggravated (seizure exacerbation)	2	1
Digestive
Nausea	19	10
Vomiting	9	4
Diarrhea	6	4
Dyspepsia	5	2
Constipation	4	3
Tooth disorder	3	2
Anorexia	2	1
Musculoskeletal
Arthralgia	2	0
Nervous
Dizziness	38	13
Ataxia	22	6
Somnolence	14	7
Incoordination	6	2
Insomnia	6	2
Tremor	4	1
Depression	4	3
Anxiety	4	3
Convulsion	3	1
Irritability	3	2
Speech disorder	3	0
Concentration disturbance	2	1
Respiratory
Rhinitis	14	9
Pharyngitis	10	9
Cough increased	8	6
Skin and appendages
Rash	10	5
Pruritus	3	2
Special senses
Diplopia	28	7
Blurred vision	16	5
Vision abnormality	3	1
Urogenital
Female patients only	(n = 365)	(n = 207)
Dysmenorrhea	7	6
Vaginitis	4	1
Amenorrhea	2	1
* Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL or placebo. Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category. † Adverse experiences reported by at least 2% of patients treated with LAMICTAL are included.

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

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

	Percent of Patients Experiencing Adverse Experiences
Adverse Experience	Placebo (n = 73)	LAMICTAL 300 mg (n = 71)	LAMICTAL 500 mg (n = 72)
Ataxia	10	10	28*†
Blurred vision	10	11	25*†
Diplopia	8	24*	49*†
Dizziness	27	31	54*†
Nausea	11	18	25*
Vomiting	4	11	18*
*Significantly greater than placebo group (p<0.05). † Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).

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

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

Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures

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

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

Body System/ Adverse Experience†	Percent of Patients Receiving LAMICTAL Monotherapy‡ (n = 43)	Percent of Patients Receiving Low-Dose Valproate§ Monotherapy (n = 44)
Body as a whole
Pain	5	0
Infection	5	2
Chest pain	5	2
Digestive
Vomiting	9	0
Dyspepsia	7	2
Nausea	7	2
Metabolic and nutritional
Weight decrease	5	2
Nervous
Coordination	7	0
abnormality
Dizziness	7	0
Anxiety	5	0
Insomnia	5	2
Respiratory
Rhinitis	7	2
Urogenital (female patients only)	(n = 21)	(n = 28)
Dysmenorrhea	5	0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category. † Adverse experiences reported by at least 5% of patients are included. ‡ Up to 500 mg/day. § 1,000 mg/day.

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

Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

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

Respiratory: Epistaxis, bronchitis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy

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

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

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

Bipolar Disorder

The most commonly observed (≥5%) adverse experiences seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months' duration, and numerically more frequent than in placebo-treated patients are included in Table 8. Adverse events that occurred in at least 5% of patients and were numerically more common during the dose escalation phase of LAMICTAL in these trials (when patients may have been receiving concomitant medications) compared to the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).

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

Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance Treatment of Bipolar I Disorder

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

Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials in
Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with
LAMICTAL monotherapy and numerically more frequent than in the placebo group.)

Body System/ Adverse Experience†	Percent of Patients Receiving LAMICTAL n = 227	Percent of Patients Receiving Placebo n = 190
General
Back pain	8	6
Fatigue	8	5
Abdominal pain	6	3
Digestive
Nausea	14	11
Constipation	5	2
Vomiting	5	2
Nervous System
Insomnia	10	6
Somnolence	9	7
Xerostomia (dry mouth)	6	4
Respiratory
Rhinitis	7	4
Exacerbation of cough	5	3
Pharyngitis	5	4
Skin
Rash (nonserious)‡	7	5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category. † Adverse experiences reported by at least 5% of patients are included. ‡In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy (see WARNINGS).

These adverse events were usually mild to moderate in intensity.

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

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

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

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

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Events Following Abrupt Discontinuation

In the 2 maintenance trials, there was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients (see DOSAGE AND ADMINISTRATION).

Mania/Hypomania/Mixed Episodes

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

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

Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders

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

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

Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise.

Rare: Abdomen enlarged, abscess, and suicide/suicide attempt.

Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation.

Rare: Angina pectoris, atrial fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria.

Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.

Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration.

Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.

Endocrine System: Rare: Goiter and hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia.

Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.

Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.

Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.

Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.

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

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

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

Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence, menorrhagia, polyuria, urinary incontinence, and urine abnormality.

Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and vaginal moniliasis.

Postmarketing and Other Experience

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

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

Gastrointestinal: Esophagitis.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Immunologic: Lupus-like reaction, vasculitis.

Lower Respiratory: Apnea.

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

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

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

Drug Abuse And Dependence

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

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

Oral Contraceptives

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

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

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

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

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

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

Other Hormonal Contraceptives or Hormone Replacement Therapy

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

Bupropion

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

Carbamazepine

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

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

Felbamate

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

Folate Inhibitors

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

Gabapentin

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

Levetiracetam

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

Lithium

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

Olanzapine

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

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

Oxcarbazepine

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

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

Phenobarbital, Primidone

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

Phenytoin

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

Pregabalin

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

Rifampin

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

Topiramate

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

Valproate

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

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

Zonisamide

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

Known Inducers or Inhibitors of Glucuronidation

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

Other

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

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

Table 3. Summary of Drug Interactions With LAMICTAL

Drug	Drug Plasma Concentration With Adjunctive LAMICTAL*	Lamotrigine Plasma Concentration With Adjunctive Drugs†
Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)‡	↔ §	↑
Bupropion	Not assessed	↔
Carbamazepine (CBZ)	↔	↑
CBZ epoxide||	?
Felbamate	Not assessed	↔
Gabapentin	Not assessed	↔
Levetiracetam	↔	↔
Lithium	↔	Not assessed
Olanzapine	↔	↔¶
Oxcarbazepine	↔	↔
10-monohydroxy oxcarbazepine metabolite#	↔
Phenobarbital/primidone	↔	↑
Phenytoin (PHT)	↔	↑
Pregabalin	↔	↔
Rifampin	Not assessed	↑
Topiramate	↔**	↔
Valproate	↓	↑
Valproate + PHT and/or CBZ	Not assessed	↔
Zonisamide	Not assessed	↔
* From adjunctive clinical trials and volunteer studies. † Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteers studies. ‡ The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials and the effect may not be similar to that seen with the ethinylestradiol/levonorgestrel combinations. §Modest decrease in levonorgestrel (see PRECAUTIONS: DRUG INTERACTIONS: Effect of LAMICTAL on Oral Contraceptives). Not administered, but an active metabolite of carbamazepine. ¶ Slight decrease, not expected to be clinically relevant. ||Not administered, but an active metabolite of oxcarbazepine. ** Slight increase not expected to be clinically relevant. ↔= No significant effect. ? = Conflicting data.

Drug/Laboratory Test Interactions

None known.

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

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

Serious Rash

Pediatric Population

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

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

Adult Population

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

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

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

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

Hypersensitivity Reactions

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

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

Acute Multiorgan Failure

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