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LAMOTRIGINE TABLETS, 25 mg, 100 mg, 150 mg and 200 mg
0039
0463
7247
7248
Rx only

SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF LAMOTRIGINE. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN PEDIATRIC PATIENTS (AGE < 16 YEARS) RECEIVING LAMOTRIGINE AS ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER 1,000) IN ADULT PATIENTS RECEIVING LAMOTRIGINE AS INITIAL MONOTHERAPY AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMOTRIGINE AS ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMOTRIGINE, THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH ASSOCIATED WITH LAMOTRIGINE. THERE ARE SUGGESTIONS, YET TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1) COADMINISTRATION OF LAMOTRIGINE WITH VALPROATE (INCLUDES VALPROIC ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF LAMOTRIGINE, OR (3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR LAMOTRIGINE. HOWEVER, CASES HAVE BEEN REPORTED IN THE ABSENCE OF THESE FACTORS.

NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH LAMOTRIGINE HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER PROLONGED TREATMENT (e.g., 6 MONTHS). ACCORDINGLY, DURATION OF THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.

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

DESCRIPTION

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. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M hydrochloride (4.1 mg/mL at 25°C). The structural formula is:

C9H7N5Cl2 M.W. 256.09

Lamotrigine tablets are supplied for oral administration as 25 mg (white to off-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: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and sodium starch glycolate. In addition, the 100 mg strength contains FD&C Yellow #6, the 150 mg strength contains ferric oxide yellow, and the 200 mg strength contains FD&C Blue #2.

CLINICAL PHARMACOLOGY

Mechanism of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

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

Pharmacological Properties

Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50 > 100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC50 > 200 µM) when tested in rat synaptosomes and/or human platelets in vitro.

Pharmacokinetics and Drug Metabolism

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

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

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

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

Adult Study PopulationNumber of SubjectsTmax: Time of Maximum Plasma Concentration (h)t½: Elimination Half-life (h)Cl/F: Apparent Plasma Clearance (mL/min/kg)
Healthy volunteers taking no other medications:
Single-dose Lamotrigine1792.2 (0.25 to 12.0)32.8 (14.0 to 103.0)0.44 (0.12 to 1.10)
Multiple-dose Lamotrigine361.7 (0.5 to 4.0)25.4 (11.6 to 61.6)0.58 (0.24 to 1.15)
Healthy volunteers taking valproate:
Single-dose Lamotrigine61.8 (1.0 to 4.0)48.3 (31.5 to 88.6)0.30 (0.14 to 0.42)
Multiple-dose Lamotrigine181.9 (0.5 to 3.5)70.3 (41.9 to 113.5)0.18 (0.12 to 0.33)
Patients with epilepsy taking valproate only:
Single-dose Lamotrigine44.8 (1.8 to 8.4)58.8 (30.5 to 88.8)0.28 (0.16 to 0.40)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone plus valproate:
Single-dose Lamotrigine253.8 (1.0 to 10.0)27.2 (11.2 to 51.6)0.53 (0.27 to 1.04)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:
Single-dose Lamotrigine242.3 (0.5 to 5.0)14.4 (6.4 to 30.4)1.10 (0.51 to 2.22)
Multiple-dose Lamotrigine172.0 (0.75 to 5.93)12.6 (7.5 to 23.1)1.21 (0.66 to 1.82)

Special Populations

Age

CLINICAL STUDIES

Epilepsy

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

Bipolar Disorder

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

In both studies, patients were titrated to a target dose of 200 mg of 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 Study 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. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with 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. The mean lamotrigine dose was about 211 mg/day.

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

INDICATIONS AND USAGE

Epilepsy

Bipolar Disorder

Lamotrigine tablets are 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 lamotrigine in the acute treatment of mood episodes has not been established.

The effectiveness of lamotrigine 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 lamotrigine tablets for periods extending beyond 18 months should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Lamotrigine tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

WARNINGS

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

ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMOTRIGINE, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMOTRIGINE 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

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 patients should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with lamotrigine, 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 lamotrigine. 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 lamotrigine in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause.

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

Blood Dyscrasias

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

Withdrawal Seizures

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

PRECAUTIONS

Concomitant Use With Oral Contraceptives

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

Dermatological Events (see BOX WARNING, WARNINGS)

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

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

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

It is recommended that 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, Pharmacokinetics and Drug Metabolism, and DOSAGE AND ADMINISTRATION).

Use in Patients With Epilepsy

Use in Patients With Bipolar Disorder

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

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

Use in Patients With Concomitant Illness

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

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

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

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

Binding in the Eye and Other Melanin-Containing Tissues

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

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

Information for Patients

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

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

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

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

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

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

Laboratory Tests

The value of monitoring plasma concentrations of lamotrigine has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs including AEDs (see Table 3), 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.

Drug Interactions

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

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2, respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.

Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.

No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy

Teratogenic Effects

Pregnancy Exposure Registry

To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians should encourage patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, to register in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).

Labor and Delivery

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

Use in Nursing Mothers

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

Pediatric Use

Lamotrigine tablets are indicated as adjunctive therapy for partial seizures and for the generalized seizures of Lennox-Gastaut syndrome in patients above 2 years of age.

In pediatric patients, use of lamotrigine as adjunctive therapy for primary generalized tonic-clonic seizures in pediatric patients greater than or equal to 2 years of age is approved for GlaxoSmithKline’s lamotrigine tablets. However, due to GlaxoSmithKline’s marketing exclusivity rights, this drug product is not labeled for this indication.

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

Geriatric Use

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

ADVERSE REACTIONS

SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF LAMOTRIGINE, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH THERAPY WITH LAMOTRIGINE. 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

Bipolar Disorder

The most commonly observed (≥ 5%) adverse experiences seen in association with the use of lamotrigine 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 lamotrigine 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 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 experience. The adverse events which most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse events (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 experience; most commonly due to rash (5%) and mania/hypomania/mixed mood adverse events (2%).

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

Lamotrigine 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 lamotrigine who experienced an event of the type cited on at least one occasion while receiving lamotrigine. All reported events are included except those already uled 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 lamotrigine, the following adverse experiences have been reported in patients receiving marketed lamotrigine and from worldwide noncontrolled investigational use. These adverse experiences have not been uled 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 lamotrigine have not been evaluated in human studies.

OVERDOSAGE

Human Overdose Experience

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

Management of Overdose

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

DOSAGE AND ADMINISTRATION

Epilepsy

Bipolar Disorder

Lamotrigine tablets are 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 lamotrigine tablets 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 lamotrigine tablets 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 lamotrigine tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine tablets, or (3) exceeding the recommended dose escalation for lamotrigine tablets. 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 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.

Special Populations

Epilepsy

Adjunctive Therapy with Lamotrigine 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.

Bipolar Disorder

The goal of maintenance treatment with lamotrigine tablets 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 lamotrigine tablets 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 lamotrigine tablets 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 lamotrigine tablets should be adjusted. For patients discontinuing valproate, the dose of lamotrigine tablets 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 lamotrigine tablets 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 lamotrigine tablets 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 lamotrigine (see DOSAGE AND ADMINISTRATION, Special Populations, Women and oral contraceptives, Adjustments to the maintenance dose of lamotrigine).

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

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

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

* See CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions for a description of known drug interactions.

Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine.

Valproate has been shown to decrease the apparent clearance of lamotrigine.

For Patients Not Taking Carbamazepine (or Other Enzyme-Inducing Drugs) or ValproateFor Patients Taking ValproateFor Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate
Weeks 1 and 225 mg daily25 mg every other day50 mg daily
Weeks 3 and 450 mg daily25 mg daily100 mg daily, in divided doses
Week 5100 mg daily50 mg daily200 mg daily, in divided doses
Week 6200 mg daily100 mg daily300 mg daily, in divided doses
Week 7200 mg daily100 mg dailyup to 400 mg daily, in divided doses
Table 14. Adjustments to Lamotrigine Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications*

* See CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions for a description of known drug interactions.

Carbamazepine, phenytoin, phenobarbital, primidone, rifampin, have been shown to increase the apparent clearance of lamotrigine.

Valproate has been shown to decrease the apparent clearance of lamotrigine.

 Discontinuation of Psychotropic Drugs (excluding Valproate, Carbamazepine, or Other Enzyme-Inducing Drugs)After Discontinuation of ValproateAfter Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs
Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400
Week 1Maintain current lamotrigine dose150400
Week 2Maintain current lamotrigine dose200300
Week 3 onwardMaintain current lamotrigine dose200200

There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine tablet therapy. Systematic evaluation of the efficacy of lamotrigine 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 lamotrigine 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.

HOW SUPPLIED

Lamotrigine tablets are supplied as follows:

25 mg – white to off-white, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “39” on the other side of the tablet. They are available in bottles of 60, 100 and 1000.

100 mg – peach, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “463” on the other side of the tablet. They are available in bottles of 60, 100 and 1000.

150 mg – cream, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “7247” on the other side of the tablet. They are available in bottles of 60, 100 and 1000.

200 mg – blue, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “7248” on the other side of the tablet. They are available in bottles of 60, 100 and 1000.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in a dry place and protect from light.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

PATIENT INFORMATION

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

INFORMATION FOR THE PATIENT

LAMOTRIGINE TABLETS

ALWAYS CHECK THAT YOU RECEIVE LAMOTRIGINE

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

  • make sure you can read it clearly.
  • talk to your pharmacist to check that you are given the correct medicine.
  • check the tablets you receive against the information about the tablets below. The wording describes the actual tablet shape, size, color and printing that is on each strength of lamotrigine tablets.

25 mg – white to off-white, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “39” on the other side of the tablet.

100 mg – peach, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “463” on the other side of the tablet.

150 mg – cream, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “7247” on the other side of the tablet.

200 mg – blue, diamond-shaped tablets, debossed with the number “93” on one side and scored between the two numbers, and debossed “7248” on the other side of the tablet.

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

Information About Your Medicine:

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

1. The Purpose of Your Medicine:

For Patients With Epilepsy: Lamotrigine is intended to be used either alone or in combination with other medicines to treat seizures in people aged 2 years or older.

For Patients With Bipolar Disorder: Lamotrigine tablets are used as maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or older treated for acute mood episodes with standard therapy.

If you are taking lamotrigine tablets to help prevent extreme mood swings, you may not experience the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder may include thoughts of harming yourself or committing suicide. Tell your doctor immediately or go to the nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time. Also contact your doctor if you experience any worsening of your condition or develop other new symptoms at any time during your treatment.

Some medicines used to treat depression have been associated with suicidal thoughts and suicidal behavior in children or teenagers. Lamotrigine tablets are not approved for treating children or teenagers with mood disorders such as bipolar disorder or depression.

2. Who Should Not Take Lamotrigine:

You should not take lamotrigine if you had an allergic reaction to it in the past.

3. Side Effects to Watch for:

  • Most people who take lamotrigine tolerate it well. Common side effects with lamotrigine include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. Lamotrigine may cause other side effects not uled in this leaflet. If you develop any side effects or symptoms you are concerned about or need more information, call your doctor.
  • Although most patients who develop rash while receiving lamotrigine have mild to moderate symptoms, some individuals may develop a serious skin reaction that requires hospitalization. Rarely, deaths have been reported. These serious skin reactions are most likely to happen within the first 8 weeks of treatment with lamotrigine. Serious skin reactions occur more often in children than in adults.
  • Rashes may be more likely to occur if you: (1) take lamotrigine in combination with valproate [DEPAKENE® (valproic acid) or DEPAKOTE® (divalproex sodium)], (2) take a higher starting dose of lamotrigine than your doctor prescribed, or (3) increase your dose of lamotrigine faster than prescribed.
  • It is not possible to predict whether a mild rash will develop into a more serious reaction. Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor immediately, since these symptoms may be the first signs of a serious reaction. A doctor should evaluate your condition and decide if you should continue taking lamotrigine.

4. The Use of Lamotrigine During Pregnancy and Breastfeeding:

The effects of lamotrigine during pregnancy are not known at this time. If you are pregnant or are planning to become pregnant, talk to your doctor. Some lamotrigine passes into breast milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you should discuss this with your doctor to determine if you should continue to take lamotrigine.

5. Use of Birth Control Pills or Other Female Hormonal Products

  • Do not start or stop using birth control pills or other female hormonal products until you have consulted your doctor. Stopping or starting these products may cause side effects (such as dizziness, lack of coordination, or double vision) or decrease the effectiveness of lamotrigine.
  • Tell your doctor as soon as possible if you experience side effects or changes in your menstrual pattern (e.g., break-through bleeding) while taking lamotrigine and birth control pills or other female hormonal products.

6. How to Use Lamotrigine:

  • It is important to take lamotrigine exactly as instructed by your doctor. The dose of lamotrigine must be increased slowly. It may take several weeks or months before your final dosage can be determined by your doctor, based on your response.
  • Do not increase your dose of lamotrigine or take more frequent doses than those indicated by your doctor. Contact your doctor, if you stop taking lamotrigine for any reason. Do not restart without consulting your doctor.
  • If you miss a dose of lamotrigine, do not double your next dose.
  • Always tell your doctor and pharmacist if you are taking any other prescription or over-the-counter medicines. Tell your doctor before you start any other medicines.
  • Do NOT stop taking lamotrigine or any of your other medicines unless instructed by your doctor.
  • Use caution before driving a car or operating complex, hazardous machinery until you know if lamotrigine affects your ability to perform these tasks.
  • If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types of seizures.
  • Always tell your doctor and pharmacist if you are taking or plan to take any other prescription or over-the-counter medicines.

7. How to Take Lamotrigine:

Lamotrigine tablets should be swallowed whole. Chewing the tablets may leave a bitter taste.

8. Storing Your Medicine:

Store lamotrigine tablets at room temperature away from heat and light. Always keep your medicines out of the reach of children.

This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder. Do not give the drug to others.

If your doctor decides to stop your treatment, do not keep any leftover medicine unless your doctor tells you to. Throw away your medicine as instructed.

DEPAKENE® and DEPAKOTE® are registered trademarks of Abbott Laboratories.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. A 10/2006

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