Lamotrigine (lamotrigine 200 mg) Dailymed

Drug & Or 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 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities. No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m2 basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy

No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased. A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m2 basis, respectively. Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis. When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A noobserved-effect level (NOEL) could not be determined for this study. Although lamotrigine was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects:

As with other antiepileptic drugs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Exposure Registry:

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

Labor & Delivery

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

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 is indicated as adjunctive therapy for partial seizures, for the generalized seizures of Lennox-Gastaut syndrome in patients above 2 years of age. . 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: Adjunctive Therapy in Adults With Epilepsy: The most commonly observed (adverse experiences seen in association with Lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with Lamotrigine than in patients receiving other AEDs with Lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate (see

WARNINGS

). Approximately 11% of the 3,378 adult patients who received Lamotrigine 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 Lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults With Epilepsy: The most commonly observed (adverse experiences seen in association with the use of Lamotrigine 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 (adverse experiences associated with the use of Lamotrigine 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 Lamotrigine 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 (adverse experiences seen in association with the use of Lamotrigine 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 Lamotrigine 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 Lamotrigine and deterioration of seizure control for patients treated with placebo. Approximately 11.5% of the 1,081 pediatric patients who received Lamotrigine 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 uls treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with Lamotrigine in placebo-controlled trials and were numerically more common in the patients treated with Lamotrigine. In these studies, either Lamotrigine 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 lamotrigine and numerically more frequent than in the placebo group.)

* Adverse experiences reported by at least 2% of patients treated with Lamotrigine are included.Body System/Adverse Experience Percent of Patients Receiving Adjunctive Lamotrigine (n = 711)Percent of Patients Receiving Adjunctive Placebo (n = 419)Body as a wholeHeadache2919Flu syndrome76Fever64Abdominal pain54Neck pain21Reaction aggravated (seizure exacerbation)21DigestiveNausea1910Vomiting94Diarrhea64Dyspepsia52Constipation43Tooth disorder32Anorexia21MusculoskeletalArthralgia20Nervous Dizziness3813Ataxia226Somnolence147Incoordination62Insomnia62Tremor41Depression43Anxiety43Convulsion31Irritability32Speech disorder30Concentration disturbance21RespiratoryRhinitis149Pharyngitis109Cough increased86Skin and appendagesRash105Pruritus32Special sensesDiplopia287Blurred vision165Vision abnormality31UrogenitalFemale patients only(n = 365)(n = 207)Dysmenorrhea76Vaginitis41Amenorrhea21In a randomized, parallel study comparing placebo and 300 and 500 mg/day of Lamotrigine, 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 *Significantly greater than placebo group (p<0.05). Significantly greater than group receiving Lamotrigine 300 mg (p<0.05).Percent of Patients Experiencing Adverse ExperiencesAdverse ExperiencePlacebo (n = 73)Lamotrigine 300 mg (n = 71)Lamotrigine 500 mg (n = 72)Ataxia Blurred vision Diplopia Dizziness Nausea Vomiting10 10 8 27 11 410 11 24 *31 18 1128 *25 *49 *54 *25 *18 *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 lamotrigine 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 Lamotrigine 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 lamotrigine or placebo were more likely to report adverse experiences than males. The only adverse experience for which the reports on lamotrigine 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 lamotrigine for individual adverse experiences. Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures: Table 6 uls treatment-emergent signs and symptoms that occurred in at least 5% of patients with epilepsy treated with monotherapy with Lamotrigine 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 lamotrigine and numerically more frequent than in the valproate group.) * Adverse experiences reported by at least 5% of patients are included. Up to 500 mg/day. 1,000 mg/day.Body System/Adverse Experience Percent of Patients Receiving Lamotrigine Monotherapy (n = 43)Percent of Patients Receiving Low- Dose Valproate (n = 44)Body as a wholePain50Infection52Chest pain52DigestiveVomiting90Dyspepsia72Nausea72Metabolic and nutritionalWeight decrease52Nervous Coordination abnormality70Dizziness70Anxiety50Insomnia52RespiratoryRhinitis72Urogenital (female patients only)(n = 21)(n = 28)Dysmenorrhea50Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients receiving Lamotrigine 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 uls adverse events that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received Lamotrigine 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 lamotrigine and numerically more frequent than in the placebo group.) Body System/ Adverse ExperiencePercent of Patients Receiving Lamotrigine (n = 168)Percent of Patients Receiving Placebo (n = 171)Body as a whole Infection2017Fever1514Accidental injury1412Abdominal pain105Asthenia84Flu syndrome76Pain54Facial edema21Photosensitivity20CardiovascularHemorrhage21DigestiveVomiting2016Diarrhea119Nausea102Constipation42Dyspepsia21Tooth disorder21Hemic and lymphaticLymphadenopathy21Metabolic and nutritionalEdema20Nervous system Somnolence1715Dizziness144Ataxia113Tremor101Emotional lability42Gait abnormality42Thinking abnormality32Convulsions21Nervousness21Vertigo21RespiratoryPharyngitis1411Bronchitis75Increased cough76Sinusitis21Bronchospasm21SkinRash1412Eczema21Pruritus21Special sensesDiplopia51Blurred vision41Ear disorder21Visual abnormality20UrogenitalMale and female patients Urinary tract infection0Male patients onlyn=92 0 -Bipolar Disorder The most commonly observed (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%). Incidence in Controlled Clinical Studies of Lamotrigine for the Maintenance Treatment of Bipolar I Disorder Table 8 uls treatment-emergent signs and symptoms that occurred in at least 5% of patients with Bipolar Disorder treated with Lamotrigine 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 lamotrigine monotherapy and numerically more frequent than in the placebo group.) * 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 adultpatients who received Lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy (see WARNINGS).Body System/ Adverse Experience Percent of Patients Receiving Lamotrigine n = 227Percent of Patients Receiving Placebo n = 190GeneralBack pain86Fatigue85Abdominal pain63DigestiveNausea1411Constipation52Vomiting52Nervous System Insomnia106Somnolence97Xerostomia (dry mouth)64RespiratoryRhinitis74Exacerbation of cough53Pharyngitis54SkinRash (nonserious) 75These 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 Lamotrigine and numerically more frequent than placebo were: General:Fever,neck pain. Cardiovascular:Migraine. Digestive: Flatulence. Metabolic and Nutritional: Weight gain, edema. Musculoskeletal: Arthralgia, myalgia. Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia. Respiratory: Sinusitis. Urogenital: Urinary frequency. 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 Lamotrigine therapy. 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 (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 Lamotrigine 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 Lamotrigine (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 lamotrigine (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 lamotrigine 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 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. Hepatobiiary 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

Dosage & Administration

Epilepsy Adjunctive Use: Lamotrigine is indicated as adjunctive therapy for partial seizures and the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (years of age). Monotherapy Use: Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) are 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 lamotrigine tablets and lamotrigine tablets (chewable, dispersible)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 Lamotrigine tablets and lamotrigine tablets (chewable, dispersible) 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. 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 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 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 (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. Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible)Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those uled in

PRECAUTIONS: Drug Interactions

have not been systematically evaluated in combination with Lamotrigine. 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 Lamotrigine 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 lamotrigine should be based on therapeutic response. The half-life of lamotrigine 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 Lamotrigine Tablets and LamotrigineTablets (Chewable, Dispersible)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 lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine based on the concomitant AED (see

Table 11

). See below for adjustments to maintenance doses of lamotrigine in women taking estrogen-containing oral contraceptives. Adjustments to the Maintenance Dose of Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of Lamotrigine 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 Lamotrigine 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 lamotrigine 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 Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary to the dose of Lamotrigine. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine 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 Lamotrigine 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 lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment to the dose of lamotrigine 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 lamotrigine 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 lamotrigine tablets and lamotrigine tablets (chewable, dispersible) 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 lamotrigine. Because there is inadequate experience in this population, lamotrigine should be used with caution in these patients. Epilepsy: Adjunctive Therapy With Lamotrigine Tablets and Lamotrigine Tablets (Chewable, Dispersible) 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 uled 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. Table 9. Escalation Regimen for Lamotrigine in Patients 2 to 12 Years of Age With Epilepsy

*

Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see

PRECAUTIONS: Drug Interactions

).For Patients Taking Valproate (see Table 10 for weight- based dosing guide)For Patients Taking AEDs Other Than Carbamazepine, Phenytoi n, Phenobarbital, Primidone

*

, or ValproateFor Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone

*

and Not Taking ValproateWeeks 1 and 20.15 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 40.3 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 maintenanceThe 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 doseThe 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 doseUsual Maintenance Dose1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone4.5 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 kgMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseMay need to be increased by as much as 50%, based on clinical responseNote: Only whole tablets should be used for dosing 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 isGive this daily dose, using the most appropriate combination of lamotrigine tablets (chewable, dispersible), 5 mgGreater thanAnd less thanWeeks 1 and 2Weeks 3 and 434.1 kg40 kg5 mg every day10 mg every dayPatients Over 12 Years of Age: Recommended dosing guidelines are summarized in Table 11. Table 11. Escalation Regimen for Lamotrigine in Patients Over 12 Years of Age With Epilepsy

*

Rifampin and estrogen-containing oral contraceptives have also been shown to increase the apparent clearance of lamotrigine (see

PRECAUTIONS: Drug Interactions

).For Patients Taking ValproateFor Patients Taking AEDs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate

*

For Patients Taking Carbamazepine, Phenytoin, PhenobarbitaL, Primidone

*

and Not Taking ValproateWeeks 1 and 225 mg every other day25 mg every day50 mg/dayWeeks 3 and 425 mg every day50 mg/day100 mg/day (in 2 divided doses)Weeks 5 onwards to maintenanceIncrease by 25 to 50 mg/ day every 1 to 2 weeksIncrease by 50 mg/ day every 1 to 2 weeksIncrease by 100 mg/ day every 1 to 2 weeks.Usual Maintenance Dose100 to 400 mg/day (1 or 2 divided doses) 100 to 200 mg/day with Valproate alone225 to 375 mg/day (in 2 divided doses).300 to 500 mg/day (in 2 divided doses).Conversion from Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy: The goal of the transition regimen is to effect the conversion to monotherapy with Lamotrigine under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine. The recommended maintenance dose of lamotrigine 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 lamotrigine should not be exceeded (see

BOX WARNING

). Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With Lamotrigine: After achieving a dose of 500 mg/day of lamotrigine 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 Lamotrigine The conversion regimen involves 4 steps (see

Table 12

). Table 12. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine in PatientsYears of Age With Epilepsy LamotrigineValproateStep 1Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/ day).Maintain previous stable dose.Step 2Maintain 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 3Increase to 300 mg/day and maintain for 1 week.Simultaneously decrease to 250 mg/day and maintain for 1 week.Step 4Increase 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 Lamotrigine: No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine 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 lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive Lamotrigine as high as 200 mg/ day have been used. The advantage of using doses above those recommended in Tables 9-12 has not been established in controlled trials. Discontinuation Strategy for Patients With Epilepsy: For patients receiving lamotrigine 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 Lamotrigine, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see

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 lamotrigine 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 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 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 should be adjusted. For patients discontinuing valproate, the dose of lamotrigine 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 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 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 Maintenace Dose of Lamotrigine

). If other drugs are subsequently introduced, the dose of Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of Lamotrigine (see

CLINICAL PHARMACOLOGY: Drug Interactions

). To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of Lamotrigine 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, Phenytoin, Phenobarbital, Primidone or Rifampin

and Not Taking Valproate

For Patients Taking Valproate

For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate

Weeks 1 and 225 mg daily25 mg every other day50 mg dailyWeeks 3 and 450 mg daily25 mg daily100 mg daily, in divided dosesWeek 5100 mg daily50 mg daily200 mg daily, in divided dosesWeek 6200 mg daily100 mg daily300 mg daily, in divided dosesWeek 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, and 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 Valproate

After Discontinuation of Carbamazepine or Other Enzyme-Inducing Drugs

Current Lamotrigine dose (mg/day) 100Current Lamotrigine dose (mg/day) 400Week 1Maintain current lamotrigine dose150400Week 2Maintain current lamotrigine dose200300Week 3 onwardMaintain current lamotrigine dose200200There is no body of evidence available to answer the question of how long the patient should remain on lamotrigine 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. Discontinuation Strategy in Bipolar Disorder: As with other AEDs, lamotrigine 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 lamotrigine. 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. Discontinuation of lamotrigine 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 Lamotrigine Tablets (Chewable, Dispersible) Lamotrigine tablets (Chewable, Dispersible) 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 lamotrigine tablets (chewable, dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

How Supplied

Lamotrigine Tablets, 25-mg White to off white, round shape, flat face beveled edge, uncoated tablets debossed with "45" on one side and break line on other side. Bottle of 30 NDC-13668-045-30 Bottle of 60 NDC-13668-045-60 Bottle of 100 NDC-13668-045-01 Bottle of 500 NDC-13668-045-05 Bottle of 6600 NDC-13668-045-66 10 x 10 unit dose NDC-13668-045-74

Storage And Handling

Store at 20- 25(68- 77- 30(59- 86[See USP Controlled Room Temperature].

Information For Patients

See

Medication Guide

that accompanies the product.

Rash

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.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including lamotrigine, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Worsening of Seizures

Patients should be advised to notify their physician if worsening of seizure control occurs.

CNS Adverse Effects

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.

Blood Dyscrasias and/or Acute Multiorgan Failure

Patients should be advised of the possibility of blood dyscrasias and/or acute multiorgan failure and to contact their physician immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions].

Pregnancy

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 breastfeed or are breastfeeding an infant. Patients should also be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations

Oral Contraceptive Use

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 Warnings and Precautions , Clinical Pharmacology]. 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.

Discontinuing lamotrigine

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.

Potential Medication Errors

Medication errors involving lamotrigine have occurred. In particular the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine clearly. Depictions of the lamotrigine tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid a medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine, as well as the correct formulation of lamotrigine, each time they fill their prescription [see Dosage Forms and Strengths, How Supplied/Storage and Handling].