LAMOTRIGINE

The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling Serious Skin Rashes [see Warnings and Precautions (5.1)] Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.2)] Multiorgan Hypersensitivity Reactions and Organ Failure [see Warnings and Precautions (5.3)] Blood Dyscrasias [see Warnings and Precautions (5.4)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)] Aseptic Meningitis [see Warnings and Precautions (5.6)] Withdrawal Seizures [see Warnings and Precautions (5.9)] Status Epilepticus [see Warnings and Precautions (5.10)] Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.11)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Epilepsy Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see Warnings and Precautions (5.1)]. Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%). In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions 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 (≥5% for lamotrigine and more common on drug than placebo) adverse reactions 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 reaction. The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%). Adjunctive Therapy in Pediatric Patients with Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years 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 aged 2 to 16 years with partial-onset 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 reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash. Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%). Controlled Adjunctive Clinical Trials in Adults with Epilepsy: Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these trials, either lamotrigine or placebo was added to the patient's current AED therapy. Table 8. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy a,b a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant antiepileptic drugs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo. Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category. Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419) Body as a whole Headache Flu syndrome Fever Abdominal pain Neck pain Reaction aggravated (seizure exacerbation) 29 7 6 5 2 2 19 6 4 4 1 1 Digestive Nausea Vomiting Diarrhea Dyspepsia Constipation Anorexia 19 9 6 5 4 2 10 4 4 2 3 1 Musculoskeletal Arthralgia 2 0 Nervous system Dizziness Ataxia Somnolence Incoordination Insomnia Tremor Depression Anxiety Convulsion Irritability Speech disorder Concentration disturbance 38 22 14 6 6 4 4 4 3 3 3 2 13 6 7 2 2 1 3 3 1 2 0 1 Respiratory Rhinitis Pharyngitis Cough increased 14 10 8 9 9 6 Skin and appendages Rash Pruritis 10 3 5 2 Special senses Diplopia Blurred vision Vision abnormality 28 16 3 7 5 1 Urogenital Female patients only Dysmenorrhea Vaginitis Amenorrhea (n = 365) 7 4 2 (n = 207) 6 1 1 In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related (see Table 9). Table 9. Dose-Related Adverse Reactions from a Randomized, Placebo-Controlled, Adjunctive Trial in Adults with Epilepsy a Significantly greater than placebo group (P <0.05). b Significantly greater than group receiving lamotrigine 300 mg (P <0.05). Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72) Ataxia Blurred vision Diplopia Dizziness Nausea Vomiting 10 10 8 27 11 4 10 11 24a 31 18 11 28a,b 25a,b 49a,b 54 a,b 25a 18a The overall adverse reaction 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 reaction reports by race. Generally, females receiving either lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine were > 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 reactions. Controlled Monotherapy Trial in Adults with Partial-Onset Seizures: Table 10 lists adverse reactions that occurred in 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 10. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with Partial-Onset Seizuresa,b a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients. b Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. c Up to 500 mg/day. d 1,000 mg/day. Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine c As Monotherapy (n = 43) Percent of Patients Receiving Low Dose Valproated Monotherapy (n = 44) Body as a whole Pain Infection Chest pain 5 5 5 0 2 2 Digestive Vomiting Dyspepsia Nausea 9 7 7 0 2 2 Metabolic and nutritional Weight decrease 5 2 Nervous system Coordination abnormality Dizziness Anxiety Insomnia 7 7 5 5 0 0 0 2 Respiratory Rhinitis 7 2 Urogenital (female patients only) Dysmenorrhea (n = 21) 5 (n = 28) 0 Adverse reactions that occurred with a frequency of < 5% and > 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 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day. Table 11. Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric Patients with Epilepsya a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole Infection Fever Accidental injury Abdominal pain Asthenia Flu syndrome Pain Facial edema Photosensitivity 20 15 14 10 8 7 5 2 2 17 14 12 5 4 6 4 1 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting Diarrhea Nausea Constipation Dyspepsia 20 11 10 4 2 16 9 2 2 1 Hemic and Lymphatic Lymphadenopathy 2 1 Metabolic and nutritional Edema 2 0 Nervous system Somnolence Dizziness Ataxia Tremor Emotional lability Gait abnormality Thinking abnormality Convulsions Nervousness Vertigo 17 14 11 10 4 4 3 2 2 2 15 4 3 1 2 2 2 1 1 1 Respiratory Pharyngitis Bronchitis Increased cough Sinusitis Bronchospasm 14 7 7 2 2 11 5 6 1 1 Skin Rash Eczema Pruritus 14 2 2 12 1 1 Special senses Diplopia Blurred vision Visual abnormality 5 4 2 1 1 0 Urogenital Male and female patients Urinary tract infection 3 0 Bipolar Disorder in Adults The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind placebo-controlled trials of 18 months' duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%). During the monotherapy phase of the double-blind placebo-controlled trials of 18 months' duration, 13% of 227 patients who received lamotrigine (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse reaction. The adverse reactions that most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%). The overall adverse reaction profile for lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups. Table 12. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with Bipolar I Disordera,b Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 227) Percent of Patients Receiving Placebo (n = 190) General Back pain Fatigue Abdominal Pain 8 8 6 6 5 3 Digestive Nausea Constipation Vomiting 14 5 5 11 2 2 Nervous system Insomnia Somnolence Xerostomia (dry mouth) 10 9 6 6 7 4 Respiratory Rhinitis Exacerbation of cough Pharyngitis 7 5 5 4 3 4 Skin Rash (nonserious)c 7 5 aAdverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than placebo. bPatients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. cIn the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine as adjunctive therapy [see Warnings and Precautions (5.1)]. Other reactions that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia. Adverse reactions that occurred with a frequency of 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 Reactions following Abrupt Discontinuation: In the 2 controlled clinical trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after abruptly terminating therapy with lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine [see Warnings and Precautions (5.9)]. Mania/Hypomania/Mixed Episodes: During the double-blind placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with lamotrigine (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 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 reactions 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). 6.2 Other Adverse Reactions Observed in All Clinical Trials Lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions 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 1 occasion while receiving lamotrigine. All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug. Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent: Allergic reaction, chills, malaise. Cardiovascular System Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation. Dermatological Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash. Digestive System Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema. Endocrine System Rare: Goiter, hypothyroidism. Hematologic and Lymphatic System Infrequent: Ecchymosis, leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, 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, hyperglycemia. Musculoskeletal System Infrequent: Arthritis, leg cramps, myasthenia, twitching. Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture. Nervous System Frequent: Confusion, paresthesia. Infrequent: Akathisia, apathy, aphasia, central nervous system 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, suicidal ideation. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis. Respiratory System Infrequent: Yawn. Rare: Hiccup, hyperventilation. Special Senses Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect. Urogenital System Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence. 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. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of lamotrigine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder. 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. Nervous System Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics. Non-site Specific Progressive immunosuppression.

Lamotrigine tablets are contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1, 5.3)].

Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. It's chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is: [Molecular Structure] Lamotrigine tablets USP are supplied for oral administration as 25 mg, 100 mg, 150 mg or 200 mg tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. In addition, the 200 mg tablets contain FD&C Blue No. 2 Lake.

2.1 General Dosing Considerations Rash There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine 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 occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely. The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine tablets is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that lamotrigine tablets 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 tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)]. Lamotrigine Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for lamotrigine tablets in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for lamotrigine tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13. Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)]. Women Taking Estrogen-Containing Oral Contraceptives Starting Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets 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 tablets based on the concomitant AED or other concomitant medications (see Tables 1, 5, and 7). See below for adjustments to maintenance doses of lamotrigine tablets in women taking estrogen-containing oral contraceptives. Adjustments to the Maintenance Dose of Lamotrigine Tablets in Women Taking Estrogen-Containing Oral Contraceptives: (1) Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level. (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold 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 (see Tables 1 and 5) unless lamotrigine plasma levels or clinical response support larger increases. 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 reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine tablets 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 tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine tablets 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 tablets 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 Clinical Pharmacology (12.3)]. In women taking lamotrigine tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine tablets 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 tablets in the presence of progestogens alone will likely not be needed. Patients Taking Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine tablets should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine tablets based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). In patients already taking maintenance doses of lamotrigine tablets and not taking glucuronidation inducers, the dose of lamotrigine tablets may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients with Renal Impairment Initial doses of lamotrigine tablets should be based on patients' concomitant medications (see Tables 1-3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine tablets. Because there is inadequate experience in this population, lamotrigine tablets should be used with caution in these patients. Discontinuation Strategy Epilepsy: For patients receiving lamotrigine tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. If a decision is made to discontinue therapy with lamotrigine tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.9)]. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. Bipolar Disorder: In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine tablets. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets. Discontinuation of lamotrigine tablets 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 [see Warnings and Precautions (5.9)]. 2.2 Epilepsy—Adjunctive Therapy This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3. Patients Older than 12 Years Recommended dosing guidelines are summarized in Table 1. Table 1. Escalation Regimen for Lamotrigine Tablets in Patients Older than 12 Years with Epilepsy In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Weeks 5 onwards to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks Increase by 50 mg/day every 1 to 2 weeks Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose 100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses) 225 to 375 mg/day (in 2 divided doses) 300 to 500 mg/day (in 2 divided doses) aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1),Drug Interactions (7), and Clinical Pharmacology (12.3)]. Patients Aged 2 to 12 Years Recommended dosing guidelines are summarized in Table 2. Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response. Table 2. Escalation Regimen for Lamotrigine Tablets in Patients Aged 2 to 12 Years with Epilepsy In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight- based dosing guide). 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet. 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. Weeks 3 and 4 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 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. Week 5 onwards to maintenance The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose Usual Maintenance Dose 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). 1 to 3 mg/kg/day with valproate alone 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients less than 30 kg May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response May need to be increased by as much as 50%, based on clinical response Note: Only whole tablets should be used for dosing. aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) With Epilepsy If the patient's weight is Give this daily dose, using the most appropriate combination of Lamotrigine 2-mg and 5-mg tablets Greater than And less than Weeks 1 and 2 Weeks 3 and 4 6.7 kg 14 kg 2 mg every other day 2 mg every day 14.1 kg 27 kg 2 mg every day 4 mg every day 27.1 kg 34 kg 4 mg every day 8 mg every day 34.1 kg 40 kg 5 mg every day 10 mg every day Usual Adjunctive Maintenance Dose for Epilepsy The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine tablets was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive lamotrigine tablets as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive lamotrigine tablets as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1-4 has not been established in controlled trials. 2.3 Epilepsy—Conversion From Adjunctive Therapy to Monotherapy The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine tablets. The recommended maintenance dose of lamotrigine tablets 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 for lamotrigine tablets should not be exceeded [see Boxed Warning]. Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with Lamotrigine Tablets After achieving a dose of 500 mg/day of lamotrigine tablets using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. Conversion from Adjunctive Therapy with Valproate to Monotherapy with Lamotrigine Tablets The conversion regimen involves the 4 steps outlined in Table 4. Table 4. Conversion From Adjunctive Therapy With Valproate to Monotherapy With Lamotrigine Tablets in Patients Aged 16 Years and Older With Epilepsy Lamotrigine Tablets Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1. Maintain established stable dose. Step 2 Maintain at 200 mg/day. Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week. Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue. Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with Lamotrigine Tablets No specific dosing guidelines can be provided for conversion to monotherapy with lamotrigine tablets with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. 2.4 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 [see Indications and Usage (1.2)]. Patients taking lamotrigine tablets for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment. Adults 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 other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day [see Clinical Studies (14.2)]. Accordingly, doses above 200 mg/day are not recommended. Treatment with lamotrigine tablets is introduced, based on concurrent medications, according to the regimen outlined in Table 5. If other psychotropic medications are withdrawn following stabilization, the dose of lamotrigine tablets should be adjusted. In patients discontinuing valproate, the dose of lamotrigine tablets should be doubled over a 2-week period in equal weekly increments (see Table 6). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of lamotrigine 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 6). The dose of lamotrigine tablets may then be further adjusted to the target dose (200 mg) as clinically indicated. 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 Drug Interactions (7), Clinical Pharmacology (12.3)]. To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of lamotrigine tablets should not be exceeded [see Boxed Warning]. Table 5. Escalation Regimen for Lamotrigine Tablets in Adults with Bipolar Disorder In Patients TAKING Valproatea In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)]. Table 6. Dosage Adjustments to Lamotrigine Tablets in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications Discontinuation of Psychotropic Drugs (excluding Valproate,a Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb) After Discontinuation of Valproatea After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb Current dose of lamotrigine tablets (mg/day) 100 Current dose of lamotrigine tablets (mg/day) 400 Weeks 1 Maintain current dose of lamotrigine tablets 150 400 Weeks 2 Maintain current dose of lamotrigine tablets 200 300 Week 3 onward Maintain current dose of lamotrigine tablets 200 200 aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. bDrugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance [see Dosage and Administration (2.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

1.1 Epilepsy Adjunctive Therapy Lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: partial-onset seizures. primary generalized tonic-clonic (PGTC) seizures. generalized seizures of Lennox-Gastaut syndrome. Monotherapy Lamotrigine tablets are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). Safety and effectiveness of lamotrigine tablets 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. 1.2 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 [see Clinical Studies (14.1)]. Limitations of Use Treatment of acute manic or mixed episodes is not recommended. Effectiveness of lamotrigine tablets in the acute treatment of mood episodes has not been established.

10.1 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, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay. 10.2 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; usual precautions should be taken to protect the airway. It should be kept in mind that immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. 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.

Significant drug interactions with lamotrigine are summarized in this section. Uridine 5´-diphospho-glucuronyl transferases (UGT) have been identified as the enzymes responsible for metabolism of lamotrigine. Drugs that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGT, may also enhance the metabolism of lamotrigine. Those drugs that have been demonstrated to have a clinically significant impact on lamotrigine metabolism are outlined in Table 13. Specific dosing guidance for these drugs is provided in the Dosage and Administration section [see Dosage and Administration (2.1)]. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)]. Table 13. Established and Other Potentially Significant Drug Interactions ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. Carbamazepine and carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. Lopinavir/ritonavir ↓ lamotrigine Decreased lamotrigine concentration approximately 50%. Atazanavir/ritonavir ↓ lamotrigine Decreased lamotrigine AUC approximately 32%. Phenobarbital/primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%. Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. Effect of Lamotrigine on Organic Cationic Transporter 2 Substrates Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins [see Clinical Pharmacology (12.3)]. This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

12.1 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). Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor–Mediated Activity Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC 50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM. The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established. 12.2 Pharmacodynamics Folate Metabolism In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid. Accumulation in Kidneys Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to α-2 microglobulin, a species-and sex-specific protein that has not been detected in humans or other animal species. Melanin Binding Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents. Cardiovascular In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation). 12.3 Pharmacokinetics The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric subjects and healthy normal volunteers are summarized in Tables 14 and 16. Table 14. Mean Pharmacokinetic Parametersa in Healthy Volunteers and Adult Subjects with Epilepsy Adult Study Population Number of Subjects Tmax: 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 lamotrigine Multiple-dose lamotrigine 179 36 2.2 (0.25-12) 1.7 (0.5-4.0) 32.8 (14.0-103.0) 25.4 (11.6-61.6) 0.44 (0.12-1.10) 0.58 (0.24-1.15) Healthy volunteers taking valproate: Single-dose lamotrigine Multiple-dose lamotrigine 6 18 1.8 (1.0-4.0) 1.9 (0.5-3.5) 48.3 (31.5-88.6) 70.3 (41.9-113.5) 0.30 (0.14-0.42) 0.18 (0.12-0.33) Subjects with epilepsy taking valproate only: Single-dose lamotrigine 4 4.8 (1.8-8.4) 58.8 (30.5-88.8) 0.28 (0.16-0.40) Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate: Single-dose lamotrigine 25 3.8 (1.0-10.0) 27.2 (11.2-51.6) 0.53 (0.27-1.04) Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b Single-dose lamotrigine Multiple-dose lamotrigine 24 17 2.3 (0.5-5.0) 2.0 (0.75-5.93) 14.4 (6.4-30.4) 12.6 (7.5-23.1) 1.10 (0.51-2.22) 1.21 (0.66-1.82) aThe 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/subjects in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/subject values across studies. bCarbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)]. Absorption Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether administered as dispersed in water, chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets, whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine compressed tablets swallowed with water. Dose Proportionality In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily. Distribution Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers. Protein Binding Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites. Metabolism Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of C14-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-Nglucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%). Enzyme Induction The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated. Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t ½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7)]. Elimination The elimination half-life and apparent clearance of lamotrigine following oral administration of lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 14. Half-life and apparent oral clearance vary depending on concomitant AEDs. Drug Interactions The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions (5.8, 5.12), Drug Interactions (7)]. The net effects of drug interactions with lamotrigine are summarized in Tables 13 and 15, followed by details of the drug interaction studies below. Table 15. Summary of Drug Interactions with Lamotrigine a From adjunctive clinical trials and volunteer trials. b Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer trials. c The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations. d Modest decrease in levonorgestrel. e Slight decrease, not expected to be clinically meaningful. f Compared to historical controls. g Not administered, but an active metabolite of carbamazepine. h Not administered, but an active metabolite of oxcarbazepine. i Not administered, but an active metabolite of risperidone. j Slight increase, not expected to be clinically meaningful. ↔ = No significant effect. ? = Conflicting data. Drug Drug Plasma Concentration With Adjunctive Lamotriginea Lamotrigine Plasma Concentration With Adjunctive Drugsb Oral contraceptives (e.g. ethinylestradiol/levonorgestrel)c Aripiprazole Atazanavir/ritonavir Bupropion Carbamazepine Carbamazepine epoxideg Felbamate Gabapentin Lacosamide Levetiracetam Lithium Lopinavir/ritonavir Olanzapine Oxcarbazepine 10-Monohydroxy oxcarbazepine metaboliteh Perampanel Phenobarbital/primidone Phenytoin Pregabalin Rifampin Risperidone 9-hydroxyrisperidonei Topiramate Valproate Valproate + phenytoin and/or carbamazepine Zonisamide ↔d Not assessed ↔f Not assessed ↔ ? Not assessed Not assessed Not assessed ↔ ↔ ↔e ↔ ↔ ↔ Not assessed ↔ ↔ ↔ Not assessed ↔ ↔ ↔j ↓ Not assessed Not assessed ↓ ↔e ↓ ↔ ↓ ↔ ↔ ↔ ↔ Not assessed ↓ ↔e ↔ ↔e ↓ ↓ ↔ ↓ Not assessed ↔ ↑ ↔ ↔

20230508

3

3.1 Tablets 25 mg, White, caplet shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '111' debossed on other side. 100 mg, White, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '112' debossed on other side. 150 mg, White, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '113' debossed on other side. 200 mg, Light blue, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '114' debossed on other side.

LAMOTRIGINE LAMOTRIGINE CELLULOSE, MICROCRYSTALLINE LAMOTRIGINE LAMOTRIGINE LACTOSE MONOHYDRATE ANHYDROUS LACTOSE MAGNESIUM STEARATE POVIDONE, UNSPECIFIED SODIUM STARCH GLYCOLATE TYPE A POTATO U;U;112 Trigonal

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenicity was seen in mouse or rat following oral administration of lamotrigine for up to 2 years at doses up to 30 mg/kg/day and 10 to 15 mg/kg/day in mouse and rat, respectively. The highest doses tested are less than the human dose of 400 mg/day on a body surface area (mg/m2) basis. Lamotrigine was negative in in vitro gene mutation (Ames and mouse lymphoma tk) assays and in clastogenicity (in vitro human lymphocyte and in vivo rat bone marrow) assays. No evidence of impaired fertility was detected in rats given oral doses of lamotrigine up to 20 mg/kg/day. The highest dose tested is less than the human dose of 400 mg/day on a mg/m2basis.

ANDA090170

LAMOTRIGINE

LAMOTRIGINE

61919-534

HUMAN PRESCRIPTION DRUG

ORAL

534-30

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Additional medication guides can be obtained by calling Unichem at 1-866-562-4616. Rash Prior to initiation of treatment with lamotrigine, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their healthcare providers immediately. Hemophagocytic Lymphohistiocytosis Prior to initiation of treatment with lamotrigine, inform patients that excessive immune activation may occur with lamotrigine and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately. Multiorgan Hypersensitivity Reactions, Blood Dyscrasias, and Organ Failure Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Instruct patients to contact their healthcare providers immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.3, 5.4)]. Suicidal Thinking and Behavior Inform patients, their caregivers, and families that AEDs, including lamotrigine, may increase the risk of suicidal thoughts and behavior. Instruct them 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 or behavior or thoughts about self-harm. Instruct them to immediately report behaviors of concern to their healthcare providers. Worsening of Seizures Instruct patients to notify their healthcare providers if worsening of seizure control occurs. Central Nervous System Adverse Effects Inform patients that lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, instruct them 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. Pregnancy and Nursing Instruct patients to notify their healthcare providers if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant. Encourage patients to enroll in the 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 (8.1)]. Inform patients who intend to breastfeed that lamotrigine is present in breast milk and advise them to monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of continuing breastfeeding. Oral Contraceptive Use Instruct women to notify their healthcare providers 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 (5.7), Clinical Pharmacology (12.3)]. Also instruct women to promptly notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine in combination with these medications. Discontinuing Lamotrigine Instruct patients to notify their healthcare providers if they stop taking lamotrigine for any reason and not to resume lamotrigine without consulting their healthcare providers. Aseptic Meningitis Inform patients that lamotrigine may cause aseptic meningitis. Instruct them to notify their healthcare providers immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking lamotrigine. Potential Medication Errors To avoid a medication error of using the wrong drug or formulation, strongly advise patients 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 (3.1), How Supplied/Storage and Handling (16)]. Refer the patient to the Medication Guide that provides depictions of the lamotrigine tablets. 12-R-08/2018

MEDICATION GUIDE Lamotrigine Tablets, USP What is the most important information I should know about lamotrigine tablets? 1. Lamotrigine tablets may cause a serious skin rash that may cause you to be hospitalized or even cause death. There is no way to tell if a mild rash will become more serious. A serious skin rash can happen at any time during your treatment with lamotrigine tablets, but is more likely to happen within the first 2 to 8 weeks of treatment. Children and teenagers aged between 2 and 17 years have a higher chance of getting this serious skin rash while taking lamotrigine tablets. The risk of getting a serious skin rash is higher if you: take lamotrigine tablets while taking valproate (valproic acid or divalproex sodium). take a higher starting dose of lamotrigine tablets than your healthcare provider prescribed. increase your dose of lamotrigine tablets faster than prescribed. Call your healthcare provider right away if you have any of the following: a skin rash blistering or peeling of your skin hives painful sores in your mouth or around your eyes These symptoms may be the first signs of a serious skin reaction. A healthcare provider should examine you to decide if you should continue taking lamotrigine tablets. 2. Other serious reactions, including serious blood problems or liver problems. Lamotrigine tablets can also cause other types of allergic reactions or serious problems that may affect organs and other parts of your body like your liver or blood cells. You may or may not have a rash with these types of reactions. Call your healthcare provider right away if you have any of these symptoms: fever frequent infections severe muscle pain swelling of your face, eyes, lips, or tongue swollen lymph glands unusual bruising or bleeding weakness, fatigue yellowing of your skin or the white part of your eyes 3. Like other antiepileptic drugs, lamotrigine tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempt to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop lamotrigine tablets without first talking to a healthcare provider. Stopping lamotrigine tablets suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions in myself or a family member? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. 4. Lamotrigine tablets may cause aseptic meningitis, a serious inflammation of the protective membrane that covers the brain and spinal cord. Call your healthcare provider right away if you have any of the following symptoms: headache fever nausea vomiting stiff neck rash unusual sensitivity to light muscle pains chills confusion drowsiness Meningitis has many causes other than lamotrigine tablets, which your doctor would check for if you developed meningitis while taking lamotrigine tablets. Lamotrigine tablets can cause other serious side effects. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you. Be sure to read the section below entitled "What are the possible side effects of lamotrigine tablets?" 5. People prescribed lamotrigine tablets have sometimes been given the wrong medicine because many medicines have names similar to lamotrigine tablets, so always check that you receive lamotrigine tablets. Taking the wrong medication can cause serious health problems. When your healthcare provider gives you a prescription for lamotrigine tablets: Make sure you can read it clearly. Talk to your pharmacist to check that you are given the correct medicine. Each time you fill your prescription, check the tablets you receive against the pictures of the tablets below. These pictures show the distinct wording, colors, and shapes of the tablets that help to identify the right strength of lamotrigine tablets. Immediately call your pharmacist if you receive a lamotrigine tablet that does not look like one of the tablets shown below, as you may have received the wrong medication. Lamotrigine Tablets, USP [tablet pictorial view] What are lamotrigine tablets? Lamotrigine tablets are a prescription medicine used: together with other medicines to treat certain types of seizures (partial-onset seizures, primary generalized tonic-clonic seizures, generalized seizures of Lennox-Gastaut syndrome) in people aged 2 years and older. alone when changing from 1 other medicine used to treat partial-onset seizures in people aged 16 years and older. for the long-term treatment of bipolar I disorder to lengthen the time between mood episodes in people who have been treated for mood episodes with other medicine. It is not known if lamotrigine tablets are safe or effective in people younger than 18 years with mood episodes such as bipolar disorder or depression. It is not known if lamotrigine tablets are safe or effective when used alone as the first treatment of seizures. It is not known if lamotrigine tablets are safe or effective for people with mood episodes who have not already been treated with other medicines. Lamotrigine tablets should not be used for acute treatment of manic or mixed mood episodes. Who should not take lamotrigine tablets? You should not take lamotrigine tablets if you have had an allergic reaction to lamotrigine or to any of the inactive ingredients in lamotrigine tablets. See the end of this leaflet for a complete list of ingredients in lamotrigine tablets. What should I tell my healthcare provider regarding my health conditions before taking lamotrigine tablets? Before taking lamotrigine tablets, tell your healthcare provider about all of your medical conditions, including if you: have had a rash or allergic reaction to another antiseizure medicine. have or have had depression, mood problems, or suicidal thoughts or behavior. have had aseptic meningitis after taking lamotrigine tablets. are taking oral contraceptives (birth control pills) or other female hormonal medicines. Do not start or stop taking birth control pills or other female hormonal medicine until you have talked with your healthcare provider. Tell your healthcare provider if you have any changes in your menstrual pattern such as breakthrough bleeding. Stopping these medicines while you are taking lamotrigine tablets may cause side effects (such as dizziness, lack of coordination, or double vision). Starting these medicines may lessen how well lamotrigine tablets works. are pregnant or plan to become pregnant. It is not known if lamotrigine tablets may harm your unborn baby. If you become pregnant while taking lamotrigine tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. are breastfeeding. Lamotrigine tablets passes into breast milk and may cause side effects in a breastfed baby. If you breastfeed while taking lamotrigine tablets, watch your baby closely for trouble breathing, episodes of temporarily stopping breathing, sleepiness, or poor sucking. Call your baby's healthcare provider right away if you see any of these problems. Talk to your healthcare provider about the best way to feed your baby if you take lamotrigine tablets. Tell your healthcare provider about all the medicines you take or if you are planning to take a new medicine, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Lamotrigine tablets and certain other medicines may interact with each other. This may cause serious side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take lamotrigine tablets? Take lamotrigine tablets exactly as prescribed. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider Do not stop taking lamotrigine tablets without talking to your healthcare provider. Stopping lamotrigine tablets suddenly may cause serious problems. For example, if you have epilepsy and you stop taking lamotrigine tablets suddenly, you may have seizures that do not stop. Talk with your healthcare provider about how to stop lamotrigine tablets slowly. If you miss a dose of lamotrigine tablets, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time. If you take too much lamotrigine tablets, call your healthcare provider or your local Poison Control Center or go to the nearest hospital emergency room right away. You may not feel the full effect of lamotrigine tablets for several weeks. If you have epilepsy, tell your healthcare provider if your seizures get worse or if you have any new types of seizures. Swallow lamotrigine tablets whole. If you have trouble swallowing lamotrigine tablets, tell your healthcare provider because there may be another form of lamotrigine tablets you can take. What should I avoid while taking lamotrigine tablets? Do not drive, operate machinery, or do other dangerous activities until you know how lamotrigine tablets affects you. What are the possible side effects of lamotrigine tablets? Lamotrigine tablets can cause serious side effects. See "What is the most important information I should know about lamotrigine tablets?" Common side effects of lamotrigine tablets include: dizziness tremor headache rash blurred or double vision fever lack of coordination abdominal pain infections, including seasonal flu sleepiness back pain nausea, vomiting diarrhea tiredness insomnia dry mouth stuffy nose sore throat Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of lamotrigine tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088. How should I store lamotrigine tablets? Store lamotrigine tablets at 20oto 25oC (68oto 77oF). Keep lamotrigine tablets and all medicines out of the reach of children. General information about the safe and effective use of lamotrigine tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use lamotrigine tablets for a condition for which it was not prescribed. Do not give lamotrigine tablets to other people, even if they have the same symptoms you have. It may harm them. If you take a urine drug screening test, lamotrigine tablets may make the test result positive for another drug. If you require a urine drug screening test, tell the healthcare professional administering the test that you are taking lamotrigine tablets. This Medication Guide summarizes the most important information about lamotrigine tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about lamotrigine tablets that is written for healthcare professionals. For more information, call Unichem Pharmaceuticals (USA), Inc.,1-866-62-4616. What are the ingredients in lamotrigine tablets? Active ingredient: lamotrigine USP. Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. In addition, the 200 mg tablets contain FD&C Blue No. 2 Lake. This Medication Guide has been approved by the U.S. Food and Drug Administration. Additional medication guides can be obtained by calling Unichem at 1-866-562-4616. Manufactured by: UNICHEM LABORATORIES LTD. Pilerne Ind. Estate, Pilerne, Bardez, Goa 403511, India Manufactured for: [logo] Hasbrouck Heights, NJ 07604 11-R-08/2018 13010620

14.1 Epilepsy Monotherapy with Lamotrigine in Adults with Partial-Onset Seizures Already Receiving Treatment with Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single Antiepileptic Drug The effectiveness of monotherapy with lamotrigine was established in a multicenter double-blind clinical trial enrolling 156 adult outpatients with partial-onset seizures. The patients experienced at least 4 simple partial-onset, complex partial-onset, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period. Trial endpoints were completion of all weeks of trial treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized tonic-clonic seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria. The percentages of patients who met escape criteria were 42% (32/76) in the group receiving lamotrigine and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (P = 0.0012) in favor of lamotrigine. No differences in efficacy based on age, sex, or race were detected. Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this trial was to demonstrate the effectiveness and safety of monotherapy with lamotrigine, and cannot be interpreted to imply the superiority of lamotrigine to an adequate dose of valproate. Adjunctive Therapy with Lamotrigine in Adults with Partial-Onset Seizures The effectiveness of lamotrigine as adjunctive therapy (added to other AEDs) was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures. The patients had a history of at least 4 partial-onset seizures per month in spite of receiving 1 or more AEDs at therapeutic concentrations and in 2 of the trials were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third trial, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, lamotrigine or placebo was then added to the existing therapy. In all 3 trials, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial-onset seizures in the intent-to-treat population (all patients who received at least 1 dose of treatment) in each trial, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy trials. One trial (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of lamotrigine, or a target dose of 500 mg/day of lamotrigine. The median reductions in the frequency of all partial-onset seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of lamotrigine, and 36% in patients receiving 500 mg/day of lamotrigine. The seizure frequency reduction was statistically significant in the 500-mg/day group compared with the placebo group, but not in the 300-mg/day group. A second trial (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of lamotrigine was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on lamotrigine compared with placebo (P<0.001). The third trial (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12-week treatment periods separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of lamotrigine. The 28 other patients had a target dose of 300 mg/day of lamotrigine. The median change in seizure frequency was a 26% reduction on lamotrigine compared with placebo (P<0.01). No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected. Adjunctive Therapy with Lamotrigine in Pediatric Patients with Partial-Onset Seizures The effectiveness of lamotrigine as adjunctive therapy in pediatric patients with partial-onset seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on lamotrigine, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 250 mg/day) and 15 mg/kg/day for the patients not taking valproate (maximum dose: 750 mg/day). The primary efficacy endpoint was percentage change from baseline in all partial-onset seizures. For the intent-to-treat population, the median reduction of all partial-onset seizures was 36% in patients treated with lamotrigine and 7% on placebo, a difference that was statistically significant (P<0.01). Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Lennox-Gastaut Syndrome The effectiveness of lamotrigine as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on lamotrigine, n = 90 on placebo). Following a 4-week, single-blind, placebo phase, patients were randomized to 16 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg/day for patients taking valproate (maximum dose: 200 mg/day) and 15 mg/kg/day for patients not taking valproate (maximum dose: 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with lamotrigine and 9% on placebo, a difference that was statistically significant (P<0.05). Drop attacks were significantly reduced by lamotrigine (34%) compared with placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for lamotrigine and placebo, respectively). Adjunctive Therapy with Lamotrigine in Pediatric and Adult Patients with Primary Generalized Tonic-Clonic Seizures The effectiveness of lamotrigine as adjunctive therapy in patients with PGTC seizures was established in a multicenter, double-blind, placebo-controlled trial in 117 pediatric and adult patients aged 2 years and older (n = 58 on lamotrigine, n = 59 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 to 24 weeks of treatment with lamotrigine or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 3 to 12 mg/kg/day for pediatric patients and from 200 to 400 mg/day for adult patients based on concomitant AEDs. The primary efficacy endpoint was percentage change from baseline in PGTC seizures. For the intent-to-treat population, the median percent reduction in PGTC seizures was 66% in patients treated with lamotrigine and 34% on placebo, a difference that was statistically significant (P = 0.006). 14.2 Bipolar Disorder Adults The effectiveness of lamotrigine in the maintenance treatment of bipolar I disorder was established in 2 multicenter, double-blind, placebo-controlled trials in adult patients (aged 18 to 82 years) who met DSM-IV criteria for bipolar I disorder. Trial 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Trial 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both trials included a cohort of patients (30% of 404 subjects in Trial 1 and 28% of 171 patients in Trial 2) with rapid cycling bipolar disorder (4 to 6 episodes per year). In both trials, patients were titrated to a target dose of 200 mg of lamotrigine as add-on therapy or as monotherapy with gradual withdrawal of any psychotropic medications during an 8-to 16week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of lamotrigine. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with lamotrigine, were randomized to a placebo-controlled double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to bipolar disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode. In Trial 1, patients received double-blind monotherapy with lamotrigine 50 mg/day (n = 50), lamotrigine 200 mg/day (n = 124), lamotrigine 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine (200-and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode (Figure 1). Separate analyses of the 200-and 400-mg/day dose groups revealed no added benefit from the higher dose. In Trial 2, patients received double-blind monotherapy with lamotrigine (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamotrigine was superior to placebo in delaying time to occurrence of a mood episode (Figure 2). The mean dose of lamotrigine was about 211 mg/day. Although these trials were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 trials revealed a statistically significant benefit for lamotrigine over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression. Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 1) [Figure 1] Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Mood Episode (Trial 2) [Figure 2]

8.1 Pregnancy As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response. Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, lamotrigine was developmentally toxic at doses lower than those administered clinically. Lamotrigine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2) basis. In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, behavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the higher dose tested. When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg2/basis. Maternal toxicity was observed at the 2 highest doses tested. Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse pregnancy outcomes in animals and humans. Pregnancy Registry To provide information regarding the effects of in utero exposure to lamotrigine, physicians are advised to recommend that pregnant patients taking lamotrigine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org. 8.2 Labor and Delivery The effect of lamotrigine on labor and delivery in humans is unknown. 8.3 Nursing Mothers Lamotrigine is present in milk from lactating women taking lamotrigine. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should be exercised when lamotrigine is administered to a nursing woman. 8.4 Pediatric Use Epilepsy Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures. Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months). Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea. Additional information describing a clinical study in which efficacy was not demonstrated in pediatric patients ages 10 to 17 years is approved for GlaxoSmithKline LLC's LAMICTAL® (lamotrigine) products. However, due to GlaxoSmithKline LLC's marketing exclusivity rights, this drug product is not labeled with that pediatric information. Juvenile Animal Data In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2basis. 8.5 Geriatric Use Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. 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. 8.6 Hepatic Impairment Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response [see Dosage and Administration (2.1)]. 8.7 Renal Impairment Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see Clinical Pharmacology (12.3)]. Initial doses of lamotrigine should be based on patients' AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. 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 [see Dosage and Administration (2.1)].

Lamotrigine Tablets USP, 25 mg White, caplet shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '111' debossed on other side. Bottles of 100: NDC 29300-111-01 Bottles of 500: NDC 29300-111-05 Bottles of 1000: NDC 29300-111-10 Lamotrigine Tablets USP, 100 mg White, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '112' debossed on other side. Bottles of 100: NDC 29300-112-01 Bottles of 500: NDC 29300-112-05 Bottles of 1000: NDC 29300-112-10 Lamotrigine Tablets USP, 150 mg White, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '113' debossed on other side. Bottles of 60: NDC 29300-113-16 Bottles of 500: NDC 29300-113-05 Bottles of 1000: NDC 29300-113-10 Lamotrigine Tablets USP, 200 mg Light blue, trigonal shaped, biconvex tablets with 'U' debossed on either side of break line on one side and '114' debossed on other side. Bottles of 60: NDC 29300-114-16 Bottles of 500: NDC 29300-114-05 Bottles of 1000: NDC 29300-114-10 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] in a dry place. Dispense in tight, light-resistant container as defined in the USP.

Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is ... WARNING: SERIOUS SKIN RASHES Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (aged 2 to 17 years) and 0.08% to 0.3% in adults receiving lamotrigine. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking lamotrigine as adjunctive therapy. 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 caused by 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 occurred in the absence of these factors. Nearly all cases of life-threatening rashes caused by lamotrigine have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes are also caused by 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 [see Warnings and Precautions (5.1)].