1.1 Adjunctive Therapy Lamotrigine extended-release tablets are indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial-onset seizures with or without secondary generalization in patients aged 13 years and older.

1.2 Monotherapy Lamotrigine extended-release tablets are indicated for conversion to monotherapy in patients aged 13 years and older with partial-onset seizures who are receiving treatment with a single antiepileptic drug (AED).

Safety and effectiveness of lamotrigine extended-release have not been established (1) as initial monotherapy or (2) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

1.3 Limitation of Use Safety and effectiveness of lamotrigine extended-release for use in patients younger than 13 years have not been established.

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)] Cardiac Rhythm and Conduction Abnormalities [see Warnings and Precautions (5.4)] Blood Dyscrasias [see Warnings and Precautions (5.5)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)] Aseptic Meningitis [see Warnings and Precautions (5.7)] Withdrawal Seizures [see Warnings and Precautions (5.10)] Status Epilepticus [see Warnings and Precautions (5.11)] Sudden Unexplained Death in Epilepsy [see Warnings and Precautions (5.12)] 6.1 Clinical Trial Experience with Lamotrigine Extended-Release for Treatment of Primary Generalized Tonic-Clonic and Partial-Onset Seizures Most Common Adverse Reactions in Clinical Trials: Adjunctive Therapy in Patients with Epilepsy: 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.

In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving lamotrigine extended-release.

Dizziness was the most common reason for withdrawal in the group receiving lamotrigine extended-release (5 patients [3%]).

The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus.

Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled trials of patients with PGTC and partial onset seizures.

Table 4 Adverse Reactions in Pooled, Placebo-Controlled, Adjunctive Trials in Patients with Epilepsya aAdverse reactions that occurred in at least 2% of patients treated with lamotrigine extended-release and at a greater incidence than placebo.

Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Extended-Release (n = 190) Percent of Patients Receiving Adjunctive Placebo (n = 195) Ear and labyrinth disorders Vertigo 3 <1 Eye disorders Diplopia Vision blurred 5 3 <1 2 Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Dry mouth 7 6 5 2 2 4 3 3 <1 1 General disorders and administration site conditions Asthenia and fatigue 6 4 Infections and infestations Sinusitis 2 1 Metabolic and nutritional disorders Anorexia 3 2 Musculoskeletal and connective tissue disorder Myalgia 2 0 Nervous system Dizziness Tremor and intention tremor Somnolence Cerebellar coordination and balance disorder Nystagmus 14 6 5 3 2 6 1 3 0 <1 Psychiatric disorders Depression Anxiety 3 3 <1 0 Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain 3 2 Vascular disorder Hot flush 2 0 Note: In these trials the incidence of nonserious rash was 2% for lamotrigine extended-release and 3% for placebo.

In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy [see BOXED WARNING].

Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase.

The incidence for many adverse reactions caused by treatment with lamotrigine extended-release was increased relative to placebo (i.e., treatment difference between lamotrigine extended-release and placebo ≥2%) in either the titration or maintenance phases of the trial.

During the titration phase, an increased incidence (shown in descending order of percent treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety.

During the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia.

Some adverse reactions developing in the titration phase were notable for persisting (>7 days) into the maintenance phase.

These persistent adverse reactions included somnolence and dizziness.

There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of adverse reactions because, although patients were randomized to different target doses based upon concomitant AEDs, the plasma exposure was expected to be generally similar among all patients receiving different doses.

However, in a randomized, parallel trial comparing placebo with 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions (>5%) such as ataxia, blurred vision, diplopia, and dizziness were dose related.

Less common adverse reactions (<5%) were not assessed for dose-response relationships.

Monotherapy in Patients with Epilepsy: Adverse reactions observed in this trial were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive lamotrigine extended-release placebo-controlled trials.

Only 2 adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of >3% and not reported at a similar rate in previous trials.

Because this trial did not include a placebo control group, causality could not be established [see Clinical Studies (14.3)].

6.2 Other Adverse Reactions Observed during the Clinical Development of Immediate-Release Lamotrigine Immediate-Release Lamotrigine All reported 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.

Adjunctive Therapy in Adults with Epilepsy: In addition to the adverse reactions reported above from the development of lamotrigine extended-release, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults.

These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Headache, flu syndrome, fever, neck pain.

Musculoskeletal: Arthralgia.

Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.

Respiratory: Pharyngitis, cough increased.

Skin and Appendages: Rash, pruritus.

Urogenital (female patients only): Vaginitis, amenorrhea, dysmenorrhea.

Monotherapy in Adults with Epilepsy: In addition to the adverse reactions reported above from the development of lamotrigine extended-release, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults.

These reactions occurred in >2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.

Body as a Whole: Chest pain.

Digestive: Rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Weight decrease, peripheral edema.

Nervous: Hypesthesia, libido increase, decreased reflexes.

Respiratory: Epistaxis, dyspnea.

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

Special Senses: Vision abnormality.

Urogenital (female patients only): Dysmenorrhea.

Other Clinical Trial Experience: Immediate-release 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.

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.

Cardiovascular System: Infrequent: Hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria.

Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.

Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration.

Rare: Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena, stomach ulcer.

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, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous contracture.

Nervous System: Frequent: Confusion.

Infrequent: Akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, stupor.

Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis, peripheral neuritis.

Respiratory System: 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, breast neoplasm, creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

6.3 Postmarketing Experience with Immediate-Release Lamotrigine The following adverse reactions have been identified during postapproval use of immediate-release 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: Hypogammaglobulinemia, 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.

Renal and Urinary Disorders: Tubulointerstitial nephritis (has been reported alone and in association with uveitis).