Lamotrigineside effects

Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor.

Bipolar disorder: Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. To report SUSPECTED ADVERSE REACTIONS, contact OWP Pharmaceuticals Inc. at 1-800-273-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes Hemophagocytic Lymphohistiocytosis Multiorgan Hypersensitivity Reactions and Organ Failure Cardiac Rhythm and Conduction Abnormalities Blood Dyscrasias Suicidal Behavior and Ideation Aseptic Meningitis Withdrawal Seizures Status Epilepticus

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 SUBVENITE and more common on drug than placebo) adverse reactions seen in association with SUBVENITE 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 SUBVENITE than in patients receiving other AEDs with SUBVENITE. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate. Approximately 11% of the 3,378 adult patients who received SUBVENITE 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 SUBVENITE for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for SUBVENITE and more common on drug than placebo) adverse reactions seen in association with the use of SUBVENITE 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 SUBVENITE and more common on drug than placebo) adverse reactions associated with the use of SUBVENITE 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 SUBVENITE 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 SUBVENITE and more common on drug than placebo) adverse reactions seen in association with the use of SUBVENITE 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 SUBVENITE and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of SUBVENITE was rash. Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received SUBVENITE 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 SUBVENITE in placebo-controlled trials. In these trials, either SUBVENITE 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 SUBVENITE and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant AEDs carbamazepine, phenytoin, phenobarbital, or primidone in addition to SUBVENITE 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 SUBVENITE ( 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 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 Pruritus 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 SUBVENITE, 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 SUBVENITE 300 mg ( P <0.05). Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo ( n = 73 ) SUBVENITE 300 mg ( n = 71 ) SUBVENITE 500 mg ( n = 72 ) Ataxia Blurred vision Diplopia Dizziness Nausea Vomiting 10 10 8 27 11 4 10 11 24 a 31 18 11 28 a, b 25 a, b 49 a, b 54 a, b 25 a 18 a The overall adverse reaction profile for SUBVENITE 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 SUBVENITE 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 SUBVENITE as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on SUBVENITE 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 SUBVENITE 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 SUBVENITE 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 Seizures a, b a Adverse reactions that occurred in at least 5% of patients treated with SUBVENITE and at a greater incidence than valproate-treated patients. b Patients in this trial were converted to SUBVENITE 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 SUBVENITE c as Monotherapy ( n = 43 ) Percent of Patients Receiving Low - Dose Valproate d 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 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 SUBVENITE 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 SUBVENITE 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 Epilepsy a a Adverse reactions that occurred in at least 2% of patients treated with SUBVENITE and at a greater incidence than placebo. Body System / Adverse Reaction Percent of Patients Receiving SUBVENITE ( 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 SUBVENITE 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 SUBVENITE 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 SUBVENITE (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 SUBVENITE were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received SUBVENITE (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 SUBVENITE 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 Disorder a, b Body System / Adverse Reaction Percent of Patients Receiving SUBVENITE ( 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 a Adverse reactions that occurred in at least 5% of patients treated with SUBVENITE and at a greater incidence than placebo. b Patients in these trials were converted to SUBVENITE (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. c In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received SUBVENITE as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received SUBVENITE as adjunctive therapy. 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 <5% and >1% of patients receiving SUBVENITE 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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE.

Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with SUBVENITE (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 SUBVENITE (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 SUBVENITE (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 SUBVENITE 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 SUBVENITE who experienced an event of the type cited on at least 1 occasion while receiving SUBVENITE. 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 SUBVENITE. 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, pseudolymphoma. 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). Skin and Subcutaneous Tissue Disorders Photosensitivity reaction.