FDA label 3b150fff-e0b3-e5ab-e063-6394a90aaa26

WARNING: SERIOUS SKIN RASHES Lamotrigine tablets 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 tablets. 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 tablets 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 tablets. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine tablets with valproate (includes valproic acid and divalproex sodium), (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. Nearly all cases of life-threatening rashes caused by lamotrigine tablets 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 tablets, it is not possible to predict reliably which rashes will prove to be serious or life threatening. Accordingly, lamotrigine tablets 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) ]. WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed warning. • Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include: • coadministration with valproate. • exceeding recommended initial dose of lamotrigine tablets. • exceeding recommended dose escalation for lamotrigine tablets ( 5.1 ) • Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life-threatening. Lamotrigine tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug related. ( 5.1 )

5.9 Concomitant Use with Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3) ] . Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine tablets [see Dosage and Administration (2.1) ] . During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

5.10 Withdrawal Seizures As with other AEDs, lamotrigine tablets should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine tablets should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1) ] ;

5.11 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made.

5.12 Sudden Unexplained Death in Epilepsy (SUDEP) During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).; Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving lamotrigine tablets and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

6 ADVERSE REACTIONS 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 [see Warnings and Precautions (5.12) ] • 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. (6.1) • Bipolar disorder : Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Limited, at 888-413-0949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 tablets and more common on drug than placebo) adverse reactions seen in association with lamotrigine tablets 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 tablets than in patients receiving other AEDs with lamotrigine tablets. 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 tablets 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 tablets for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine tablets and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine tablets 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 tablets and more common on drug than placebo) adverse reactions associated with the use of lamotrigine tablets 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 tablets 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 tablets and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine tablets 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 tablets and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine tablets was rash.; Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine tablets 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 tablets in placebo-controlled trials. In these trials, either lamotrigine tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Tablets (n=711) Percent of Patients Receiving Adjunctive Placebo (n-419) Body as a whole ;Headache 29 19 ;Flu syndrome 7 6 ;Fever 6 4 ;Abdominal pain 5 4 ;Neck pain 2 1 ;Reaction aggravated (seizure exacerbation) 2 1 Digestive ;Nausea 19 10 ;Vomiting 9 4 ;Diarrhea 6 4 ;Dyspepsia 5 2 ;Constipation 4 3 ;Anorexia 2 1 Musculoskeletal ;Arthralgia 2 0 Nervous ;Dizziness 38 13 ;Ataxia 22 6 ;Somnolence 14 7 ;Incoordination 6 2 ;Insomnia 6 2 ;Tremor 4 1 ;Depression 4 3 ;Anxiety 4 3 ;Convulsion 3 1 ;Irritability 3 2 ;Speech disorder 3 0 ;Concentration disturbance 2 1 Respiratory ;Rhinitis 14 9 ;Pharyngitis 10 9 ;Cough increased 8 6 Skin and appendages ;Rash 10 5 ;Pruritus 3 2 Special senses ;Diplopia 28 7 ;Blurred vision 16 5 ;Vision abnormality 3 1 Urogenital ;Female patients only (n = 365) (n = 207) ;Dysmenorrhea 7 6 ;Vaginitis 4 1 ;Amenorrhea 2 1 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. In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine tablets, 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 Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo (n=73) Lamotrigine Tablets 300 mg (n=71) Lamotrigine Tablets 500 mg (n=72) Ataxia 10 10 28 a, b Blurred vision 10 11 25 a, b Diplopia 8 24 a 49 a, b Dizziness 27 31 54 a, b Nausea 11 18 25 a Vomiting 4 11 18 a a Significantly greater than placebo group ( P <0.05). b Significantly greater than group receiving lamotrigine tablets 300 mg ( P <0.05). The overall adverse reaction profile for lamotrigine tablets 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 tablets 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 tablets as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine tablets were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of lamotrigine tablets 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 tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Lamotrigine Tablets c as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate d Monotherapy (n = 44) Body as a whole ;Pain 5 0 ;Infection 5 2 ;Chest pain 5 2 Digestive ;Vomiting 9 0 ;Dyspepsia 7 2 ;Nausea 7 2 Metabolic and nutritional ;Weight decrease 5 2 Nervous ;Coordination abnormality 7 0 ;Dizziness 7 0 ;Anxiety 5 0 ;Insomnia 5 2 Respiratory ;Rhinitis 7 2 Urogenital (female patients only) (n = 21) (n = 28) ;Dysmenorrhea 5 0 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. Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving lamotrigine tablets 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 tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Lamotrigine Tablets (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole ;Infection 20 17 ;Fever 15 14 ;Accidental injury 14 12 ;Abdominal pain 10 5 ;Asthenia 8 4 ;Flu syndrome 7 6 ;Pain 5 4 ;Facial edema 2 1 ;Photosensitivity 2 0 Cardiovascular ;Hemorrhage 2 1 Digestive ;Vomiting 20 16 ;Diarrhea 11 9 ;Nausea 10 2 ;Constipation 4 2 ;Dyspepsia 2 1 Hemic and lymphatic ;Lymphadenopathy 2 1 Metabolic and nutritional ;Edema 2 0 Nervous system ;Somnolence 17 15 ;Dizziness 14 4 ;Ataxia 11 3 ;Tremor 10 1 ;Emotional lability 4 2 ;Gait abnormality 4 2 ;Thinking abnormality 3 2 ;Convulsions 2 1 ;Nervousness 2 1 ;Vertigo 2 1 Respiratory ;Pharyngitis 14 11 ;Bronchitis 7 5 ;Increased cough 7 6 ;Sinusitis 2 1 ;Bronchospasm 2 1 Skin ;Rash 14 12 ;Eczema 2 1 ;Pruritus 2 1 Special senses ;Diplopia 5 1 ;Blurred vision 4 1 ;Visual abnormality 2 0 Urogenital Male and female patients Urinary tract infection 3 0 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine tablets and at a greater incidence than placebo. Bipolar Disorder in Adults The most common adverse reactions seen in association with the use of lamotrigine tablets 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 tablets 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 tablets (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 tablets were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine tablets (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 tablets 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 Lamotrigine Tablets (n = 227) Percent of Patients Receiving Placebo (n = 190) General ;Back pain 8 6 ;Fatigue 8 5 ;Abdominal pain 6 3 Digestive ;Nausea 14 11 ;Constipation 5 2 ;Vomiting 5 2 Nervous System ;Insomnia 10 6 ;Somnolence 9 7 ;Xerostomia (dry mouth) 6 4 Respiratory ;Rhinitis 7 4 ;Exacerbation of cough 5 3 ;Pharyngitis 5 4 Skin ;Rash (nonserious) c 7 5 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine tablets and at a greater incidence than placebo. b Patients in these trials were converted to lamotrigine tablets (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 lamotrigine tablets as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine tablets 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 tablets 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 tablets. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets [ see Warnings and Precautions (5.10) ] ; 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 tablets (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 tablets (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 tablets (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 tablets have 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 tablets who experienced an event of the type cited on at least 1 occasion while receiving lamotrigine tablets. 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, and 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 tablets. 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).

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 tablets and more common on drug than placebo) adverse reactions seen in association with lamotrigine tablets 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 tablets than in patients receiving other AEDs with lamotrigine tablets. 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 tablets 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 tablets for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. Monotherapy in Adults with Epilepsy: The most commonly observed (≥5% for lamotrigine tablets and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine tablets 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 tablets and more common on drug than placebo) adverse reactions associated with the use of lamotrigine tablets 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 tablets 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 tablets and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine tablets 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 tablets and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine tablets was rash.; Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine tablets 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 tablets in placebo-controlled trials. In these trials, either lamotrigine tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine Tablets (n=711) Percent of Patients Receiving Adjunctive Placebo (n-419) Body as a whole ;Headache 29 19 ;Flu syndrome 7 6 ;Fever 6 4 ;Abdominal pain 5 4 ;Neck pain 2 1 ;Reaction aggravated (seizure exacerbation) 2 1 Digestive ;Nausea 19 10 ;Vomiting 9 4 ;Diarrhea 6 4 ;Dyspepsia 5 2 ;Constipation 4 3 ;Anorexia 2 1 Musculoskeletal ;Arthralgia 2 0 Nervous ;Dizziness 38 13 ;Ataxia 22 6 ;Somnolence 14 7 ;Incoordination 6 2 ;Insomnia 6 2 ;Tremor 4 1 ;Depression 4 3 ;Anxiety 4 3 ;Convulsion 3 1 ;Irritability 3 2 ;Speech disorder 3 0 ;Concentration disturbance 2 1 Respiratory ;Rhinitis 14 9 ;Pharyngitis 10 9 ;Cough increased 8 6 Skin and appendages ;Rash 10 5 ;Pruritus 3 2 Special senses ;Diplopia 28 7 ;Blurred vision 16 5 ;Vision abnormality 3 1 Urogenital ;Female patients only (n = 365) (n = 207) ;Dysmenorrhea 7 6 ;Vaginitis 4 1 ;Amenorrhea 2 1 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. In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine tablets, 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 Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo (n=73) Lamotrigine Tablets 300 mg (n=71) Lamotrigine Tablets 500 mg (n=72) Ataxia 10 10 28 a, b Blurred vision 10 11 25 a, b Diplopia 8 24 a 49 a, b Dizziness 27 31 54 a, b Nausea 11 18 25 a Vomiting 4 11 18 a a Significantly greater than placebo group ( P <0.05). b Significantly greater than group receiving lamotrigine tablets 300 mg ( P <0.05). The overall adverse reaction profile for lamotrigine tablets 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 tablets 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 tablets as adjunctive therapy or placebo were more likely to report adverse reactions than males. The only adverse reaction for which the reports on lamotrigine tablets were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of lamotrigine tablets 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 tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Lamotrigine Tablets c as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate d Monotherapy (n = 44) Body as a whole ;Pain 5 0 ;Infection 5 2 ;Chest pain 5 2 Digestive ;Vomiting 9 0 ;Dyspepsia 7 2 ;Nausea 7 2 Metabolic and nutritional ;Weight decrease 5 2 Nervous ;Coordination abnormality 7 0 ;Dizziness 7 0 ;Anxiety 5 0 ;Insomnia 5 2 Respiratory ;Rhinitis 7 2 Urogenital (female patients only) (n = 21) (n = 28) ;Dysmenorrhea 5 0 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. Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving lamotrigine tablets 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 tablets 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 Body System/Adverse Reaction Percent of Patients Receiving Lamotrigine Tablets (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole ;Infection 20 17 ;Fever 15 14 ;Accidental injury 14 12 ;Abdominal pain 10 5 ;Asthenia 8 4 ;Flu syndrome 7 6 ;Pain 5 4 ;Facial edema 2 1 ;Photosensitivity 2 0 Cardiovascular ;Hemorrhage 2 1 Digestive ;Vomiting 20 16 ;Diarrhea 11 9 ;Nausea 10 2 ;Constipation 4 2 ;Dyspepsia 2 1 Hemic and lymphatic ;Lymphadenopathy 2 1 Metabolic and nutritional ;Edema 2 0 Nervous system ;Somnolence 17 15 ;Dizziness 14 4 ;Ataxia 11 3 ;Tremor 10 1 ;Emotional lability 4 2 ;Gait abnormality 4 2 ;Thinking abnormality 3 2 ;Convulsions 2 1 ;Nervousness 2 1 ;Vertigo 2 1 Respiratory ;Pharyngitis 14 11 ;Bronchitis 7 5 ;Increased cough 7 6 ;Sinusitis 2 1 ;Bronchospasm 2 1 Skin ;Rash 14 12 ;Eczema 2 1 ;Pruritus 2 1 Special senses ;Diplopia 5 1 ;Blurred vision 4 1 ;Visual abnormality 2 0 Urogenital Male and female patients Urinary tract infection 3 0 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine tablets and at a greater incidence than placebo. Bipolar Disorder in Adults The most common adverse reactions seen in association with the use of lamotrigine tablets 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 tablets 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 tablets (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 tablets were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine tablets (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 tablets 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 Lamotrigine Tablets (n = 227) Percent of Patients Receiving Placebo (n = 190) General ;Back pain 8 6 ;Fatigue 8 5 ;Abdominal pain 6 3 Digestive ;Nausea 14 11 ;Constipation 5 2 ;Vomiting 5 2 Nervous System ;Insomnia 10 6 ;Somnolence 9 7 ;Xerostomia (dry mouth) 6 4 Respiratory ;Rhinitis 7 4 ;Exacerbation of cough 5 3 ;Pharyngitis 5 4 Skin ;Rash (nonserious) c 7 5 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine tablets and at a greater incidence than placebo. b Patients in these trials were converted to lamotrigine tablets (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 lamotrigine tablets as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received lamotrigine tablets 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 tablets 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 tablets. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine tablets [ see Warnings and Precautions (5.10) ] ; 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 tablets (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 tablets (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 tablets (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 tablets have 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 tablets who experienced an event of the type cited on at least 1 occasion while receiving lamotrigine tablets. 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, and 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 tablets. 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).