1.

INDICATIONS AND USAGE Lamotrigine tablets is an antiepileptic drug (AED) indicated for: Epilepsy — adjunctive therapy in patients ≥2 years of age: ( 1.1 ) • partial seizures • primary generalized tonic-clonic seizures • generalized seizures of Lennox-Gastaut syndrome Epilepsy—monotherapy in patients ≥ 16 years of age: conversion to monotherapy in patients with partial seizures who are receiving treatment with carbamazepine, phenobarbital, phenytoin, primidone, or valproate as the single AED.

( 1.1 ) Bipolar Disorder in patients ≥ 18 years of age: maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy.

( 1.2 ) 1.1 Epilepsy Adjunctive Therapy: Lamotrigine tablets are indicated as adjunctive therapy for the following seizure types in patients ≥ 2 years of age: • partial seizures • primary generalized tonic-clonic seizures • generalized seizures of Lennox-Gastaut syndrome Monotherapy: Lamotrigine tablets are indicated for conversion to monotherapy in adults (≥16 years of age) with partial 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 adults (≥18 years of age) treated for acute mood episodes with standard therapy.

The effectiveness of lamotrigine tablets in the acute treatment of mood episodes has not been established.

The effectiveness of lamotrigine tablets as maintenance treatment was established in 2 placebo-controlled trials in patients with Bipolar I Disorder as defined by DSM-IV [see Clinical Studies (14.2 )].

The physician who elects to prescribe lamotrigine tablets for periods extending beyond 16 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

6.

ADVERSE REACTIONS • Most common adverse reactions (incidence ≥10%) in adult epilepsy clinical studies were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, and rash.

Additional adverse reactions (incidence ≥10%) reported in children in epilepsy clinical studies included vomiting, infection, fever, accidental injury, pharyngitis, abdominal pain, and tremor.

( 6.1 ) • Most common adverse reactions (incidence >5%) in adult bipolar clinical studies were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, CONTACT Unichem Pharmaceuticals (USA), Inc.

at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: • Serious skin rashes [see Warnings and Precautions (5.1) ] • Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2) ] • Blood dyscrasias [see Warnings and Precautions (5.3) ] • Suicidal behavior and ideation [see Warnings and Precautions (5.4) ] • 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 Trials 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.

Lamotrigine has been evaluated for safety in patients with epilepsy and in patients with Bipolar I Disorder.

Adverse reactions reported for each of these patient populations are provided below.

Excluded are adverse reactions considered too general to be informative and those not reasonably attributable to the use of the drug.

Epilepsy: Most Common Adverse Reactions in All Clinical Studies: 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 study in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose-related.

Monotherapy in Adults With Epilepsy: The most commonly observed (≥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 2 to 16 years of age 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 2 to 16 years of age with partial seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on lamotrigine and 2.9% of patients on placebo discontinued due to adverse reactions.

The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash.

Approximately 11.5% of the 1,081 pediatric patients 2 to 16 years of age 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 Studies in Adults With Epilepsy: Table 8 lists treatment-emergent adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with lamotrigine in placebo-controlled trials and were numerically more common in the patients treated with lamotrigine.

In these studies, either lamotrigine or placebo was added to the patient's current AED therapy.

Adverse reactions were usually mild to moderate in intensity.

Table 8.

Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy a (Adverse reactions in at least 2% of patients treated with lamotrigine and numerically more frequent than in the placebo group.) Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419) a Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to lamotrigine or placebo.

Patients may have reported multiple adverse reactions during the study or at discontinuation; thus, patients may be included in more than one category.

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 In a randomized, parallel study comparing placebo and 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 Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72) a Significantly greater than placebo group (p<0.05).

b Significantly greater than group receiving lamotrigine 300 mg (p<0.05).

Ataxia 10 10 28 ab Blurred vision 10 11 25 ab Diplopia 8 24 a 49 ab Dizziness 27 31 54 ab Nausea 11 18 25 a Vomiting 4 11 18 a 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 greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%).

There was little difference between females and males in the rates of discontinuation of lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults With Partial Seizures: Table 10 lists treatment-emergent adverse reactions that occurred in at least 5% of patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 10.

Treatment-Emergent Adverse Reaction Incidence in Adults With Partial Seizures in a Controlled Monotherapy Trial a (Adverse reactions in at least 5% of patients treated with lamotrigine and numerically more frequent than in the valproate group.) Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine as Monotherapy b (n = 43) Percent of Patients Receiving Low-Dose Valproate c Monotherapy (n = 44) a Patients in these studies were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin.

Patients may have reported multiple adverse reactions during the study; thus, patients may be included in more than one category.

b Up to 500 mg/day.

c 1,000 mg/day.

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 Adverse reactions that occurred with a frequency of less than 5% and greater than 2% of patients receiving lamotrigine and numerically more frequent than placebo were: Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

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

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 11 lists adverse reactions that occurred in at least 2% of 339 pediatric patients with partial seizures or generalized seizures of Lennox-Gastaut syndrome, who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day.

Reported adverse reactions were classified using COSTART terminology.

Table 11.

Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Adjunctive Trials in Pediatric Patients With Epilepsy (Adverse reactions in at least 2% of patients treated with lamotrigine and numerically more frequent than in the placebo group.) Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (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 Bipolar Disorder: The most commonly observed (≥5%) treatment-emergent adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (≥18 years of age) with Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration, and numerically more frequent than in placebo-treated patients are included in Table 12.

Adverse reactions that occurred in at least 5% of patients and were numerically more common during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared 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 which 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.

Treatment-Emergent Adverse Reaction Incidence in Two Placebo-Controlled Trials in Adults With Bipolar I Disorder a (Adverse reactions in at least 5% of patients treated with lamotrigine as monotherapy and numerically more frequent than in the placebo group.) Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 227) Percent of Patients Receiving Placebo (n = 190) a Patients in these studies 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 study; thus, patients may be included in more than one category.

b 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 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) ].

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) b 7 5 These adverse reactions were usually mild to moderate in intensity.

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 two maintenance trials, there was no increase in the incidence, severity or type of adverse reactions in Bipolar Disorder patients after abruptly terminating therapy with lamotrigine.

In clinical trials in patients with Bipolar Disorder, two patients experienced seizures shortly after abrupt withdrawal of lamotrigine.

However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients [see Warnings and Precautions (5.9) ].

Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients 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 one 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, and malaise.

Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria.

Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, and vesiculobullous rash.

Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration.

Rare: Gatrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, and tongue edema.

Endocrine System: Rare: Goiter and hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia.

Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.

Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.

Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching.

Rare: Bursitis, muscle atrophy, pathological fracture, and tendinous contracture.

Nervous System: Frequent: Confusion and paresthesia.

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

Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.

Respiratory System: Infrequent: Yawn.

Rare: Hiccup and hyperventilation.

Special Senses: Frequent: Amblyopia.

Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus.

Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.

Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, and 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, and urinary urgency.

6.3 Post-marketing Experience The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during post-approval use of lamotrigine.

Because these events 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.

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.

Neurology: Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.

Non-site Specific: Progressive immunosuppression.