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adverse reactions
6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions ( 5.1 )] Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions ( 5.3 )] Neurotoxicity [see Warnings and Precautions ( 5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.5 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions ( 5.6 )] Anemia [see Warnings and Precautions ( 5.7 )] Somnolence and Fatigue [see Warnings and Precautions ( 5.8) ] Peripheral Neuropathy [see Warnings and Precautions ( 5.9 )] Weight Gain [see Warnings and Precautions ( 5.10) ] Edema [see Warnings and Precautions ( 5.11 )] Refractory Complex Partial Seizures Most common adverse reactions in controlled studies include (incidence ≥5% over placebo): Adults: blurred vision, somnolence, dizziness, abnormal coordination, tremor and fatigue ( 6.1 ) Pediatric patients (3 to 16 years of age): weight gain ( 6.1 ) Infantile Spasms (incidence >5% and greater than on placebo) Somnolence, bronchitis, ear infection, and acute otitis media ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact NaviSci Pte Ltd. at +65-65322122 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash. The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression. In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin-treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures Vigabatrin dosage (mg/day) Body System Adverse Reaction 3,000 [N=134] % 6,000 [N=43] % Placebo [N=135] % Ear Disorders Tinnitus 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract 7 9 6 Infection Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 3 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 2 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving vigabatrin or placebo as adjunctive therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of vigabatrin-treated patients and more frequently than placebo. The median vigabatrin dose was 49.4 mg/kg (range of 8 to 105.9 mg/kg). Table 6. Adverse Reactions in Pooled, Add-On Trials in Pediatric Patients 3 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All Vigabatrin [N=165] % Placebo [N=104] % Eye Disorders Diplopia 3 2 Blurred vision 2 0 Gastrointestinal Disorders Upper abdominal pain 4 3 Constipation 2 1 General Disorders Fatigue 10 7 Infections and Infestations Upper respiratory tract infection 15 11 Influenza 7 3 Otitis media 6 4 Streptococcal pharyngitis 4 3 Viral gastroenteritis 2 0 Investigations Weight gain 15 2 Nervous System Disorders Somnolence 6 5 Tremor 4 3 Nystagmus 4 2 Psychomotor hyperactivity 2 1 Psychiatric Disorders Abnormal behavior 7 6 Aggression 6 2 Disorientation 3 0 Safety of vigabatrin for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age. Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving vigabatrin and that occurred more frequently than in placebo patients were somnolence (vigabatrin 45%, placebo 30%), bronchitis (vigabatrin 30%, placebo 15%), ear infection (vigabatrin 10%, placebo 5%), and acute otitis media (vigabatrin 10%, placebo 0%). In a dose response study of low-dose (18 to 36 mg/kg/day) versus high-dose (100 to 148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 7. Table 7. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms Body System Adverse Reaction Vigabatrin Low Dose [N=114] % Vigabatrin High Dose [N=108] % Eye Disorders (other than field or acuity changes) Strabismus 5 5 Conjunctivitis 5 2 Gastrointestinal Disorders Vomiting 14 20 Constipation 14 12 Diarrhea 13 12 General Disorders Fever 29 19 Infections Upper respiratory tract infection 51 46 Otitis media 44 30 Viral infection 20 19 Pneumonia 13 11 Candidiasis 8 3 Ear infection 7 14 Gastroenteritis viral 6 5 Sinusitis 5 9 Urinary tract infection 5 6 Influenza 5 3 Croup infectious 5 1 Metabolism & Nutrition Disorders Decreased appetite 9 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 6 4 Lethargy 5 7 Convulsion 4 7 Hypotonia 4 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Respiratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11 6.2 Post Marketing Experience The following adverse reactions have been identified during post approval use of vigabatrin. 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 casual relationship to drug exposure. Adverse reactions are categorized by system organ class. Birth Defects : Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears , renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes Ear Disorders : Deafness Endocrine Disorders : Delayed puberty Gastrointestinal Disorders : Gastrointestinal hemorrhage, esophagitis General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure Hepatobiliary Disorders: Cholestasis Nervous System Disorders : Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia Psychiatric Disorders : Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia
adverse reactions
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash. The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression. In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin-treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures Vigabatrin dosage (mg/day) Body System Adverse Reaction 3,000 [N=134] % 6,000 [N=43] % Placebo [N=135] % Ear Disorders Tinnitus 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract 7 9 6 Infection Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 3 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 2 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving vigabatrin or placebo as adjunctive therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of vigabatrin-treated patients and more frequently than placebo. The median vigabatrin dose was 49.4 mg/kg (range of 8 to 105.9 mg/kg). Table 6. Adverse Reactions in Pooled, Add-On Trials in Pediatric Patients 3 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All Vigabatrin [N=165] % Placebo [N=104] % Eye Disorders Diplopia 3 2 Blurred vision 2 0 Gastrointestinal Disorders Upper abdominal pain 4 3 Constipation 2 1 General Disorders Fatigue 10 7 Infections and Infestations Upper respiratory tract infection 15 11 Influenza 7 3 Otitis media 6 4 Streptococcal pharyngitis 4 3 Viral gastroenteritis 2 0 Investigations Weight gain 15 2 Nervous System Disorders Somnolence 6 5 Tremor 4 3 Nystagmus 4 2 Psychomotor hyperactivity 2 1 Psychiatric Disorders Abnormal behavior 7 6 Aggression 6 2 Disorientation 3 0 Safety of vigabatrin for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age. Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving vigabatrin and that occurred more frequently than in placebo patients were somnolence (vigabatrin 45%, placebo 30%), bronchitis (vigabatrin 30%, placebo 15%), ear infection (vigabatrin 10%, placebo 5%), and acute otitis media (vigabatrin 10%, placebo 0%). In a dose response study of low-dose (18 to 36 mg/kg/day) versus high-dose (100 to 148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 7. Table 7. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms Body System Adverse Reaction Vigabatrin Low Dose [N=114] % Vigabatrin High Dose [N=108] % Eye Disorders (other than field or acuity changes) Strabismus 5 5 Conjunctivitis 5 2 Gastrointestinal Disorders Vomiting 14 20 Constipation 14 12 Diarrhea 13 12 General Disorders Fever 29 19 Infections Upper respiratory tract infection 51 46 Otitis media 44 30 Viral infection 20 19 Pneumonia 13 11 Candidiasis 8 3 Ear infection 7 14 Gastroenteritis viral 6 5 Sinusitis 5 9 Urinary tract infection 5 6 Influenza 5 3 Croup infectious 5 1 Metabolism & Nutrition Disorders Decreased appetite 9 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 6 4 Lethargy 5 7 Convulsion 4 7 Hypotonia 4 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Respiratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11
adverse reactions
6.2 Post Marketing Experience The following adverse reactions have been identified during post approval use of vigabatrin. 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 casual relationship to drug exposure. Adverse reactions are categorized by system organ class. Birth Defects : Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears , renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes Ear Disorders : Deafness Endocrine Disorders : Delayed puberty Gastrointestinal Disorders : Gastrointestinal hemorrhage, esophagitis General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure Hepatobiliary Disorders: Cholestasis Nervous System Disorders : Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia Psychiatric Disorders : Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia
adverse reactions table
<table width="640px" border="1" cellspacing="3" cellpadding="3"><caption>Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures</caption><colgroup><col width="40%"/><col width="20%"/><col width="20%"/><col width="20%"/></colgroup><thead><tr><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Lrule Rrule" colspan="3"><content styleCode="bold">Vigabatrin dosage (mg/day)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule"><content styleCode="bold">Body System</content> Adverse Reaction</td><td styleCode="Botrule Lrule Rrule" align="center"><content styleCode="bold">3,000 [N=134] %</content></td><td styleCode="Botrule Lrule Rrule" align="center"><content styleCode="bold">6,000 [N=43] %</content></td><td styleCode="Botrule Lrule Rrule" align="center"><content styleCode="bold">Placebo [N=135] %</content></td></tr></thead><tbody align="center"><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Ear Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Tinnitus</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Vertigo</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Eye Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Blurred vision</td><td styleCode="Botrule Lrule Rrule" align="center">13</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Diplopia</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Asthenopia</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Eye pain</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Diarrhea</td><td styleCode="Botrule Lrule Rrule" align="center">10</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Nausea</td><td styleCode="Botrule Lrule Rrule" align="center">10</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">8</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Vomiting</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Constipation</td><td styleCode="Botrule Lrule Rrule" align="center">8</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Upper abdominal pain</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Dyspepsia</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Stomach discomfort</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abdominal pain</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Toothache</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abdominal distension</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">General Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Fatigue</td><td styleCode="Botrule Lrule Rrule" align="center">23</td><td styleCode="Botrule Lrule Rrule" align="center">40</td><td styleCode="Botrule Lrule Rrule" align="center">16</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Gait disturbance</td><td styleCode="Botrule Lrule Rrule" align="center">6</td><td styleCode="Botrule Lrule Rrule" align="center">12</td><td styleCode="Botrule Lrule Rrule" align="center">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Asthenia</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Edema peripheral</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Fever</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Chest pain</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Thirst</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Malaise</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Infections</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Nasopharyngitis</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">10</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Upper respiratory tract</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Infection</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Influenza</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">4</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Urinary tract infection</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Bronchitis</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Injury</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Contusion</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Joint sprain</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Muscle strain</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Wound secretion</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Increased appetite</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Weight gain</td><td styleCode="Botrule Lrule Rrule" align="center">6</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Musculoskeletal Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Arthralgia</td><td styleCode="Botrule Lrule Rrule" align="center">10</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Back pain</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Pain in extremity</td><td styleCode="Botrule Lrule Rrule" align="center">6</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">4</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Myalgia</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Muscle twitching</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Muscle spasms</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Headache</td><td styleCode="Botrule Lrule Rrule" align="center">33</td><td styleCode="Botrule Lrule Rrule" align="center">26</td><td styleCode="Botrule Lrule Rrule" align="center">31</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Somnolence</td><td styleCode="Botrule Lrule Rrule" align="center">22</td><td styleCode="Botrule Lrule Rrule" align="center">26</td><td styleCode="Botrule Lrule Rrule" align="center">13</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Dizziness</td><td styleCode="Botrule Lrule Rrule" align="center">24</td><td styleCode="Botrule Lrule Rrule" align="center">26</td><td styleCode="Botrule Lrule Rrule" align="center">17</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Nystagmus</td><td styleCode="Botrule Lrule Rrule" align="center">13</td><td styleCode="Botrule Lrule Rrule" align="center">19</td><td styleCode="Botrule Lrule Rrule" align="center">9</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Tremor</td><td styleCode="Botrule Lrule Rrule" align="center">15</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">8</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Memory impairment</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abnormal coordination</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">16</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Disturbance in attention</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Sensory disturbance</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Hyporeflexia</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Paraesthesia</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Lethargy</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Hyperreflexia</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Hypoaesthesia</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Sedation</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Status epilepticus</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Dysarthria</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Postictal state</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Sensory loss</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Irritability</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">23</td><td styleCode="Botrule Lrule Rrule" align="center">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Depression</td><td styleCode="Botrule Lrule Rrule" align="center">6</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Confusional state</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Anxiety</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Depressed mood</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abnormal thinking</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abnormal behavior</td><td styleCode="Botrule Lrule Rrule" align="center">3</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Expressive language disorder</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Nervousness</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Abnormal dreams</td><td styleCode="Botrule Lrule Rrule" align="center">1</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Reproductive System</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Dysmenorrhea</td><td styleCode="Botrule Lrule Rrule" align="center">9</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Erectile dysfunction</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Respiratory and Thoracic Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Pharyngolaryngeal pain</td><td styleCode="Botrule Lrule Rrule" align="center">7</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Cough</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">14</td><td styleCode="Botrule Lrule Rrule" align="center">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Pulmonary congestion</td><td styleCode="Botrule Lrule Rrule" align="center">0</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Sinus headache</td><td styleCode="Botrule Lrule Rrule" align="center">6</td><td styleCode="Botrule Lrule Rrule" align="center">2</td><td styleCode="Botrule Lrule Rrule" align="center">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left">Rash</td><td styleCode="Botrule Lrule Rrule" align="center">4</td><td styleCode="Botrule Lrule Rrule" align="center">5</td><td styleCode="Botrule Lrule Rrule" align="center">4</td></tr></tbody></table>