VIGAFYDE

WARNING: PERMANENT VISION LOSS VIGAFYDE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGAFYDE also can damage the central retina and may decrease visual acuity [see Warnings and Precautions ( 5.1 )]. The onset of vision loss from VIGAFYDE is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years. Symptoms of vision loss from VIGAFYDE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function. The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. Vision assessment is recommended at baseline (no later than 4 weeks after starting VIGAFYDE), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of therapy. Once detected, vision loss due to VIGAFYDE is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. Risk of new or worsening vision loss continues as long as VIGAFYDE is used. It is possible that vision loss can worsen despite discontinuation of VIGAFYDE. Because of the risk of vision loss, VIGAFYDE should be withdrawn from patients with infantile spasms who fail to show substantial clinical benefit within 2 to 4 weeks of initiation, or sooner if treatment failure becomes obvious. Patient response to and continued need for VIGAFYDE should be periodically reassessed. VIGAFYDE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. VIGAFYDE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks. Use the lowest dosage and shortest exposure to VIGAFYDE consistent with clinical objectives [see Dosage and Administration ( 2.1 )]. Because of the risk of permanent vision loss, VIGAFYDE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS [see Warnings and Precautions ( 5.1 ) ] . Further information is available at www.vigabatrinREMS.com or call 1 -866-244-8175. WARNING: PERMANENT VISION LOSS See full prescribing information for complete boxed warning. VIGAFYDE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGAFYDE may also decrease visual acuity. ( 5.1 ) Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to VIGAFYDE known to be free of risk of vision loss. ( 5.1 ) Risk of new and worsening vision loss continues as long as VIGAFYDE is used, and possibly after discontinuing VIGAFYDE. ( 5.1 ) Baseline and periodic vision assessment is recommended for patients on VIGAFYDE. However, this assessment cannot always prevent vision damage. ( 5.1 ) VIGAFYDE is available only through a restricted program called the Vigabatrin REMS. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with infantile spasms receiving VIGAFYDE. ( 5.3 , 5.4 ) Withdrawal of AEDs: Taper dose to avoid withdrawal seizures. ( 5.5 ) Anemia: Monitor for symptoms of anemia. ( 5.6 ) 5.1 Permanent Vision Loss VIGAFYDE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGAFYDE provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed. VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in pediatric patients older than 2 years of age or in adults. Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, VIGAFYDE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGAFYDE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function. Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from VIGAFYDE may be more common, more severe, or have more severe functional consequences in infants than in adults cannot be excluded. The onset of vision loss from VIGAFYDE is unpredictable and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years. The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. In patients with infantile spasms, VIGAFYDE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.5 )]. VIGAFYDE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from VIGAFYDE has not been well-characterized, but is likely adverse. VIGAFYDE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks. Monitoring of Vision Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is recommended [see Warnings and Precautions ( 5.2 )]. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving VIGAFYDE, vision assessment is recommended at baseline (no later than 4 weeks after starting VIGAFYDE), at least every 3 months while on therapy, and about 3 to 6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation. In cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient. In patients who cannot be tested, treatment may continue according to clinical judgment, with appropriate caregiver counseling. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient. The onset and progression of vision loss from VIGAFYDE is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to VIGAFYDE is not reversible. It is expected that even with frequent monitoring, some VIGAFYDE patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. It is possible that vision loss can worsen despite discontinuation of VIGAFYDE. 5.2 Vigabatrin REMS VIGAFYDE is available only through a restricted distribution program called the Vigabatrin REMS, because of the risk of permanent vision loss. Notable requirements of the Vigabatrin REMS include the following: Prescribers must be certified by enrolling in the program, agreeing to counsel caregivers on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to the REMS program. Patients must enroll in the program. Pharmacies must be certified and must only dispense to patients authorized to receive VIGAFYDE. Further information is available at www.vigabatrinREMS.com or by calling 1-866-244-8175. 5.3 Magnetic Resonance Imaging Abnormalities in Infants Abnormal magnetic resonance imaging (MRI) signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin. In a retrospective epidemiologic study in infants with infantile spasms (N=205), the prevalence of MRI changes was 22% in vigabatrin-treated patients versus 4% in patients treated with other therapies. In this study, in postmarketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied. Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.1 )] . 5.4 Neurotoxicity Intramyelinic Edema (IME) has been reported in postmortem examination of infants being treated for infantile spasms with vigabatrin. Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have also been observed in some infants treated for IS with vigabatrin [see Warnings and Precautions ( 5.3 )] . Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory EP. Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin-treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants [see Use in Specific Populations ( 8.4 )] . In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5 to 7. 5.5 Withdrawal of Antiepileptic Drugs As with all antiepileptic drugs, VIGAFYDE should be withdrawn gradually [see Dosage and Administration ( 2.4 )] . However, if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered. Caregivers should be told not to suddenly discontinue VIGAFYDE therapy. 5.6 Anemia Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in vigabatrin and placebo-treated patients, respectively, and a mean decrease in hematocrit of about 1% in vigabatrin-treated patients compared to a mean gain of about 1% in patients treated with placebo. In controlled and open-label epilepsy trials in adults and pediatric patients, 3 vigabatrin patients (0.06%, 3/4,855) discontinued for anemia and 2 vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%. 5.7 Somnolence and Fatigue VIGAFYDE causes somnolence and fatigue. Pooled data from three vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No vigabatrin patients discontinued from clinical trials due to somnolence or fatigue. VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adults. Pooled data from two vigabatrin controlled trials in adults demonstrated that 24% (54/222) of vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue. 5.8 Peripheral Neuropathy VIGAFYDE is indicated for treatment in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adults. Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy, but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms was related to duration of vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of vigabatrin. 5.9 Weight Gain VIGAFYDE causes weight gain in pediatric patients. Data pooled from randomized controlled trials in pediatric patients with a different indication found that 47% (77/163) of vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight. In all epilepsy trials, 0.6% (31/4,855) of VIGAFYDE patients discontinued for weight gain. The long-term effects of vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema. 5.10 Edema VIGAFYDE is approved for use in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adults. Vigabatrin causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema-based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. Pooled data from controlled trials demonstrated increased risk among patients treated with vigabatrin powder for oral solution compared to placebo patients for peripheral edema (vigabatrin powder for oral solution 2%, placebo 1%), and edema (vigabatrin powder for oral solution 1%, placebo 0%). In these studies, one patient treated with vigabatrin powder for oral solution and no placebo patients discontinued for an edema related adverse event. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. 5.11 Suicidal Behavior and Ideation with Unapproved Use in Adolescents and Adults VIGAFYDE is approved for use in patients 1 month to 2 years of age [see Indications and Usage ( 1 )]. VIGAFYDE is not approved for use in adolescents or adults. Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in adolescents and adults. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that adult patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to adult patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated adult patients was 0.43%, compared to 0.24% among 16,029 placebo-treated adult patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 adult patients treated. There were four suicides in drug-treated adult patients in the trials and none in placebo-treated adult patients, but the number was too small to allow any conclusion about AED effect on suicide. The increased risk of suicidal thoughts or behavior in adults with AEDs was observed as early as one week after starting AED treatment and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

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 )] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions ( 5.5 )] Anemia [see Warnings and Precautions ( 5.6 )] Somnolence and Fatigue [see Warnings and Precautions ( 5.7 )] Peripheral Neuropathy [see Warnings and Precautions ( 5.8 )] Weight Gain [see Warnings and Precautions ( 5.9 )] Edema [see Warnings and Precautions ( 5.10 )] Suicidal Behavior and Ideation with Unapproved use in Adolescents and Adults [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (incidence ˃5% and greater than on placebo) in patients with infantile spasms include somnolence, bronchitis, ear infection, and acute otitis media. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. Infantile Spasms In a randomized, placebo-controlled study in patients with infantile spasms (IS) 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 patients with IS, 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. In a dose response study of low-dose (18 to 36 mg/kg/day, which is below the recommended starting dose for IS of 50 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 2. Table 2. 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 Re s piratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11 6.2 Postm arketing Experience The following adverse reactions have been identified during postapproval 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 causal relationship to drug exposure. 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

<table><caption>Table 2. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms</caption><colgroup><col width="369"/><col width="130"/><col width="125"/></colgroup><tbody><tr><td styleCode="Toprule"> <content styleCode="bold">Body System</content> Adverse Reaction</td><td styleCode="Toprule" align="center">Vigabatrin Low Dose [N=114] %</td><td styleCode="Toprule" align="center">Vigabatrin High Dose [N=108] %</td></tr><tr><td styleCode="Toprule" colspan="3"><content styleCode="bold">Eye Disorders (other than field or acuity changes)</content></td></tr><tr><td> Strabismus</td><td align="center">5</td><td align="center">5</td></tr><tr><td> Conjunctivitis</td><td align="center">5</td><td align="center">2</td></tr><tr><td colspan="3"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td> Vomiting</td><td align="center">14</td><td align="center">20</td></tr><tr><td> Constipation</td><td align="center">14</td><td align="center">12</td></tr><tr><td> Diarrhea</td><td align="center">13</td><td align="center">12</td></tr><tr><td colspan="3"><content styleCode="bold">General Disorders</content></td></tr><tr><td> Fever</td><td align="center">29</td><td align="center">19</td></tr><tr><td><content styleCode="bold">Infections</content></td><td align="center"/><td align="center"/></tr><tr><td> Upper respiratory tract infection</td><td align="center">51</td><td align="center">46</td></tr><tr><td> Otitis media</td><td align="center">44</td><td align="center">30</td></tr><tr><td> Viral infection</td><td align="center">20</td><td align="center">19</td></tr><tr><td> Pneumonia</td><td align="center">13</td><td align="center">11</td></tr><tr><td> Candidiasis</td><td align="center">8</td><td align="center">3</td></tr><tr><td> Ear infection</td><td align="center">7</td><td align="center">14</td></tr><tr><td> Gastroenteritis viral</td><td align="center">6</td><td align="center">5</td></tr><tr><td> Sinusitis</td><td align="center">5</td><td align="center">9</td></tr><tr><td> Urinary tract infection</td><td align="center">5</td><td align="center">6</td></tr><tr><td> Influenza</td><td align="center">5</td><td align="center">3</td></tr><tr><td> Croup infectious</td><td align="center">5</td><td align="center">1</td></tr><tr><td><content styleCode="bold">Metabolism &amp;</content><content styleCode="bold"> Nutrition Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td> Decreased appetite</td><td align="center">9</td><td align="center">7</td></tr><tr><td><content styleCode="bold">Nervous System Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td> Sedation</td><td align="center">19</td><td align="center">17</td></tr><tr><td> Somnolence</td><td align="center">17</td><td align="center">19</td></tr><tr><td> Status epilepticus</td><td align="center">6</td><td align="center">4</td></tr><tr><td> Lethargy</td><td align="center">5</td><td align="center">7</td></tr><tr><td> Convulsion</td><td align="center">4</td><td align="center">7</td></tr><tr><td> Hypotonia</td><td align="center">4</td><td align="center">6</td></tr><tr><td><content styleCode="bold">Psychiatric Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td> Irritability</td><td align="center">16</td><td align="center">23</td></tr><tr><td> Insomnia</td><td align="center">10</td><td align="center">12</td></tr><tr><td><content styleCode="bold">Re</content><content styleCode="bold">s</content><content styleCode="bold">piratory Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td> Nasal congestion</td><td align="center">13</td><td align="center">4</td></tr><tr><td> Cough</td><td align="center">3</td><td align="center">8</td></tr><tr><td><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td><td align="center"/><td align="center"/></tr><tr><td> Rash</td><td align="center">8</td><td align="center">11</td></tr></tbody></table>