FDA label b9acd365-1b80-4428-bd33-3a5eac814677

WARNINGS Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including levetiracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. 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 patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to 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 patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs 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. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 7 shows absolute and relative risk by indication for all evaluated AEDs. Table 7 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk : Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference : Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Neuropsychiatric Adverse Events Partial Onset Seizures Adults In adults experiencing partial onset seizures, levetiracetam use is associated with the occurrence of central nervous system adverse events that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced. A total of 3.4% of levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of levetiracetam-treated patients experienced psychotic symptoms compared to 1(0.2%) placebo patient. Two (0.3%) levetiracetam-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1 to 5 months and resolved within 2 to 7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized. Pediatric Patients In pediatric patients experiencing partial onset seizures, levetiracetam is associated with somnolence, fatigue, and behavioral abnormalities. In the double-blind, controlled trial in children with epilepsy experiencing partial onset seizures, 22.8% of levetiracetam-treated patients experienced somnolence, compared to 11.3% of placebo patients. The design of the study prevented accurately assessing dose-response effects. No patient discontinued treatment for somnolence. In about 3.0% of levetiracetam-treated patients and in 3.1% of placebo patients the dose was reduced as a result of somnolence. Asthenia was reported in 8.9% of levetiracetam-treated patients, compared to 3.1% of placebo patients. No patient discontinued treatment for asthenia, but asthenia led to a dose reduction in 3.0% of levetiracetam-treated patients compared to 0% of placebo patients. A total of 37.6% of the levetiracetam-treated patients experienced behavioral symptoms (reported as agitation, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesia, nervousness, neurosis, and personality disorder), compared to 18.6% of placebo patients. Hostility was reported in 11.9% of levetiracetam-treated patients, compared to 6.2% of placebo patients. Nervousness was reported in 9.9% of levetiracetam-treated patients, compared to 2.1% of placebo patients. Depression was reported in 3.0% of levetiracetam-treated patients, compared to 1.0% of placebo patients. A total of 3.0% of levetiracetam-treated patients discontinued treatment due to psychotic and nonpsychotic adverse events, compared to 4.1% of placebo patients. Overall, 10.9% of levetiracetam-treated patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients. Myoclonic Seizures During clinical development, the number of patients with myoclonic seizures exposed to levetiracetam was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse events was more likely to occur in the myoclonic seizure population. In adult and adolescent patients experiencing myoclonic seizures, levetiracetam is associated with somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME. In the double-blind, controlled trial in adults and adolescents with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of levetiracetam-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of levetiracetam-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence. Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the levetiracetam-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients compared to 3.3% of placebo patients. A total of 5.0% of levetiracetam-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients. Primary Generalized Tonic-Clonic Seizures During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g. somnolence and gait disturbance), these events may not have been observed because of the smaller sample size. In patients 6 years of age and older experiencing primary generalized tonic-clonic seizures, levetiracetam is associated with behavioral abnormalities. In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (including anger, apathy, depression, mood altered, mood swings, negativism, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam. In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation. Withdrawal Seizures Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

<table cellspacing="0" cellpadding="0" border="0" width="100%"> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Indication </td> <td valign="top" styleCode="Rrule">Placebo Patients with Events Per 1000 Patients </td> <td valign="top" styleCode="Rrule">Drug Patients with Events Per 1000 Patients </td> <td valign="top" styleCode="Rrule">Relative Risk : Incidence of Events in Drug Patients/Incidence in Placebo Patients </td> <td valign="top" styleCode="Rrule">Risk Difference : Additional Drug Patients with Events Per 1000 Patients </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Epilepsy </td> <td valign="top" styleCode="Rrule">1.0 </td> <td valign="top" styleCode="Rrule">3.4 </td> <td valign="top" styleCode="Rrule">3.5 </td> <td valign="top" styleCode="Rrule">2.4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Psychiatric </td> <td valign="top" styleCode="Rrule">5.7 </td> <td valign="top" styleCode="Rrule">8.5 </td> <td valign="top" styleCode="Rrule">1.5 </td> <td valign="top" styleCode="Rrule">2.9 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Other </td> <td valign="top" styleCode="Rrule">1.0 </td> <td valign="top" styleCode="Rrule">1.8 </td> <td valign="top" styleCode="Rrule">1.9 </td> <td valign="top" styleCode="Rrule">0.9 </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule">Total </td> <td valign="top" styleCode="Rrule">2.4 </td> <td valign="top" styleCode="Rrule">4.3 </td> <td valign="top" styleCode="Rrule">1.8 </td> <td valign="top" styleCode="Rrule">1.9 </td> </tr> </tbody> </table>

ADVERSE REACTIONS The prescriber should be awarethat the adverse event incidence figures in the following tables, obtained whenlevetiracetam was added to concurrent AED therapy,cannot be used to predict the frequency of adverse experiences in the course ofusual medical practice where patient characteristics and other factors maydiffer from those prevailing during clinical studies. Similarly, the citedfrequencies cannot be directly compared with figures obtained from otherclinical investigations involving different treatments, uses, or investigators.An inspection of these frequencies, however, does provide the prescriber withone basis to estimate the relative contribution of drug and non-drug factors tothe adverse event incidences in the population studied. Partial Onset Seizures In well-controlled clinical studies in adults with partialonset seizures, the most frequently reported adverse events associated with theuse of levetiracetam in combination with other AEDs, not seen at an equivalentfrequency among placebo-treated patients, were somnolence, asthenia, infectionand dizziness. In the well-controlled pediatric clinical study in children 4 to16 years of age with partial onset seizures, the adverse events most frequentlyreported with the use of levetiracetam in combination with other AEDs, not seenat an equivalent frequency among placebo-treated patients, were somnolence,accidental injury, hostility, nervousness, and asthenia. Table8 lists treatment-emergent adverse events that occurred in at least 1% of adultepilepsy patients treated with levetiracetamparticipating in placebo-controlled studies and were numerically more commonthan in patients treated with placebo. Table 9 lists treatment-emergent adverseevents that occurred in at least 2% of pediatric epilepsy patients (ages 4 to16 years) treated with levetiracetam participatingin the placebo-controlled study and were numerically more common than inpediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AEDtherapy. Adverse events were usually mild to moderate in intensity. Table 8: Incidence (%) Of Treatment-EmergentAdverse Events In Placebo-Controlled, Add-On Studies In Adults Experiencing PartialOnset Seizures By Body System (Adverse Events Occurred In At Least 1% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients) Body System/ Adverse Event Levetiracetam (N=769) % Placebo (N=439) % Body as a Whole Asthenia 15 9 Headache 14 13 Infection 13 8 Pain 7 6 Digestive System Anorexia 3 2 Nervous System Somnolence 15 8 Dizziness 9 4 Depression 4 2 Nervousness 4 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Hostility 2 1 Paresthesia 2 1 Emotional Lability 2 0 Respiratory System Pharyngitis 6 4 Rhinitis 4 3 Cough Increased 2 1 Sinusitis 2 1 Special Senses Diplopia 2 1 Otherevents reported by at least 1% of adult levetiracetam-treatedpatients but as or more frequent in the placebo group were the following:abdominal pain, accidental injury, amblyopia, arthralgia, back pain,bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, druglevel increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection,gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitismedia, rash, thinking abnormal, tremor, urinary tract infection, vomiting andweight gain. Table 9: Incidence (%) Of Treatment-EmergentAdverse Events In A Placebo-Controlled, Add-On Study In Pediatric Patients Ages4 to 16 Years Experiencing Partial Onset Seizures By Body System (Adverse EventsOccurred In At Least 2% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients) Body System/Adverse Event Levetiracetam (N=101)% Placebo (N=97) % Body as a Whole Accidental Injury 17 10 Asthenia 9 3 Pain 6 3 Flu Syndrome 3 2 Face Edema 2 1 Neck Pain 2 1 Viral Infection 2 1 Digestive System Vomiting 15 13 Anorexia 13 8 Diarrhea 8 7 Gastroenteritis 4 2 Constipation 3 1 Hemic and Lymphatic System Ecchymosis 4 1 Metabolic and Nutritional Dehydration 2 1 Nervous System Somnolence 23 11 Hostility 12 6 Nervousness 10 2 Personality Disorder 8 7 Dizziness 7 2 Emotional Lability 6 4 Agitation 6 1 Depression 3 1 Vertigo 3 1 Reflexes Increased 2 1 Confusion 2 0 Respiratory System Rhinitis 13 8 Cough Increased 11 7 Pharyngitis 10 8 Asthma 2 1 Skin and Appendages Pruritus 2 0 Skin Discoloration 2 0 Vesiculobullous Rash 2 0 Special Senses Conjunctivitis 3 2 Amblyopia 2 0 Ear Pain 2 0 Urogenital System Albuminuria 4 0 Urine Abnormality 2 1 Other events occurring in at least 2% of pediatric levetiracetam-treated patients but as or more frequentin the placebo group were the following: abdominal pain, allergic reaction,ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection,insomnia, nausea, otitis media, rash, sinusitis, status epilepticus (nototherwise specified), thinking abnormal, tremor, and urinary incontinence. Myoclonic Seizures Although the pattern of adverse events in this study seemssomewhat different from that seen in patients with partial seizures, this islikely due to the much smaller number of patients in this study compared topartial seizure studies. The adverse event pattern for patients with JME isexpected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included bothadolescent (12 to 16 years of age) and adult patients with myoclonic seizures,the most frequently reported adverse events associated with the use of levetiracetam in combinationwith other AEDs, not seen at an equivalent frequency among placebo-treatedpatients, were somnolence, neck pain, and pharyngitis. Table 10 lists treatment-emergent adverse events that occurredin at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonicseizures treated with levetiracetam and were numerically more common than in patients treatedwith placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverseevents were usually mild to moderate in intensity. Table 10: Incidence (%) Of Treatment-Emergent Adverse Events In APlacebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older WithMyoclonic Seizures By Body System (Adverse Events Occurred In At Least 5% Of Levetiracetam-TreatedPatients And Occurred More Frequently Than Placebo-Treated Patients) Body System /MedDRA preferred term Levetiracetam (N=60) % Placebo (N=60) % Ear and labyrinth disorders Vertigo 5 3 Infections and infestations Pharyngitis 7 0 Influenza 5 2 Musculoskeletal and connective tissue disorder Neck pain 8 2 Nervous system disorders Somnolence 12 2 Psychiatric disorders Depression 5 2 Other events occurring in at least 5% of levetiracetam-treated patients with myoclonic seizures but as or more frequent in theplacebo group were the following: fatigue and headache. Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse events in this study seemssomewhat different from that seen in patients with partial seizures, this islikely due to the much smaller number of patients in this study compared topartial seizure studies. The adverse event pattern for patients with PGTCseizures is expected to be essentially the same as for patients with partialseizures. In the well-controlled clinical study that includedpatients 4 years of age and older with primary generalized tonic-clonic (PGTC)seizures, the most frequently reported adverse event associated with the use oflevetiracetam incombination with other AEDs, not seen at an equivalent frequency amongplacebo-treated patients, was nasopharyngitis. Table 11 lists treatment-emergent adverseevents that occurred in at least 5% of idiopathic generalized epilepsy patientsexperiencing PGTC seizures treated with levetiracetamand were numerically more common than in patients treated with placebo. In thisstudy, either levetiracetam or placebo was addedto concurrent AED therapy. Adverse events were usually mild to moderate inintensity. Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In APlacebo-Controlled, Add-On Study In Patients 4 Years Of Age And Older With PGTCSeizures By MedDRA System Organ Class (Adverse Events Occurred In At Least 5%Of Levetiracetam-Treated Patients And Occurred More Frequently ThanPlacebo-Treated Patients) MedDRA System Organ Class/ Preferred Term Levetiracetam (N=79) % Placebo (N=84) % Gastrointestinal disorders 8 7 Diarrhea General disorders and administration site conditions Fatigue 10 8 Infections and infestations Nasopharyngitis 14 5 Psychiatric disorders Irritability 6 2 Mood swings 5 1 Other events occurring in at least 5% of levetiracetam-treated patients with PGTC seizures but as or more frequent in theplacebo group were the following: dizziness, headache, influenza, andsomnolence. Time Course Of Onset Of Adverse Events For Partial Onset Seizures Of the most frequently reported adverse eventsin adults experiencing partial onset seizures, asthenia, somnolence anddizziness appeared to occur predominantly during the first 4 weeks of treatmentwith levetiracetam. Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies Partial Onset Seizures In well-controlled adult clinical studies, 15.0% of patientsreceiving levetiracetam and 11.6% receivingplacebo either discontinued or had a dose reduction as a result of an adverseevent. Table 12 lists the most common (>1%) adverse events that resulted indiscontinuation or dose reduction. Table12: Adverse Events That Most Commonly Resulted In Discontinuation Or DoseReduction In Placebo-Controlled Studies In Adult Patients Experiencing PartialOnset Seizures Number (%) Levetiracetam (N=769) Placebo (N=439) Asthenia 10 (1.3%) 3 (0.7%) Convulsion 23 (3.0%) 15 (3.4%) Dizziness 11 (1.4%) 0 Rash 0 5 (1.1%) Somnolence 34 (4.4%) 7 (1.6%) Inthe well-controlled pediatric clinical study, 16.8% of patients receiving levetiracetam and 20.6% receiving placebo eitherdiscontinued or had a dose reduction as a result of an adverse event. Theadverse events most commonly associated (≥3% in patients receiving levetiracetam) with discontinuation or dose reduction inthe well-controlled study are presented in Table 13. Table 13: Adverse Events Most CommonlyAssociated With Discontinuation Or Dose Reduction In The Placebo-ControlledStudy In Pediatric Patients Ages 4 to 16 Years Experiencing Partial OnsetSeizures Number (%) Levetiracetam (N=101) Placebo (N=97) Asthenia 3 (3.0%) 0 Hostility 7 (6.9%) 2 (2.1%) Somnolence 3 (3.0%) 3 (3.1%) Myoclonic Seizures In the placebo-controlled study, 8.3%of patients receiving levetiracetam and 1.7% receiving placebo eitherdiscontinued or had a dose reduction as a result of an adverse event. Theadverse events that led to discontinuation or dose reduction in thewell-controlled study are presented in Table 14. Table 14: Adverse Events That Resulted In Discontinuation Or DoseReduction In The Placebo-Controlled Study In Patients With Juvenile MyoclonicEpilepsy Body System/ MedDRA preferred term Levetiracetam (N=60) n (%) Placebo (N=60) n (%) Anxiety 2 (3.3%) 1 (1.7%) Depressed mood 1 (1.7%) 0 Depression 1 (1.7%) 0 Diplopia 1 (1.7%) 0 Hypersomnia 1 (1.7%) 0 Insomnia 1 (1.7%) 0 Irritability 1 (1.7%) 0 Nervousness 1 (1.7%) 0 Somnolence 1 (1.7%) 0 PrimaryGeneralized Tonic-Clonic Seizures In the placebo-controlled study, 5.1% of patients receivinglevetiracetam and 8.3% receiving placebo either discontinued or had a dosereduction during the treatment period as a result of a treatment-emergent adverseevent. This study was too small to adequately characterize the adverse eventsleading to discontinuation. It is expected that the adverse events that wouldlead to discontinuation in this population would be similar to those resultingin discontinuation in other epilepsy trials (see tables 12 to 14). Comparison Of Gender, Age And Race The overall adverse experience profile of levetiracetam was similar between females and males.There are insufficient data to support a statement regarding the distributionof adverse experience reports by age and race. Postmarketing Experience Thefollowing adverse events have been identified during postapproval use oflevetiracetam. Because these events are reported voluntarily from a populationof uncertain size, it is not always possible to reliably estimate theirfrequency or establish a casual relationship to drug exposure. In addition to the adverse experiences listed above,the following have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized:abnormal liver function test, hepatic failure, hepatitis, leukopenia,neutropenia, pancreatitis, pancytopenia (with bone marrow suppressionidentified in some of these cases), thrombocytopenia, and weight loss. Alopeciahas been reported with levetiracetam use; recoverywas observed in majority of cases where levetiracetamwas discontinued. These adverse experiences have not been listed above, anddata are insufficient to support an estimate of their incidence or to establishcausation.

<table cellspacing="0" cellpadding="0" border="0" width="100%"> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Body System/</content> <content styleCode="bold"> Adverse Event</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Levetiracetam</content> <content styleCode="bold">(N=769)</content> <content styleCode="bold"> %</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold"> Placebo</content> <content styleCode="bold">(N=439)</content> <content styleCode="bold"> %</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Body as a Whole</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Asthenia </td> <td valign="top" styleCode="Rrule" align="center">15 </td> <td valign="top" styleCode="Rrule" align="center">9 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Headache </td> <td valign="top" styleCode="Rrule" align="center">14 </td> <td valign="top" styleCode="Rrule" align="center">13 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Infection </td> <td valign="top" styleCode="Rrule" align="center">13 </td> <td valign="top" styleCode="Rrule" align="center">8 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pain </td> <td valign="top" styleCode="Rrule" align="center">7 </td> <td valign="top" styleCode="Rrule" align="center">6 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Digestive System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Anorexia </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Nervous System</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold"> </content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Somnolence </td> <td valign="top" styleCode="Rrule" align="center">15 </td> <td valign="top" styleCode="Rrule" align="center">8 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Dizziness </td> <td valign="top" styleCode="Rrule" align="center">9 </td> <td valign="top" styleCode="Rrule" align="center">4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Depression </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Nervousness </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Ataxia </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Vertigo </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Amnesia </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Anxiety </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Hostility </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Paresthesia </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Emotional Lability </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pharyngitis </td> <td valign="top" styleCode="Rrule" align="center">6 </td> <td valign="top" styleCode="Rrule" align="center">4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Rhinitis </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Cough Increased </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Sinusitis </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule" align="left"> <content styleCode="bold">Special Senses</content> </td> <td valign="top" styleCode="Rrule" align="left"> </td> <td valign="top" styleCode="Rrule" align="left"> </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule"> Diplopia </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule" align="center"> <content styleCode="bold">Body System/Adverse Event</content> </td> <td valign="top" styleCode="Rrule"> <content styleCode="bold">Levetiracetam</content> <content styleCode="bold"/> <content styleCode="bold"/> <content styleCode="bold"> (N=101)%</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold">Placebo (N=97) %</content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Body as a Whole</content> </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Accidental Injury </td> <td valign="top" styleCode="Rrule" align="center">17 </td> <td valign="top" styleCode="Rrule" align="center">10 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Asthenia </td> <td valign="top" styleCode="Rrule" align="center">9 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pain </td> <td valign="top" styleCode="Rrule" align="center">6 </td> <td valign="top" styleCode="Rrule" align="center">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Flu Syndrome </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Face Edema </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Neck Pain </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Viral Infection </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Digestive System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Vomiting </td> <td valign="top" styleCode="Rrule" align="center">15 </td> <td valign="top" styleCode="Rrule" align="center">13 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Anorexia </td> <td valign="top" styleCode="Rrule" align="center">13 </td> <td valign="top" styleCode="Rrule" align="center">8 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Diarrhea </td> <td valign="top" styleCode="Rrule" align="center">8 </td> <td valign="top" styleCode="Rrule" align="center">7 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Gastroenteritis </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Constipation </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Hemic and Lymphatic System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Ecchymosis </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Metabolic and Nutritional</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Dehydration </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Nervous System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Somnolence </td> <td valign="top" styleCode="Rrule" align="center">23 </td> <td valign="top" styleCode="Rrule" align="center">11 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Hostility </td> <td valign="top" styleCode="Rrule" align="center">12 </td> <td valign="top" styleCode="Rrule" align="center">6 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Nervousness </td> <td valign="top" styleCode="Rrule" align="center">10 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Personality Disorder </td> <td valign="top" styleCode="Rrule" align="center">8 </td> <td valign="top" styleCode="Rrule" align="center">7 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Dizziness </td> <td valign="top" styleCode="Rrule" align="center">7 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Emotional Lability </td> <td valign="top" styleCode="Rrule" align="center">6 </td> <td valign="top" styleCode="Rrule" align="center">4 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Agitation </td> <td valign="top" styleCode="Rrule" align="center">6 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Depression </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Vertigo </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Reflexes Increased </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Confusion </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Respiratory System</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Rhinitis </td> <td valign="top" styleCode="Rrule" align="center">13 </td> <td valign="top" styleCode="Rrule" align="center">8 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Cough Increased </td> <td valign="top" styleCode="Rrule" align="center">11 </td> <td valign="top" styleCode="Rrule" align="center">7 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pharyngitis </td> <td valign="top" styleCode="Rrule" align="center">10 </td> <td valign="top" styleCode="Rrule" align="center">8 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Asthma </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Skin and Appendages</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pruritus </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Skin Discoloration </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Vesiculobullous Rash </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Special Senses</content> </td> <td valign="top" styleCode="Rrule" align="center"> </td> <td valign="top" styleCode="Rrule" align="center"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Conjunctivitis </td> <td valign="top" styleCode="Rrule" align="center">3 </td> <td valign="top" styleCode="Rrule" align="center">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Amblyopia </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Ear Pain </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> <content styleCode="bold">Urogenital System</content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold"> </content> </td> <td valign="top" styleCode="Rrule" align="center"> <content styleCode="bold"> </content> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Albuminuria </td> <td valign="top" styleCode="Rrule" align="center">4 </td> <td valign="top" styleCode="Rrule" align="center">0 </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule"> Urine Abnormality </td> <td valign="top" styleCode="Rrule" align="center">2 </td> <td valign="top" styleCode="Rrule" align="center">1 </td> </tr> </tbody> </table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"> <tbody> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Body System /MedDRA preferred term </td> <td valign="top" styleCode="Rrule">Levetiracetam (N=60) % </td> <td valign="top" styleCode="Rrule">Placebo (N=60) % </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Ear and labyrinth disorders </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Vertigo </td> <td valign="top" styleCode="Rrule">5 </td> <td valign="top" styleCode="Rrule">3 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Infections and infestations </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Pharyngitis </td> <td valign="top" styleCode="Rrule">7 </td> <td valign="top" styleCode="Rrule">0 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Influenza </td> <td valign="top" styleCode="Rrule">5 </td> <td valign="top" styleCode="Rrule">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Musculoskeletal and connective tissue disorder </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Neck pain </td> <td valign="top" styleCode="Rrule">8 </td> <td valign="top" styleCode="Rrule">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Nervous system disorders </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule"> Somnolence </td> <td valign="top" styleCode="Rrule">12 </td> <td valign="top" styleCode="Rrule">2 </td> </tr> <tr styleCode="Botrule"> <td valign="top" styleCode="Lrule Rrule">Psychiatric disorders </td> <td valign="top" styleCode="Rrule"> </td> <td valign="top" styleCode="Rrule"> </td> </tr> <tr> <td valign="top" styleCode="Lrule Rrule"> Depression </td> <td valign="top" styleCode="Rrule">5 </td> <td valign="top" styleCode="Rrule">2 </td> </tr> </tbody> </table>