FDA label 42621047-cc14-635d-e054-00144ff8d46c

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 clini cal trials (mono- an d 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 w as 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 th e 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 IndicationPlacebo Patientswith Events Per1000 PatientsDrug Patientswith Events Per1000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1000 PatientsEpilepsy1.03.43.52.4Psychiatric5.78.51.52.9Other1.01.81.90.9Total2.44.31.81.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epile psy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were sim ilar 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 levetiracetamtreated 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.

ADVERSE REACTIONS The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. Partial Onset Seizures In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age with partial onset seizures, the adverse events most frequently reported with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia. Table 8 lists treatment-emergent adverse events that occurred in at least 1% of adult epilepsy patients treated with levetiracetam participating in placebostudies and were numerically more common than in patients treated with placebo. Table 9 lists treatment-emergent adverse events that occurred in at least 2% of pediatric epilepsy patients (ages 4 to 16 years) treated with levetiracetam participating in the placebo-controlled study and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Table 8: Incidence (%) Of Treatment-Emergent Adverse Events In PlaceboAdd-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 1% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients). Body System/LevetiracetamPlaceboAdverse Event(N=769)(N=439)%%Body as a WholeAsthenia159Headache1413Infection138Pain76Digestive SystemAnorexia32Nervous SystemSomnolence158Dizziness94Depression42Nervousness42Ataxia31Vertigo31Amnesia21Anxiety21Hostility21Paresthesia21Emotional Lability20Respiratory SystemPharyngitis64Rhinitis43Cough Increased21Sinusitis21Special SensesDiplopia21Other events reported by at least 1% of adult levetiracetamtreated patients 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, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary tract infection, vomiting and weight gain. Table 9: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 2% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System/ Adverse EventLevetiracetam(N=101) %Placebo (N=97) %Body as a WholeAccidental Injury1710Asthenia93Pain63Flu Syndrome32Face Edema21Neck Pain21Viral Infection21Digestive SystemVomiting1513Anorexia138Diarrhea87Gastroenteritis42Constipation31Hemic and Lymphatic SystemEcchymosis41Metabolic and NutritionalDehydration21Nervous SystemSomnolence2311Hostility126Nervousness102Personality Disorder87Dizziness72Emotional Lability64Agitation61Depression31Vertigo31Reflexes Increased21Confusion20Respiratory SystemRhinitis138Cough Increased117Pharyngitis108Asthma21Skin and AppendagesPruritus20Skin Discoloration20Vesiculobullous Rash20Special SensesConjunctivitis32Amblyopia20Ear Pain20Urogenital SystemAlbuminuria40Urine Abnormality21Other events occurring in at least 2% of pediatric levetiracetam-treated patients but as or more frequent in 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 (not otherwise specified), thinking abnormal, tremor, and urinary incontinence. Myoclonic Seizures Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included both adolescent (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 combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis. Table 10 lists treatment-emergent adverse events that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Table 10: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older With Myoclonic Seizures By Body System (Adverse Events Occurred In At Least 5% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System / MedDRA preferred termLevetiracetam (N=60) %Placebo (N=60) %Ear and labyrinth disordersVertigo53Infections and infestationsPharyngitis70Influenza52Musculoskeletal and connective tissue disordersNeck pain82Nervous system disordersSomnolence122Psychiatric disordersDepression52Other events occurring in at least 5% of levetiracetam-treated patients with myoclonic seizures but as or more frequent in the placebo group were the following: fatigue and headache. Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse event associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis. Table 11 lists treatment-emergent adverse events that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity. Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 4 Years Of Age And Older With PGTC Seizures By MedDRA System Organ Class (Adverse Events Occurred In At Least 5% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) MedDRA System Organ Class/ Preferred TermLevetiracetam (N=79) %Placebo (N=84) %Gastrointestinal disordersDiarrhea87General disorders and administration site conditionsFatigue108Infections and infestationsNasopharyngitis145Psychiatric disordersIrritability62Mood swings51Other events occurring in at least 5% of levetiracetam-treated patients with PGTC seizures but as or more frequent in the placebo group were the following: dizziness, headache, influenza, and somnolence. Time Course of Onset of Adverse Events for Partial Onset Seizures Of the most frequently reported adverse events in adults, experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with levetiracetam. Discontinuation or Dose Reduction in Well-Controlled Clinical Studies Partial Onset Seizures In well-controlled adult clinical studies, 15.0% of patients receiving levetiracetam and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 12 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction. Table 12: Adverse Events That Most Commonly Resulted In Discontinuation Or Dose Reduction In Placebo-Controlled Studies In Adult Patients Experiencing Partial Onset Seizures Number (%)LevetiracetamPlacebo(N=769)(N=439)Asthenia10 (1.3%)3 (0.7%)Convulsion23 (3.0%)15 (3.4%)Dizziness11 (1.4%)0Rash05 (1.1%)Somnolence34 (4.4%)7 (1.6%)In the well-controlled pediatric clinical study, 16.8% of patients receiving levetiracetam and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events most commonly associated (in patients receiving levetiracetam) with discontinuation or dose reduction in the well-controlled study are presented in Table 13. Table 13: Adverse Events Most Commonly Associated With Discontinuation Or Dose ReductionIn The Placebo-Controlled Study In Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures Number (%)Levetiracetam (N=101)Placebo(N=97)Asthenia3 (3.0%)0Hostility7 (6.9%)2 (2.1%)Somnolence3 (3.0%)3 (3.1%) Myoclonic Seizures In the placebo-controlled study, 8.3% of patients receiving levetiracetam and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events that led to discontinuation or dose reduction in the well-controlled study are presented in Table 14. Table 14: Adverse Events That Resulted In Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Patients With Juvenile Myoclonic Epilepsy Body System/ MedDRA preferred termLevetiracetam (N=60) n (%)Placebo (N=60) n (%)Anxiety2 (3.3%)1 (1.7%)Depressed mood1 (1.7%)0Depression1 (1.7%)0Diplopia1 (1.7%)0Hypersomnia1 (1.7%)0Insomnia1 (1.7%)0Irritability1 (1.7%)0Nervousness1 (1.7%)0Somnolence1 (1.7%)0 Primary Generalized Tonic-Clonic Seizures In the placebo-controlled study, 5.1% of patients receiving levetiracetam and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment-emergent adverse event. This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see tables 12 - 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 distribution of adverse experience reports by age and race. Postmarketing Experience