warnings and cautions
5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation . ( 5.1 ) Neuropsychiatric Adverse Reactions: Levetiracetam extended-release tablets causes somnolence, dizziness, and behavioral abnormalities. The adverse reactions that may be seen in patients receiving Levetiracetam extended-release tablets are expected to be similar to those seen in patients receiving immediate-release Levetiracetam tablets. ( 5.2 ) In controlled trials of immediate-release Levetiracetam extended-release tablets in patients experiencing partial onset seizures, immediate- release Levetiracetam causes somnolence and fatigue, coordination difficulties, and behavioral abnormalities (e.g., psychotic symptoms, suicidal ideation, and other abnormalities).( 5.2 ) Withdrawal Seizures: Levetiracetam extended-release tablets must be gradually withdrawn. ( 5.3 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, 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 (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: 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 extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior 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. 5.2 Neuropsychiatric Adverse Reactions Levetiracetam extended-release tablets In some patients experiencing partial onset seizures, levetiracetam extended-release causes somnolence, dizziness, and behavioral abnormalities. In the levetiracetam extended-release tablet double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of levetiracetam extended-release tablet treated patients experienced somnolence compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of levetiracetam extended-release tablet treated patients compared to 2.5% of placebo-treated patients. A total of 6.5% of levetiracetam extended-release tablet-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of levetiracetam extended-release tablet treated patients. Aggression was reported in 1.3% oflevetiracetam extended-release tablet treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled trials may also occur in patients receiving levetiracetam extended-release tablets. Immediate-Release Levetiracetam Tablets In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, immediate-release levetiracetam tablets cause the occurrence of central nervous system adverse reactions 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 immediate-release levetiracetam tablet-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. 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. A total of 3.4% of immediate-release levetiracetam tablet-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. 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%) immediate-release levetiracetam tablet-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. A total of 13.3% of immediate-release levetiracetam tablet 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. 5.3 Withdrawal Seizures Antiepileptic drugs, including levetiracetam extended-release tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency. 5.4 Hematologic Abnormalities Although there were no obvious hematologic abnormalities observed in treated patients in the levetiracetam extended-release tablet controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release levetiracetam tablets controlled studies should be considered to be relevant for levetiracetam extended-release tablet-treated patients. In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 6 /mm 3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 10 9 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 10 9 /L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. 5.5 Hepatic Abnormalities There were no meaningful changes in mean liver function tests (LFT) in the levetiracetam extended-release tablets controlled trial. No patients were discontinued from the controlled trial for LFT abnormalities. There were no meaningful changes in mean liver function tests (LFT) in controlled trials of immediate-release levetiracetam tablets in adult patients; lesser LFT abnormalities were similar in drug and placebo-treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. 5.6 Laboratory Tests Although effects on laboratory tests were not clinically significant with levetiracetam extended-release tablet treatment, it is expected that the data from immediate-release levetiracetam tablets controlled studies would be considered relevant for levetiracetam extended-release tablet-treated patients. Although most laboratory tests are not systematically altered with immediate-release levetiracetam tablets treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.