Psychiatric Reactions: In some patients Levetiracetam Tablets causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult and pediatric partial onset seizure studies. A total of 13.3% of adult Levetiracetam Tablets-treated patients and 37.6% of pediatric Levetiracetam Tablets-treated patients (4 to 16 years of age) compared to 6.2% and 18.6% of adult and pediatric placebo patients respectively, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional liability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder). A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam Tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in Levetiracetam Tablets-treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18). In pediatric patients 1 month to <4 years of age, irritability was reported in 11.7% of the Levetiracetam Tablets-treated patients compared to 0% of placebo patient. A total of 1.7% of adult Levetiracetam Tablets-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult Levetiracetam Tablets-treated patients and in 0.5% of placebo patients. Overall, 10.9% of Levetiracetam Tablets-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients. One percent of adult Levetiracetam Tablets-treated patients, 2% of children 4 to 16 years of age, and 17% of children 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% respectively, in the placebo patients. In the controlled study that assessed the neurocognitive and behavioral effects of Levetiracetam Tablets in pediatric patients 4 to 16 years of age, 1 (1.6%) Levetiracetam Tablets-treated patient experienced paranoia compared to no placebo patients. There were 2 (3.1%) Levetiracetam Tablets-treated patients that experienced confusional state compared to no placebo patients. Two (0.3%) adult Levetiracetam Tablets-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. The previously mentioned psychiatric signs symptoms should be monitored.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Levetiracetam 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 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 shows absolute and relative risk by indication for all evaluated AEDs. (See table).
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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 Tablets 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.
Somnolence and Fatigue: In some patients, Levetiracetam Tablets causes somnolence and fatigue. The incidences of somnolence and fatigue provided as follows are from controlled adult partial onset seizure studies. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of in the controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of Levetiracetam Tablets-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 Tablets-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 Levetiracetam Tablets-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia 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 due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Tablets to gauge whether it adversely affects their ability to drive or operate machinery.
Serious Dermatological Reactions: Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam Tablets should be discontinued at the first sign of a rash, unless the rash is clearly not drug related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Coordination Difficulties: Coordination difficulties were only observed in the adult partial onset seizure studies. A total of 3.4% of adult Levetiracetam Tablets-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or in coordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued Levetiracetam Tablets 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. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Tablets to gauge whether it could adversely affect their ability to drive or operate machinery.
Withdrawal Seizures: Antiepileptic drugs, including Levetiracetam Tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities: Partial Onset Seizures in Adults: 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 Levetiracetam Tablets-treated patients in controlled trials. 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.
Pediatric Patients 4 Years To <16 Years: Statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam Tablets treated patients as compared to placebo. The mean decreases from baseline in the Levetiracetam Tablets-treated group were -0.4 x 10
9/L and -0.3 x 10
9/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in Levetiracetam Tablets-treated patients, compared to a decrease of 4% in placebo patients (statistically significant). In the controlled trial, more Levetiracetam Tablets-treated patients had a possibly clinically significant abnormally low WBC value (3.0% Levetiracetam Tablets-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% Levetiracetam Tablets-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts. In the controlled cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the Levetiracetam Tablets-treated group had high eosinophil count values that were possibly clinically significant (
310% or
30.7 x 10
9/L).
Juvenile Myoclonic Epilepsy: Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.
Blood Pressure Increases: In a randomized, placebo-controlled study in patients aged 1 month to <4 years of age, a significantly higher risk of at least one measured increase in diastolic blood pressure was observed in the Levetiracetam Tablets-treated patients (17%) compared to the placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the Levetiracetam Tablets and placebo treatment groups was not observed in the studies of older children or in adults.
Seizure Control During Pregnancy: Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.
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