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Psychiatric Reactions/Behavioral Abnormalities and Psychotic Symptoms: In some patients, levetiracetam 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.
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 AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts of behavior, and/or any unusual changes in mood or behavior.
The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed.
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.
Somnolence and fatigue: Levetiracetam may cause somnolence and fatigue. 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 seizures studies were comparable to those of the adult partial onset seizure studies.
Somnolence and asthenia occurred most frequently within the first four 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 to gauge whether it adversely affects their ability to drive or operate machinery.
Serious Dermatological/Hypersensitivity Reactions: Serious dermatological/hypersensitivity reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Reaction with Eosinophilia and Systematic Symptoms (DRESS) have been reported in both children and adults treated with levetiracetam. Such serious skin reactions may be life-threatening, and some patients have required hospitalization with very rare reports of fatal outcome. There is no way to tell if a mild rash will become a severe skin reaction. If any of these hypersensitivity reactions are suspected, and an alternative cause cannot be established, levetiracetam should be discontinued. Recurrence of the serious skin reactions following re-challenge with levetiracetam has been reported. The median time of onset of SJS and TEN is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. The time to onset of DRESS may be longer than for SJS and TEN, e.g., Up to six weeks or more after treatment initiation. Typically, although not exclusively, DRESS initially presents with fever and rash, and then with other organ system involvement that may or may not include eosinophilia, lymphadenopathy, hepatitis, nephritis, and/or myocarditis. Since DRESS is variable in its expression, other organ system signs and symptoms not noted may also occur. Organ involvement may be more severe than skin involvement.
Coordination difficulties: Coordination difficulties were only observed in the adult partial onset seizure studies. 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 to gauge whether it could adversely affect their ability to drive or operate machinery.
Withdrawal seizures: AEDs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities: Hematologic abnormalities such as decrease in red blood cells (RBC) count, hemoglobin, hematocrit, and increases in eosinophil counts have occurred in clinical trials using levetiracetam. Decreased white blood cell (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.
Minor decreases in total mean erythrocyte count have been reported. Leukopenia, neutropenia, pancytopenia (with myelosuppression in some cases), and thrombocytopenia have also been observed, although a casual relationship to the drug has not been established.
Increase in Blood Pressure: A significantly higher risk of increased diastolic blood pressure was observed in levetiracetam-treated patients (17%) compared with placebo-controlled patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity was not observed in the studies of older children or in adults. It is recommended to monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.
Acute Kidney Injury: Levetiracetam has been very rarely associated with acute kidney injury, with a time to onset varying from a few days to several months.
Effects on Ability to Drive and Use Machine: No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience, at the beginning of treatment or following a dosage increase, somnolence or other CNS related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g., vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.
Renal Impairment: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Hepatic Impairment: Safety and efficacy demonstrated in a limited number of epileptic patients with chronic liver disease. No dosage adjustment is necessary in patients with hepatic impairment.
Use in Children: The safety and efficacy of levetiracetam in infants and children less than four years old has not been established.
Use in Elderly: No overall differences in safety were observed between elderly (65 years and older) and younger subjects. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection; monitoring of renal function may be useful.
