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Nervous System Effects: Adverse neuropsychiatric effects reported during levetiracetam therapy are classified into 3 categories: somnolence and fatigue, coordination difficulties, and behavioral/psychiatric abnormalities. Patients should be monitored for these adverse effects during therapy. In addition, patients should be advised not to drive or operate machinery until the effects of levetiracetam are known.
In controlled studies in adults, approximately 15% of patients with partial onset seizures who received levetiracetam (as an oral conventional preparation) experienced somnolence compared with 8% of placebo-treated patients, and about 3% of levetiracetam-treated patients discontinued treatment because of somnolence. Pediatric patients and adults with other seizure types who receive levetiracetam appear to experience similar rates of somnolence and fatigue. In controlled study in adults, asthenia was reported in about 15% of patients who received levetiracetam (as conventional preparations) compared with 9% of placebo-treated patients, and 0.8% of levetiracetam-treated patients discontinued treatment because of asthenia. Coordination difficulties (e.g., ataxia, abnormal gait, incoordination) were experienced by 3.4% of levetiracetam patients receiving levetiracetam (as conventional preparations) compared with 1.6% of placebo-treated patients. Somnolence, asthenia, and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In studies with extended-release levetiracetam, behavioral abnormalities (irritability and aggression) were reported in 7% of patients receiving the drug compared with none of the patients receiving placebo; however, the number of patients exposed to the extended release preparation is considerably less than that of the immediate-release preparation.
Suicidality Risk: The US FDA has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including levetiracetam, compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidal risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.
Based on the current analysis of the available data, US FDA recommends that clinicians inform patients, their families, and caregivers about the potential for an increase in the risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.
Clinicians who prescribe levetiracetam or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.
Dermatologic Reactions: Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in both adults and pediatric patients receiving levetiracetam. The median time of onset is reported to be between 14 and 17 days, although cases have occurred at least 4 months after initiation of therapy.
Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If manifestations suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur, levetiracetam therapy should be permanently discontinued and alternative therapy considered.
Discontinuance of Therapy: Because of the possibility of increased seizure frequency, anticonvulsant drugs, including levetiracetam, should not be discontinued suddenly. The manufacturer recommends that oral levetiracetam be withdrawn gradually by reducing the dosage by 1 g daily at 2-week intervals.
Hematologic Effects: Hematologic abnormalities (e.g., decreased red blood cell, white blood cell, and neutrophil counts) were reported in patients receiving levetiracetam in clinical studies. Agranulocytosis, leukopenia, neutropenia, pancytopenia, and thrombocytopenia also have occurred during postmarketing experience.
A complete blood count (CBC) is recommended in patients who experience any signs or symptoms of hematologic abnormalities (e.g., severe weakness, pyrexia, recurrent infections, coagulation disorders) during levetiracetam therapy.
Increased Blood Pressure: In a study of pediatric patients 1 month to younger than 4 years of age, increased diastolic blood pressure was observed in levetiracetam-treated patients (17%) compared with those receiving placebo (2%). However, there was no overall difference in mean diastolic blood pressure between the treatment groups. These findings were not observed in older children or adults receiving the drug.
Pediatric patients younger than 4 years of age should be monitored for increased diastolic blood pressure during levetiracetam therapy.
Sensitivity Reactions: Anaphylaxis and Angioedema: Anaphylaxis and angioedema, in some cases life-threatening and/or requiring emergency treatment, have been reported during postmarketing experience in patients receiving levetiracetam. (See Contraindications.) Manifestations have included hypotension, hives, rash, respiratory distress, facial swelling, and swelling of the tongue, throat, and feet. Such reactions can occur at any time during therapy.
If any signs or symptoms of anaphylaxis or angioedema occur, patients should discontinue levetiracetam immediately and seek medical attention. Levetiracetam therapy should be permanently discontinued if an alternative etiology cannot be identified.
Use in Pregnancy: Category C. The effect of levetiracetam on labor and delivery is unknown.
Seizure Control During Pregnancy: Physiologic changes that occur during pregnancy may gradually decrease plasma levels of levetiracetam in pregnant women. This effect is most notable during the third trimester.
Patients should be closely monitored during pregnancy and throughout the postpartum period, especially if levetiracetam dosage is adjusted during pregnancy.
Use in Lactation: Levetiracetam is distributed into milk. Because of the potential for serious adverse reactions to levetiracetam in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account possible risk to an infant and the importance of the drug to the woman.
Use in Children: Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of partial onset seizures have not been established in pediatric patients younger than 1 month of age. Behavioral abnormalities (e.g., paranoia, confusional state, increased aggression) have been observed in pediatric patients 4-16 years of age with partial onset seizures receiving the drug.
Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of myoclonic seizures have not been established in pediatric patients younger than 12 years of age.
Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of primary generalized tonic-clonic seizures have not been established in pediatric patients younger than 6 years of age.
Safety and efficacy of levetiracetam in sodium chloride injection have not been established in pediatric patients younger than 16 years of age.
