Levetiracetam is a pyrrolidine derivative anticonvulsant used for the treatment of a variety of seizures types (partial onset, primary generalized tonic-clonic, myoclonic). Guidelines recommend levetiracetam as a reasonable second-therapy option for convulsive status epilepticus (after a benzodiazepine) in children, adolescents, and adults. Interactions with concomitantly administered antiepileptic drugs are minimal, and it has minimal adverse reactions. Antiepileptic drugs (AEDs) such as levetiracetam also increase the risk of suicidal ideation and behavior; monitor all patients receiving levetiracetam for emerging or worsening suicidal thoughts/behavior or depression. Additionally, levetiracetam has been associated with rare but serious reactions, including Drug Reaction with eosinophilia and systemic symptoms (DRESS).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
Oral Solid Formulations
Immediate-release tablets (Keppra):
-Swallow whole; do not chew or crush.
Fast-melting tablets (Spritam)
-Administer only whole tablets.
-Peel the foil from the blister; do not attempt to push the tablet through the foil.
-With dry hands, place the tablet on the tongue and follow with a sip of liquid. Swallow only after the tablet disintegrates; do not swallow the intact tablet. Spritam disintegrates in a mean time of 11 seconds (range, 2 to 27 seconds).
-Alternatively, whole tablets can be added to a small volume of liquid (1 tablespoon or enough to cover the medicine) in a cup. Swirl gently. Consume the entire contents of the cup after the tablet has dispersed. If there is medicine left in the cup, add a small volume of liquid to the cup, swirl gently, and swallow the full amount. Do not attempt to administer partial quantities of the dispersed tablet.
Extended-release tablets (Keppra XR and Elepsia XR):
-Swallow whole; do not break, chew, or crush.
-The biologically inert components of this tablet may remain intact and appear as a soft, hydrated mass in the stool or as fragments of the coating; this is normal.
Oral Liquid Formulations
-Oral solution (100 mg/mL): Measure using a calibrated oral measuring device for accurate dosage administration. NOTE: Levetiracetam (Keppra) oral solution does not contain alcohol, dye, gluten, lactose, starch, sugar, or sucrose.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Dilute the dose in 100 mL of compatible diluent (0.9% Sodium Chloride Injection, Lactated Ringer's Injection, or 5% Dextrose Injection). A smaller volume may be used for pediatric or fluid-restricted patients; FDA-approved labeling does not recommend exceeding a maximum levetiracetam concentration of 15 mg/mL.
-Infuse dose over 15 minutes.
-Rapid administration of more concentrated solution has been studied in pediatric and young adult patients (age range: 4 to 32 years). Doses of 20 mg/kg (Max: 1,000 mg), 40 mg/kg (Max: 2,000 mg), or 60 mg/kg (Max: 3,000 mg) were diluted 1:1 with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection and infused over 5 minutes (20 mg/kg and 40 mg/kg doses) or 6 minutes (60 mg/kg dose); all doses administered at this rate and concentration were well tolerated as there were no significant changes in blood pressure or ECGs, and local infusion site reactions were not reported.
-Diluted preparation is physically compatible with lorazepam, diazepam, and valproate sodium.
-Storage: Discard unused vial contents. Diluted preparations stored in polyvinyl chloride (PVC) bags at controlled room temperature between 15 to 30 degrees C (59 to 86 degrees F) are stable as follows: 4 hours (UCB [Keppra] , X-GEN , West-Ward , Sagent , Mylan , AuroMedics , and Jubilant ); and 24 hours (Hospira , Fresenius Kabi , American Regent , Nexus ).
During clinical trials for the adjunct treatment of all seizure types studied in adult or pediatric patients 4 years of age and older, centrally-mediated effects reported more frequently in patients receiving levetiracetam vs. placebo included: headache (14% vs. 13%), dizziness (5% to 9% vs. 2% to 4%), vertigo (3% to 5% vs. 1% to 3%), paresthesias (2% vs. 1%), hyperreflexia (2% vs. 1%), and fatigue (10% vs. 8%). Ataxia (3% vs. 1%) was reported, causing treatment discontinuation in 0.4% of treated patients (vs. 0% placebo) and one levetiracetam-treated patient was hospitalized due to worsening of pre-existing ataxia. Drowsiness was reported in these trials (12% to 23% vs. 2% to 11%) and also in trials of pediatric patients 1 month to less than 4 years of age (13% vs. 2% placebo); of note, drowsiness occurred more frequently within the first 4 weeks of treatment. Approximately 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. During clinical trials of extended-release tablets, drowsiness occurred in 8% of adults who received levetiracetam. Somnolence was among the most frequently reported adverse reactions when levetiracetam was used in conjunction with other antiepileptic drugs. Dose reductions because of coordination difficulties occurred in 0.7% of treated patients and 0.2% of placebo patients. Insomnia resulted in discontinuation of treatment in 1.7% of pediatric patients in a clinical trial for myoclonic epilepsy. Adverse reactions are similar between oral and parenteral formulations. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug can not be adequately determined. Choreoathetosis and dyskinesia have been reported with postmarketing use.
During clinical trials for adjunct treatment of all seizure types, in adult or pediatric patients 4 years of age or older, the following were reported more frequently in patients receiving levetiracetam than placebo: lethargy (6% vs. 2% to 5%; this was reported specifically in pediatric patients), asthenia (9% to 15% vs. 3% to 9%), unspecified pain (6% to 7% vs. 3% to 6%), accidental injury (17% vs. 10%), musculoskeletal pain (neck) (2% to 8% vs. 1% to 2%), and arthralgia (2% vs. 0%; this was reported specifically in pediatric patients). Muscular weakness (myasthenia) has been reported with post-marketing use.
During clinical trials of levetiracetam in the adjunct treatment of partial onset seizures in pediatric patients >= 4 years of age, dehydration was reported more frequently in patients receiving levetiracetam (2%) than placebo (1%). The possibility of a similar adverse effect profile should be considered in pediatric patients 1 month to 4 years of age; clinical trial data for this patient population were obtained over a 7-day period and incidences of adverse reactions observed are expected to be lower than in studies of longer duration in older pediatric patients. Adverse reactions to levetiracetam are similar between oral and parenteral formulations. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug can not be adequately determined. Hyponatremia has been reported with post-marketing use.
During clinical trials of levetiracetam in the adjunct treatment of all seizure types studied in adult or pediatric patients 4 years of age and older, the following respiratory effects, infections, and related symptoms were reported more frequently in patients receiving levetiracetam than placebo: cough (2% to 11% vs. 1% to 7%), infection (13% vs. 8%), rhinitis (4% to 13% vs. 3% to 8%), pharyngitis (6% to 10% vs. 0% to 8%), influenza (3% to 8% vs. 2% to 4%), nasopharyngitis (7% to 14% vs. 5%), viral infection (2% vs. 1%), and sinusitis (2% vs. 1%). Nasal congestion (9% vs. 2%) was also reported in pediatric patients. Infection was among the most frequently reported adverse reactions when levetiracetam was used in conjunction with other antiepileptic drugs. The possibility of a similar adverse effect profile should be considered in pediatric patients 1 month to 4 years of age; clinical trial data for this patient population were obtained over a 7-day period, and incidences of adverse reactions observed are expected to be lower than in studies of longer duration in older pediatric patients. Adverse reactions to levetiracetam are similar between oral and parenteral formulations. Respiratory failure led to levetiracetam discontinuation during a clinical trial of the extended-release tablets. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug cannot be adequately determined.
During clinical trials of levetiracetam in the adjunct treatment of all seizure types studied in adult or pediatric patients 4 years and older, the following gastrointestinal effects were reported more frequently in patients receiving levetiracetam than placebo: nausea (5% vs. 3%), anorexia (3% to 13% vs. 2% to 8%), vomiting (15% vs. 14%), diarrhea (8% vs. 7%), gastroenteritis (4% vs. 2%), constipation (3% vs. 1%), upper abdominal pain (9% vs. 8% pediatric). Weight loss has been reported in patients receiving levetiracetam worldwide, although the data are insufficient to establish causation for these postmarketing reports or to support an estimate of their incidence. The possibility of a similar adverse effect profile should be considered in pediatric patients 1 month to 4 years of age; clinical trial data for this patient population were obtained over a 7-day period, and incidences of adverse reactions observed are expected to be lower than in studies of longer duration in older pediatric patients. Adverse reactions to levetiracetam are similar between oral and parenteral formulations. Oral ulceration led to levetiracetam discontinuation during a clinical trial of the extended-release tablets. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug cannot be adequately determined.
Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Rare cases of suicidal ideation have been noted in the manufacturer's labeling. Four (0.5%) patients receiving immediate-release levetiracetam attempted suicide compared to no placebo patients; one of these patients was successful. In the other 3 patients, treatment was not discontinued nor was the levetiracetam dose reduced. Depression was reported in 3-5% of adult or pediatric patients >= 4 years of age receiving levetiracetam versus 1-2% of those receiving placebo in the adjunct treatment of all seizure types studied. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
Non-psychotic behavioral symptoms (e.g., aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesis, irritability, nervousness, neurosis, and personality disorder) were reported more frequently with levetiracetam than placebo in adults (13% vs. 6%) and children 4 to 16 years (38% vs. 19%) during clinical trials. Results from a study assessing neurocognitive and behavioral effects in children 4 to 16 years showed a worsening in aggressive behavior among those receiving levetiracetam. Depression (3% to 5% vs. 1% to 2%), anxiety (2% vs. 1%), nervousness (4% vs. 2%), amnesia (2% vs. 1%), hostility (2% vs. 1%), and emotional lability (2% to 5% vs. 0% to 1%) were reported more frequently in adults and pediatric patients 4 years and older receiving levetiracetam than those receiving placebo in clinical trials for the adjunct treatment of all seizure types. Altered mood (3% vs. 1%), confusion (2% vs. 0%), affect lability (2% vs. 1%), agitation (4% vs. 1%), abnormal behavior (7% vs. 4%), and aggression (10% vs. 5%) were reported more frequently in pediatric patients receiving levetiracetam than those receiving placebo. Irritability was reported more frequently in adults and children receiving levetiracetam than those receiving placebo (6% to 7% vs. 1% to 2%) and was also reported in pediatric patients 1 month to 4 years (11.7% vs. 0%). During clinical trials of extended-release tablets, irritability occurred in 7% of adults who received levetiracetam. The possibility of other psychiatric effects should be considered in pediatric patients 1 month to 3 years; clinical trial data for this patient population were obtained over a 7-day period, and incidences of adverse effects observed are expected to be lower than in studies of longer duration in older pediatric patients. Psychosis (e.g., hallucinations) was reported more frequently with levetiracetam than placebo in adults (1% vs. 0.2%) and children 1 month to 4 years (17% vs. 5%). Two (0.3%) adults were hospitalized due to psychosis; symptoms resolved within 1 to 2 weeks of treatment discontinuation. The incidence of psychosis in children 4 to 16 years was similar between active treatment and placebo (2%). Paranoia was reported in 1.6% of children 4 to 16 years receiving levetiracetam vs. none receiving placebo. Panic attacks and obsessive-compulsive disorder (OCD) have been described during postmarketing use.
The incidence of rash with levetiracetam use is low (less than 1%); however, those that do occur can be severe. Erythema multiforme, as well as more serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported, although the frequencies are unknown. In addition, rare cases describing widespread pruritic reticular eruption, acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been associated with levetiracetam use. Severe hypersensitivity reactions usually occur within 1 month of treatment; however, a prolonged duration of therapy should not preclude the possibility of an association to the drug. For SJS and TEN, the median time to onset is 14 to 17 days, although symptoms have developed 4 months or longer after initiation of treatment. DRESS can develop 2 to 8 weeks after starting therapy and typically presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection; other organ systems may be involved. Eosinophilia is often present. Early manifestations of hypersensitivity, such as fever and lymphadenopathy, may be present without evidence of a rash. Discontinue levetiracetam in persons presenting with a rash or symptoms indicative of a hypersensitivity reaction in whom an unrelated etiology cannot be identified. Recurrence of serious skin reactions has been reported upon re-challenge with levetiracetam; do not resume therapy if a severe hypersensitivity reaction is suspected. Levetiracetam has also been associated with pulmonary hypersensitivity reaction; a 9-year-old girl with a history of epilepsy, cerebral palsy, mental retardation, microcephaly, asthma, and recurrent aspiration pneumonia receiving low dose levetiracetam for more than 2 years developed diffuse interstitial pneumonitis presumably triggered by a levetiracetam dosage escalation. The pneumonitis resolved after drug discontinuation and steroid therapy. Less severe hypersensitivity reactions such as pruritus and alopecia have been reported during clinical trials and postmarketing experience, respectively. In cases of alopecia, recovery occurred after drug discontinuation in most cases.
During clinical trials of levetiracetam in the adjunct treatment of all seizure types studied in adult or pediatric patients >= 4 years of age, the following ophthalmic or otic effects were reported more frequently in patients receiving levetiracetam than placebo: diplopia (2% vs. 1%), conjunctivitis (3% vs. 2%), amblyopia (2% vs. 0%), and otalgia (2% vs. 0%). During a controlled clinical trial in pediatric patients evaluating immediate-release levetiracetam in conjunction with other anticonvulsants for myoclonic seizures, a dose reduction or discontinuation of levetiracetam occurred in 1.7% of patients due to diplopia. The possibility of a similar adverse effect profile should be considered in pediatric patients 1 month to 4 years of age; clinical trial data for this patient population were obtained over a 7-day period and incidences of adverse reactions observed are expected to be lower than in studies of longer duration in older pediatric patients. Adverse reactions to levetiracetam are similar between oral and parenteral formulations. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug can not be adequately determined.
Levetiracetam can cause hematologic abnormalities, including anemia, leukopenia, decreased neutrophil count, and eosinophilia. Pancytopenia (with bone marrow suppression identified in some cases), thrombocytopenia, and agranulocytosis have been reported with postmarketing use. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders. In a study assessing neurocognitive and behavioral effects in children 4 to 16 years of age, 8.6% of those receiving levetiracetam had a high eosinophil count that was possibly clinically significant (vs. 6.1% placebo). Adult patients having at least one possibly significant report of decrease in white blood cell count (WBC of 2.8 x 109/L or less) was reported (3.2% levetiracetam vs. 1.8% placebo). Similarly, at least one possibly significant report of decreased neutrophil count (1 x 109/L or less) was reported in adult patients (2.4% levetiracetam vs. 1.4% placebo); of the adults with neutropenia, all but one increased towards or to baseline counts with continued treatment. Mean decreases from baseline seen in pediatric patients were -0.4 x 109/L for WBC and -0.3 x 109/L for neutrophil count, compared to small increases in the placebo group. Mean lymphocyte counts increased significantly by 1.7% in the levetiracetam pediatric group (vs. decrease of 4% in placebo patients). More pediatric patients had a possibly clinically significant abnormally low WBC value (3% levetiracetam vs. 0% placebo); there was no apparent difference in neutrophil count between treatment groups. No pediatric or adult patient discontinued treatment secondary to low WBC or neutrophil counts. Minor, but statistically significant, decreases compared to placebo in total mean red blood cell count (0.03 x 106/L), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were observed in levetiracetam-treated patients in controlled trials. Ecchymosis was reported in one pediatric study of partial onset seizures (4% levetiracetam vs. 1% placebo).
During clinical trials of orally administered levetiracetam in the adjunct treatment of all seizure types studied in adults or pediatric patients 4 years of age and older, the following renal effects were reported more frequently in patients receiving levetiracetam than placebo: proteinuria reported as albuminuria (4% vs. 0%) and urine abnormality (2% vs. 1%). Acute kidney injury has been observed during post-marketing experience. The following hepatic effects have been reported in patients receiving levetiracetam worldwide: elevated hepatic enzymes, hepatitis, and hepatic failure. The data are insufficient to establish causation for these post-marketing reports or to provide an estimate of their incidence.
Pancreatitis has been noted in post-marketing spontaneous reports, but causality with levetiracetam cannot be made and data are insufficient to support an estimate of the incidence. Adverse reactions to levetiracetam are similar between oral and parenteral formulations. Since levetiracetam is used as adjunctive therapy, the incidence of adverse reactions attributable to the drug can not be adequately determined.
Levetiracetam can cause anaphylactoid reactions, including anaphylactic shock, or angioedema after the first dose or at any time during treatment. During the postmarketing period, hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet have been reported. In some cases, reactions were life-threatening and required emergency treatment. If signs or symptoms of anaphylaxis or angioedema develop, discontinue levetiracetam, and administer appropriate pharmacological therapy (e.g. antihistamines, epinephrine, etc.) and supportive care as needed. Permanently discontinue levetiracetam if a clear alternative etiology for the reaction cannot be established. Anaphylactic shock was reported in a neonate receiving levetiracetam 10 mg/kg IV for seizures after initial anticonvulsant medications (unspecified in the report) were not effective. Within seconds, an erythematous rash and urticaria developed on the face and scalp, covering the entire body in approximately 3 minutes. The patient developed hypotension and severe metabolic acidosis; other laboratory values were normal and blood culture was negative. Intramuscular epinephrine was given and cardiopulmonary resuscitation was performed. Blood pressure and blood gases normalized within 60 minutes and the rash began to fade in 18 hours. The event was classified as anaphylactic or anaphylactoid reactions by investigators based on the timing of the reaction in relation to levetiracetam administration, bearing in mind that immunoglobulin E (IgE)-mediated anaphylaxis in neonates is not common due to their weak immune system.
Seizures and drug inefficacy were the predominant serious adverse events in pediatric patients associated with levetiracetam and reported to the FDA during a 5-year time span (2008 to 2012). Worsening of seizures including in persons with SCN8A mutations has been reported with postmarketing use.
During clinical trials, a significantly higher risk of hypertension (increased diastolic pressure) was observed in children 1 month to 3 years of age who were treated with levetiracetam (17%) compared to those treated with placebo (2%). There was no overall difference in the mean diastolic blood pressure between treatment groups and an increased risk was not observed in studies of older children or adults. Monitor young patients for increases in diastolic blood pressure.
Several case reports have implicated levetiracetam as a cause of rhabdomyolysis in both pediatric and adult patients. Symptoms and/or elevated creatine kinase (CK) appeared within days of starting levetiracetam treatment and immediately improved after drug withdrawal. In some cases, patients were asymptomatic with no complaints of myalgia, muscle cramps, or weakness. It has been suggested that seizures cause a slight CK elevation (less than 180 units/L), with peaks 36 to 40 hours post-event. Discontinuation of levetiracetam in patients with persistent CK elevations post-convulsive seizures should be considered. A causality assessment of 48 reports through the Naranjo algorithm deemed a possible correlation between levetiracetam and rhabdomyolysis. No relevant drug interactions were detected in the analysis. Median time to onset was a few days. The pathophysiological mechanism of levetiracetam-induced rhabdomyolysis is unknown.
Levetiracetam is contraindicated in patients with levetiracetam hypersensitivity. Anaphylaxis and angioedema have occurred during treatment.
Avoid abrupt discontinuation of levetiracetam to reduce the risk of increased seizure frequency and status epilepticus. In the event of a serious adverse reaction, rapid discontinuation can be considered.
The clearance of levetiracetam is reduced in patients with renal disease or renal impairment and is correlated with creatinine clearance. The dosage of levetiracetam should be reduced in patients with impaired renal function. Patients on dialysis should not receive extended-release levetiracetam for therapy; immediate-release should be used. Supplemental immediate-release doses are recommended after dialysis for those patients with renal failure who are on hemodialysis.
There are no adequate and well-controlled studies of levetiracetam in pregnant women. Data from pregnancy registries and the published literature spanning 2 decades have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. In animal studies, there was evidence that levetiracetam produced developmental toxicity at doses similar to or greater than human therapeutic doses. Embryofetal death, increased fetal and skeletal malformations, and decreased fetal weight occurred in the offspring of pregnant rabbits given levetiracetam during organogenesis. The no-effect dose for adverse effects on development was approximately equal to the maximum recommended human dose (MRHD) of 3,000 mg on the basis of body surface area (mg/m2). Administration of levetiracetam to rats throughout pregnancy and lactation resulted in increased fetal skeletal variations, decreased fetal weight, and decreased growth in offspring. Increased fetal death and neurobehavioral alterations were seen at the highest dose tested. The no-effect dose for adverse effects on pre- and post-natal development was less than the MRHD on the basis of body surface area. The effect of levetiracetam on labor and delivery in humans is not known. Maternal clearance of levetiracetam is higher during pregnancy compared to baseline, especially during the third trimester; if levetiracetam is continued during pregnancy, monitor seizure frequency closely. A dosage adjustment may be necessary for some patients. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to levetiracetam; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.
Levetiracetam is excreted in human breast milk. In a case series, foremilk samples were taken 3 to 5 days postpartum from 7 women who were taking levetiracetam 1,500 to 3,500 mg/day orally. The mean milk:maternal serum concentration ratio was 1 (range 0.76 to 1.33); however, 6 of the infant corresponding serum concentrations were very low or below the level of quantification. The remaining infant did not have a serum concentration measured at 3 to 5 days of age. Milk concentrations were measured again from 1 or more women at 2 weeks, 4 weeks, 6 to 8 weeks, 4 months, and 10 months postpartum, and the maternal milk:serum ratios were similar to those at 3 to 5 days postpartum. No infant-related adverse effects were noted. In another case series including 11 mother-infant pairs, levetiracetam was excreted into breast milk at a concentration similar to that in maternal plasma; the mean milk:plasma ratio was 1.05 (range 0.78 to 1.55). Assuming a daily milk intake of 150 mL/kg/day, the infant dose was estimated to be approximately 2.4 mg/kg/day. In this study, milk concentrations were single, morning trough concentrations collected between day 4 and 23 after delivery; therefore, total infant exposure over a 24-hour period may differ from this estimate. Although no safe dosage range has been established in the neonatal population, initial doses of 14 mg/kg/day PO are FDA approved for patients as young as 1 month of age. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.
Levetiracetam commonly causes somnolence, fatigue, and dizziness. Somnolence occurs most frequently within the first 4 weeks of treatment. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether levetiracetam adversely affects their mental and/or motor performance. Levetiracetam has been associated with somnolence, fatigue, and behavioral abnormalities.
In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2-2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. Rare cases of suicidal ideation, suicide attempts, and completed suicide have been noted in the manufacturer's labeling. In a controlled clinical trial for the treatment of juvenile myoclonic epilepsy, a dose reduction or discontinuation of levetiracetam occurred in 1.7% of patients due to depressed mood or depression. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Levetiracetam may cause behavioral abnormalities and psychotic symptoms; use with caution in patients who have pre-existing psychosis or schizophrenia. Monitor all patients for psychiatric signs and symptoms and consider therapy discontinuation if such symptoms become apparent. Numerous non-psychotic behavioral symptoms, including aggression, agitation, depression, and irritability, have been reported. Behavioral symptoms were associated with drug discontinuation or dose reduction during clinical trials. Psychosis was reported within the first week of treatment and resolved within 1 to 2 weeks after discontinuation during clinical trials.
No overall differences in safety were observed between geriatric and younger adults in controlled clinical trials for epilepsy; however, there were insufficient numbers of geriatric subjects to adequately assess the effectiveness of the drug in older adult patients. Levetiracetam is known to be substantially excreted by the kidney; the risk of adverse reactions to this drug may be greater in patients with impaired renal function and care should be taken in dose selection based on the degree of renal impairment. Monitoring of renal function may be useful. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If levetiracetam must be used consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
Monitor blood pressure in neonates, infants, and children < 4 years of age receiving levetiracetam. During clinical trials, children 1 month to < 4 years who were treated with levetiracetam had a significantly higher risk of increased diastolic pressure compared to those treated with placebo (17% vs. 2%, respectively). There was no overall difference in the mean diastolic blood pressure between treatment groups, and an increased risk was not observed in studies of older children or adults.
For the treatment of partial seizures:
Oral dosage (immediate-release tablets):
Adults: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.
Adolescents 16 to 17 years: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.
Children and Adolescents 4 to 15 years weighing more than 40 kg: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily.
Children and Adolescents 4 to 15 years weighing 20 to 40 kg: 250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.
Oral dosage (solution):
Adults: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.
Adolescents 16 to 17 years: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.
Children and Adolescents 4 to 15 years: 10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day.
Infants and Children 6 months to 3 years: 10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 25 mg/kg/dose PO twice daily. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day.
Infants 1 to 5 months: 7 mg/kg/dose PO twice daily, initially. Increase the dose by 14 mg/kg/day every 2 weeks to a dose of 21 mg/kg/dose PO twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day.
Neonates*: Safety and efficacy have not been established; however, limited data are available. Initial doses of 10 to 30 mg/kg/day PO titrated to 45 to 60 mg/kg/day PO have been studied. Initial doses of 10 mg/kg/day titrated to 30 mg/kg/day over 3 days were studied in 38 premature and term neonates 23 to 42 weeks gestational age with various seizure types and etiologies. Further dose increases up to 45 to 60 mg/kg/day were allowed at the end of the first week of treatment in cases of persistent seizures or EEG suggestive of low seizure threshold. Therapy was initiated intravenously and changed to oral solution as soon as feasible based on the patient condition. Thirty patients were seizure free at the end of 1 week, and 27 remained seizure free at the end of 4 weeks. A smaller study in 6 neonates 31 to 41 weeks gestational age with various seizure types and etiologies used an initial dose of 10 mg/kg/day PO titrated in increments of 10 mg/kg/day PO to a maximum of 50 mg/kg/day PO. All patients became seizure free within 6 days, and 5 remained seizure free at 3 months.
Oral dosage (fast-melting tablets):
Adults: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.
Children and Adolescents 4 to 17 years weighing more than 40 kg: 500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.
Children and Adolescents 4 to 17 years weighing 20 to 40 kg: 250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.
Oral dosage (extended-release tablets):
Adults: 1,000 mg PO once daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day.
Children and Adolescents 12 to 17 years weighing 50 kg or more: 1,000 mg PO once daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day.
Intravenous dosage:
Adults: 500 mg IV twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.
Adolescents 16 to 17 years: 500 mg IV twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.
Children and Adolescents 4 to 15 years: 10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose IV twice daily. Max: 3,000 mg/day. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day.
Infants and Children 6 months to 3 years: 10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 25 mg/kg/dose IV twice daily. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day.
Infants 1 to 5 months: 7 mg/kg/dose IV twice daily, initially. Increase the dose by 14 mg/kg/day every 2 weeks to a dose of 21 mg/kg/dose IV twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day.
Neonates*: Safety and efficacy have not been established; however, limited data are available. Initial doses of 5 to 30 mg/kg/day IV titrated to 45 to 80 mg/kg/day IV divided twice daily have been studied. Initial doses of 10 mg/kg/day IV titrated to 30 mg/kg/day IV over 3 days were studied in 38 premature and term neonates 23 to 42 weeks gestational age with various seizure types and etiologies. Further dose increases up to 45 to 60 mg/kg/day IV were allowed at the end of the first week of treatment in cases of persistent seizures or EEG suggestive of low seizure threshold. Therapy was changed to oral solution as soon as feasible based on the patient condition. Thirty patients were seizure free at the end of one week and 27 remained seizure free at the end of 4 weeks. A retrospective study in 23 neonates 0 to 41 days of age with various seizure types and etiologies found mean initial doses of 16 mg/kg IV (range 5 to 22 mg/kg) and mean maximum doses of 45 mg/kg/day IV (range 10 to 80 mg/kg/day) administered twice daily. A greater than 50% reduction in seizures occurred within 24 hours in 8 of the 23 patients with seizure termination occurring in 7 patients.
For the treatment of myoclonic seizures in persons with juvenile myoclonic epilepsy as adjunctive therapy:
Oral dosage (immediate-release and fast-melting tablets and solution):
Adults: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 12 to 17 years: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Infants* and Children* 1 to 11 years: 5 to 10 mg/kg/dose PO twice daily, initially. Increase the dose gradually to a dose of 30 to 50 mg/kg/day PO divided twice daily. These doses have been described in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children younger than 4 years. However, a wide dosage range has been used (9 to 139 mg/kg/day). A prospective, observational study of 285 children age 0 to 17 years with refractory epilepsy reported that the majority of children that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range.
Intravenous dosage:
Adults: 500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 12 to 17 years: 500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Infants* and Children* 1 to 11 years: Safety and efficacy have not been established. A mean dose of 50.4 mg/kg/day IV was used in a small retrospective review of 10 pediatric patients ranging in age from 3 weeks to 19 years for a variety of seizure disorders or prophylaxis. Three of the 10 patients were receiving oral levetiracetam before presentation and received IV therapy temporarily due to an inability to continue oral therapy because of intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. An every 12 hours dosage schedule was used for all patients. No adverse effects were reported. The authors note that the majority of patients were very ill, and therefore, adverse effects such as sedation or behavioral problems may have been overlooked.
For the treatment of primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy as adjunctive therapy:
Oral dosage (immediate-release tablets):
Adults: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Adolescents 16 to 17 years: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 6 to 15 years weighing 20 kg or more: 10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. Round dose to the nearest whole tablet. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.
Oral dosage (solution):
Adults: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Adolescents 16 to 17 years: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 6 to 15 years: 10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.
Infants and Children 1 month to 5 years*: 5 to 10 mg/kg/dose PO twice daily, initially. Increase the dose gradually to a dose of 30 to 50 mg/kg/day PO divided twice daily. These doses have been described in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children younger than 4 years. However, a wide dosage range has been used (9 to 139 mg/kg/day). A prospective, observational study of 285 children age 0 to 17 years with refractory epilepsy reported that the majority of children that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range.
Neonates*: 10 to 30 mg/kg/day PO, initially. Increase the dose by 10 mg/kg/day every 3 days or more to a dose of 45 to 60 mg/kg/day. Initial doses of 10 mg/kg/day titrated to 30 mg/kg/day over 3 days were studied in 38 premature and term neonates 23 to 42 weeks gestational age with various seizure types and etiologies. Further dose increases up to 45 to 60 mg/kg/day were allowed at the end of the first week of treatment in cases of persistent seizures or EEG suggestive of low seizure threshold. Therapy was initiated intravenously and changed to oral solution as soon as feasible based on the neonate's condition. At the end of 1 week, 30 neonates were seizure free, and at the end of 4 weeks, 27 remained seizure free. A smaller study in 6 neonates 31 to 41 weeks gestational age with various seizure types and etiologies used an initial dose of 10 mg/kg/day PO titrated in increments of 10 mg/kg/day PO to a maximum of 50 mg/kg/day. All neonates became seizure free within 6 days and 5 remained seizure free at 3 months.
Oral dosage (fast-melting tablets):
Adults: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 6 to 17 years weighing more than 40 kg: 500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 6 to 17 years weighing 20 to 40 kg: 250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.
Intravenous dosage:
Adults: 500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Adolescents 16 to 17 years: 500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Children and Adolescents 6 to 15 years: 10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose IV twice daily. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.
Infants and Children 1 month to 5 years*: Safety and efficacy have not been established. A mean dose of 50.4 mg/kg/day IV was used in a small retrospective review of 10 pediatric patients ranging in age from 3 weeks to 19 years for a variety of seizure disorders or prophylaxis. Three of the 10 patients were receiving oral levetiracetam prior to presentation and received IV therapy temporarily due to an inability to continue oral therapy because of intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. An every 12 hours dosage schedule was used for all patients. No adverse effects were reported. The authors note that the majority of patients were very ill, and therefore, adverse effects such as sedation or behavioral problems may have been overlooked.
Neonates*: Safety and efficacy have not been established; however, limited data are available. Initial doses of 5 to 30 mg/kg/day IV titrated to 45 to 80 mg/kg/day IV divided twice daily have been studied. Initial doses of 10 mg/kg/day IV titrated to 30 mg/kg/day IV over 3 days were studied in 38 premature and term neonates 23 to 42 weeks gestational age with various seizure types and etiologies. Further dose increases up to 45 to 60 mg/kg/day IV were allowed at the end of the first week of treatment in cases of persistent seizures or EEG suggestive of low seizure threshold. Therapy was changed to oral solution as soon as feasible based on the patient's condition. Thirty patients were seizure free at the end of 1 week, and 27 remained seizure free at the end of 4 weeks. A retrospective study in 23 neonates 0 to 41 days of age with various seizure types and etiologies found mean initial doses of 16 mg/kg/dose IV (range 5 to 22 mg/kg/dose) and mean maximum doses of 45 mg/kg/day IV (range 10 to 80 mg/kg/day) administered twice daily. A greater than 50% reduction in seizures occurred within 24 hours in 8 of the 23 patients with seizure termination occurring in 7 patients.
For the treatment of status epilepticus* or acute repetitive seizures*:
-for the first-line treatment of status epilepticus* in adults:
Intravenous dosage:
Adults: 60 mg/kg/dose (Max: 4,500 mg/dose) IV as a single dose, or alternatively, 1,000 to 4,500 mg IV as a single dose.
-for the treatment of status epilepticus* in infants, children, and adolescents:
Intravenous dosage:
Infants, Children, and Adolescents: 60 mg/kg (Max: 4,500 mg) IV as a single dose.
-for the treatment of status epilepticus* or acute repetitive seizures* in neonates:
Intravenous dosage:
Neonates: Safety and efficacy have not been established. In a retrospective study of 22 neonates, a loading dose of 50 mg/kg IV was used in the majority of patients (n = 20); 1 patient each received loading doses of 10 and 20 mg/kg IV. Maintenance doses of 25 mg/kg IV every 12 hours were used in the majority of patients (range 10 to 25 mg/kg IV given every 8 to 12 hours). Immediate seizure cessation (within 1 hour of loading dose) was seen in 86% of patients and all 22 patients achieved complete seizure cessation by 72 hours of therapy.
For seizure prophylaxis*:
-for seizure prophylaxis* after traumatic brain injury:
Intravenous dosage:
Adults: 500 to 1000 mg IV every 12 hours for 7 days; adjust as needed for clinical effect up to Max: 3000 mg/day. A 20 mg/kg IV loading dose may be considered. Clinical practice guidelines support anticonvulsant use to prevent early post traumatic seizures, within 7 days of injury.
-for early post-traumatic seizure prophylaxis* after traumatic brain injury in pediatric patients:
Intravenous dosage:
Infants, Children, and Adolescents: 20 to 40 mg/kg/day IV divided twice daily, with a range of 5 to 40 mg/kg/day has been reported. Seizure prophylaxis is recommended to reduce the occurrence of early post-traumatic seizures; levetiracetam may be considered. In a prospective, observational study of 34 pediatric patients (age range: 5 days to 16 years, median 6 years) with moderate to severe traumatic brain injury (TBI), the median dose was 20 mg/kg/day, with a dosage range of 5 to 40 mg/kg/day. Seizures developed in 6 of 34 treated patients (17.6%) and were more likely to develop in younger patients (median age 4 months vs. 10 years; p less than 0.0001). In 2 retrospective studies of pediatric patients (median age 6 to 7.5 years) with TBI, the median dose was 20 mg/kg/day, with a dosage range of 5 to 40 mg/kg/day. The incidence of seizures in treated patients ranged from 9% to 13.6%.
-for late post-traumatic seizure prophylaxis* after traumatic brain injury in pediatric patients:
Oral dosage:
Children and Adolescents: 55 mg/kg/day PO divided twice daily. In a phase 2 trial of 20 patients aged 6 to 17 years with traumatic brain injury (TBI) treated with levetiracetam within 8 hours of injury and continued for 30 days, 1 patient developed post-traumatic epilepsy more than 7 days after the trauma.
-for seizure prophylaxis* after subarachnoid hemorrhage:
Intravenous dosage:
Adults: Dosage not established. 500 mg IV twice daily for 3 days was associated with a higher rate of in-hospital seizures compared to an extended course of phenytoin. Clinical practice guidelines do not recommend routine use of anticonvulsants after subarachnoid hemorrhage; however, they may be considered in the immediate posthemorrhagic period.
Therapeutic Drug Monitoring:
Usual therapeutic serum/plasma concentration: not established
-Therapeutic plasma concentration ranges have not been established. Routine monitoring of plasma concentrations is not recommended; dosing should be based on clinical response. Some experts suggest that there may, however, be a role for periodic plasma concentration measurement in select patients (e.g., critically ill patients with rapid changes in clinical status, patients receiving aggressive dosages and in need of alterations in their drug regimen). In addition, monitoring of plasma concentrations may be beneficial during pregnancy. Obtaining concentrations at baseline prior to planned pregnancy in optimally-managed patients can provide a reference range for comparison during pregnancy, when physiologic changes may result in gradual decreases in levetiracetam concentrations as the pregnancy advances. Monitoring should continue into the postpartum period, particularly if the dosage was changed during pregnancy.
-Therapeutic efficacy has been reported with a wide range of plasma concentrations (5-65 mcg/ml) in retrospective reviews of pediatric and adult patients with various seizure types. There is also no standard for when to measure plasma concentrations (i.e., peak, trough, or random). -In one review of 29 patients (79% with partial seizures and 21% with generalized seizures), plasma concentrations >= 35 mcg/ml were associated with a >= 75% reduction in seizures ; however, data from another review suggests that behavioral adverse events are more common in patients with higher plasma concentrations. Other investigations have not found a direct correlation between blood concentration and efficacy.
-No clear correlation between levetiracetam plasma concentrations and drug efficacy was found in a prospective analysis of 37 pediatric patients (mean age: 11.45 years [range: 2.75-18 years]) with generalized or partial epilepsy taking oral levetiracetam. A >= 50% reduction in seizure frequency occurred in 30 patients (81%); 11 of these patients (30% of the total group) were seizure-free. Of the seizure-free patients, plasma levetiracetam concentrations ranged from 6.85-40 mcg/ml; patients considered non-responders (n = 6) had plasma concentrations that ranged from 1.89-46.66 mcg/ml.
-A plasma concentration of 10-40 mcg/ml was used as the predetermined therapeutic range in a prospective study of 30 patients (mean age: 39.4 years, 25 with focal epilepsy and 5 with generalized epilepsy) receiving 2000-3000 mg of oral levetiracetam as an addition to their current antiepileptic regimen. At the time of levetiracetam plasma concentration evaluation, 5 patients were seizure free; 3 of these patients had drug concentrations at mid-therapeutic range and 2 had concentrations at the lowest end of the range. In addition, 13 patients achieved a >= 50% reduction in seizure frequency; in most of them, plasma concentrations were at the lowest end of the range with the remaining at the mid-high range. Twelve patients were considered non-responders; of these patients, 2 had plasma concentrations below the therapeutic range, 8 at the lowest end of the range, and 2 at the mid-high range. Levetiracetam concentrations were used to aid in making decisions regarding dosage adjustments.
-Peak levetiracetam concentrations of >= 10 mcg/ml, drawn 1-2 hours after oral ingestion, correlated to a clear suppression or abolishment of intermittent photic stimulation (IPS)-evoked photoparoxysmal EEG response in 9 of 12 patients with photosensitive epilepsy (mean age: 21.5 years [range 13-38 years]). The suppressive effect lasted between 6 and 30 hours despite plasma concentrations < 3 mcg/ml during that time period.
Maximum Dosage Limits:
-Adults
3,000 mg/day PO or IV.
-Geriatric
3,000 mg/day PO or IV.
-Adolescents
16 to 17 years: 3,000 mg/day PO or IV; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
13 to 15 years: 60 mg/kg/day PO or IV (Max: 3,000 mg/day); 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
-Children
12 years weighing more than 40 kg: 60 mg/kg/day PO (oral solution) or IV (Max: 3,000 mg/day); 3,000 mg/day for immediate-release, fast-melting, and extended-release tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
12 years weighing 20 to 40 kg: 60 mg/kg/day PO (oral solution) or IV; 1,500 mg/day for immediate-release and fast-melting tablets; 3,000 mg/day for extended-release tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
4 to 11 years weighing more than 40 kg: 60 mg/kg/day PO (oral solution) or IV (Max: 3,000 mg/day); 3,000 mg/day for immediate-release and fast-melting tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
4 to 11 years weighing 20 to 40 kg: 60 mg/kg/day PO (oral solution) or IV; 1,500 mg/day for immediate-release and fast-melting tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
1 to 3 years: 50 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
-Infants
6 to 11 months: 50 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
1 to 5 months: 42 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
-Neonates
Safety and efficacy have not been established; doses of up to 60 mg/kg/day PO and 80 mg/kg/day IV have been have been reported for the off-label treatment of seizures.
Patients with Hepatic Impairment Dosing
According to the FDA-approved labeling, no dosage adjustment is necessary in patients with hepatic impairment unless decreased renal function is also present, in which case the adjustment for renal dysfunction should be followed. Serum creatinine may not always be a reliable indicator for renal function in severe liver disease. Levetiracetam is not extensively metabolized by the liver. According to an in vivo pharmacokinetic study, patients with severe hepatic impairment (Child-Pugh Class C) should initially receive one-half of the recommended dose.
Patients with Renal Impairment Dosing
Adults
CrCl more than 80 mL/minute/1.73m2: No dosage adjustment necessary.
CrCl 50 to 80 mL/minute/1.73m2: 500 to 1,000 mg PO immediate-release tablets or IV every 12 hours; 1,000 to 2,000 mg PO extended-release tablets every 24 hours.
CrCl 30 to 49 mL/minute/1.73m2: 250 to 750 mg PO immediate-release tablets or IV every 12 hours; 500 to 1,500 mg extended-release tablets every 24 hours (Keppra XR and generic equivalents). Elepsia XR is not recommended.
CrCl less than 30 mL/minute/1.73m2: 250 to 500 mg PO immediate-release tablets or IV every 12 hours; 500 to 1,000 mg extended-release tablets every 24 hours (Keppra XR and generic equivalents). Elepsia XR is not recommended.
Pediatrics
Dosage adjustment is necessary; however, pediatric-specific recommendations are not provided in FDA-approved labeling. Elepsia XR is not recommended in patients with moderate to severe renal impairment. The following dose adjustments have been recommended for pediatric patients:
GFR more than 50 mL/minute/1.73m2: No dosage adjustment necessary.
GFR 50 mL/minute/1.73m2 or less: Reduce the usual dose by 50%.
Intermittent hemodialysis
Adults
500 to 1,000 mg PO immediate-release tablets or IV every 24 hours with a supplemental 250 to 500 mg dose after dialysis. Do not use extended-release levetiracetam in patients with ESRD on dialysis. Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours.
Pediatrics
Reduce the usual dose by 50% and administer every 24 hours; give a supplemental dose after hemodialysis. Do not use extended-release levetiracetam in patients with ESRD on dialysis. Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours.
Peritoneal dialysis
Adults
500 to 1,000 mg PO immediate-release tablets or IV every 24 hours.
Pediatrics
Reduce the usual dose by 50%.
Continuous renal replacement therapy
Adults
250 to 750 mg PO immediate-release tablets or IV every 12 hours.
Pediatrics
Reduce the usual dose by 50%.
Augmented renal clearance
Adults
Dosage adjustment may be required; further studies are necessary to determine a safe and effective dose in patients with augmented renal clearance (ARC). Pharmacokinetic simulation has suggested doses of 1,500 mg and 2,000 mg IV every 12 hours for adult patients with CrCl of 80 and 120 mL/minute, respectively, and doses of 1,500 mg and 2,000 mg IV every 8 hours for adult patients with CrCl of 160 and 200 mL/minute, respectively, maybe required to attain a therapeutic trough concentration (more than 12 mg/L). Extending infusion time did not increase the probability of reaching the targeted trough. CrCl more than 130 mL/minute/1.73 m2 is the most widely used threshold to define ARC in adults. Urinary CrCl is the most accurate and feasible method to identify ARC. ARC is a state of increased renal function from baseline which leads to enhanced elimination and subtherapeutic drug concentrations in critical care patients.
Pediatrics
Dosage adjustment may be required. Age-dependent thresholds for pediatric patients have not been defined, but CrCl more than 130 mL/minute/1.73 m2 is the most widely used threshold in adults. Urinary CrCl is the most accurate and feasible method to identify augmented renal clearance (ARC). ARC is a state of increased renal function from baseline which leads to enhanced elimination and subtherapeutic drug concentrations in critical care patients.
*non-FDA-approved indication
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
Carbamazepine: (Moderate) Closely monitor patients for signs or symptoms of carbamazepine toxicity, such as vision changes, unstable gait, ataxia, dizziness, nausea, or vomiting during coadministration of carbamazepine and levetiracetam. Carbamazepine toxicity, unrelated to elevated concentrations of carbamazepine or the epoxide, may occur when levetiracetam is added to carbamazepine therapy. The interaction appears to be pharmacodynamic in nature rather than pharmacokinetic. Toxicity was reversed when the dose of carbamazepine was reduced.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of levetiracetam if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants such as levetiracetam at least 1 hour before or at least 4 hours after colesevelam.
Hydroxychloroquine: (Moderate) Monitor persons with epilepsy for seizure activity during concomitant levetiracetam and hydroxychloroquine use. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Some, but not all anticonvulsants, induce CYP3A4 and may increase the metabolism of mefloquine. Use of enzyme-inducing anticonvulsants can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Probenecid: (Minor) The renal clearance of the major metabolite of levetiracetam, UCB L057, is decreased by 60 percent in the presence of probenecid. This is probably related to competitive inhibition of tubular secretion of UCB L057. The clinical significance of this is unknown.
Probenecid; Colchicine: (Minor) The renal clearance of the major metabolite of levetiracetam, UCB L057, is decreased by 60 percent in the presence of probenecid. This is probably related to competitive inhibition of tubular secretion of UCB L057. The clinical significance of this is unknown.
Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
The precise mechanism of action of levetiracetam is not known. Its antiepileptic effect does not appear to involve known mechanisms relating to inhibitory and excitatory neurotransmission. In animal models, levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants. It also showed only minimal activity in submaximal stimulation in threshold tests. Levetiracetam did, however, protect against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, which is another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain.
In vitro studies show that levetiracetam, up to 1700 mcg/ml, did not result in significant ligand displacement at known receptor binding sites. Second messenger systems, ion channel proteins, glutamate receptor-mediated neurotransmission, muscimol-induced chloride flux, and gamma-aminobutyric acid (GABA)-transaminase and glutamate decarboxylase activities were unaffected by levetiracetam. Benzodiazepine receptor antagonists (e.g., flumazenil) had no effect on levetiracetam's protection against seizures. Conversely, a stereoselective binding site for the drug has been demonstrated to exist exclusively in synaptic plasma membranes in the CNS, but not in peripheral tissue.
In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability. This suggests that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
Levetiracetam is administered orally and intravenously. Protein binding is less than 10%, making competition for protein binding sites and clinically significant interactions with other drugs unlikely. Vd is 0.7 L/kg. Levetiracetam is not extensively metabolized. Approximately 24% of the administered dose is metabolized via enzymatic hydrolysis of the acetamide group, producing a pharmacologically inactive carboxylic acid metabolite, ucb L057. Two minor metabolites produced via hydroxylation (2% of administered dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of administered dose) have also been identified. Metabolism is not dependent on hepatic cytochrome P450 isoenzymes (CYP), although research has identified that minor CYP metabolism may exist. Levetiracetam is excreted renally via glomerular filtration with subsequent partial tubular reabsorption; approximately 66% of the administered dose is eliminated unchanged. Total body clearance is 0.96 mL/kg/minute and renal clearance is 0.6 mL/kg/minute in adults. The metabolite ucb L057 is excreted via glomerular filtration and active tubular secretion with a renal clearance of 4 mL/kg/minute. Levetiracetam plasma half-life in adults is about 6 to 8 hours for all dosage forms. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra- and inter-patient variability.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
Bioavailability of immediate-release (IR) and extended-release (ER) formulations are similar. Administration of levetiracetam with food does not affect overall bioavailability, but prolongs Tmax and alters Cmax.
Immediate-release formulations
Levetiracetam fast-melting tablets (Spritam) disintegrate in a mean time of 11 seconds (range, 2 to 27 seconds), when taken with a small sip of liquid, resulting in small particles that may be swallowed. Absorption of IR levetiracetam is rapid, with peak plasma concentrations occurring approximately 1 hour after oral administration under fasting conditions in both pediatric and adult patients. Oral bioavailability of the IR tablets is 100%; IR tablets and oral solution are bioequivalent. In addition, fast-melting tablets (Spritam) have been shown to have equivalent rate and extent of absorption to IR levetiracetam tablets. Food does not affect the extent of absorption, but decreases Cmax by 20% to 36% and delays Tmax by 1.5 to 3.4 hours. The pharmacokinetics are linear and dose-proportional over a dosage range of 500 to 5,000 mg/day in adult patients. Steady state is achieved after 2 days of twice-daily dosing.
Extended-release formulations
Absorption of the ER tablets is slower, with peak plasma concentrations occurring approximately 4 hours after oral administration. Oral bioavailability of the ER tablets is nearly 100%. Single administration of equivalent daily doses (e.g., two 500 mg ER tablets once daily compared to one 500 mg IR tablet twice daily) produces a comparable Cmax and AUC under fasting conditions to those of IR tablets. After multiple dose administration, AUC is similar between the 2 dosage forms; however, Cmax and Cmin are 17% and 26% lower, respectively, with administration of the ER tablets compared to the IR tablets. Intake of a high fat, high calorie breakfast before ER tablet administration results in a higher Cmax and longer mean Tmax; Tmax is approximately 2 hours longer when administered with food. The pharmacokinetics of ER levetiracetam are linear and dose-proportional over a dosage range of 1,000 to 3,000 mg/day in adult patients. Elepsia XR and Keppra XR tablets are bioequivalent in the fed and fasted states.
Intravenous Route
Levetiracetam injection and immediate-release oral formulations are bioequivalent. Equivalent doses of each formulation result in comparable Cmax, Cmin, and AUC when the IV formulation is administered as a 15 minute infusion. This equivalence was demonstrated in a bioavailability study of 17 healthy adult volunteers, where levetiracetam 1,500 mg IV, administered over 15 minutes, provided similar plasma concentrations at the end of infusion compared to those achieved at the Tmax of an equivalent oral dose.
-Special Populations
Hepatic Impairment
The pharmacokinetics of levetiracetam are unchanged in adult patients with mild to moderate hepatic impairment (Child Pugh Class A or B). In patients with severe hepatic impairment (Child Pugh Class C), total body clearance is 50% that of normal subjects; decreased renal clearance accounts for most of the decrease. The rate of formation of ucb L057, the major metabolite, is not influenced by liver disease.
Renal Impairment
The clearance of levetiracetam is correlated with creatinine clearance (CrCl). Total body clearance is reduced by 40% in adult patients with mild renal impairment (CrCl 50 to 80 mL/minute), 50% in those with moderate impairment (CrCl 30 to 50 mL/minute), 60% in those with severe impairment (CrCl less than 30 mL/minute), and 70% in those with anuria (end stage renal disease).
Hemodialysis
Approximately 50% of the total levetiracetam pool in the body is removed during a standard 4-hour hemodialysis session.
Pediatrics
A population pharmacokinetic analysis for the IV formulation was conducted in 49 pediatric patients (1 month to 15 years) weighing 3 to 79 kg. After receiving levetiracetam 14 to 60 mg/kg/day administered as two 15-minute infusions each day, plasma concentrations and model derived steady state exposure were within the range of the exposure observed in pediatric patients receiving equivalent oral doses.
Infants, Children, and Adolescents
The pharmacokinetic profile of levetiracetam in infants and children is similar to that of adults with the exception of more rapid clearance. Small multicenter, open-label, single-dose studies have highlighted minor pharmacokinetic differences between infants and young children (n = 12; age range: 2 months to 4 years) and older children (n = 24; age range: 5 to 12 years) with epilepsy. In both studies, absorption of levetiracetam after a 20 mg/kg dose was rapid, reaching a mean Cmax of 31 +/- 7 mcg/mL in 1.4 +/- 0.9 hours in infants and young children and 26 +/- 9 mcg/mL in 2.3 +/- 1.2 hours in older children. Mean AUC ranged from 241 to 248 mcg x hour/mL. Among all age groups, infants younger than 6 months showed the highest mean Cmax and AUC. Elimination half-lives were comparable among all age groups, reported as 5.3 +/- 1.3 hours, 6 +/- 1.1 hours, and 7 +/- 1 hours in infants and young children, older children, and adults, respectively. Clearance values in infants younger than 6 months (1.23 mL/kg/minute), infants and children 6 months to 4 years (1.57 mL/kg/minute), and children 6 to 12 years (1.43 mL/kg/minute) were significantly greater than those of adults (0.96 mL/kg/minute); clearance values in children are approximately 30% to 40% higher than in adults. These age-dependent differences suggest infants and children may require higher weight-based doses of levetiracetam compared to adults.
Neonates
In newly born neonates, limited data suggest the clearance of levetiracetam is lower, the Vd is higher, and the half-life is longer as compared to older children and adults. A pharmacokinetic study in 18 neonates receiving levetiracetam found a median clearance of 1.21 mL/kg/minute (range 0.47 to 2.89 mL/kg/minute), a median Vd of 0.89 L/kg (range 0.37 to 1.26 L/kg), and a median half-life of 8.9 hours (range 3.2 to 13.3 hours). This effect is even more pronounced in the first week of life. In a small case series that included 12 neonates exposed to levetiracetam in utero, the mean elimination half-life during the first 36 hours after delivery was 18 hours (range 6 to 28). All but 1 neonate were breastfed and may have been exposed to levetiracetam via breast milk.
Geriatric
In elderly subjects aged 61 to 88 years receiving immediate-release levetiracetam, total body clearance decreased by 38% compared to younger healthy adults, but this change was most likely due to a decrease in renal function.
Gender Differences
The Cmax and AUC of extended-release levetiracetam were higher in women compared to men in a limited number of patients. However, the clearances adjusted for body weight were comparable.
Obesity
Children and Adolescents with Obesity
Differences in exposures between pediatric patients who are obese and those who are non-obese are not expected to be clinically significant. The recommended dose titration at treatment initiation should establish an appropriate dose for each individual. When the recommended oral solution dose is administered, patients who are obese have a 25% higher median Cmax and 41% higher median Cmin compared to those who are non-obese. When the recommended tablet dose is administered to patients weighing less than 40 kg, patients who are obese have a 27% higher median Cmax and 19% higher Cmin compared to patients who are non-obese. For patients weighing 40 kg or more, those with obesity have a 10% to 11% lower median Cmax and 2% lower median Cmin compared to patients who are non-obese.
Other
Pregnancy
Levetiracetam crosses the placenta, and maternal clearance of levetiracetam is increased during pregnancy. In a small case series, the mean umbilical cord blood to maternal plasma concentration ratio at delivery was 1.09 (range 0.64 to 2, n = 13). The maternal apparent clearance was higher during all 3 trimesters compared to baseline, with the fastest clearance in the third trimester (mean apparent clearance was 427.3 +/- 211.3 L/day during the third trimester compared to 124.7 +/- 57.9 L/day at baseline, n = 12). Of note, the authors did not account for changes in maternal body weight in the clearance calculations.