LEVETIRACETAM ER (Generic for KEPPRA XR)

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; 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. Do not use if particulate matter or discoloration is present.
Intravenous Administration
-Dilute the dose in 100 mL of compatible diluent (0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's 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 ).

With the exception of increased diastolic blood pressure in children younger than 4 years, the adverse reaction profile of levetiracetam is expected to be similar across pediatric age groups. Clinical trial data for patients 1 month to 3 years of age was obtained over a 7-day period, and because of the shorter exposure period, reported incidences of adverse reactions are most likely lower than in other pediatric studies in older patients. Additionally, because levetiracetam is used as adjunctive antiepileptic therapy, the incidence of adverse reactions attributable to the drug may not be adequately portrayed.

Headache (19% vs. 15%), dizziness (7% vs. 5%), vertigo (5% vs. 3%), fatigue (10% to 11% vs. 5% to 8%), drowsiness (12% to 13% vs. 2% to 9%), hypersomnia (2% vs. 0%), and insomnia (5% vs. 3%) were reported more frequently in patients receiving levetiracetam than those receiving placebo during clinical trials. Insomnia and somnolence resulted in discontinuation of treatment in 2% of patients 12 years and older receiving levetiracetam in a clinical trial for juvenile myoclonic epilepsy. In pediatric patients 1 month to 3 years, drowsiness occurred in 13% of those treated with levetiracetam vs. 2% in the placebo group. Drowsiness occurred more frequently within the first 4 weeks of treatment. Somnolence was among the most frequently reported adverse reactions when levetiracetam was used in conjunction with other antiepileptic drugs. Coordination difficulties, including ataxia and abnormal gait, were reported in 3.4% of adult patients receiving levetiracetam in clinical trials compared to 1.6% of patients receiving placebo. Other adverse reactions reported in adult trials, which included patients 16 years and older, include paresthesias (2%) and hyperreflexia (2%). Choreoathetosis and dyskinesia have been reported with postmarketing use.

During clinical trials of levetiracetam in the adjunct treatment of all seizure types studied in pediatric patients 4 years of age and older, the following general reactions were reported more frequently in patients receiving levetiracetam than placebo: lethargy (6% vs. 2% to 5%), head injury (4% vs. 0%), contusion (3% vs. 1%), fall (3% vs. 2%), joint sprain (2% vs. 1%), musculoskeletal pain (neck) (2% to 8% vs. 1% to 2%), and arthralgia (2% vs. 0%). Asthenia (10% to 15%) has been reported in adult patients. Muscular weakness (myasthenia) has been reported with postmarketing use.

During clinical trials, a significantly higher risk of hypertension (increased diastolic pressure) was observed in pediatric patients 1 month to 3 years 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 pediatric patients or adults. Monitor young patients for increases in diastolic blood pressure.

Dehydration was reported more frequently in patients receiving levetiracetam (2%) than placebo (1%) during clinical trials in pediatric patients 4 years and older. The possibility of a similar adverse reaction profile should be considered in pediatric patients 1 month to 3 years; clinical trial data for this patient population was 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. Hyponatremia has been reported with postmarketing use.

Levetiracetam can cause hematologic abnormalities, including anemia, leukopenia, neutropenia, 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 compared to 6.1% of those receiving placebo. Mean decreases from baseline for white blood cell (WBC) and neutrophil counts were -400 million/L and -300 million/ L, respectively, in pediatric patients compared to small increases in the placebo group. Mean lymphocyte counts increased significantly by 1.7% in the levetiracetam pediatric group vs. a decrease of 4% in placebo patients. More pediatric patients had a possibly clinically significant abnormally low WBC value (3% levetiracetam vs. 0% placebo); however, there was no apparent difference between treatment groups with respect to neutrophil count. No pediatric 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 (30,000/L), mean hemoglobin (0.09 gram/dL), and mean hematocrit (0.38%), were observed in levetiracetam-treated adult patients in controlled trials. Ecchymosis was reported in 1 pediatric study of partial onset seizures in 4% of levetiracetam-treated patients and 1% of placebo-treated patients.

Cough (9% vs. 5%), nasal congestion (9% vs. 2%), rhinitis (2% vs. 0%), pharyngitis (7% vs. 0%), influenza (3% to 5% vs. 1% to 2%), nasopharyngitis (14% to 15% vs. 5% to 12%), and pharyngolaryngeal pain (7% vs. 4%) were reported more frequently in patients receiving levetiracetam than those receiving placebo during clinical trials of oral levetiracetam in pediatric patients 4 years and older. Infection was among the most frequently reported adverse reactions in adult patients when levetiracetam was used in conjunction with other antiepileptic drugs; sinusitis was reported in 2% of adult patients. Respiratory failure led to levetiracetam discontinuation during a clinical trial of the extended-release tablets in adult patients.

Upper abdominal pain (9% vs. 8%), decreased appetite (8% vs. 2%), anorexia (4% vs. 3%), vomiting (15% vs. 12%), diarrhea (6% to 8% vs. 2% to 7%), gastroenteritis (2% vs. 0%), and constipation (3% vs. 1%) were reported more frequently in patients receiving levetiracetam than those receiving placebo during clinical trials of oral levetiracetam in pediatric patients 4 years and older. Nausea was reported in adults during orally administered levetiracetam clinical trials; oral ulceration led to drug discontinuation with extended-release tablets during adult clinical trials. Anorexia and diarrhea have also been reported with the IV formulation. Weight loss has been reported in patients receiving all forms of levetiracetam worldwide; however, frequency and causality have not been established.

Antiepileptic drugs (AEDs) such as levetiracetam increase the risk of suicidal ideation and behavior. Monitor all patients beginning treatment with AEDs or currently receiving such treatment closely 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. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (5 years and older) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2 to 2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur any time during treatment. Rare cases of suicidal ideation have been noted with levetiracetam use. Four (0.5%) patients receiving immediate-release levetiracetam attempted suicide compared to 0% of placebo patients; 1 of these patients was successful. Depression was reported in 3% to 5% of pediatric patients 4 years and older receiving orally administered levetiracetam vs. 1% to 2% of those receiving placebo in the adjunct treatment of all seizure types studied.

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 pediatric patients 4 to 16 years (38% vs. 19%) during clinical trials. Results from a study assessing neurocognitive and behavioral effects in pediatric patients 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%), irritability (6% to 7% vs. 1% to 2%), 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 patients receiving levetiracetam than those receiving placebo during clinical trials in pediatric patients 4 years and older. In pediatric patients 1 month to 4 years, irritability occurred in 12% of those treated with levetiracetam vs. 0% in the placebo group. The possibility of other psychiatric effects should be considered in pediatric patients 1 month to 3 years; clinical trial data for this patient population was 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. Psychosis (e.g., hallucinations) was reported more frequently with levetiracetam than placebo in pediatric patients 1 month to 3 years (17% vs. 5%); the incidence of psychosis in pediatric patients 4 to 16 years was similar between active treatment and placebo (2%). Paranoia and confusional state were reported in 1.6% and 3.1% of pediatric patients 4 to 16 years receiving levetiracetam vs. none receiving placebo. Two (0.3%) adults were hospitalized due to psychosis; symptom resolution occurred within 1 to 2 weeks of treatment discontinuation. Panic attacks and obsessive-compulsive disorder (OCD) have been described during postmarketing use, and amnesia has been reported in adults.

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.

Conjunctivitis (2% vs. 0%) and otalgia (2% vs. 1%) were reported more frequently in patients receiving levetiracetam than those receiving placebo during clinical trials. During a pediatric trial evaluating levetiracetam in conjunction with other anticonvulsants for myoclonic seizures, a dose reduction or discontinuation of levetiracetam occurred in 2% of patients due to diplopia.

Proteinuria reported as albuminuria (4% vs. 0%) and urine abnormality (2% vs. 1%) were reported more frequently in patients receiving oral levetiracetam than those receiving placebo during clinical trials. Acute kidney injury has been observed during postmarketing experience. Elevated hepatic enzymes, hepatitis, and hepatic failure have been reported in patients receiving levetiracetam worldwide; however, frequency and causality have not been established.

Pancreatitis has been noted in postmarketing spontaneous reports; however, frequency and causality have not been established.

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 patients with SCN8A mutations has been reported with postmarketing use.

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. Supplemental doses after dialysis are recommended to those patients with renal failure who are on hemodialysis.

Levetiracetam commonly causes somnolence, fatigue, dizziness, and coordination difficulties. Patients should be advised to use caution when performing activities requiring coordination and concentration (e.g., gymnastics, riding a bicycle, operating a vehicle) until they are aware of whether levetiracetam adversely affects their mental and/or motor performance.

There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. All patients beginning treatment with levetiracetam should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them 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. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (at least 5 years of age) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs 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 to 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.

Levetiracetam may cause behavioral abnormalities and psychotic symptoms; use with caution in patients with preexisting psychosis or schizophrenia. Monitor all patients treated with levetiracetam for psychiatric signs and symptoms, and consider therapy discontinuation if such symptoms become apparent. During clinical trials in adults, psychosis developed within the first week of treatment and resolved within 1 to 2 weeks of discontinuation.

Monitor blood pressure in neonates, infants, and children younger than 4 years of age receiving levetiracetam. During clinical trials, children 1 month to 3 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.

Description: Levetiracetam is a pyrrolidine derivative anticonvulsant used for the treatment of a variety of seizures types (partial-onset, primary generalized tonic-clonic, myoclonic). In children and adolescents, levetiracetam, fosphenytoin, and valproate are equally effective in benzodiazepine-refractory status epilepticus. Levetiracetam should be considered as add-on therapy to decrease seizure frequency in patients with treatment-resistant childhood focal (partial) epilepsy, generalized tonic-clonic seizures, or juvenile myoclonic epilepsy. 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). Both the oral solution and IV formulation are FDA-approved for the treatment of partial seizures in patients as young as 1 month of age; fixed-dose immediate-release tablets are labeled for patients weighing at least 20 kg. The extended-release tablets are approved for use in patients 12 years and older.

General dosing information:
-The conversion of oral to IV levetiracetam is 1:1. When switching from an immediate-release oral product, the initial IV dosage should be equivalent to the dosage and frequency of oral levetiracetam and vice versa.

For the treatment of partial seizures:
Oral dosage (oral solution):
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'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 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.
Infants 1 to 5 months: Initially, 7 mg/kg/dose PO twice daily. Increase the dose every 2 weeks by 7 mg/kg/dose (i.e., 14 mg/kg/day) increments to the recommended dose of 21 mg/kg/dose PO twice daily. If the patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 35 mg/kg/day PO.
Infants and Children 6 months to 3 years: Initially, 10 mg/kg/dose PO twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dose of 25 mg/kg/dose PO twice daily. If the patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day PO.
Children and Adolescents 4 to 15 years: Initially, 10 mg/kg/dose PO twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dose of 30 mg/kg/dose PO twice daily. If the patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day PO (Max: 3,000 mg/day).
Adolescents 16 to 17 years: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to a maximum recommended dosage of 1,500 mg PO twice daily (Max: 3,000 mg/day). Doses greater than 3,000 mg/day have been used in open-label studies for 6 months and longer; however, there is no evidence that doses greater than 3,000 mg/day provide additional benefit.
Oral dosage (immediate-release tablets and fast-melting tablets):
Children and Adolescents 4 to 15 years weighing less than 20 kg: Tablets are not recommended. See dosing for oral solution.
Children and Adolescents 4 to 15 years weighing 20 to 40 kg: Initially, 250 mg PO twice daily. Increase the dosage every 2 weeks by 250 mg/dose (i.e., 500 mg/day) increments to a maximum recommended dose of 750 mg PO twice daily (Max: 1,500 mg/day).
Children and Adolescents 4 to 15 years weighing more than 40 kg: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to a maximum recommended dosage of 1,500 mg PO twice daily (Max: 3,000 mg/day).
Adolescents 16 to 17 years: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to a maximum recommended dosage of 1,500 mg PO twice daily (Max: 3,000 mg/day). Doses greater than 3,000 mg/day have been used in open-label studies for 6 months and longer; however, there is no evidence that doses greater than 3,000 mg/day provide additional benefit.
Oral dosage (extended-release tablets):
Children and Adolescents 12 to 17 years: Initially, 1,000 mg PO once daily. The daily dosage may be increased every 2 weeks in increments of 1,000 mg as needed. Max: 3,000 mg/day.
Intravenous dosage:
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 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.
Infants 1 to 5 months: Initially, 7 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 7 mg/kg/dose (i.e., 14 mg/kg/day) increments to the recommended dose of 21 mg/kg/dose IV twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day in this age group; the effectiveness of lower doses has not been studied.
Infants and Children 6 months to 3 years: Initially, 10 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dose of 25 mg/kg/dose IV twice daily. If a patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day in this age group.
Children and Adolescents 4 to 15 years: Initially, 10 mg/kg/dose IV twice daily. Increase the dosage every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dosage of 30 mg/kg/dose IV twice daily. If a patient cannot tolerate this dose, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day (Max: 3,000 mg/day) in this age group.
Adolescents 16 to 17 years: Initially, 500 mg IV twice daily. The dose may be increased every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments as needed. Max: 3,000 mg/day. There is no evidence that doses greater than 3,000 mg/day provide additional benefit.

For the adjunctive treatment of myoclonic seizures in those with juvenile myoclonic epilepsy:
Oral dosage (oral solution, immediate-release tablets, and fast-melting tablets):
Infants and Children 1 month to 11 years*: Safety and efficacy have not been established. Initial doses of 5 to 10 mg/kg/dose PO twice daily titrated to a mean total daily dose of 30 to 50 mg/kg/day have been used in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children less than 4 years of age. However, a wide dosage range has been used (9 to 139 mg/kg/day PO). One prospective, observational study of 285 pediatric patients ages 0 to 17 years with refractory epilepsy reported that the majority of patients that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range. Infants and young children were included in this study, but their data were not reported separately.
Children and Adolescents 12 to 17 years: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dose of 1,500 mg PO twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 3,000 mg/day are effective.
Intravenous dosage:
Infants and Children 1 month 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 seizure 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.
Children and Adolescents 12 to 17 years: Initially, 500 mg IV twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dosage of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 3,000 mg/day are effective.

For the adjunctive treatment of primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy:
Oral dosage (oral solution and immediate-release tablets [Keppra and generic equivalents]):
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's condition. Thirty patients were seizure free at the end of one 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.
Infants and Children 1 month to 5 years*: Safety and efficacy have not been established. Initial doses of 5 to 10 mg/kg PO twice daily titrated to a mean daily dose of 30 to 50 mg/kg/day PO divided twice daily have been used in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children less than 4 years of age. However, a wide dosage range has been used (9 to 139 mg/kg/day PO). One prospective, observational study of 285 pediatric patients ages 0 to 17 years with refractory epilepsy reported that the majority of patients that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range. Infants and young children were included in this study, but their data were not reported separately.
Children and Adolescents 6 to 15 years: Initially, 10 mg/kg/dose PO twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to a recommended dose of 30 mg/kg/dose PO twice daily rounded to the nearest whole tablet size. Max: 3,000 mg/day. It is unknown whether doses lower than 60 mg/kg/day are effective. If body weight 20 kg or less, administer oral solution; if body weight more than 20 kg, administer either solution or tablets.
Adolescents 16 to 17 years: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dosage of 1,500 mg PO twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 3,000 mg/day are effective.
Oral dosage (fast-melting tablets [Spritam]):
Children and Adolescents 6 to 17 years weighing 20 to 40 kg: Initially, 250 mg PO twice daily. Increase the dosage every 2 weeks by 250 mg/dose (i.e., 500 mg/day) increments to a maximum recommended dose of 750 mg PO twice daily (Max: 1,500 mg/day).
Children and Adolescents 6 to 17 years weighing more than 40 kg: Initially, 500 mg PO twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dosage of 1,500 mg PO twice daily (Max: 3,000 mg/day). The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.
Intravenous dosage:
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 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.
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 seizure 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.
Children and Adolescents 6 to 15 years: Initially, 10 mg/kg/dose IV twice daily. Increase the dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) increments to the recommended dosage of 30 mg/kg/dose IV twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 60 mg/kg/day are effective.
Adolescents 16 to 17 years: Initially, 500 mg IV twice daily. Increase the dose every 2 weeks by 500 mg/dose (i.e., 1,000 mg/day) increments to the recommended dosage of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown whether doses lower than 3,000 mg/day are effective.

For the treatment of status epilepticus* or acute repetitive seizures*:
-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 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 seizure prophylaxis*:
-for early post-traumatic seizure prophylaxis* after traumatic brain injury:
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:
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.

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).
-Therapeutic efficacy has been reported with a wide range of plasma concentrations (5 to 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 1 review of 29 patients (79% with partial seizures and 21% with generalized seizures), plasma concentrations of 35 mcg/mL or more were associated with a 75% or more reduction in seizures; however, data from another review suggests that behavioral adverse reactions 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 to 18 years]) with generalized or partial epilepsy taking oral levetiracetam. A 50% or more 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 to 40 mcg/mL; patients considered non-responders (n = 6) had plasma concentrations that ranged from 1.89 to 46.66 mcg/mL.
-A plasma concentration of 10 to 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 2,000 to 3,000 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% or more 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 or more, drawn 1 to 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 to 38 years]). The suppressive effect lasted between 6 and 30 hours despite plasma concentrations less than 3 mcg/mL during that time period.


Maximum Dosage Limits:
-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.
-Infants
1 to 5 months: 42 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
6 to 11 months: 50 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
-Children
1 to 3 years: 50 mg/kg/day PO or IV; 60 mg/kg 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.
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.
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.
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.
-Adolescents
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.
16 to 17 years: 3,000 mg/day PO or IV; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.

Patients with Hepatic Impairment Dosing
Specific recommendations for hepatic dosage adjustment in pediatric patients are not available. 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 in adults, patients with severe hepatic impairment (Child-Pugh Class C) should initially receive one-half of the recommended dose.

Patients with Renal Impairment Dosing
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
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. In adults with end-stage renal disease (ESRD) receiving standard hemodialysis, the recommended dose is 500 to 1,000 mg PO or IV every 24 hours with a supplemental 250 to 500 mg dose after dialysis. Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours.

Peritoneal dialysis
Reduce the usual dose by 50%.

Continuous renal replacement therapy
Reduce the usual dose by 50%.

Augmented renal clearance
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

Monograph content under development

Mechanism of Action: 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 1,700 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) did not affect 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 central nervous system, 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.

Pharmacokinetics: Levetiracetam is administered orally and intravenously. Protein binding is less than 10%, making competition for protein binding sites and clinically significant interactions with other protein-bound drugs unlikely. Vd is 0.6 to 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 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 formulations 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. 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 injection 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. Additionally, 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.


-Special Populations
Pediatrics
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.

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 hour 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.

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.

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.