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  • CLASSES

    Anticonvulsants, SV2A Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Pyrrolidine derivative and brivaracetam analog
    For certain types of partial, myoclonic, and generalized tonic-clonic seizures as adjunct therapy
    Monitor for emerging or worsening suicidal thoughts/behavior and depression

    COMMON BRAND NAMES

    Keppra, Keppra XR, Roweepra, Spritam

    HOW SUPPLIED

    Keppra XR/Levetiracetam Oral Tab ER: 500mg, 750mg
    Keppra/Levetiracetam Oral Sol: 1mL, 100mg
    Keppra/Levetiracetam/Levetiracetam, Sodium Chloride Intravenous Inj Sol: 1mL, 100mg, 10-0.75%, 15-0.54%, 5-0.82%
    Keppra/Levetiracetam/Roweepra Oral Tab: 250mg, 500mg, 750mg, 1000mg
    Spritam Oral Tab Orally Dis: 250mg, 500mg, 750mg, 1000mg

    DOSAGE & INDICATIONS

    For the adjunctive treatment of partial seizures.
    Oral dosage (oral solution)
    Adults

    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.

    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.

    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).

    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.

    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 may be reduced. In clinical trials, the mean daily dose was 35 mg/kg/day PO.

    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.[51541] [51546] 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.[51541] 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.[51546]

    Oral dosage (immediate-release tablets and fast-melting tablets)
    Adults

    Initially, 500 mg PO twice daily. Increase 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.

    Adolescents 16 to 17 years

    Initially, 500 mg PO twice daily. Increase 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.

    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 dose of 1,500 mg PO twice daily (Max: 3,000 mg/day).

    Children and Adolescents 4 to 15 years weighing 20 to 40 kg

    Initially, 250 mg PO twice daily. Increase the dose every 2 weeks by increments of 250 mg/dose (i.e., 500 mg/day) to a maximum recommended dose of 750 mg PO twice daily (Max: 1,500 mg/day).

    Children and Adolescents 4 to 15 years weighing less than 20 kg

    Tablets are not recommended. See dosing for oral solution.

    Oral dosage (extended-release tablets)
    Adults

    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.[48849] [63855]

    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.[48849] [63855]

    Intravenous dosage
    Adults

    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.

    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.

    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 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.

    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.

    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.

    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.[51541] [51542] 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.[51541] 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.[51542]

    For the adjunctive treatment of myoclonic seizures in those with juvenile myoclonic epilepsy.
    Oral dosage (oral solution, immediate-release tablets, and fast-melting tablets)
    Adults, Adolescents, and Children 12 years and older

    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 if doses lower than 3,000 mg/day are effective.

    Infants† and Children younger than 12 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.

    Intravenous dosage
    Adults, Adolescents, and Children 12 years and older

    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 dose 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.

    Infants† and Children younger than 12 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 an intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. For acute repetitive seizures or SE, levetiracetam was administered every 8 hours in infants and every 12 hours in older children; for maintenance or prophylactic therapy, 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 adjunctive treatment of primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy.
    Oral dosage (immediate-release tablets and oral solution [Keppra and generic equivalents])
    Adults

    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.

    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.

    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.

    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 younger 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.

    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.

    Oral dosage (fast-melting tablets [Spritam])
    Adults

    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). 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

    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). 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

    Initially, 250 mg PO twice daily. Increase the dose 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).

    Intravenous dosage
    Adults

    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 dose of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown if doses lower than 3,000 mg/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 dose of 1,500 mg IV twice daily. Max: 3,000 mg/day. It is unknown if doses lower than 3,000 mg/day are effective.

    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.

    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 an intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. For acute repetitive seizures or SE, levetiracetam was administered every 8 hours in infants and every 12 hours in older children; for maintenance or prophylactic therapy, 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 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 convulsive status epilepticus†.
    For the treatment of status epilepticus† or acute seizures† in infants, children, and adolescents.
    Intravenous dosage
    Infants, Children, and Adolescents

    Safety and efficacy have not been established. Guidelines propose 60 mg/kg IV (Max: 4,500 mg/dose) for convulsive status epilepticus. Loading doses of 25 to 50 mg/kg IV have been reported most often (range 6.5 to 89 mg/kg) in retrospective studies in patients ranging from 1 day to 18 years of age. One study noted clinical and electrographic improvement in all patients (n = 32) within 25 to 30 minutes of receiving levetiracetam. Maintenance doses of 25 mg/kg IV every 12 hours were initiated after the loading dose. A larger study (n = 73) determined that 89% of patients were seizure free at 1 hour after levetiracetam administration; however, this number declined over the next 72 hours. Most patients (71%) were started on levetiracetam maintenance dosing within 24 hours of the loading dose; however, the maintenance dose was not specified.

    For the first-line treatment of convulsive status epilepticus in adults†.
    Intravenous dosage
    Adults

    20 mg/kg IV over 15 minutes. Clinical practice guidelines include levetiracetam as urgent control antiepileptic drug (AED) therapy, where goal is to quickly achieve therapeutic concentrations of AED and establish maintenance therapy in patients responding to initial emergent therapy or to abate seizures in patients who fail to respond to initial emergent therapy.

    For the treatment of status epilepticus† or acute 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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; guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV (Max: 4,500 mg).
    13 to 15 years: 60 mg/kg/day PO or IV (Max: 3,000 mg/day); guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV (Max: 4,500 mg).

    Children

    4 to 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 and fast-melting tablets. Guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV (Max: 4,500 mg).
    4 to 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. Guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV.
    1 to 4 years: 50 mg/kg/day PO or IV; guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV.

    Infants

    6 to 11 months: 50 mg/kg/day PO or IV; guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV.
    1 to 5 months: 42 mg/kg/day PO or IV; guidelines for convulsive status epilepticus propose a load of 60 mg/kg IV.

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.[31309]

    Renal Impairment

    Dosage adjustments for adults (adjust creatinine clearance for body surface area):
    CrCl more than 80 mL/minute: No dosage adjustment necessary.
    CrCl 50 to 80 mL/minute: 500 to 1,000 mg PO immediate-release tablets or IV every 12 hours; 1,000 to 2,000 mg extended-release tablets every 24 hours; Maximum daily dose is 2,000 mg.
    CrCl 30 to 49 mL/minute: 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); Maximum daily dose is 1,500 mg. Elepsia XR is not recommended.
    CrCl less than 30 mL/minute: 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); Maximum daily dose is 1,000 mg. Elepsia XR is not recommended.
     
    Dosage adjustments for pediatrics:
    Recommendations from the FDA-approved labeling are not available. However, the following adjustments have been recommended:[32569]
    GFR more than 50 mL/minute/1.73m2: No dosage adjustment necessary.
    GFR 50 mL/minute/1.73m2 or less: Reduce usual dose by 50%.
     
    Intermittent hemodialysis
    Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours. In adults, administer 500 to 1,000 mg PO or IV every 24 hours. A 250 to 500 mg supplemental PO or IV dose is recommended after dialysis. In pediatric patients, reducing the usual dose by 50% and giving every 24 hours with a supplemental dose after hemodialysis has been recommended.[32569] The extended-release formulation should not be used in patients on dialysis.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Solid Formulations

    Immediate-release tablets (Keppra):
    Swallow whole; do not chew or crush.[30641]
     
    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.[60063]
     
    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.[48849] [63855]

    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 ).

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Keppra:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Keppra XR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Roweepra :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Spritam:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Levetiracetam is contraindicated in patients with levetiracetam hypersensitivity. Anaphylaxis and angioedema have occurred during treatment.

    Abrupt discontinuation

    Abrupt discontinuation of levetiracetam therapy should not be undertaken. Levetiracetam and other antiepileptic drugs should be withdrawn gradually to minimize the potential of increased seizure frequency.

    Dialysis, renal disease, renal failure, renal impairment

    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.

    Pregnancy

    Levetiracetam is classified as FDA pregnancy risk category C. In animal studies, there was evidence that levetiracetam produced developmental toxicity at doses similar to or greater than human therapeutic doses. There are no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effect of levetiracetam on labor and delivery in humans is not known. NOTE: Maternal clearance of levetiracetam is higher during pregnancy compared to baseline, especially during the third trimester (see Pharmacokinetics); if levetiracetam is continued during pregnancy, monitor seizure frequency closely. A dosage adjustment may be necessary for some patients. Physicians are advised to recommend that pregnant patients receiving levetiracetam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry. The manufacturer of Keppra, UCB, has also established a pregnancy registry that patients or healthcare providers can enroll in by calling 1-888-537-7734.

    Breast-feeding

    Levetiracetam is excreted in human breast milk. According to the manufacturer, because of the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue breast-feeding or discontinue levetiracetam. Other experts suggest that breast-feeding may be continued during levetiracetam therapy in some cases. In one small case series, foremilk samples were taken 3—5 days postpartum from 7 women who were taking levetiracetam 1,500—3,500 mg/day PO. The mean milk:maternal serum concentration ratio was 1 (range 0.76—1.33); however, six 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—5 days of age. Milk concentrations were measured again from one or more women at 2 weeks, 4 weeks, 6—8 weeks, 4 months, and 10 months postpartum, and the maternal milk:serum ratios were similar to those at 3—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—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. 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 one month of age (see Dosage). NOTE: 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated seizure disorder. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Driving or operating machinery

    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.

    Depression, suicidal ideation

    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.

    Psychosis, schizophrenia

    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.[30641]

    Geriatric

    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. There are no pharmacokinetic differences in the geriatric adult compared to younger adults based on age alone. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function 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 patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. The Beers expert panel also recommends reducing the dose of levetiracetam in geriatric patients with a creatinine clearance of 80 mL/minute or less due to the potential for adverse CNS effects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Children, infants, neonates

    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.

    ADVERSE REACTIONS

    Severe

    proteinuria / Delayed / 4.0-4.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    acute generalized exanthematous pustulosis (AGEP) / Delayed / 0-1.0
    suicidal ideation / Delayed / 0.5-0.5
    erythema multiforme / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    hallucinations / Early / 1.0-17.0
    psychosis / Early / 1.0-17.0
    hypertension / Early / 0-17.0
    eosinophilia / Delayed / 8.6-8.6
    depression / Delayed / 3.0-5.0
    constipation / Delayed / 3.0-3.0
    conjunctivitis / Delayed / 3.0-3.0
    dehydration / Delayed / 2.0-2.0
    confusion / Early / 2.0-2.0
    amnesia / Delayed / 2.0-2.0
    hostility / Early / 2.0-2.0
    pneumonitis / Delayed / 0-1.0
    myasthenia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known

    Mild

    asthenia / Delayed / 9.0-15.0
    vomiting / Early / 15.0-15.0
    infection / Delayed / 13.0-13.0
    rhinitis / Early / 4.0-13.0
    anorexia / Delayed / 3.0-13.0
    irritability / Delayed / 6.0-11.7
    cough / Delayed / 2.0-11.0
    pharyngitis / Delayed / 6.0-10.0
    nasal congestion / Early / 9.0-9.0
    abdominal pain / Early / 0-9.0
    musculoskeletal pain / Early / 2.0-8.0
    influenza / Delayed / 3.0-8.0
    diarrhea / Early / 8.0-8.0
    lethargy / Early / 6.0-6.0
    nausea / Early / 5.0-5.0
    emotional lability / Early / 2.0-5.0
    agitation / Early / 4.0-4.0
    ecchymosis / Delayed / 4.0-4.0
    arthralgia / Delayed / 2.0-2.0
    sinusitis / Delayed / 2.0-2.0
    anxiety / Delayed / 2.0-2.0
    diplopia / Early / 2.0-2.0
    otalgia / Early / 2.0-2.0
    paranoia / Early / 1.6-1.6
    rash / Early / 0-1.0
    weight loss / Delayed / Incidence not known
    hyperkinesis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Amphetamines: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Azelastine; Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Beclomethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Betamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Budesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Budesonide; Formoterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Carbamazepine: (Moderate) 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.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Ciclesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    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.
    Corticosteroids: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Corticotropin, ACTH: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Deflazacort: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Dexamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Fludrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Flunisolide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Formoterol; Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Hydrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as levetiracetam. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Isocarboxazid: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    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.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anticonvulsants. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    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 is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Methylprednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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.
    Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Monoamine oxidase inhibitors: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Perphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Phenelzine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant levetiracetam, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Prednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Prednisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Selegiline: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Thiethylperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    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).
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant levetiracetam, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tranylcypromine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Triamcinolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.

    PREGNANCY AND LACTATION

    Pregnancy

    Levetiracetam is classified as FDA pregnancy risk category C. In animal studies, there was evidence that levetiracetam produced developmental toxicity at doses similar to or greater than human therapeutic doses. There are no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The effect of levetiracetam on labor and delivery in humans is not known. NOTE: Maternal clearance of levetiracetam is higher during pregnancy compared to baseline, especially during the third trimester (see Pharmacokinetics); if levetiracetam is continued during pregnancy, monitor seizure frequency closely. A dosage adjustment may be necessary for some patients. Physicians are advised to recommend that pregnant patients receiving levetiracetam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry. The manufacturer of Keppra, UCB, has also established a pregnancy registry that patients or healthcare providers can enroll in by calling 1-888-537-7734.

    Levetiracetam is excreted in human breast milk. According to the manufacturer, because of the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue breast-feeding or discontinue levetiracetam. Other experts suggest that breast-feeding may be continued during levetiracetam therapy in some cases. In one small case series, foremilk samples were taken 3—5 days postpartum from 7 women who were taking levetiracetam 1,500—3,500 mg/day PO. The mean milk:maternal serum concentration ratio was 1 (range 0.76—1.33); however, six 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—5 days of age. Milk concentrations were measured again from one or more women at 2 weeks, 4 weeks, 6—8 weeks, 4 months, and 10 months postpartum, and the maternal milk:serum ratios were similar to those at 3—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—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. 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 one month of age (see Dosage). NOTE: 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. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated seizure disorder. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    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 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.

    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 drugs unlikely.[30641] Vd is 0.7 L/kg.[56347] 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.[30641] [31309] 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.[30641] [44410] [48849]
     
    Affected cytochrome P450 isoenzymes: none

    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.[30641] [48849]
     
    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.[30641] [60063]
     
    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.[48849] Elepsia XR and Keppra XR tablets are bioequivalent in the fed and fasted states.[63855]

    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.[44410]