Keppra XR

Anticonvulsants, SV2A Inhibitors

May be administered without regard to meals.

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 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.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

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 ).

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

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
amnesia / Delayed / 2.0-2.0
hostility / Early / 2.0-2.0
confusion / 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

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

ELEPSIA XR, Keppra, Keppra XR, Roweepra, Spritam

Rx

Oral and intravenous pyrrolidine derivative antiepileptic drug
Used for the treatment of certain types of partial, myoclonic, and generalized tonic-clonic seizures
Monitor for emerging or worsening suicidal thoughts/behavior and depression

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily.

250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day confer additional benefit.

10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day.

10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 25 mg/kg/dose PO twice daily. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day.

7 mg/kg/dose PO twice daily, initially. Increase the dose by 14 mg/kg/day every 2 weeks to a dose of 21 mg/kg/dose PO twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day.

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]

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.

500 mg PO twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.

250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.

1,000 mg PO once daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day.[48849] [63855]

1,000 mg PO once daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day.[48849] [63855]

500 mg IV twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.

500 mg IV twice daily, initially. May increase the dose by 1,000 mg/day every 2 weeks. Max: 3,000 mg/day. There is no evidence that doses more than 3,000 mg/day provide additional benefit.

10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose IV twice daily. Max: 3,000 mg/day. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 44 mg/kg/day.

10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 25 mg/kg/dose IV twice daily. If this dose is not tolerated, it may be reduced. In clinical trials, the mean daily dose was 47 mg/kg/day.

7 mg/kg/dose IV twice daily, initially. Increase the dose by 14 mg/kg/day every 2 weeks to a dose of 21 mg/kg/dose IV twice daily. In clinical trials, the mean daily dose was 35 mg/kg/day.

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]

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.[30641] [60063]

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.[30641] [60063]

5 to 10 mg/kg/dose PO twice daily, initially. Increase the dose gradually to a dose of 30 to 50 mg/kg/day PO divided twice daily. These doses have been described in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children younger than 4 years. However, a wide dosage range has been used (9 to 139 mg/kg/day). A prospective, observational study of 285 children age 0 to 17 years with refractory epilepsy reported that the majority of children that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range.

500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

Safety and efficacy have not been established. A mean dose of 50.4 mg/kg/day IV was used in a small retrospective review of 10 pediatric patients ranging in age from 3 weeks to 19 years for a variety of seizure disorders or prophylaxis. Three of the 10 patients were receiving oral levetiracetam before presentation and received IV therapy temporarily due to an inability to continue oral therapy because of intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. An every 12 hours dosage schedule was used for all patients. No adverse effects were reported. The authors note that the majority of patients were very ill, and therefore, adverse effects such as sedation or behavioral problems may have been overlooked.[34602]

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. Round dose to the nearest whole tablet. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

10 mg/kg/dose PO twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose PO twice daily. Max: 3,000 mg/day. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

5 to 10 mg/kg/dose PO twice daily, initially. Increase the dose gradually to a dose of 30 to 50 mg/kg/day PO divided twice daily. These doses have been described in multiple retrospective reviews, controlled trials, and case series that include over 360 infants and children younger than 4 years. However, a wide dosage range has been used (9 to 139 mg/kg/day). A prospective, observational study of 285 children age 0 to 17 years with refractory epilepsy reported that the majority of children that responded to levetiracetam did so at doses in the 30 to 40 mg/kg/day range.

10 to 30 mg/kg/day PO, initially. Increase the dose by 10 mg/kg/day every 3 days or more to a dose of 45 to 60 mg/kg/day.[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 neonate's condition. At the end of 1 week, 30 neonates were seizure free, and at the end of 4 weeks, 27 remained seizure free.[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. All neonates became seizure free within 6 days and 5 remained seizure free at 3 months.[51546]

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

500 mg PO twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg PO twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

250 mg PO twice daily, initially. Increase the dose by 500 mg/day every 2 weeks to a dose of 750 mg PO twice daily.

500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

500 mg IV twice daily, initially. Increase the dose by 1,000 mg/day every 2 weeks to a dose of 1,500 mg IV twice daily. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

10 mg/kg/dose IV twice daily, initially. Increase the dose by 20 mg/kg/day every 2 weeks to a dose of 30 mg/kg/dose IV twice daily. The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

Safety and efficacy have not been established. A mean dose of 50.4 mg/kg/day IV was used in a small retrospective review of 10 pediatric patients ranging in age from 3 weeks to 19 years for a variety of seizure disorders or prophylaxis. Three of the 10 patients were receiving oral levetiracetam prior to presentation and received IV therapy temporarily due to an inability to continue oral therapy because of intercurrent illness. For those patients, the IV dosage used was equivalent to their previous oral regimen. An every 12 hours dosage schedule was used for all patients. No adverse effects were reported. The authors note that the majority of patients were very ill, and therefore, adverse effects such as sedation or behavioral problems may have been overlooked.[34602]

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's 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 retrospective study in 23 neonates 0 to 41 days of age with various seizure types and etiologies found mean initial doses of 16 mg/kg/dose IV (range 5 to 22 mg/kg/dose) and mean maximum doses of 45 mg/kg/day IV (range 10 to 80 mg/kg/day) administered twice daily. A greater than 50% reduction in seizures occurred within 24 hours in 8 of the 23 patients with seizure termination occurring in 7 patients.[51542]

60 mg/kg (Max: 4,500 mg) IV as a single dose.

60 mg/kg/dose (Max: 4,500 mg/dose) IV as a single dose, or alternatively, 1,000 to 4,500 mg IV as a single dose.

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.

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.

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%.

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.

†Indicates off-label use

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]

Adults
CrCl more than 80 mL/minute/1.73m2: No dosage adjustment necessary.
CrCl 50 to 80 mL/minute/1.73m2: 500 to 1,000 mg PO immediate-release tablets or IV every 12 hours; 1,000 to 2,000 mg PO extended-release tablets every 24 hours.
CrCl 30 to 49 mL/minute/1.73m2: 250 to 750 mg PO immediate-release tablets or IV every 12 hours; 500 to 1,500 mg extended-release tablets every 24 hours (Keppra XR and generic equivalents). Elepsia XR is not recommended.
CrCl less than 30 mL/minute/1.73m2: 250 to 500 mg PO immediate-release tablets or IV every 12 hours; 500 to 1,000 mg extended-release tablets every 24 hours (Keppra XR and generic equivalents). Elepsia XR is not recommended.
Pediatrics
Dosage adjustment is necessary; however, pediatric-specific recommendations are not provided in FDA-approved labeling. Elepsia XR is not recommended in patients with moderate to severe renal impairment.[63855] 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%.[32569]
 
Intermittent hemodialysis
Adults
500 to 1,000 mg PO immediate-release tablets or IV every 24 hours with a supplemental 250 to 500 mg dose after dialysis. Do not use extended-release levetiracetam in patients with ESRD on dialysis. Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours.
Pediatrics
Reduce the usual dose by 50% and administer every 24 hours; give a supplemental dose after hemodialysis.[32569] Do not use extended-release levetiracetam in patients with ESRD on dialysis. Standard hemodialysis results in a roughly 50% clearance of levetiracetam in 4 hours.
 
Peritoneal dialysis
Adults
500 to 1,000 mg PO immediate-release tablets or IV every 24 hours.
Pediatrics
Reduce the usual dose by 50%.
 
Continuous renal replacement therapy
Adults
250 to 750 mg PO immediate-release tablets or IV every 12 hours.
Pediatrics
Reduce the usual dose by 50%.
 
Augmented renal clearance
Adults
Dosage adjustment may be required; further studies are necessary to determine a safe and effective dose in patients with augmented renal clearance (ARC). Pharmacokinetic simulation has suggested doses of 1,500 mg and 2,000 mg IV every 12 hours for adult patients with CrCl of 80 and 120 mL/minute, respectively, and doses of 1,500 mg and 2,000 mg IV every 8 hours for adult patients with CrCl of 160 and 200 mL/minute, respectively, maybe required to attain a therapeutic trough concentration (more than 12 mg/L). Extending infusion time did not increase the probability of reaching the targeted trough. CrCl more than 130 mL/minute/1.73 m2 is the most widely used threshold to define ARC in adults. Urinary CrCl is the most accurate and feasible method to identify ARC. ARC is a state of increased renal function from baseline which leads to enhanced elimination and subtherapeutic drug concentrations in critical care patients.
Pediatrics
Dosage adjustment may be required. Age-dependent thresholds for pediatric patients have not been defined, but CrCl more than 130 mL/minute/1.73 m2 is the most widely used threshold in adults. Urinary CrCl is the most accurate and feasible method to identify augmented renal clearance (ARC). ARC is a state of increased renal function from baseline which leads to enhanced elimination and subtherapeutic drug concentrations in critical care patients.

Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
Carbamazepine: (Moderate) Closely monitor patients for signs or symptoms of carbamazepine toxicity, such as vision changes, unstable gait, ataxia, dizziness, nausea, or vomiting during coadministration of carbamazepine and levetiracetam. Carbamazepine toxicity, unrelated to elevated concentrations of carbamazepine or the epoxide, may occur when levetiracetam is added to carbamazepine therapy. The interaction appears to be pharmacodynamic in nature rather than pharmacokinetic. Toxicity was reversed when the dose of carbamazepine was reduced.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of levetiracetam if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants such as levetiracetam at least 1 hour before or at least 4 hours after colesevelam.
Hydroxychloroquine: (Moderate) Monitor persons with epilepsy for seizure activity during concomitant levetiracetam and hydroxychloroquine use. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Some, but not all anticonvulsants, induce CYP3A4 and may increase the metabolism of mefloquine. Use of enzyme-inducing anticonvulsants can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Probenecid: (Minor) The renal clearance of the major metabolite of levetiracetam, UCB L057, is decreased by 60 percent in the presence of probenecid. This is probably related to competitive inhibition of tubular secretion of UCB L057. The clinical significance of this is unknown.
Probenecid; Colchicine: (Minor) The renal clearance of the major metabolite of levetiracetam, UCB L057, is decreased by 60 percent in the presence of probenecid. This is probably related to competitive inhibition of tubular secretion of UCB L057. The clinical significance of this is unknown.
Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).

ELEPSIA XR/Keppra XR/Levetiracetam/Roweepra Oral Tab ER: 500mg, 750mg, 1000mg, 1500mg
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

3,000 mg/day PO or IV.

3,000 mg/day PO or IV.

16 to 17 years: 3,000 mg/day PO or IV; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
13 to 15 years: 60 mg/kg/day PO or IV (Max: 3,000 mg/day); 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.

12 years weighing more than 40 kg: 60 mg/kg/day PO (oral solution) or IV (Max: 3,000 mg/day); 3,000 mg/day for immediate-release, fast-melting, and extended-release tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
12 years weighing 20 to 40 kg: 60 mg/kg/day PO (oral solution) or IV; 1,500 mg/day for immediate-release and fast-melting tablets; 3,000 mg/day for extended-release tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
4 to 11 years weighing more than 40 kg: 60 mg/kg/day PO (oral solution) or IV (Max: 3,000 mg/day); 3,000 mg/day for immediate-release and fast-melting tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
4 to 11 years weighing 20 to 40 kg: 60 mg/kg/day PO (oral solution) or IV; 1,500 mg/day for immediate-release and fast-melting tablets; 60 mg/kg (Max: 4,500 mg) IV for status epilepticus.
1 to 3 years: 50 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.

6 to 11 months: 50 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.
1 to 5 months: 42 mg/kg/day PO or IV; 60 mg/kg IV for status epilepticus.

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.

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.

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

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]

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]

There are no adequate and well-controlled studies of levetiracetam in pregnant women. Data from pregnancy registries and the published literature spanning 2 decades have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. In animal studies, there was evidence that levetiracetam produced developmental toxicity at doses similar to or greater than human therapeutic doses. Embryofetal death, increased fetal and skeletal malformations, and decreased fetal weight occurred in the offspring of pregnant rabbits given levetiracetam during organogenesis. The no-effect dose for adverse effects on development was approximately equal to the maximum recommended human dose (MRHD) of 3,000 mg on the basis of body surface area (mg/m2). Administration of levetiracetam to rats throughout pregnancy and lactation resulted in increased fetal skeletal variations, decreased fetal weight, and decreased growth in offspring. Increased fetal death and neurobehavioral alterations were seen at the highest dose tested. The no-effect dose for adverse effects on pre- and post-natal development was less than the MRHD on the basis of body surface area. The effect of levetiracetam on labor and delivery in humans is not known. Maternal clearance of levetiracetam is higher during pregnancy compared to baseline, especially during the third trimester; if levetiracetam is continued during pregnancy, monitor seizure frequency closely. A dosage adjustment may be necessary for some patients. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to levetiracetam; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

Levetiracetam is excreted in human breast milk. In a case series, foremilk samples were taken 3 to 5 days postpartum from 7 women who were taking levetiracetam 1,500 to 3,500 mg/day orally. The mean milk:maternal serum concentration ratio was 1 (range 0.76 to 1.33); however, 6 of the infant corresponding serum concentrations were very low or below the level of quantification. The remaining infant did not have a serum concentration measured at 3 to 5 days of age. Milk concentrations were measured again from 1 or more women at 2 weeks, 4 weeks, 6 to 8 weeks, 4 months, and 10 months postpartum, and the maternal milk:serum ratios were similar to those at 3 to 5 days postpartum. No infant-related adverse effects were noted. In another case series including 11 mother-infant pairs, levetiracetam was excreted into breast milk at a concentration similar to that in maternal plasma; the mean milk:plasma ratio was 1.05 (range 0.78 to 1.55). Assuming a daily milk intake of 150 mL/kg/day, the infant dose was estimated to be approximately 2.4 mg/kg/day. In this study, milk concentrations were single, morning trough concentrations collected between day 4 and 23 after delivery; therefore, total infant exposure over a 24-hour period may differ from this estimate. Although no safe dosage range has been established in the neonatal population, initial doses of 14 mg/kg/day PO are FDA approved for patients as young as 1 month of age. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.