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Pronunciation
(lee va tye RA se tam)
Generic Available (U.S.)
Yes
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM152832.pdf, must be dispensed with this medication.
REMS Components
Keppra®, Keppra XR™: Released from REMS requirement 8/10/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunctive therapy in the treatment of partial onset, myoclonic, and/or primary generalized tonic-clonic seizures
Pregnancy Risk Factor
C
Pregnancy Considerations
Developmental toxicities were observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Two registries are available for women exposed to levetiracetam during pregnancy: Antiepileptic Drug Pregnancy Registry (888-233-2334 or http://www.mgh.harvard.edu/aed/) UCB AED Pregnancy Registry (888-537-7734)
Lactation
Enters breast milk/not recommended
Contraindications
There are no contraindications listed in the U.S. manufacturer's labeling.
Canadian labeling: Hypersensitivity to levetiracetam or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: Impaired coordination, weakness, dizziness, and somnolence may occur, most commonly during the first month of therapy; use caution when driving or operating heavy machinery.
• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported; onset usually within ~2 weeks of treatment initiation, but may be delayed (>4 months); drug should be discontinued if there are any signs of a hypersensitivity reaction or unspecified rash.
• Hematologic effects: Although rare, decreases in red blood cell counts, hemoglobin, hematocrit, white blood cell counts and neutrophils have been observed. Cases of eosinophilia have also been reported.
• Hypertension: Isolated elevations in diastolic blood pressure measurements have been reported in children <4 years of age; however, no observable differences were noted in mean diastolic measurements of children receiving levetiracetam vs placebo. Similar effects have not been observed in older children and adults.
• Psychiatric symptoms: Psychosis, hallucinations and behavioral symptoms (including aggression, anger, anxiety, depersonalization, depression, personality disorder) may occur; dose reduction or discontinuation may be required.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Renal impairment: Use caution with renal impairment; dosage adjustment may be necessary.
Concurrent drug therapy issues:
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Pediatrics: Safety and efficacy of I.V. and extended release tablet formulations have not been established in children <16 years of age. Children may have increased incidence of psychiatric symptoms; dose reduction or discontinuation may be required.
Other warnings/precautions:
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
>10%:
Central nervous system: Behavioral symptoms (agitation, aggression, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis and personality disorder: adults 5% to 13%; children 5% to 38%), somnolence (8% to 23%), headache (14%), hostility (2% to 12%)
Gastrointestinal: Vomiting (15%), anorexia (3% to 13%)
Neuromuscular & skeletal: Weakness (9% to 15%)
Respiratory: Pharyngitis (6% to 14%), rhinitis (4% to 13%), cough (2% to 11%)
Miscellaneous: Accidental injury (17%), infection (2% to 13%)
1% to 10%:
Cardiovascular: Facial edema (2%)
Central nervous system: Fatigue (10%), nervousness (4% to 10%), dizziness (5% to 9%), personality disorder (8%), pain (6% to 7%), agitation (6%), irritability (6% to 7%), emotional lability (2% to 6%), mood swings (5%), depression (3% to 5%), vertigo (3% to 5%), ataxia (3%), amnesia (2%), anxiety (2%), confusion (2%)
Dermatologic: Bruising (4%), pruritus (2%), rash (2%), skin discoloration (2%)
Endocrine & metabolic: Dehydration (2%)
Gastrointestinal: Diarrhea (8%), nausea (5%), gastroenteritis (4%), constipation (3%)
Genitourinary: Urine abnormality (2%)
Hematologic: Leukocytes decreased (2% to 3%)
Neuromuscular & skeletal: Neck pain (2% to 8%), paresthesia (2%), reflexes increased (2%)
Ocular: Conjunctivitis (3%), diplopia (2%), amblyopia (2%)
Otic: Ear pain (2%)
Renal: Albuminuria (4%)
Respiratory: Influenza (5%), asthma (2%), sinusitis (2%)
Miscellaneous: Flu-like syndrome (3% to 8%), viral infection (2%)
<1%, postmarketing and/or case reports: Alopecia, anemia, catatonia, hematocrit decreased, hemoglobin decreased, hepatic failure, hepatitis, leukopenia, LFTs abnormal, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression), psychotic symptoms, red blood cells decreased, suicide attempt, suicide behavior, suicide ideation, thrombocytopenia, weight loss
Metabolism/Transport Effects
None known.
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Food may delay, but does not affect the extent of absorption.
Storage
Oral solution, tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Premixed solution for infusion: Store at 20°C to 25°C (68°F to 77°F).
Vials for injection: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Admixed solution is stable for 24 hours in PVC bags kept at room temperature.
Reconstitution
Vials for injection: Must dilute dose in 100 mL of NS, LR, or D5W.
Compatibility
Stable in NS, LR, D5W
Mechanism of Action
The precise mechanism by which levetiracetam exerts its antiepileptic effect is unknown. However, several studies have suggested the mechanism may involve one or more of the following central pharmacologic effects: inhibition of voltage-dependent N-type calcium channels; facilitation of GABA-ergic inhibitory transmission through displacement of negative modulators; reduction of delayed rectifier potassium current; and/or binding to synaptic proteins which modulate neurotransmitter release.
Pharmacodynamics/Kinetics
Absorption: Oral: Rapid and almost complete
Distribution: Vd: Similar to total body water
Protein binding: <10%
Metabolism: Not extensive; primarily by enzymatic hydrolysis; forms metabolites (inactive)
Bioavailability: 100%
Half-life elimination: ~6-8 hours; extended release tablet: ~7 hours; half-life increased in renal dysfunction
Time to peak, plasma: Oral: Immediate release: ~1 hour; Extended release: ~4 hours
Excretion: Urine (66% as unchanged drug)
Dosage
Oral: Note: Use oral solution in children ≤20 kg; oral solution or immediate release tablets may be used in children >20 kg.
Children 1 to <6 months: Partial onset seizures: Immediate release: Initial: 7 mg/kg/dose twice daily; may increase every 2 weeks by 7 mg/kg/dose to a maximum of 21 mg/kg/dose twice daily
Children 6 months to <4 years: Partial onset seizures: Immediate release: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to a maximum of 25 mg/kg/dose twice daily
Children 4 to <16 years: Partial onset seizures: Immediate release: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to a maximum of 30 mg/kg/dose twice daily (maximum daily dose: 3000 mg/day)
Children 6 to <16 years: Tonic-clonic seizures: Immediate release: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to the recommended dose of 30 mg/kg twice daily. Efficacy of doses other than 60 mg/kg/day has not been established.
Children ≥12 years and Adults: Myoclonic seizures: Immediate release: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1500 mg twice daily. Efficacy of doses other than 3000 mg/day has not been established.
Children ≥16 years and Adults:
Partial onset seizure:
Immediate release: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to a maximum of 1500 mg twice daily. Doses >3000 mg/day have been used in trials; however, there is no evidence of increased benefit.
Extended release: Initial: 1000 mg once daily; may increase every 2 weeks by 1000 mg/day to a maximum of 3000 mg once daily.
Tonic-clonic seizures: Immediate release: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1500 mg twice daily. Efficacy of doses other than 3000 mg/day has not been established.
Adults: Loading dose (unlabeled): Immediate release: Initial doses of 1500-2000 mg have been well-tolerated (Betts, 2000; Koubeissi, 2008), although the necessity of a loading dose has not been established.
I.V.:
Children ≥16 years and Adults: Note: When switching from oral to I.V. formulations, the total daily dose should be the same.
Myoclonic seizures: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1500 mg twice daily. Efficacy of doses other than 3000 mg /day has not been established.
Partial onset seizure: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to a maximum of 1500 mg twice daily. Doses >3000 mg/day have been used in trials; however, there is no evidence of increased benefit.
Tonic-clonic seizures: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1500 mg twice daily. Efficacy of doses other than 3000 mg/day has not been established.
Adults: Refractory status epilepticus (unlabeled use): 1000-3000 mg administered over 15 minutes (Meierkord, 2010); 2500 mg has been safely administered over 5 minutes in one report (Uges, 2009). Note: Levetiracetam has not been well studied in comparison to other agents routinely used in this setting.
Dosing adjustment in renal impairment: Adults:
Immediate release and I.V. formulations:
Clcr >80 mL/minute/1.73 m2: 500-1500 mg every 12 hours
Clcr 50-80 mL/minute/1.73 m2: 500-1000 mg every 12 hours
Clcr 30-50 mL/minute/1.73 m2: 250-750 mg every 12 hours
Clcr <30 mL/minute/1.73 m2: 250-500 mg every 12 hours
End-stage renal disease (ESRD) requiring hemodialysis: 500-1000 mg every 24 hours; supplemental dose of 250-500 mg is recommended posthemodialysis
Peritoneal dialysis (PD): 500-1000 mg every 24 hours (Aronoff, 2007)
Continuous renal replacement therapy (CRRT): 250-750 mg every 12 hours (Arnoff, 2007)
Extended release tablets:
Clcr >80 mL/minute/1.73 m2: 1000-3000 mg every 24 hours
Clcr 50-80 mL/minute/1.73 m2: 1000-2000 mg every 24 hours
Clcr 30-50 mL/minute/1.73 m2: 500-1500 mg every 24 hours
Clcr <30 mL/minute/1.73 m2: 500-1000 mg every 24 hours
End-stage renal disease (ESRD) requiring hemodialysis: Use of immediate release formulation is recommended
Dosing adjustment in hepatic impairment:
U.S. labeling: No dosage adjustment necessary
Canadian labeling:
Mild-to-moderate impairment: No dosage adjustment necessary
Severe impairment: Reduce maintenance dose by 50% in patients who also have Clcr <60 mL/minute/1.73 m2
Administration: Oral
May be administered without regard to meals.
Oral solution: Should be administered with a calibrated measuring device (not a household teaspoon or tablespoon)
Tablet (immediate release and extended release): Only administer as whole tablet; do not crush, break or chew.
Administration: I.V.
Infuse over 15 minutes
Administration: I.V. Detail
pH: 5.5
Monitoring Parameters
Suicidality (eg, suicidal thoughts, depression, behavioral changes)
Dietary Considerations
May be taken without regard to meals.
Patient Education
While using this medication, do not use alcohol. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, blurred vision, nausea, vomiting, loss of appetite, or dry mouth. Wear identification of epileptic status and medications. Report CNS changes, mentation changes, suicide ideation, depression, or changes in cognition; muscle cramping, weakness, tremors, changes in gait; persistent GI symptoms (cramping, constipation, vomiting, anorexia); rash or skin irritations; unusual bruising or bleeding (mouth, urine, stool); or worsening of seizure activity or loss of seizure control.
Geriatric Considerations
In a study of 16 older adults (61-88 years of age) receiving levetiracetam daily and with creatinine clearances ranging from 30-74 mL/minute, a decrease in creatinine clearance (38%) and a 2.5 hour longer half-life were recorded in the elderly compared to younger adults. The authors concluded that the difference was due to renal function. Other studies show no overall difference in safety and efficacy, although larger numbers in studies are needed to verify efficacy. Levetiracetam has demonstrated a low incidence of cognitive effects. When using the drug in elderly, it is essential to base the dose on estimated creatinine clearance and adjust appropriately.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Associated with somnolence and fatigue, psychosis, hallucinations, psychotic depression, and other behavioral symptoms (agitation, anger, aggression, irritability, hostility, anxiety, apathy, emotional lability, depersonalization, and depression)
Mental Health: Effects on Psychiatric Treatment
May cause leukopenia, neutropenia, pancytopenia, and thrombocytopenia; use caution with clozapine, carbamazepine, and valproic acid
Nursing: Physical Assessment/Monitoring
Monitor for CNS depression (somnolence and fatigue), behavioral abnormalities (psychosis, hallucinations, psychotic depression), and other behavioral symptoms (agitation, anger, aggression, irritability, hostility, anxiety, apathy, emotional lability, depersonalization, and depression). Taper dosage slowly when discontinuing. Observe and teach seizure/safety precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Infusion, premixed in sodium chloride 0.54%: 1500 mg (100 mL)
Infusion, premixed in sodium chloride 0.75%: 1000 mg (100 mL)
Infusion, premixed in sodium chloride 0.82%: 500 mg (100 mL)
Injection, solution: 100 mg/mL (5 mL)
Keppra®: 100 mg/mL (5 mL)
Solution, oral: 100 mg/mL (5 mL, 118 mL, 472 mL, 473 mL, 480 mL, 500 mL)
Keppra®: 100 mg/mL (480 mL) [dye free; grape flavor]
Tablet, oral: 250 mg, 500 mg, 750 mg, 1000 mg
Keppra®: 250 mg, 500 mg, 750 mg [scored; gluten free]
Tablet, extended release, oral: 500 mg, 750 mg
Keppra XR™: 500 mg, 750 mg
Pricing: U.S. (www.drugstore.com)
Solution (Keppra)
100 mg/mL (473): $437.98
Solution (Levetiracetam)
100 mg/mL (473): $259.99
Tablet, 24-hour (Keppra XR)
500 mg (60): $245.98
750 mg (60): $407.01
Tablet, 24-hour (LevETIRAcetam)
500 mg (60): $65.99
Tablets (Keppra)
250 mg (10): $51.99
500 mg (30): $149.99
750 mg (30): $189.99
1000 mg (60): $570.02
Tablets (Levetiracetam)
250 mg (60): $23.99
500 mg (30): $29.99
750 mg (60): $61.99
1000 mg (60): $210.99
References
Betts T, Waegemans T, and Crawford P, “A Multicentre, Double-Blind, Randomized, Parallel Group Study to Evaluate the Tolerability and Efficacy of Two Oral Doses of Levetiracetam, 2000 mg Daily and 4000 mg Daily, Without Titration in Patients With Refractory Epilepsy,” Seizure, 2000, 9(2): 80-7.
Ferrendelli JA, “Concerns With Antiepileptic Drug Initiation: Safety, Tolerability, and Efficacy,” Epilepsia, 2001, 42(Suppl 4):28-30.
Glauser TA, Pellock JM, Bebin EM, et al, “Efficacy and Safety of Levetiracetam in Children with Partial Seizures: An Open-label Trial,” Epilepsia, 2002, 43(5):518-24.
Hovinga CA, “Levetiracetam: A Novel Antiepileptic Drug,” Pharmacotherapy, 2001, 21(11):1375-88.
Koubeissi MZ, Amina S, Pita I, et al, “Tolerability and Efficacy of Oral Loading of Levetiracetam,” Neurology, 2008, 70(22 pt 2):2166-70.
Meador KJ, Gevins A, Loring DW, et al, “Neuropsychological and Neurophysiologic Effects of Carbamazepine and Levetiracetam,” Neurology, 2007, 69(22):2076-84.
Meierkord H, Boon P, Engelsen B, et al, “EFNS Guideline on the Management of Status Epilepticus in Adults,” Eur J Neurol, 2010, 17(3):348-55.
Roberts GM, Majoie HJ, Leenen LA, et al, “Ketter's Hypothesis of the Mood Effects of Antiepileptic Drugs Coupled to the Mechanism of Action of Topiramate and Levetiracetam,” Epilepsy Behav, 2005, 6(3):366-72.
Sankar R and Holmes GL, “Mechanisms of Action for the Commonly Used Antiepileptic Drugs: Relevance to Antiepileptic Drug-Associated Neurobehavioral Adverse Effects,” J Child Neurol, 2004, 19(Suppl 1):6-14.
“Two New Drugs for Epilepsy,” Med Lett Drugs Ther, 2000, 42(1076):33-5.
Uges JW, van Huizen MD, Engelsman J, et al, "Safety and Pharmacokinetics of Intravenous Levetiracetam Infusion as Add-On in Status Epilepticus," Epilepsia, 2009, 50(3):415-21.
Welty TE, Gidal BE, Ficker DM, et al, “Levetiracetam: A Different Approach to the Pharmacotherapy of Epilepsy,” Ann Pharmacother, 2002, 36(2):296-304.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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