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Medication Safety Issues
Sound-alike/look-alike issues:
Keppra® may be confused with Keflex®, Keppra XR™
Levetiracetam may be confused with levofloxacin
Potential for dispensing errors between Keppra® and Kaletra® (lopinavir/ritonavir)
Pronunciation
(lee va tye RA se tam)
U.S. Brand Names
Generic Available
Yes: Oral solution, tablet
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunctive therapy in the treatment of partial onset, myoclonic, and/or primary generalized tonic-clonic seizures
Use: Unlabeled/Investigational
Bipolar disorder
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/) Keppra® pregnancy registry (888-537-7734 or http://www.keppra.com)
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to levetiracetam or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: Weakness, dizziness, and somnolence occur mostly during the first month of therapy.
• Hematologic effects: Although rare, decreases in red blood cell counts, hemoglobin, hematocrit, white blood cell counts and neutrophils have been observed.
• Psychotic symptoms: Psychosis, hallucinations and behavioral symptoms (including aggression, anger, anxiety, depersonalization, depression, personality disorder) may occur; dose reduction 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 have not been established in children <4 years of age (oral formulation) or <16 years (I.V. formulation and extended release tablets). Children may have increased incidence of psychotic symptoms; dose reduction 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
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: Olopatadine, Ophthalmic. Risk C: Monitor therapy
Ketorolac: 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
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
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).
Injection solution: 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
Injection solution: Must dilute dose in 100 mL of NS, LR, or D5W.
Compatibility
Stable in NS, LR, D5W
Compatibility when admixed: Compatible: Diazepam, lorazepam, valproic acid
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:
Children 4-15 years: Partial onset seizures: Immediate release: 10 mg/kg/dose given twice daily; may increase every 2 weeks by 10 mg/kg/dose to a maximum of 30 mg/kg/dose twice daily
Children 6-15 years: Tonic-clonic seizures: Immediate release: Initial: 10 mg/kg dose given 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 >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 >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 >3000 mg/day has not been established.
Bipolar disorder (unlabeled use): Immediate release: Initial: 500 mg twice daily; if tolerated, increase by 500 mg twice daily; dose may be increased every 3 days until target dose of 3000 mg/day is reached; maximum: 4000 mg/day
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: 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.
Note: When switching from oral to I.V. formulations, the total daily dose should be the same.
Dosing adjustment in renal impairment: Adults:
Immediate release and I.V. formulations:
Clcr >80 mL/minute: 500-1500 mg every 12 hours
Clcr 50-80 mL/minute: 500-1000 mg every 12 hours
Clcr 30-50 mL/minute: 250-750 mg every 12 hours
Clcr <30 mL/minute: 250-500 mg every 12 hours
End-stage renal disease patients using dialysis: 500-1000 mg every 24 hours; a supplemental dose of 250-500 mg following dialysis is recommended
Extended release tablets:
Clcr >80 mL/minute: 1000-3000 mg every 24 hours
Clcr 50-80 mL/minute: 1000-2000 mg every 24 hours
Clcr 30-50 mL/minute: 500-1500 mg every 24 hours
Clcr <30 mL/minute: 500-1000 mg every 24 hours
Dosing adjustment in hepatic impairment: No adjustment required
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
Take exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, vomiting, loss of appetite, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). 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. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
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
Assess effectiveness and interactions of other medications patient may be taking. Monitor therapeutic effectiveness, laboratory values, and adverse reactions at beginning of therapy and periodically with long-term use. 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. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
Keppra®: 100 mg/mL (5 mL)
Solution, oral: 100 mg/mL (500 mL)
Keppra®: 100 mg/mL (480 mL) [dye free; grape flavor]
Tablet: 250 mg, 500 mg, 750 mg, 1000 mg
Keppra®: 250 mg, 500 mg, 750 mg, 1000 mg
Tablet, extended release:
Keppra XR™: 500 mg, 750 mg
Pricing: U.S. (www.drugstore.com)
Solution (Keppra)
100 mg/mL (473): $350.45
Solution (Levetiracetam)
100 mg/mL (473): $259.96
Tablet, 24-hour (Keppra XR)
500 mg (60): $224.69
Tablets (Keppra)
250 mg (10): $37.99
500 mg (30): $125.99
750 mg (30): $161.26
1000 mg (60): $484.10
Tablets (Levetiracetam)
250 mg (120): $245.98
500 mg (30): $85.99
750 mg (120): $399.97
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.
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.
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 January 2010
Content last modified January 2010
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