Brand name: Keppra
Drug class: Anticonvulsants, Miscellaneous

Medically reviewed by Drugs.com on Dec 17, 2023. Written by ASHP.

Introduction

Anticonvulsant; a pyrrolidine derivative.

Uses for Levetiracetam

Seizure Disorders

Conventional (immediate-release) tablets, oral solution, and injection: Management (in combination with other anticonvulsants) of partial onset seizures in patients ≥1 month of age, myoclonic seizures in patients ≥12 years of age, and primary generalized tonic-clonic seizures in patients ≥6 years of age.

Extended-release tablets: Management (in combination with other anticonvulsants) of partial onset seizures in patients ≥12 years of age.

Also commercially available as an IV formulation for management of such seizure disorders when oral therapy temporarily not feasible.

Levetiracetam Dosage and Administration

General

• Withdraw gradually (e.g., by reducing dosage by 1 g daily at 2-week intervals) to minimize potential for increased seizure frequency.

• Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.

Administration

Administer orally (as immediate-release tablets, extended-release tablets, or oral solution); may be administered by IV infusion when oral therapy temporarily not feasible.

Commercially available levetiracetam conventional (immediate-release) tablets, oral solution, and IV formulations are bioequivalent.

Oral Administration

Immediate-release Tablets

Administer twice daily without regard to meals.

Swallow tablets whole; do not chew or crush.

Oral Solution

Administer twice daily without regard to meals.

Use a calibrated dosing device to measure and administer oral solution; household teaspoon or tablespoon not an adequate measuring device.

Extended-release Tablets

Administer once daily.

Swallow tablets whole; do not chew, break, or crush.

IV Administration

Dilution

Must dilute levetiracetam concentrate for injection prior to use. Withdraw appropriate dose and dilute in 100 mL of 0.9% sodium chloride injection, lactated Ringer’s, or 5% dextrose injection. May use a smaller volume of diluent if necessary (e.g., in pediatric patients or patients who may be susceptible to fluid volume overload), but concentration of diluted solution should not exceed 15 mg/mL. Discard unused contents of vial after use.

Alternatively, may use commercially available premixed injection (containing 500 mg, 1 g, or 1.5 g of levetiracetam in sodium chloride 0.82, 0.75, or 0.54%, respectively) without further dilution in adults ≥16 years of age. For doses that are not commercially available as a premixed solution (e.g., 250 or 750 mg), withdraw appropriate volume from commercial infusion bag and transfer to a separate sterile, empty infusion bag. Discard unused contents of original infusion bag; do not reuse or store.

Rate of Administration

Administer by IV infusion over 15 minutes. Do not use in series connections.

Dosage

When switching from oral to IV therapy, initial total daily IV dosage should be equivalent to daily dose and frequency of oral therapy. At completion of the IV treatment period, may switch back to oral therapy at same daily dose and frequency as IV therapy.

Pediatric Patients

Seizure Disorders

Partial Seizures in Pediatric Patients 1 to <6 Months of Age (Immediate-release Preparations)

Oral

Children weighing ≤20 kg should receive oral solution.

Initially, 14 mg/kg daily (administered as 7 mg/kg twice daily). Increase by 14 mg/kg daily at 2-week intervals up to recommended dosage of 42 mg/kg daily (administered as 21 mg/kg twice daily).

In clinical trial, mean daily dosage was 35 mg/kg in this age group; efficacy of lower dosages not established.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Partial Seizures in Pediatric Patients 6 months to <4 Years of Age (Immediate-release Preparations)

Oral

Children weighing ≤20 kg should receive oral solution; children weighing >20 kg may receive either tablets or oral solution.

Initially, 20 mg/kg daily (administered as 10 mg/kg twice daily).

Increase by 20 mg/kg daily at 2-week intervals up to recommended dosage of 50 mg/kg daily (administered as 25 mg/kg twice daily).

May reduce dosage if patient unable to tolerate a dosage of 50 mg/kg daily. In clinical trial, mean daily dosage was 47 mg/kg in this age group.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Partial Seizures in Pediatric Patients 4 to <16 Years of Age (Immediate-release Preparations)

Oral

Children weighing ≤20 kg should receive oral solution; children weighing >20 kg may receive either tablets or oral solution.

Initially 20 mg/kg daily (administered as 10 mg/kg twice daily).

Increase by 20 mg/kg daily at 2-week intervals up to recommended dosage of 60 mg/kg daily (administered as 30 mg/kg twice daily).

May reduce dosage if patient unable to tolerate a dosage of 60 mg/kg daily. In clinical trial, mean daily dosage was 44 mg/kg and maximum daily dosage was 3 g daily.

Immediate-release tablets in pediatric patients weighing 20–40 kg: Initially, 500 mg daily (administered as 250 mg twice daily); may increase dosage by 500 mg daily every 2 weeks up to maximum of 1.5 g daily (administered as 750 mg twice daily).

Immediate-release tablets in pediatric patients weighing >40 kg: Initially, 1 g daily (administered as 500 mg twice daily); may increase dosage by 1 g daily every 2 weeks up to maximum of 3 g daily (administered as 1.5 g twice daily).

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Partial Seizures in Pediatric Patients ≥12 Years of Age (Extended-release Tablets)

Oral

Initially, 1 g once daily. May increase by 1 g daily at 2-week intervals up to maximum recommended dosage of 3 g daily.

Myoclonic Seizures in Pediatric Patients ≥12 Years of Age

Oral

Initially, 1 g daily (administered as 500 mg twice daily as immediate-release preparations).

May increase by 1 g daily at 2-week intervals up to recommended dosage of 3 g daily (administered as 1.5 g twice daily). Efficacy of dosages <3 g daily not established.

IV

When oral therapy is temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Primary Generalized Tonic-Clonic Seizures in Pediatric Patients 6 to <16 Years of Age

Oral

Children weighing ≤20 kg should receive oral solution; children weighing >20 kg may receive either the immediate-release tablets or oral solution.

Initially, 20 mg/kg daily (administered as 10 mg/kg twice daily as immediate-release preparations).

May increase by 20 mg/kg daily at 2-week intervals up to recommended dosage of 60 mg/kg daily. Efficacy of dosages <60 mg/kg daily not established.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Adults

Seizure Disorders

Partial Seizures in Adults ≥16 Years of Age

Oral

Initially, 1 g daily (administered as 500 mg twice daily as immediate-release tablets or oral solution, or 1 g once daily as extended-release tablets).

May increase by 1 g daily at 2-week intervals up to maximum of 3 g daily.

Some clinicians reportedly initiate therapy with dosages of 2–4 g daily.

Dosages >3 g daily may not be associated with increased therapeutic benefit.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Myoclonic Seizures in Adults ≥16 Years of Age

Oral

Initially, 1 g daily (administered as 500 mg twice daily as immediate-release preparations).

May increase by 1 g daily at 2-week intervals up to recommended dosage of 3 g daily (administered as 1.5 g twice daily). Efficacy of dosages <3 g daily not established.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Primary Generalized Tonic-Clonic Seizures in Adults ≥16 Years of Age

Oral

Initially, 1 g daily (administered as 500 mg twice daily as immediate-release preparations).

May increase by 1 g daily at 2-week intervals up to recommended dosage of 3 g daily (administered as 1.5 g twice daily). Efficacy of dosages <3 g daily not established.

IV

When oral therapy temporarily not feasible, may administer by IV infusion at same dosages recommended above.

Prescribing Limits

Pediatric Patients

Seizure Disorders

Partial Seizures

Oral/IV

Manufacturer recommends maximum of 3 g daily in pediatric patients weighing >40 kg and maximum of 1.5 g daily in pediatric patients weighing 20–40 kg.

Adults

Seizure Disorders

Partial Seizures

Oral/IV

Maximum 3 g daily recommended by the manufacturer.

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with hepatic impairment.

Renal Impairment

Modify dosage according to the degree of impairment based on patient’s measured or estimated Cl_cr adjusted for body surface area. (See Tables 1 and 2.)

Geriatric Patients

Select dosage carefully and consider monitoring renal function during therapy.

Cautions for Levetiracetam

Contraindications

• Known hypersensitivity to levetiracetam.

Warnings/Precautions

Warnings

Nervous System Effects

Possible adverse neuropsychiatric effects are classified into 3 categories: somnolence and fatigue; coordination difficulties; behavioral changes.

Somnolence, asthenia, and coordination difficulties occur most frequently within first 4 weeks of treatment.

Psychotic manifestations, sometimes requiring hospitalization, reported.

Nonpsychotic behavioral symptoms (e.g., aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, personality disorder) also reported.

Monitor for adverse neuropsychiatric effects during therapy. Advise patients not to drive or operate machinery until the effects of levetiracetam are known.

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks. Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression. Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.

Balance risk of suicidality with risk of untreated illness. Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.

Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), reported. Median time to onset usually 14–17 days, but may occur months after initiation of therapy.

Discontinue drug at first sign of rash, unless clearly not drug-related. If manifestations suggestive of SJS or TEN occur, permanently discontinue; consider alternative therapy.

Discontinuance of Therapy

Abrupt withdrawal may result in increased seizure frequency or status epilepticus.

Hematologic Effects

Hematologic abnormalities (e.g., decreased RBC, WBC, and neutrophil counts) reported in clinical studies. Agranulocytosis, leukopenia, neutropenia, pancytopenia, and thrombocytopenia also have occurred during postmarketing experience.

Monitor CBC in patients who experience any signs or symptoms of hematologic abnormalities (e.g., severe weakness, pyrexia, recurrent infections, coagulation disorders).

Increased BP

Increased diastolic BP observed in pediatric patients 1 month to <4 years of age; monitor such patients during therapy.

Seizure Control During Pregnancy

Physiologic changes that occur during pregnancy may gradually decrease plasma levels of levetiracetam in pregnant women. Most notable during third trimester.

Closely monitor during pregnancy and throughout postpartum period, particularly if dosage is adjusted during pregnancy.

Sensitivity Reactions

Anaphylaxis and Angioedema

Anaphylaxis and angioedema, in some cases life-threatening and/or requiring emergency treatment, reported.

Discontinue immediately and seek medical attention if any signs or symptoms occur. Manifestations have included hypotension, hives, rash, respiratory distress, facial swelling, and swelling of the tongue, throat, and feet. Permanently discontinue if an alternative etiology cannot be identified.

General Precautions

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Keppra (levetiracetam) and Kaletra (fixed combination of lopinavir and ritonavir, both antiretroviral agents) may result in errors.

Specific Populations

Pregnancy

Category C.

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334.

Lactation

Distributed into milk. Discontinue nursing or the drug because of potential risk in nursing infant.

Pediatric Use

Safety and efficacy of immediate-release tablets, oral solution, and injection for management of partial onset seizures not established in children <1 month of age.

Safety and efficacy of immediate-release tablets, oral solution, and injection for management of myoclonic seizures not established in pediatric patients <12 years of age.

Safety and efficacy of immediate-release tablets, oral solution, and injection for management of primary generalized tonic-clonic seizures not established in children <6 years of age.

Safety and efficacy of extended-release tablets not established in children <12 years of age.

Safety and efficacy of premixed injection in sodium chloride not established in pediatric patients <16 years of age.

Geriatric Use

No substantial differences in safety relative to younger adults; insufficient experience in patients ≥65 years of age to determine whether efficacy is similar.

Hepatic Impairment

Safety and efficacy demonstrated in a limited number of epileptic patients with chronic liver disease.

Renal Impairment

Dosage adjustment recommended for patients with decreased Cl_cr.

Common Adverse Effects

Adults: Somnolence, asthenia, infection, dizziness.

Pediatric patients: Fatigue, aggression, nasal congestion, decreased appetite, irritability.

Drug Interactions

Not a substrate or inhibitor of CYP isoenzymes.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.

Protein-bound Drugs

Pharmacokinetic interaction unlikely.

Specific Drugs

Levetiracetam Pharmacokinetics

Absorption

Bioavailability

Immediate-release preparations: Rapidly and almost completely absorbed (nearly 100% bioavailable) following oral administration, with peak plasma concentrations attained in approximately 1 hour.

Extended-release tablets: Absorbed more slowly, but to a similar extent as immediate-release tablets. Peak plasma concentration attained in approximately 4 hours.

Commercially available tablets (immediate-release or extended-release), oral solution, and injection formulations are bioequivalent.

Food

Immediate-release preparations: Food does not affect bioavailability but delays time to peak plasma concentration by 1.5 hours and decreases peak plasma concentration by 20%.

Extended-release tablets: Consumption of a high fat, high caloric meal delays time to peak plasma concentration by 2 hours and increases peak plasma concentrations.

Distribution

Extent

Distributed into milk.

Plasma Protein Binding

<10%.

Elimination

Metabolism

Not extensively metabolized. About 24% of an administered dose is metabolized to an inactive metabolite by hydrolysis of the acetamide group; metabolism is not dependent on CYP isoenzymes.

Elimination Route

Excreted principally as unchanged drug (66%) in urine.

Clearance is correlated with Cl_cr.

Half-life

6–8 hours.

Special Populations

In patients with renal impairment, clearance is reduced by 40, 50, and 60% in patients with mild, moderate, and severe renal impairment, respectively. In patients with end-stage renal disease, clearance is reduced by about 70%; hemodialysis removes about 50% of body stores of levetiracetam.

In patients with severe hepatic impairment (Child Pugh class C), total body clearance is reduced by 50%, principally due to decreased renal clearance; pharmacokinetics unchanged in patients with mild (Child Pugh class A) to moderate (Child Pugh class B) hepatic impairment.

In geriatric patients with Cl_cr of 30–74 mL/minute, total body clearance is reduced by 38% and half-life increased by 2.5 hours, but no pharmacokinetic differences related solely to age observed.

In pediatric patients 6–12 years of age, body weight-adjusted apparent clearance is approximately 40% higher than in adults.

Stability

Storage

Oral

Immediate-release Tablets

25°C (may be exposed to 15–30°C).

Extended-release Tablets

25°C (may be exposed to 15–30°C).

Solution

25°C (may be exposed to 15–30°C).

Parenteral

Concentrate for Injection

25°C (may be exposed to 15–30°C).

After dilution, may store in PVC bags for ≤4 hours at 15–30°C.

Injection in Sodium Chloride Injection

20–25°C.

Actions

• Structurally unrelated to other currently available anticonvulsants.

• Mechanism of anticonvulsant action is not known.

• Protection observed against secondarily generalized activity from focal seizures induced by 2 chemoconvulsants known to induce seizures that mimic some features of human complex partial seizures with secondary generalization.

• Demonstrated inhibitory properties in the kindling model in rats, another model of human complex partial seizures.

Advice to Patients

• Provide copy of manufacturer’s patient information.

• Risk of adverse neuropsychiatric effects (e.g., somnolence, fatigue, dizziness, coordination difficulties, behavioral changes), especially during the initial weeks of therapy.

• Risk of drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.

• Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people). Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).

• Risk of serious dermatologic reactions. Importance of patients immediately notifying their clinician if a rash develops.

• Risk of anaphylaxis and angioedema. Importance of patients discontinuing therapy and seeking medical care if any signs and symptoms of these reactions occur.

• Importance of adhering to prescribed directions for use.

• Importance of not abruptly discontinuing therapy.

• Use in combination with other anticonvulsants, not as monotherapy.

• Importance of informing patients who are taking levetiracetam oral solution not to use a household teaspoon or tablespoon to measure the dose; a calibrated measuring device (such as a medicine dropper, spoon, cup, or syringe) should be obtained and used when administering the oral solution.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing women about existence of and encouraging enrollment in pregnancy registries.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illness (e.g., renal disease).

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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