Levetiracetam

Pharmacologic Category

Anticonvulsant, Miscellaneous

Dosing: Adult

Note: When switching between oral and IV formulations, the total daily dose should be the same.

Craniotomy, seizure prophylaxis (off-label use): IV, Oral: 1 g/day in 2 divided doses is commonly used; a dosage range of 500 mg to 3 g/day has been studied (Fuller 2013; Pourzitaki 2016). After induction of anesthesia, administer first dose IV (eg, 500 mg to 1 g IV [Paisansathan 2020]); subsequently, adjust dose based on response and tolerability (Fuller 2013; Iuchi 2015; Pourzitaki 2016).

Focal (partial) onset seizures and generalized-onset seizures (FDA approved for monotherapy [IR tablet and oral solution only], adjunctive treatment of focal [partial] onset seizures, and adjunctive treatment of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures; may be used off label for other seizure types) (AAN/AES [Kanner 2018]; Brodie 2007; Trinka 2013):

Oral:

Immediate release (tablets, oral solution, tablets for oral suspension): Initial: 500 mg twice daily; increase every 2 weeks by 500 mg/dose based on response and tolerability to the maximum recommended dose of 1.5 g twice daily.

Extended release (FDA approved only for focal [partial] onset seizures): Initial: 1 g once daily; increase every 2 weeks by 1 g/day based on response and tolerability to a maximum of 3 g once daily.

Note: In patients with epilepsy, oral loading doses of 1.5 to 2 g (immediate release) have been well tolerated and may be useful for more rapidly achieving serum concentrations associated with seizure control (Betts 2000; Koubeissi 2008); however, the necessity of an oral loading dose has not been established.

IV: Initial: 500 mg twice daily; increase every 2 weeks by 500 mg/dose based on response and tolerability to a maximum of 1.5 g twice daily. Use >4 days has not been studied.

Note: Additional benefit of oral or IV doses >3 g/day has not been established; however, oral doses of 4 g/day have been studied in patients with refractory epilepsy but may be associated with a greater incidence of somnolence (Betts 2000; Striano 2005).

Status epilepticus (off-label use): IV: 1 to 3 g administered at a rate of 2 to 5 mg/kg/minute (NCS [Brophy 2012]) or 40 to 60 mg/kg as a single dose infused over 5 to 15 minutes in combination with a parenteral benzodiazepine. Maximum dose: 4.5 g (AES [Glauser 2016]; Drislane 2020; Jirsch 2020; Kapur 2019; Wheless 2009).

Subarachnoid hemorrhage (short-term seizure prophylaxis) (off-label use): IV:

Loading dose: 20 mg/kg (rounded to the nearest 250 mg) (Szaflarski 2010) infused over 5 to 15 minutes (AES [Glauser 2016]; Drislane 2020; Jirsch 2020; Kapur 2019; Wheless 2009).

Maintenance dose: 1 g over 15 minutes every 12 hours for 7 days; may be increased to a maximum dose of 1.5 g every 12 hours if necessary (Szaflarski 2010).

Traumatic brain injury (severe acute) (short-term seizure prophylaxis) (off-label use): IV:

Loading dose: 20 mg/kg (rounded to the nearest 250 mg) (Szaflarski 2010) infused over 5 to 15 minutes (AES [Glauser 2016]; Drislane 2020; Jirsch 2020; Kapur 2019; Wheless 2009).

Maintenance dose: 1 g over 15 minutes every 12 hours for 7 days; may be increased to a maximum dose of 1.5 g every 12 hours if necessary (Szaflarski 2010).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing; consider lowering initial dose by 30% to 50% and increasing gradually (eg, ≤125 mg/week) due to reduced drug clearance (Contin 2012; Theitler 2017).

Dosing: Renal Impairment: Adult

Note: Loading doses should be utilized when indicated (see adult dosing) and administered unadjusted for renal function or dialytic therapy. For maintenance doses, the risks/benefits favor dosing on the higher side of the recommended dosing range when initiating treatment, particularly in patients with acute seizures (expert opinion).

Altered kidney function:

Note: The manufacturer's labeling recommends estimating CrCl using the Cockcroft-Gault formula adjusted for BSA as follows: CrCl (mL/minute/1.73 m²) = CrCl (mL/minute)/BSA (m²) x 1.73.

IR and IV formulations (Bansal 2015; Yamamoto 2014; manufacturer's labeling):

CrCl 80 to 130 mL/minute/1.73 m²: 500 mg to 1.5 g every 12 hours.

CrCl 50 to <80 mL/minute/1.73 m²: 500 mg to 1 g every 12 hours.

CrCl 30 to <50 mL/minute/1.73 m²: 250 to 750 mg every 12 hours.

CrCl 15 to <30 mL/minute/1.73 m²: 250 to 500 mg every 12 hours.

CrCl <15 mL/minute/1.73 m²: 250 to 500 mg every 24 hours (expert opinion).

ER tablet:

CrCl >80 mL/minute/1.73 m²: 1 to 3 g every 24 hours.

CrCl 50 to 80 mL/minute/1.73 m²: 1 to 2 g every 24 hours.

CrCl 30 to 50 mL/minute/1.73 m²: 500 mg to 1.5 g every 24 hours.

CrCl <30 mL/minute/1.73 m²: 500 mg to 1 g every 24 hours.

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m²): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted posttrauma (eg, traumatic brain injury) or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to confirm presence of ARC in these patients (Bilbao-Meseguer 2018; Udy 2010).

Note: Doses derived from Monte Carlo simulations (Spencer 2011) and expert opinion.

IR and IV formulations: CrCl >130 mL/minute/1.73 m²: 1.5 to 2 g every 12 hours.

ER tablet: CrCl >130 mL/minute/1.73 m²: 3 to 4 g every 24 hours.

Hemodialysis, intermittent (thrice weekly): Dialyzable (50%):

IR and IV formulations: 500 mg to 1 g every 24 hours posthemodialysis; if dose administered prior to hemodialysis, a supplemental dose of 250 to 500 mg is recommended posthemodialysis (Bansal 2015).

ER tablet: Use not recommended.

Peritoneal dialysis: Note: Limited data available; dosing based on a case report demonstrating toxicity at a higher dose (Bahte 2014) and expert opinion.

IR and IV formulations: 250 to 500 mg every 24 hours.

ER tablet: Use not recommended.

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations assume high-flux dialyzers and flow rates of ~1,500 to 3,000 mL/hour, unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.

CVVH/CVVHD/CVVHDF: Note: Dose based on limited data (Smetana 2016; van Matre 2014) and expert opinion.

IR and IV formulations: 750 mg to 1 g every 12 hours.

Prolonged intermittent renal replacement therapy (eg, sustained low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.

Note: No data available; dose based on expert opinion.

IR and IV formulations: 250 to 500 mg every 12 hours.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary

Dosing: Pediatric

Note: Use oral solution in infants and children ≤20 kg. Parenteral IV therapy should be temporary and transitioned to oral when able; when switching from oral to IV formulation, the total daily dose (individual dose and frequency) should be the same.

Myoclonic seizures with juvenile myoclonic epilepsy: Children ≥12 years and Adolescents: IV, Oral (immediate release: Tablets, oral solution [eg, Keppra], or tablets for oral suspension [Spritam]): Initial 500 mg twice daily; increase dosage every 2 weeks by 500 mg/dose twice daily based on response and tolerability to the recommended dose of 1,500 mg twice daily.

Partial onset seizures:

Infants 1 to <6 months: IV, Oral (immediate release: Solution): Initial: 7 mg/kg/dose twice daily; increase dosage every 2 weeks by 7 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 21 mg/kg/dose twice daily.

Infants ≥6 months and Children <4 years: IV, Oral (immediate release: Solution or tablets): Initial: 10 mg/kg/dose twice daily; increase dosage every 2 weeks by 10 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 25 mg/kg/dose twice daily.

Children ≥4 years and Adolescents <16 years:

IV: Initial: 10 mg/kg/dose twice daily; increase dosage every 2 weeks by 10 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 30 mg/kg/dose twice daily; the maximum daily dose was 3,000 mg/day in clinical trials.

Oral:

Immediate release:

Weight-directed dosing: Oral solution: Initial: 10 mg/kg/dose twice daily; increase dosage every 2 weeks by 10 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 30 mg/kg/dose twice daily; the maximum daily dose was 3,000 mg/day in clinical trials.

Fixed dosing: Tablet (immediate release [eg, Keppra] or for oral suspension [Spritam]):

20 to 40 kg: Initial: 250 mg twice daily; increase dosage every 2 weeks by 250 mg twice daily based on response and tolerability to the maximum recommended dose of 750 mg twice daily.

>40 kg: Initial: 500 mg twice daily; increase dosage every 2 weeks by 500 mg twice daily based on response and tolerability to the maximum recommended dose of 1,500 mg twice daily.

Extended release (eg, Elepsia XR; Keppra XR): Children ≥12 years and Adolescents: Initial: 1,000 mg once daily; may increase dosage every 2 weeks by 1,000 mg/day based on response and tolerability to a maximum recommended dose of 3,000 mg once daily.

Adolescents ≥16 years:

IV: Initial: 500 mg twice daily; increase dosage every 2 weeks by 500 mg/dose twice daily based on response and tolerability to a maximum recommended dose of 1,500 mg twice daily.

Oral:

Immediate release (tablets, oral solution [eg, Keppra], tablets for oral suspension [Spritam]): Initial: 500 mg twice daily; increase dosage every 2 weeks by 500 mg twice daily based on response and tolerability to the maximum recommended dose of 1,500 mg twice daily.

Extended release (eg, Elepsia XR, Keppra XR): Initial: 1,000 mg once daily; increase dosage every 2 weeks by 1,000 mg/day based on response and tolerability to a maximum recommended dose of 3,000 mg once daily.

Seizure prophylaxis, traumatic brain injury: Note: Current guidelines state that there is not sufficient evidence to recommend levetiracetam over phenytoin (Brain Trauma Foundation [Kochanek 2019]).

Infants, Children, and Adolescents: Limited data available, optimal dose not defined: IV, Oral: 20 to 55 mg/kg/day in divided doses twice daily; reported range: 5 to 55 mg/kg/day (Chung 2016; Pearl 2013). In one prospective observational study, patients with moderate to severe traumatic brain injury (TBI) (n=34, ages 5 days to 16 years) received a median dose of 20 mg/kg/day in divided doses twice daily (range: 5 to 40 mg/kg/day). 17.6% patients experienced seizure despite therapy, with the highest percentage in younger patients and those with a history of abuse (Chung 2016). Another prospective observational study of patients with TBI at risk for seizures used a dose of 55 mg/kg/day in divided doses (n=20, ages 6 to 17 years); one patient developed seizures 7 days after initial trauma (Pearl 2013).

Status epilepticus, urgent therapy/second-phase therapy or refractory:

American epilepsy society guidelines (AES [Glauser 2016]): Limited data available: Infants, Children, and Adolescents: IV: 60 mg/kg as a single dose; maximum dose: 4,500 mg/dose; initiate maintenance therapy based upon clinical response and type of seizure disorder.

Neurocritical care guidelines (NCS [Brophy 2012]): Limited data available: Infants, Children, and Adolescents: IV: 20 to 60 mg/kg as a single dose; initiate maintenance therapy based upon clinical response and type of seizure disorder; Note: Maximum dose in adults is 3,000 mg/dose.

Tonic-clonic seizures; primary generalized:

Children ≥6 years and Adolescents <16 years:

IV: Initial: 10 mg/kg/dose twice daily; increase dosage every 2 weeks by 10 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 30 mg/kg/dose twice daily.

Oral: Immediate release:

Weight-directed: Oral solution or tablets: Initial: 10 mg/kg/dose twice daily; increase dosage every 2 weeks by 10 mg/kg/dose twice daily based on response and tolerability to the recommended dose of 30 mg/kg/dose twice daily.

Fixed-dosing: Orally disintegrating tablets [Spritam]:

20 to 40 kg: Initial: 250 mg twice daily; increase dosage every 2 weeks by 250 mg twice daily based on response and tolerability to the maximum recommended dose of 750 mg twice daily.

>40 kg: Initial: 500 mg twice daily; increase dosage every 2 weeks by 500 mg twice daily based on response and tolerability to the maximum recommended dose of 1,500 mg twice daily.

Adolescents ≥16 years: IV, Oral (immediate release: Solution or tablets [eg, Keppra], tablets for oral suspension [Spritam]): Initial: 500 mg twice daily; increase dosage every 2 weeks by 500 mg/dose twice daily based on response and tolerability to the recommended dose of 1,500 mg twice daily.

Dosing: Renal Impairment: Pediatric

Infants, Children, and Adolescents <16 years: There are no dosage adjustments provided in the manufacturer's labeling; clearance is decreased and correlates with creatinine clearance. Some have recommended the following for immediate-release tablets, oral solution, and IV formulations (Aronoff 2007):

GFR <50 mL/minute/1.73 m²: Administer 50% of the dose.

Hemodialysis: Dialyzable (50%); administer 50% of normal dose every 24 hours; a supplemental dose after hemodialysis is recommended.

CAPD: Administer 50% of normal dose.

CRRT: Administer 50% of normal dose.

Adolescents ≥16 years:

IV, Oral (immediate release [tablets, oral solution] and tablets for oral suspension [Spritam]):

CrCl >80 mL/minute/1.73 m²: 500 to 1,500 mg every 12 hours

CrCl 50 to 80 mL/minute/1.73 m²: 500 to 1,000 mg every 12 hours

CrCl 30 to 50 mL/minute/1.73 m²: 250 to 750 mg every 12 hours

CrCl <30 mL/minute/1.73 m²: 250 to 500 mg every 12 hours

End-stage renal disease patients using dialysis: Dialyzable (50%); 500 to 1,000 mg every 24 hours; a supplemental dose of 250 to 500 mg following dialysis is recommended

Peritoneal dialysis: 500 to 1,000 mg every 24 hours (Aronoff 2007)

CRRT: 250 to 750 mg every 12 hours (Aronoff 2007)

Oral extended release (Elepsia XR, Keppra XR): There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, dosage adjustment suggested.

Dosing: Hepatic Impairment: Pediatric

No dosage adjustment necessary

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)

Use: Labeled Indications

Focal (partial) onset:

IR tablets/oral solution: Treatment of focal (partial) onset seizures in adults, adolescents, children, and infants ≥1 month of age with epilepsy.

Tablets for oral suspension: Adjunctive therapy in the treatment of focal (partial) onset seizures in adults and children ≥4 years of age and >20 kg with epilepsy.

ER tablets: Treatment of focal (partial) onset seizures in adults and adolescents ≥12 years of age with epilepsy.

IV: Treatment of focal (partial) onset seizures in adults and children ≥1 month of age with epilepsy.

Limitation of use: IV use is only as an alternative when oral administration is temporarily not feasible.

Generalized onset:

Juvenile myoclonic epilepsy:

Immediate-release tablets/oral solution/tablets for oral suspension: Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years and older with juvenile myoclonic epilepsy.

IV: Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years and older with juvenile myoclonic epilepsy.

Primary generalized tonic-clonic seizures:

Immediate-release tablets/oral solution/tablets for oral suspension: Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years and older with idiopathic generalized epilepsy.

IV: Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years and older with idiopathic generalized epilepsy.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Craniotomy, seizure prophylaxisLevel of Evidence [B]

Data from a systematic review and meta-analysis support the use of levetiracetam as an alternative to phenytoin for seizure prophylaxis during craniotomy and in the postoperative period ^Ref.

Status epilepticusLevel of Evidence [B, G]

Data from a randomized, controlled trial ^Ref and meta-analyses ^Ref have reported similar efficacy and safety with levetiracetam when compared to other antiepileptics (phenytoin/fosphenytoin, valproic acid) in the treatment of status epilepticus.

Based on the Neurocritical Care Society guidelines for the evaluation and management of status epilepticus and the American Epilepsy Society guideline for the treatment of convulsive status epilepticus, the use of levetiracetam is an effective and recommended treatment option for urgent control of status epilepticus. However, benzodiazepines continue to be the agents of choice for initial therapy.

Subarachnoid hemorrhage (short-term seizure prophylaxis)Level of Evidence [C, G]

According to guidelines for the management of subarachnoid hemorrhage (SAH), prophylactic anticonvulsants may be considered following hemorrhage ^Ref; however, data presented from 2 prospective trials present inconclusive results ^Ref. Levetiracetam may be considered following SAH in patients who have a history of seizure disorder, aneurysm in the middle cerebral artery, intracerebral hematoma, infarction, and intractable hypertension. Additional randomized, controlled trials further evaluating levetiracetam for prophylaxis of seizures following SAH are necessary before it can be routinely recommended.

Traumatic brain injury, severe acute (short-term seizure prophylaxis)Level of Evidence [B]

Data from a meta-analysis that included 1 randomized, controlled trial and 7 cohort studies support the use of IV levetiracetam for early seizure prophylaxis following severe traumatic brain injury ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Comparative Efficacy

• LEVETIRACETAM

Clinical Practice Guidelines

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy,” 2018

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy, “ 2018

American Epilepsy Society, “Treatment of Convulsive Status Epilepticus in Children and Adults,” January 2016

Administration: IV

For IV use only; infuse over 5 to 15 minutes. For urgent indications, may administer over 5 to 6 minutes in doses up to 3 g (Ramael 2006; Wheless 2009) or over 10 minutes in doses up to 4.5 g (Kapur 2019).

Administration: Injectable Detail

pH: 5.5

Administration: Oral

Administer without regard to meals.

Oral solution: Administer with a calibrated measuring device (not a household teaspoon or tablespoon).

Tablet:

Disintegrating soluble tablet for oral suspension: Remove from blister by peeling back the foil (do not push tablet through the foil). Place whole tablet on the tongue with dry hand, follow with a sip of liquid and swallow only after tablet disintegrates. Do not swallow tablets intact. Partial tablets should not be administered. Tablet disintegrates in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth when taken with a sip of liquid.

Alternatively, allow whole tablet to disperse in a small volume of liquid (one tablespoon or enough to cover the tablet) in a cup; consume entire contents immediately; resuspend any residue by adding an additional small volume of liquid and swallow the full amount.

Immediate release: Manufacturer labeling recommends that tablets should be swallowed whole, not chewed or crushed; however, some studies support crushing and mixing with applesauce (Note: Levetiracetam has a bitter taste) or administering via enteral feeding tube. Mix with 120 mL of enteral nutrition formula or disperse crushed tablets (500 mg tablet strength studied) in 10 mL of water, shake for 5 minutes to dissolve, and administer immediately via enteral feeding tube (Fay 2005; White 2015).

Extended release: Only administer as whole tablet; do not crush, break, or chew.

Administration: Pediatric

Oral: May be administered without regard to meals

Extended-release tablets: Swallow tablets whole; do not break, crush, or chew.

Oral solution: Administer with calibrated measuring device (not household teaspoon or tablespoon).

Tablets for oral suspension (Spritam): Remove from blister by peeling back the foil (do not push tablet through the foil). Place whole tablet on the tongue with dry hand; follow with a sip of liquid and swallow only after tablet disintegrates; do not swallow intact tablet. Partial/split tablets should not be administered. Tablet disintegrates in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth when taken with a sip of liquid.

Alternatively, allow whole tablet to disperse in a small volume of liquid (eg, 15 mL or enough to cover the tablet[s]) in a cup; consume entire contents immediately; resuspend any residue in cup by adding an additional small volume of liquid and swallow the full amount.

Parenteral: IV: Vials must be diluted prior to use. Do not use if solution contains particulate matter or is discolored. Discard unused portions; does not contain preservative. Infuse over 15 minutes; in status epilepticus a rate of 2 to 5 mg/kg/minute has been recommended (NCS [Brophy 2012]). Others have safely used a 1:1 dilution infused over 5 to 6 minutes (with doses up to 60 mg/kg) through a peripheral site in patients 4 to 32 years of age (Wheless 2009).

Storage/Stability

Oral solution, tablets, tablets for oral suspension: 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 in NS, LR, or D5W is stable for 4 hours in PVC bags kept at room temperature (Note: The manufacturer's labeling for Keppra injection previously stated the admixed solution is stable for 24 hours in PVC bags at room temperature; this was changed to 4 hours as of April 2016 although there was no change in the formulation (Personal Communication, UCB, Inc. 2016). The manufacturer’s labeling for generic levetiracetam injectable products may have differing recommendations; refer to individual manufacturer’s labeling for details.

Preparation for Administration: Adult

Vials for injection: Manufacturer labeling recommends diluting dose in 100 mL of NS, LR, or D5W. If a smaller volume is required (eg, pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg/mL of diluted solution. Alternatively, in urgent indications (eg, status epilepticus), a 1:1 dilution of drug from vial with D5W or NS (eg, 1 g per 10 mL diluted in 10 mL of NS; total volume 20 mL) has been safely used (Wheless 2009).

Preparation for Administration: Pediatric

Parenteral: IV: Vials: Dilute dose in 100 mL of NS, LR, or D5W; if smaller diluent volume required (eg, pediatric patients), dilute dose in a compatible diluent to maximum final concentration of 15 mg/mL. A 1:1 dilution of drug from vial with D5W or NS has also been safely used in patients ≥4 years (Wheless 2009).

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat seizures.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea

• Stuffy nose

• Runny nose

• Trouble sleeping

• Abdominal pain

• Sore throat

• Nausea

• Vomiting

• Lack of appetite

• Flu-like symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Swelling in your throat

• Depression like thoughts of suicide, anxiety, emotional instability, or illogical thinking.

• Infection

• Seizures

• Sensing things that seem real but are not

• Severe loss of strength and energy

• Severe dizziness

• Severe headache

• Passing out

• Change in balance

• Abnormal gait

• Severe fatigue

• Bruising

• Bleeding

• Agitation

• Irritability

• Panic attacks

• Mood changes

• Behavioral changes

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Keppra: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021035s102,021505s042lbl.pdf#page=32

Keppra XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022285s028lbl.pdf#page=26

Spritam: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207958s008lbl.pdf#page=34

Contraindications

Hypersensitivity (eg, anaphylaxis, angioedema) to levetiracetam or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression (impaired coordination, ataxia, abnormal gait, weakness, fatigue, dizziness, and somnolence), which may impair physical or mental abilities. Symptoms occur most commonly during the first month of therapy. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported in adults and children. Onset is usually within ~2 weeks of treatment initiation, but may be delayed (>4 months); recurrence following rechallenge has been reported. Levetiracetam should be discontinued if there are any signs of a hypersensitivity reaction or unspecified rash; if signs or symptoms suggest SJS or TEN, do not resume therapy and consider alternative treatment.

• Hematologic effects: Decreases in red blood cell counts, hemoglobin, hematocrit, white blood cell counts, and neutrophils and increases in eosinophils have been observed. Cases of, agranulocytosis, pancytopenia, and thrombocytopenia have also been reported.

• Hypersensitivity reactions: Potentially life-threatening hypersensitivity reactions, including anaphylaxis, angioedema, hypotension, hives, rash and respiratory distress may occur after the first dose or at any time during treatment. If signs or symptoms of anaphylaxis or angioedema occur, discontinue levetiracetam immediately. If a clear alternative etiology for the symptoms cannot be determined, discontinue permanently.

• Hypertension: Isolated elevations in diastolic blood pressure measurements have been reported in children <4 years; 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. Monitor blood pressure in patients <4 years.

• Psychiatric symptoms: Psychosis, paranoia, hallucinations, and behavioral symptoms (including aggression, agitation, anger, anxiety, apathy, confusion, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder) may occur; dose reduction or discontinuation may be required. Increased risk for psychiatric adverse effects may be seen in females, those with lower socioeconomic status, or history of depression, anxiety, personality disorder, suicidality, or psychotropic or recreational drug use (Josephson 2019).

• 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 health care provider immediately if symptoms occur.

Disease-related concerns:

• Renal impairment: Use caution with renal impairment; dosage adjustment may be necessary. In patients with ESRD requiring hemodialysis, it is recommended that immediate-release formulations be used instead of ER formulations.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: 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.

* See Cautions in AHFS Essentials for additional information.

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.

Warnings: Additional Pediatric Considerations

Incidence of behavioral abnormalities is higher in children (37.6%) than adults (13.3%); dosage reductions may be required. In clinical trials, pediatric patients 4 to <16 years, when compared with placebo, had statistically significant decreases in WBC and neutrophil counts; in one clinical trial, possible clinically significant decreases in WBCs were observed, but no difference in neutrophil counts was observed. Isolated elevations in diastolic blood pressure (DBP) measurements have been reported in infants and children 1 month to <4 years of age receiving levetiracetam; however, no difference was noted in mean diastolic measurements of these patients vs placebo group; monitor blood pressure in infants and children <4 years. Similar effects have not been observed in older children and adults. In pediatric clinical trials, the most frequently reported adverse reactions in pediatric patients 4 to <16 years of age were fatigue, aggression, nasal congestion, decreased appetite, and irritability and in younger pediatric patients (1 month to <4 years of age) were somnolence and irritability; additionally, children may experience a higher frequency of certain adverse effects than adults, including the following: Behavioral abnormalities (37.6% vs 13.3%), aggression/hostility (10% vs 2%), vomiting (reported in children only, 15%), and cough (9% vs 2%).

A retrospective chart review of 280 neonates who had received either phenobarbital, levetiracetam, or both for treatment of neonatal seizures evaluated neurodevelopment. A subset of the study group (n=67) had a Bayley Scales of Infant Development (BSID) completed at 24 months corrected age. Based on the analysis of cumulative exposures, the investigators observed that increased levetiracetam exposure was associated with a significant decrease in BSID cognitive (2.2 points) and motor (2.6 points) scores for every 300 mg/kg of levetiracetam exposure and no increased incidence of cerebral palsy was observed; however, increased neonatal exposure to phenobarbital was associated with larger significant reductions in BSID cognitive and motor scores (8 to 9 points) and an increased probability for the development of cerebral palsy. Since most patients received both drugs and thus were included in both evaluation groups and due to the retrospective design, a direct causality between levetiracetam exposure and negative cognitive and motor outcomes could not be confirmed (Maitre 2013).

Pregnancy Considerations

Levetiracetam crosses the placenta and can be detected in the newborn following delivery (Johannessen 2005; López-Fraile 2009; Tomson 2007). An increase in the overall rate of major congenital malformations has not been observed following maternal use of levetiracetam. Available studies have not been large enough to determine if there is an increased risk of specific birth defects (Hernández-Díaz 2012; Mawhinney 2013; Mølgaard-Nielsen 2011; Vajda 2012). In general, maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiepileptic medications may be at an increased risk of SGA and a 1 minute APGAR score <7 (Harden 2009).

Due to pregnancy-induced physiologic changes, plasma concentrations of levetiracetam gradually decrease during pregnancy, especially during the third trimester; patients should be closely monitored during pregnancy and postpartum.

A registry is available for women exposed to levetiracetam during pregnancy: Pregnant women may enroll themselves into the North American Antiepileptic Drug (AED) Pregnancy Registry (888-233-2334 or http://www.aedpregnancyregistry.org/).

Breast-Feeding Considerations

Levetiracetam is present in breast milk.

The relative infant dose (RID) of levetiracetam is 7.9% when calculated using data derived from the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 1 to 3 g/day.

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).

The RID of levetiracetam was calculated using an average milk:maternal plasma ratio of 1.05, providing an estimated daily infant dose via breast milk of ~2.4 mg/kg/day. This average milk:maternal plasma ratio was calculated using samples collected from 11 mother-infant pairs 4 to 23 days postpartum following maternal administration of oral levetiracetam 1 to 3 g/day. Concomitant maternal medications included lamotrigine, carbamazepine, tiagabine, clobazam, and/or oxcarbazepine which may have impacted maternal plasma concentrations. Levetiracetam was detected in the plasma of the breastfed infants (Tomson 2007).

Adverse effects, including hypotonia, sedation, vomiting, weight loss, and poor suckling have been reported in breastfed infants (Kramer 2002; Paret 2014). Insufficient lactation and subsequent discontinuation of breastfeeding has also been reported (Paret 2014).

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants exposed to levetiracetam via breast milk should be monitored for adverse effects and for achievement of developmental milestones. Maternal plasma concentrations should be monitored postpartum.

Lexicomp Pregnancy & Lactation, In-Depth

• LevETIRAcetam

Briggs' Drugs in Pregnancy & Lactation

• Levetiracetam

Adverse Reactions

Incidences are for all indications and populations (adults and children) unless otherwise specified.

>10%:

Cardiovascular: Increased blood pressure (diastolic; infants and children: 17%)

Central nervous system: Behavioral problems (includes aggression, agitation, anger, anxiety, apathy, depersonalization, emotional lability, irritability, neurosis; children and adolescents: 7% to 38%; adults: 7% to 13%), headache (14% to 19%), psychotic symptoms (infants and children: 17%; adults: 1%), drowsiness (8% to 15%; immediate release 4 g/day, no titration: 45%; serious [patients hospitalized]: <1%), irritability (infants, children, and adolescents: 6% to 12%), fatigue (10% to 11%)

Gastrointestinal: Vomiting (children and adolescents: 15%)

Infection: Infection (13%)

Neuromuscular & skeletal: Weakness (15%)

Respiratory: Nasopharyngitis (7% to 15%)

1% to 10%:

Central nervous system: Aggressive behavior (children and adolescents: 10%; adults: 1%), dizziness (5% to 9%), pain (7%), lethargy (children and adolescents: 6%), insomnia (children and adolescents: 5%), depression (3% to 5%), vertigo (3% to 5%), emotional lability (2% to 5%), agitation (children and adolescents: 4%), nervousness (4%), ataxia (partial-onset seizures: 3%; includes abnormal gait, incoordination), falling (children and adolescents: 3%), mood changes (children and adolescents: 3%), confusion (2% to 3%), amnesia (2%), anxiety (2%), hostility (2%), paranoia (children and adolescents: 2%), paresthesia (2%), sedation (children and adolescents: 2%)

Gastrointestinal: Upper abdominal pain (children and adolescents: 9%), decreased appetite (children and adolescents: 8%), diarrhea (6% to 8%), nausea (5%), anorexia (3% to 4%), constipation (children and adolescents: 3%), gastroenteritis (children and adolescents: 2%)

Hematologic & oncologic: Eosinophilia (children and adolescents: 9%), bruise (children and adolescents: 3%), decreased white blood cell count (3%), decreased neutrophils (2%)

Infection: Influenza (3% to 8%)

Neuromuscular & skeletal: Neck pain (2% to 8%), arthralgia (children and adolescents: 2%), joint sprain (children and adolescents: 2%)

Ophthalmic: Conjunctivitis (children and adolescents: 2%), diplopia (2%)

Otic: Otalgia (children and adolescents: 2%)

Respiratory: Nasal congestion (children and adolescents: 9%), cough (2% to 9%), pharyngolaryngeal pain (children and adolescents: 7%), pharyngitis (6% to 7%), rhinitis (2% to 4%), sinusitis (2%)

Miscellaneous: Head trauma (children and adolescents: 4%)

<1%, postmarketing and/or case reports: Abnormal hepatic function tests, acute renal failure, agranulocytosis, alopecia, anaphylaxis, angioedema, blurred vision, choreoathetosis, decreased hematocrit, decreased hemoglobin, decreased red blood cells, disturbance in attention, DRESS syndrome, dyskinesia, eczema, equilibrium disturbance, erythema multiforme, granulomatous interstitial nephritis (Chau 2012), hepatic failure, hepatitis, hyperkinesia, hyponatremia, leukopenia, memory impairment, myalgia, myasthenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression in some cases), panic attack, personality disorder, pruritus, psychosis, skin rash, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, thrombocytopenia, toxic epidermal necrolysis, weight loss

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Levetiracetam Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brivaracetam: LevETIRAcetam may diminish the therapeutic effect of Brivaracetam. Specifically, the therapeutic effect of brivaracetam may be diminished and/or negligible when given to patients already receiving levetiracetam. Risk D: Consider therapy modification

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

CarBAMazepine: LevETIRAcetam may enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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

Methotrexate: LevETIRAcetam may increase the serum concentration of Methotrexate. Risk C: Monitor therapy

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

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orlistat: May decrease the serum concentration of Anticonvulsants. Risk C: Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

OXcarbazepine: May decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

PHENobarbital: May decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Food may delay, but does not affect the extent of absorption. Management: Administer without regard to meals.

Monitoring Parameters

CNS depression (impaired coordination, ataxia, abnormal gait, weakness, fatigue, dizziness, and somnolence); psychiatric and behavioral symptoms (aggression, agitation, anger, anxiety, apathy, confusion, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, suicidal thoughts and personality disorder); diastolic blood pressure in children 1 month to <4 years; CBC (in patients who experience significant weakness, pyrexia, recurrent infections or coagulation disorders).

Reference Range

Timing of serum samples: Draw trough just before next dose.

Laboratory alert level: 50 mcg/mL (SI: 294 mcmol/L) (AGNP [Hiemke 2018])

Therapeutic reference range: Note: There is no clear correlation with therapeutic levels and efficacy or tolerability; base dosing on therapeutic response as opposed to serum concentrations. However, therapeutic drug levels may be useful in elderly patients, neonates, pregnant women, and patients on enzyme-inducing drugs or with renal insufficiency due to the wide range of alterations in clearance (Sourbron 2018).

Epilepsy: 12 to 46 mcg/mL (SI: 70 to 270 mcmol/L) (AGNP [Hiemke 2018]; Patsalos 2018)

Advanced Practitioners Physical Assessment/Monitoring

Monitor for CNS depression, psychiatric abnormalities, or behavioral abnormalities. Monitor therapeutic effectiveness (seizure activity, type, duration) at beginning of therapy and throughout. Teach patient seizure safety precautions.

Nursing Physical Assessment/Monitoring

Monitor therapeutic response (seizure activity, force, type, duration) at beginning of therapy and periodically throughout. 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). Observe and teach seizure/safety precautions.

Product Availability

Elepsia XR: FDA approved December 2018; anticipated availability is currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.

Dosage Forms Considerations

Note: Tablets for oral suspension and soluble disintegrating tablet both refer to Spritam.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Keppra: 500 mg/5 mL (5 mL)

Generic: 500 mg/100 mL (100 mL); 1000 mg/100 mL (100 mL); 1500 mg/100 mL (100 mL); 500 mg/5 mL (5 mL)

Solution, Intravenous [preservative free]:

Generic: 500 mg/100 mL (100 mL); 1000 mg/100 mL (100 mL); 1500 mg/100 mL (100 mL); 500 mg/5 mL (5 mL)

Solution, Oral:

Keppra: 100 mg/mL (473 mL) [gluten free, lactose free; contains methylparaben, propylparaben; grape flavor]

Generic: 100 mg/mL (5 mL, 473 mL, 500 mL [DSC])

Tablet, Oral:

Keppra: 250 mg [scored; contains fd&c blue #2 aluminum lake]

Keppra: 500 mg [scored]

Keppra: 750 mg [scored; contains fd&c yellow #6 aluminum lake]

Keppra: 1000 mg [scored]

Roweepra: 500 mg

Roweepra: 500 mg [scored; contains corn starch]

Roweepra: 750 mg [contains corn starch, fd&c yellow #6 aluminum lake]

Roweepra: 1000 mg [contains corn starch]

Generic: 250 mg, 500 mg, 750 mg, 1000 mg

Tablet Disintegrating Soluble, Oral:

Spritam: 250 mg, 500 mg, 750 mg, 1000 mg [spearmint flavor]

Tablet Extended Release 24 Hour, Oral:

Keppra XR: 500 mg, 750 mg

Roweepra XR: 500 mg, 750 mg

Generic: 500 mg, 750 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 500 mg/5 mL (5 mL)

Tablet, Oral:

Keppra: 250 mg, 500 mg, 750 mg

Generic: 250 mg, 500 mg, 750 mg, 1000 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N03AX14

Generic Available (US)

May be product dependent

Pricing: US

Solution (Keppra Intravenous)

500 mg/5 mL (per mL): $13.11

Solution (Keppra Oral)

100 mg/mL (per mL): $1.88

Solution (levETIRAcetam in NaCl Intravenous)

500 mg/100 mL (per mL): $0.22 - $0.41

1000 mg/100 mL (per mL): $0.36 - $0.67

1500 mg/100 mL (per mL): $0.48 - $0.95

Solution (levETIRAcetam Intravenous)

500 mg/5 mL (per mL): $0.42 - $3.00

Solution (levETIRAcetam Oral)

100 mg/mL (per mL): $0.15 - $0.73

Tablet Disintegrating Soluble (Spritam Oral)

250 mg (per each): $10.37

500 mg (per each): $10.37

750 mg (per each): $10.37

1000 mg (per each): $10.37

Tablet, 24-hour (Keppra XR Oral)

500 mg (per each): $8.81

750 mg (per each): $13.24

Tablet, 24-hour (levETIRAcetam ER Oral)

500 mg (per each): $4.41 - $4.47

750 mg (per each): $6.67 - $6.68

Tablet, 24-hour (Roweepra XR Oral)

500 mg (per each): $4.44

750 mg (per each): $6.67

Tablets (Keppra Oral)

250 mg (per each): $7.96

500 mg (per each): $9.72

750 mg (per each): $13.17

1000 mg (per each): $19.45

Tablets (levETIRAcetam Oral)

250 mg (per each): $0.06 - $3.26

500 mg (per each): $0.09 - $3.52

750 mg (per each): $0.13 - $4.77

1000 mg (per each): $0.19 - $7.04

Tablets (Roweepra Oral)

500 mg (per each): $3.51

750 mg (per each): $4.76

1000 mg (per each): $4.76

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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.

Immediate release: Food decreases C_max by 20% and delays time to C_max (T_max) by 1.5 hours.

Extended release: Intake of a high-fat, high-calorie breakfast before the administration results in a higher C_max and longer median T_max; the median T_max is 2 hours longer in the fed state.

Distribution: V_d: Similar to total body water.

Infants and Children <4 years of age: 0.63 ± 0.08 L/kg (Glauser 2007).

Children 6 to 12 years of age: 0.72 ± 0.12 L/kg (Pellock 2001).

Adults: 0.5 to 0.7 L/kg.

Protein binding: <10%.

Metabolism: Not extensive; 24% of dose is metabolized by enzymatic hydrolysis of acetamide group (major metabolic pathway; hydrolysis occurs primarily in the blood; not cytochrome P450 dependent); two minor metabolites (one via hydroxylation of 2-oxo-pyrrolidine ring and one via opening of the 2-oxo-pyrrolidine ring in position 5) are also formed; metabolites are inactive and renally excreted.

Bioavailability: 100%; bioavailability of ER tablets is similar to IR tablets; tablets, oral solution, and injection are bioequivalent.

Half-life elimination: Increased in patients with renal impairment:

Infants and Children <4 years of age: 5.3 ± 1.3 hours (Glauser 2007).

Children 4 to 12 years of age: 6 ± 1.1 hours (Pellock 2001).

Adults: ~6 to 8 hours; ER tablet: ~7 hours.

Time to peak, plasma:

IV: 5 to 30 minutes (Ramael 2006).

Oral solution: Fasting infants and children <4 years of age: 1.4 ± 0.9 hours.

Oral: Immediate release: Fasting adults and children: ~1 hour.

Oral: Extended release: ~4 hours; median time to peak is 2 hours longer in the fed state.

Excretion: Urine (66% as unchanged drug and 27% as inactive metabolites); undergoes glomerular filtration and subsequent partial tubular reabsorption.

Clearance: Correlated with CrCl; clearance is decreased in patients with renal dysfunction.

Infants <6 months: 1.23 mL/minute/kg (Glauser 2007).

Infants and Children 6 months to 4 years of age: 1.57 mL/minute/kg (Glauser 2007).

Children 6 to 12 years of age: 1.43 mL/minute/kg; 30% to 40% higher than adults on a per kg basis (Pellock 2001).

Adults: 0.96 mL/minute/kg.

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance is decreased and half-life is increased.

Hepatic function impairment: Clearance is decreased in patients with severe (Child-Pugh class C) impairment.

Geriatric: Half-life is increased and clearance is decreased.

Gender: C_max and AUC are higher in women.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Adverse Effects of Anticonvulsants
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Oral Medications That Should Not Be Crushed or Altered
• Relative Infant Dose

Index Terms

Elepsia XR

FDA Approval Date

November 30, 1999

References

2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694.[PubMed 30693946]

Abend NS, Monk HM, Licht DJ, et al. Intravenous Levetiracetam in Critically Ill Children With Status Epilepticus or Acute Repetitive Seizures. Pediatr Crit Care Med. 2009;10(4):505-510.[PubMed 19325512]

Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52.[PubMed 27060684]

Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007.

Bahte SK, Hiss M, Lichtinghagen R, Kielstein JT. A missed opportunity - consequences of unknown levetiracepam pharmacokinetics in a peritoneal dialysis patient. BMC Nephrol. 2014;15:49. doi:10.1186/1471-2369-15-49.[PubMed 24739070]

Bansal AD, Hill CE, Berns JS. Use of antiepileptic drugs in patients with chronic kidney disease and end stage renal disease. Semin Dial. 2015;28(4):404-412. doi:10.1111/sdi.12385.[PubMed 25929593]

Betts T, Waegemans T, 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):80-87.[PubMed 10845730]

Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmacokinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7.[PubMed 29441476]

Brigo F, Bragazzi N, Nardone R, Trinka E. Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus. Epilepsy Behav. 2016;64(pt A):110-115. doi: 10.1016/j.yebeh.2016.09.030.[PubMed 27736657]

Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68(6):402-408.[PubMed 17283312]

Brophy GM, Bell R, Claassen J, et al; Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.[PubMed 22528274]

Chau K, Yong J, Ismail K, Griffith N, Liu M, Makris A. Levetiracetam-induced severe acute granulomatous interstitial nephritis. Clin Kidney J. 2012;5(3):234-236.[PubMed 26069773]

Chu SS, Wang HJ, Zhu LN, Xu D, Wang XP, Liu L. Therapeutic effect of intravenous levetiracetam in status epilepticus: a meta-analysis and systematic review. Seizure. 2019;74:49-55. doi: 10.1016/j.seizure.2019.11.007.[PubMed 31830677]

Chung MG, O'Brien NF. Prevalence of early posttraumatic seizures in children with moderate to severe traumatic brain injury despite levetiracetam prophylaxis. Pediatr Crit Care Med. 2016;17(2):150-156.[PubMed 26669640]

Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(6):1711-1737.[PubMed 22556195]

Contin M, Mohamed S, Albani F, Riva R, Baruzzi A. Levetiracetam clinical pharmacokinetics in elderly and very elderly patients with epilepsy [published correction appears in Epilepsy Res. 2012;101(3):295]. Epilepsy Res. 2012;98(2-3):130-134. doi: 10.1016/j.eplepsyres.2011.08.020.[PubMed 21944894]

Drislane F. Convulsive status epilepticus in adults: Treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 17, 2020.

Elepsia XR (levetiracetam) [prescribing information]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc; March 2015.

Fay MA, Sheth RD, Gidal BE. Oral absorption kinetics of levetiracetam: the effect of mixing with food or enteral nutrition formulas. Clin Ther. 2005;27(5):594-598. doi: 10.1016/j.clinthera.2005.05.010.[PubMed 15978308]

Fuller KL, Wang YY, Cook MJ, Murphy MA, D'Souza WJ. Tolerability, safety, and side effects of levetiracetam versus phenytoin in intravenous and total prophylactic regimen among craniotomy patients: a prospective randomized study. Epilepsia. 2013;54(1):45-57. doi: 10.1111/j.1528-1167.2012.03563.x.[PubMed 22738092]

Fürwentsches A, Bussmann C, Ramantani G, et al. Levetiracetam in the Treatment of Neonatal Seizures: A Pilot Study. Seizure. 2010;19(3):185-189.[PubMed 20133173]

Gaspard N, Jirsch J, Hirsch LJ. Nonconvulsive status epilepticus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 23, 2018.

Glauser TA, Mitchell WG, Weinstock A, et al. Pharmacokinetics of Levetiracetam in Infants and Young Children With Epilepsy. Epilepsia. 2007;48(6):1117-1122.[PubMed 17442002]

Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. doi:10.5698/1535-7597-16.1.48.[PubMed 26900382]

Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and Safety of Levetiracetam in Infants and Young Children With Refractory Epilepsy. Seizure. 2007;16(4):345-350.[PubMed 17368928]

Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):133-141.[PubMed 19398681]

Hernández-Díaz S, Smith CR, Shen A, et al. Comparative Safety of Antiepileptic Drugs During Pregnancy. Neurology. 2012;8(21):1692-1699.[PubMed 22551726]

Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017 [published correction appears in Pharmacopsychiatry. 2018;51(1-02):e1]. Pharmacopsychiatry. 2018;51(1-02):9-62. doi: 10.1055/s-0043-116492.[PubMed 28910830]

Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126.[PubMed 10891521]

Iuchi T, Kuwabara K, Matsumoto M, Kawasaki K, Hasegawa Y, Sakaida T. Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. J Neurol Neurosurg Psychiatry. 2015;86(10):1158-1162. doi: 10.1136/jnnp-2014-308584.[PubMed 25511789]

Jirsch J, Hirsch LJ. Nonconvulsive status epilepticus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 17, 2020.

Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia. 2005;46(5):775-777.[PubMed 15857447 ]

Josephson CB, Engbers JDT, Jette N, et al. Prescription trends and psychiatric symptoms following first receipt of one of seven common antiepileptic drugs in general practice. Epilepsy Behav. 2018;84:49-55. doi: 10.1016/j.yebeh.2018.04.012.[PubMed 29753294]

Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):74-81.[PubMed 29898971]

Kapur J, Elm J, Chamberlain JM, et al; NETT and PECARN Investigators. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381(22):2103-2113. doi: 10.1056/NEJMoa1905795.[PubMed 31774955]

Keppra (levetiracetam) injection [prescribing information]. Smyrna, GA: UCB Inc; October 2019.

Keppra (levetiracetam) tablets and oral solution [prescribing information]. Smyrna, GA: UCB Inc; October 2019.

Keppra XR (levetiracetam) [prescribing information]. Smyrna, GA: UCB Inc; October 2019.

Kochanek PM, Tasker RC, Carney N, et al. Guidelines for the management of pediatric severe traumatic brain injury, third edition: update of the Brain Trauma Foundation Guidelines [published correction appears in Pediatr Crit Care Med. 2019;20(4):404]. Pediatr Crit Care Med. 2019;20(3S)(suppl 1):S1-S82.[PubMed 30829890]

Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam Psychosis in Children With Epilepsy. Epilepsia. 2001;42(12):1611-1613.[PubMed 11879376]

Koubeissi MZ, Amina S, Pita I, Bergey GK, Werz MA. Tolerability and efficacy of oral loading of levetiracetam. Neurology. 2008;70(22, pt 2):2166-2170.[PubMed 18505995]

Kramer G, Hosli I, Glanzmann R et al. Levetiracetam accumulation in human breast milk. Epilepsia. 2002;43 (Suppl 7):105.

Levetiracetam in Sodium Chloride Injection [prescribing information]. Rockford, IL: Mylan Institutional; December 2015.

Levetiracetam injection, for intravenous use [prescribing information]. Lake Forest, IL: Hospira; September 2015.

López-Fraile IP, Cid AO, Juste AO, Modrego PJ. Levetiracetam plasma level monitoring during pregnancy, delivery, and postpartum: clinical and outcome implications. Epilepsy Behav. 2009;15(3):372-375.[PubMed 19362602 ]

Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013;33(11):841-846.[PubMed 24051577 ]

Mandelbaum DE, Bunch M, Kugler SL, et al. Efficacy of Levetiracetam at 12 Months in Children Classified By Seizure Type, Cognitive Status, and Previous Anticonvulsant Drug Use. J Child Neurol. 2005;20(7):590-594.[PubMed 16159526]

Mawhinney E, Craig J, Morrow J, et al. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80(4):400-405.[PubMed 23303847 ]

Miller GS. Pyridoxine Ameliorates Adverse Behavioral Effects of Levetiracetam in Children. Epilepsia. 2002;43(suppl 7):S62.

Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA. 2011;305(19):1996-2002.[PubMed 21586715 ]

Murphy-Human T, Welch E, Zipfel G, Diringer MN, Dhar R. Comparison of short-duration levetiracetam with extended-course phenytoin for seizure prophylaxis after subarachnoid hemorrhage. World Neurosurg. 2011;75(2):269-274.[PubMed 21492729]

Opp J, Tuxhorn I, May T, et al. Levetiracetam in Children With Refractory Epilepsy: A Multicenter Open Label Study in Germany. Seizure. 2005;14(7):476-484.[PubMed 16182573]

Paisansathan C, Ozcan MS. Anesthesia for craniotomy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 16, 2020.

Paret N, Gouraud A, Bernard N, et al. Long-term follow-up of infants exposed to levetiracetam during breastfeeding: Comparison to a control group. Birth Defects Res A Clin Mol Teratol. 2014;100:537-538.[PubMed 23911354 ]

Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit. 2018;40(5):526-548. doi: 10.1097/FTD.0000000000000546.[PubMed 29957667]

Pearl PL, McCarter R, McGavin CL, et al. Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy. Epilepsia. 2013;54(9):e135-137.[PubMed 23876024]

Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic Study of Levetiracetam in Children. Epilepsia, 2001;42(12):1574-1579.[PubMed 11879369]

Perry MS, Benatar M. Efficacy and Tolerability of Levetiracetam in Children Younger Than 4 Years: A Retrospective Review. Epilepsia. 2007;48(6):1123-1127.[PubMed 17430408]

Pourzitaki C, Tsaousi G, Apostolidou E, Karakoulas K, Kouvelas D, Amaniti E. Efficacy and safety of prophylactic levetiracetam in supratentorial brain tumour surgery: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;82(1):315-325. doi: 10.1111/bcp.12926.[PubMed 26945547]

Rakshasbhuvankar A, Rao S, Kohan R, Simmer K, Nagarajan L. Intravenous levetiracetam for treatment of neonatal seizures. J Clin Neurosci. 2013;20(8):1165-1167.[PubMed 23664133 ]

Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006;47(7):1128-1135. doi: 10.1111/j.1528-1167.2006.00586.x.[PubMed 16886975]

Ramantani G, Ikonomidou C, Walter B, et al. Levetiracetam: Safety and Efficacy in Neonatal Seizures. Eur J Paediatr Neurol. 2011;15(1):1-7.[PubMed 21094062]

Roweepra (levetiracetam) [prescribing information]. West Chicago, IL: OWP Pharmaceuticals, Inc; November 2016.

Shoemaker MT, Rotenberg JS. Levetiracetam for the Treatment of Neonatal Seizures. J Child Neurol. 2007;22(1):95-98.[PubMed 17608315]

Silverstein FS, Ferriero DM. Off-Label Use of Antiepileptic Drugs for the Treatment of Neonatal Seizures. Pediatr Neurol. 2008;39(2):77-79.[PubMed 18639748]

Smetana KS, Cook AM, Bastin ML, Oyler DR. Antiepileptic dosing for critically ill adult patients receiving renal replacement therapy. J Crit Care. 2016;36:116-124. doi:10.1016/j.jcrc.2016.06.023.[PubMed 27546759]

Sourbron J, Chan H, Wammes-van der Heijden EA, et al. Review on the relevance of therapeutic drug monitoring of levetiracetam. Seizure. 2018;62:131-135. doi: 10.1016/j.seizure.2018.09.004.[PubMed 30237016]

Spencer DD, Jacobi J, Juenke JM, Fleck JD, Kays MB. Steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients. Pharmacotherapy. 2011;31(10):934-941. doi:10.1592/phco.31.10.934.[PubMed 21950640]

Spritam (levetiracetam) [prescribing information]. East Windsor, NJ: Aprecia Pharmaceuticals; September 2018.

Striano P, Manganelli F, Boccella P, Perretti A, Striano S. Levetiracetam in patients with cortical myoclonus: a clinical and electrophysiological study. Mov Disord. 2005;20(12):1610-1614.[PubMed 16078205]

Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12(2):165-172.[PubMed 19898966]

Theitler J, Brik A, Shaniv D, Berkovitch M, Gandelman-Marton R. Antiepileptic drug treatment in community-dwelling older patients with epilepsy: a retrospective observational study of old- versus new-generation antiepileptic drugs. Drugs Aging. 2017;34(6):479-487. doi: 10.1007/s40266-017-0465-7.[PubMed 28478592]

Tomson T, Palm R, Källén K, et al. Pharmacokinetics of Levetiracetam During Pregnancy, Delivery, in the Neonatal Period, and Lactation. Epilepsia. 2007;48(6):1111-1116.[PubMed 17381438]

Trinka E, Marson AG, Van Paesschen W, et al; KOMET Study Group. KOMET: an unblinded, randomized, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry. 2013;84(10):1138-1147.[PubMed 22933814]

Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49(1):1-16. doi:10.2165/11318140-000000000-00000.[PubMed 20000886]

Vaisleib II, Neft RA. Rapid dosage titration of levetiracetam in children. Pharmacotherapy. 2008;28(3):393-396.[PubMed 18294118]

Vajda FJ, Graham J, Roten A, et al. Teratogenicity of the newer antiepileptic drugs--the Australian experience. J Clin Neurosci. 2012;19(1):57-59.[PubMed 22104350]

Van Matre ET, Mueller SW, Fish DN, et al. Levetiracetam pharmacokinetics in a patient with intracranial hemorrhage undergoing continuous veno-venous hemofiltration. Am J Case Rep. 2017;18:458-462. doi:10.12659/ajcr.902709.[PubMed 28446744]

Wheless JW, Clarke D, Hovinga CA, et al. Rapid Infusion of a Loading Dose of Intravenous Levetiracetam With Minimal Dilution: A Safety Study. J Child Neurol. 2009;24(8):946-951.[PubMed 19264738]

White R, Bradnam V; British Pharmaceutical Nutrition Group. Handbook of Drug Administration via Enteral Feeding Tubes. 3rd ed. London, England: Pharmaceutical Press; 2015.

Yamamoto J, Toublanc N, Kumagai Y, Stockis A. Levetiracetam pharmacokinetics in Japanese subjects with renal impairment. Clin Drug Investig. 2014;34(11):819–828. doi:10.1007/s40261-014-0237-7.[PubMed 25312351]

Yang Y, Zheng F, Xu X, Wang X. Levetiracetam versus phenytoin for seizure prophylaxis following traumatic brain injury: a systematic review and meta-analysis. CNS Drugs. 2016;30(8):677-688. doi: 10.1007/s40263-016-0365-0.[PubMed 27395404]

Brand Names: International

Azacetam (EG); Callexe (AR); Callexe XR (AR); Ceumid (CR, DO, EC, GT, HN, NI, PA, SV, UY); Citazar (BD); Desitrend (GB); Dretacen (NL); Dretacin (PH); E Keppra (JP); Eletam (BD); Epictal (IN); Epilen (TW); Epiletam (RO); Epilev (HR); Epsytam (PH); Erata (BD); Focale (TH); Iracet (BD, LK); Ivetra (PH); Julitam (PH); Kepcet (DE); Kepcitam (LB); Kepdin (PH); Keplidon (VN); Keppra (AE, AR, AT, AU, BB, BE, BG, BH, BM, BS, CH, CL, CN, CO, CR, CU, CY, CZ, DE, DK, DO, EC, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, ID, IE, IL, IN, IS, IT, JM, JO, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PR, PT, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TT, TW, UA, VN); Keppra I.V. (AU); Keppra XR (BB); Kerron (AU); Kevesy (NL); Kevtam (AU); Kineptia (VN); Kopodex (CL, CO, EC, PE, PY); Laurak (ES); Lecetam (TH); Lentira (PH); Lethira (ID); Letram (MY, ZW); Letta 500 (TH); Lev Desitin (CH); Levepex (EG); Levetacis (VN); Levetam (UY); Levetrim (IL); Levicitam (UA); Levim (TW); Levipil (LK, PH); Levit (PH); Levitam (ID); Levron (AR); Lumark-500 (PH); Malomibe (VN); Matever (BE, EE, IE, MT, SE); Millitam (TH); Nobelin (TW); Normeg (EE); Prepalepan (AT); Repitend (EE); Rivoleve (CH); Tietari (SG); Torleva (IN, LK, VN, ZW); Trund (NL); Vexlev (PH); Vitera (RO); Zitera (LB)

Last Updated 2/22/20