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:
Note: FDA approved for mono- and adjunctive therapy of focal (partial) onset seizures, and adjunctive therapy of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures; 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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
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 post trauma (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 pharmacokinetic simulations (Hernández-Mitre 2020; 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; a supplemental dose of 250 to 500 mg is recommended post each hemodialysis session (Bansal 2015; manufacturer’s labeling).
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 (Chappell 2021; Kalaria 2020; Smetana 2016; van Matre 2014) and expert opinion. Higher effluent rates (eg, 4,000 to 5,000 mL/hour) may require higher total daily doses (eg, up to 4 g/day), although the safety of these higher doses has not been evaluated (Kalaria 2020).
IR and IV formulations: 750 mg to 1.25 g every 12 hours.
PIRRT (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: Dose based on limited data (Chappell 2021) and expert opinion.
IR and IV formulations: 500 mg to 1 g every 12 hours.
No dosage adjustment necessary
(For additional information see "Levetiracetam: Pediatric drug information")
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. Avoid abrupt discontinuation of therapy to reduce risk of increased seizure frequency or status epilepticus.
Myoclonic seizures with juvenile myoclonic epilepsy; adjunct: 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 (focal) seizures: Note: Dosing for monotherapy or adjunct therapy is the same for indicated oral preparations.
Infants 1 to <6 months: IV, Oral (immediate release: Oral solution [monotherapy or adjunct]): 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: Oral solution or tablets [monotherapy or adjunct]): 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: Monotherapy or adjunct: 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: Monotherapy or adjunct:
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 [adjunct]; Keppra XR [monotherapy or adjunct]): 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: Monotherapy or adjunct: 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]; monotherapy or adjunct): 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 [adjunct], Keppra XR [monotherapy or adjunct]): 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 (tablets, oral solution [eg, Keppra]): 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; adjunct:
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: Oral 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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function:
IV, Oral (immediate-release formulations [tablets, oral solution] and tablets for oral suspension): Infants, Children, and Adolescents: GFR <50 mL/minute/1.73 m2: Administer 50% of the dose (Aronoff 2007).
Oral extended-release formulations (Elepsia XR, Keppra XR): Children ≥12 years and Adolescents: There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, dosage adjustment may be necessary.
Augmented renal clearance (CrCl >130 mL/minute/1.73 m2): There are no pediatric-specific recommendations for dosing in patients with augmented renal clearance; based on adult pharmacokinetic studies, dosage adjustment may be necessary.
Hemodialysis, intermittent: Dialyzable (50%):
IV, Oral (immediate-release formulations [tablets, oral solution] and tablets for oral suspension): Infants, Children, and Adolescents: Administer 50% of normal dose every 24 hours; a supplemental dose after hemodialysis is recommended (Aronoff 2007).
Oral extended-release formulations (Elepsia XR, Keppra XR): Children ≥12 years and Adolescents: There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, use not recommended.
Peritoneal dialysis:
IV, Oral (immediate-release formulations [tablets, oral solution] and tablets for oral suspension): Infants, Children, and Adolescents: Administer 50% of the dose (Aronoff 2007).
Oral extended-release formulations (Elepsia XR, Keppra XR): Children ≥12 years and Adolescents: There are no pediatric-specific recommendations provided in the manufacturer's labeling; based on experience in adult patients, use not recommended.
Continuous renal replacement therapy (CRRT):
IV, Oral (immediate-release formulations [tablets, oral solution] and tablets for oral suspension): Infants, Children, and Adolescents: Administer 50% of the dose; monitor closely (Aronoff 2007). Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of patient response and adverse reactions is recommended.
PIRRT (eg, sustained low-efficiency diafiltration): There are no pediatric-specific recommendations provided in the manufacturer's labeling. Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Based on adult experience, dose adjustment may be necessary, and close monitoring of patient response and adverse reactions is recommended.
No dosage adjustment necessary
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).
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 [DSC]
Roweepra: 500 mg [contains corn starch]
Roweepra: 500 mg [DSC] [scored; contains corn starch]
Roweepra: 750 mg [DSC] [contains corn starch, fd&c yellow #6 aluminum lake]
Roweepra: 1000 mg [DSC] [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:
Elepsia XR: 1000 mg, 1500 mg [contains fd&c blue #1 aluminum lake]
Keppra XR: 500 mg, 750 mg
Roweepra XR: 500 mg [DSC], 750 mg [DSC]
Generic: 500 mg, 750 mg
May be product dependent
Note: Tablets for oral suspension and soluble disintegrating tablet both refer to Spritam.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 500 mg/5 mL (5 mL)
Solution, Oral:
Generic: 100 mg/mL (300 mL)
Tablet, Oral:
Keppra: 250 mg, 500 mg, 750 mg
Generic: 250 mg, 500 mg, 750 mg, 1000 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Elepsia XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204417s004lbl.pdf#page=25
Keppra: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021035s104,021505s044lbl.pdf#page=31
Keppra XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022285s029lbl.pdf#page=26
Spritam: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/207958s019lbl.pdf#page=36
IV: For IV use only; manufacturer recommends infusing over 15 minutes. Various rates of IV administration have been reported; doses ≤1 g (undiluted) have been administered over 2 to 5 minutes, doses ≤3 g (diluted) over 5 to 6 minutes, and doses ≤4.5 g (diluted) over 10 minutes (Kapur 2019; Morgan 2020; Ramael 2006a; Wheless 2009).
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.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to IR tablet, orally disintegrating tablet, or oral solution.
Oral: May be administered without regard to meals
Immediate release:
Oral solution: Administer with calibrated measuring device (not household teaspoon or tablespoon).
Tablets: Manufacturer labeling recommends that tablets should be swallowed whole, not chewed or crushed; however, some studies support crushing and mixing with applesauce, or sprinkling on food; it should be noted that levetiracetam has a bitter taste which may need masked; it has also been administered via enteral feeding tube (Fay 2005; White 2015). In adults, levetiracetam 500 mg tablets were studied crushed and mixed in 120 mL of enteral nutrition formula, 4 oz of applesauce (Fay 2005), or 10 mL of water and shaken for 5 minutes to disperse (White 2015).
Tablets, disintegrating 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.
Extended-release tablets: Swallow tablets whole; do not break, crush, or chew.
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 or 3,000 mg) through a peripheral site in patients 4 to 32 years of age (Ramael 2006a; Wheless 2009); in patients ≥1 year of age, a 50 mg/mL solution was used for doses up to 60 mg/kg (up to 4,500 mg) and were infused over 10 minutes (Kapur 2019).
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: Treatment of focal (partial) onset seizures in adults and children ≥4 years of age and >20 kg.
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.
Craniotomy, seizure prophylaxis; Status epilepticus; Subarachnoid hemorrhage (short-term seizure prophylaxis); Traumatic brain injury, severe acute (short-term seizure prophylaxis)
Keppra may be confused with Keflex, Keppra XR
LevETIRAcetam may be confused with lamoTRIgine, levOCARNitine, levoFLOXacin
Potential for dispensing errors between Keppra and Kaletra (lopinavir/ritonavir)
Levetiracetam may cause CNS depression (asthenia, ataxia [includes abnormal gait, incoordination], fatigue, dizziness, and somnolence [drowsiness]), which may impair physical or mental abilities. Of note, somnolence was the most common reason for levetiracetam discontinuation in the US pivotal partial seizure trial (Ref).
Mechanism: Dose-related; most likely related to activity at the synaptic vesicle protein 2a.
Onset: Varied; generally, appear within the first month of treatment and during the up-titration period (Ref).
Risk factors:
Somnolence:
• Doses ≥4 g/day (potential risk factor) (Ref)
• Initiation and up-titration (Ref)
• IV formulation (Ref)
Levetiracetam is associated with a variety of delayed hypersensitivity reactions, ranging from mild maculopapular rash (Ref) to severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (Ref), toxic epidermal necrolysis (Ref), drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref), and acute generalized exanthematous pustulosis (Ref).
Mechanism: Non-dose-related; immunologic. Delayed hypersensitivity reactions, including maculopapular eruptions and SCARs, are T-cell-mediated (Ref).
Onset: Delayed hypersensitivity reactions: Varied; maculopapular rash usually develops within 7 to 14 days (Ref). SCARs usually occur 1 to 8 weeks after initiation (Ref); re-exposure may lead to more rapid onset (usually within 1 to 4 days) (Ref).
Risk factors:
• Cross-reactivity: Not adequately described. In patients with a history of DRESS from an aromatic antiseizure medication (eg, phenytoin, carbamazepine), levetiracetam (a non-aromatic antiseizure medication) has been well tolerated (Ref).
Psychotic symptoms, paranoid ideation, hallucinations, and behavioral problems (including aggressive behavior, agitation, anger, anxiety, apathy, confusion, depersonalization, depression, emotional lability, hostility, dyskinesia, irritability, nervousness, neurosis, and personality disorder) may occur in adult and pediatric patients; dose reduction or discontinuation may be required. Suicidal ideation and suicidal tendencies have also been reported (Ref).
Mechanism: Exact mechanism unknown; some evidence suggests that a negative modulating effect on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors contributes to increased aggressive behavior (Ref).
Onset: Varied; may occur as early as 1 week after initiation.
Risk factors:
• Developmental delays or intellectual disability (Ref)
• Females (Ref)
• Type of epilepsy, (especially frontal lobe epilepsy [including brain tumor-related], absence epilepsy, and difficult-to-treat [“treatment-resistant”] epilepsy) (Ref)
• History of psychiatric disorders (eg, ADHD, depression, anxiety, personality disorder, suicidality, or psychotropic or recreational drug use) (Ref)
• History of social deprivation (Ref)
• Pediatric patients (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidences are for all indications and populations (infants, children, adolescents, and adults) unless otherwise specified.
>10%:
Cardiovascular: Increased blood pressure (diastolic; infants and children <4 years: 17%) (table 1)
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
17% |
2% |
Infants and children |
N/A |
N/A |
N/A |
Gastrointestinal: Vomiting (children and adolescents: 15%)
Infection: Infection (adults: 13%)
Nervous system: Behavioral problems (includes anger, anxiety, apathy, depersonalization, neurosis, personality disorder; children and adolescents: 7% to 38%; adults: 7% to 13%) (table 2) , drowsiness (infants, children, adolescents, and adults: 8% to 15%) (table 3) , fatigue (children and adolescents: 10% to 11%) (table 4) , headache (14% to 19%), irritability (infants, children, and adolescents: 6% to 12%) (table 5) , psychotic symptoms (infants, children, and adolescents: 2% to 17%; adults: 1%) (table 6)
Drug (Levetiracetam) |
Placebo |
Population |
Dosage Form |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|
7% |
4% |
Children and adolescents |
N/A |
Partial-onset seizures |
165 |
131 |
38% |
19% |
Children and adolescents |
N/A |
N/A |
N/A |
N/A |
7% |
0% |
Adults |
XR tablets |
Partial-onset seizures |
N/A |
N/A |
13% |
6% |
Adults |
N/A |
N/A |
N/A |
N/A |
Drug (Levetiracetam) |
Placebo |
Population |
Dosage Form |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|
13% |
2% |
Infants and children |
N/A |
Partial-onset seizures |
60 |
56 |
13% |
9% |
Children and adolescents |
N/A |
Partial-onset seizures |
165 |
131 |
12% |
2% |
Adolescents and adults |
N/A |
Myoclonic seizures |
60 |
60 |
15% |
8% |
Adults |
N/A |
Partial-onset seizures |
769 |
439 |
8% |
3% |
N/A |
XR tablets |
Partial-onset seizure |
77 |
79 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
11% |
5% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
10% |
8% |
Children and adolescents |
PGTC seizures |
79 |
84 |
Drug (Levetiracetam) |
Placebo |
Population |
Dosage Form |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|
12% |
0% |
Infants and children |
N/A |
Partial-onset seizures |
60 |
56 |
7% |
1% |
Children and adolescents |
N/A |
Partial-onset seizures |
165 |
131 |
6% |
2% |
Children and adolescents |
N/A |
PGTC seizures |
79 |
84 |
7% |
0% |
N/A |
XR tablets |
Partial-onset seizures |
77 |
79 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
17% |
5% |
Infants and children |
N/A |
N/A |
N/A |
2% |
2% |
Children and adolescents |
N/A |
N/A |
N/A |
1% |
0.2% |
Adults |
N/A |
N/A |
N/A |
Neuromuscular & skeletal: Asthenia (adults: 15%) (table 7)
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
15% |
9% |
Adults |
Partial-onset seizures |
769 |
439 |
Respiratory: Nasopharyngitis (7% to 15%)
1% to 10%:
Gastrointestinal: Anorexia (3% to 4%), constipation (children and adolescents: 3%), decreased appetite (children and adolescents: 8%), diarrhea (children and adolescents: 6% to 8%), gastroenteritis (children and adolescents: 2%), nausea (5%), upper abdominal pain (children and adolescents: 9%)
Hematologic & oncologic: Bruise (children and adolescents: 3%), eosinophilia (children and adolescents: 9%)
Infection: Influenza (3% to 8%)
Nervous system: Aggressive behavior (children and adolescents: 10%; adults: 1%) (table 8) , agitation (children and adolescents: 4%) (table 9) , amnesia (adults: 2%), anxiety (2%) (table 10) , ataxia (adult partial-onset seizures: 3%; includes abnormal gait, incoordination) (table 11) , confusion (children and adolescents: 2% to 3%) (table 12) , depression (3% to 5%) (table 13) , dizziness (5% to 9%) (table 14) , emotional lability (2% to 5%) (table 15) , falling (children and adolescents: 3%),hostility (adults: 2%) (table 16) , insomnia (children and adolescents: 5%), lethargy (children and adolescents: 6%), mood changes (children and adolescents: 3%), nervousness (adults: 4%) (table 17) , pain (adults: 7%), paranoid ideation (children and adolescents: 2%; adults: <1%) (table 18) , paresthesia (adults: 2%), sedated state (children and adolescents: 2%), vertigo (3% to 5%)
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
10% |
5% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
4% |
1% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
1% |
Adults |
Partial-onset seizures |
769 |
439 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
3% |
1% |
Adults |
Partial-onset seizures |
769 |
439 |
3% |
2% |
Adults |
Partial-onset seizures |
N/A |
N/A |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
0% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
3% |
0% |
Children and adolescents |
N/A |
N/A |
N/A |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
3% |
1% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
5% |
2% |
Adolescents and adults |
Myoclonic Seizures |
60 |
60 |
4% |
2% |
Adults |
Partial-onset seizures |
769 |
439 |
Drug (Levetiracetam) |
Placebo |
Population |
Dosage Form |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|---|
7% |
5% |
Children and adolescents |
N/A |
Partial-onset seizures |
165 |
131 |
9% |
4% |
Adults |
N/A |
Partial-onset seizures |
769 |
439 |
5% |
3% |
N/A |
XR tablets |
Partial-Onset Seizure |
77 |
79 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
1% |
Children and adolescents |
Partial-onset seizures |
165 |
131 |
5% |
1% |
Children and adolescents |
PGTC seizures |
79 |
84 |
2% |
0% |
Adults |
Partial-onset seizures |
769 |
439 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
1% |
Adults |
Partial-onset seizures |
769 |
439 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
4% |
2% |
Adults |
Partial-onset seizures |
769 |
439 |
Drug (Levetiracetam) |
Placebo |
Population |
Indication |
Number of Patients (Levetiracetam) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
2% |
0% |
Children and adolescents |
N/A |
N/A |
N/A |
Neuromuscular & skeletal: Arthralgia (children and adolescents: 2%), joint sprain (children and adolescents: 2%), neck pain (children and adolescents: 2% to 8%)
Ophthalmic: Conjunctivitis (children and adolescents: 2%), diplopia (adults: 2%)
Otic: Otalgia (children and adolescents: 2%)
Respiratory: Cough (2% to 9%), nasal congestion (children and adolescents: 9%), pharyngitis (6% to 7%), pharyngolaryngeal pain (children and adolescents: 7%), rhinitis (2% to 4%), sinusitis (adults: 2%)
Miscellaneous: Head trauma (children and adolescents: 4%)
Frequency not defined: Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin, leukopenia, lymphocytosis, neutropenia (Taberner Bonastre 2015)
Postmarketing:
Dermatologic: Acute generalized exanthematous pustulosis (Lee 2014), alopecia, eczema, erythema multiforme, maculopapular rash (Kim 2020), Stevens-Johnson syndrome (Park 2019), toxic epidermal necrolysis (Duong 2013)
Endocrine & metabolic: Hyponatremia, weight loss
Gastrointestinal: Pancreatitis
Hematologic & oncologic: Agranulocytosis, pancytopenia (with bone marrow suppression in some cases) (Gohil 2018, Garcia Carretero 2016), thrombocytopenia (Kim 2017)
Hepatic: Hepatic failure (Jayashankar 2019), hepatitis
Hypersensitivity: Anaphylaxis (Koklu 2014), angioedema (Alkhotani 2012)
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Bayram 2016)
Nervous system: Balance impairment, choreoathetosis, disturbance in attention, memory impairment, myasthenia, panic attack, suicidal ideation (rare: <1%) (Cramer 2003), suicidal tendencies (rare: <1%) (Cramer 2003)
Neuromuscular & skeletal: Dyskinesia (Yim 2019), myalgia
Ophthalmic: Blurred vision
Renal: Acute kidney injury, granulomatous interstitial nephritis (Chau 2012)
Hypersensitivity (eg, anaphylaxis, angioedema) to levetiracetam or any component of the formulation.
Disease-related concerns:
• Renal impairment: Use caution with renal impairment; dosage adjustment may be necessary.
Other warnings/precautions:
• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency and status epilepticus; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
None known.
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
Apixaban: LevETIRAcetam may diminish the therapeutic effect of Apixaban. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with 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. Management: Consider alternatives to the combined use of levetiracetam and brivaracetam due to an apparent lack of brivaracetam effectiveness in patients 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
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. 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
Dabigatran Etexilate: LevETIRAcetam may diminish the therapeutic effect of Dabigatran Etexilate. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of 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
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. 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. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fosphenytoin-Phenytoin: May decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy
Gabapentin: LevETIRAcetam may enhance the CNS depressant effect of Gabapentin. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
LamoTRIgine: LevETIRAcetam may enhance the CNS depressant effect of LamoTRIgine. 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
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. 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 Antiseizure Agents. Mefloquine may decrease the serum concentration of Antiseizure Agents. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If antiseizure drugs are being used for another indication, monitor antiseizure drug 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Mianserin: May diminish the therapeutic effect of Antiseizure Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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 Antiseizure Agents. 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
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
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. Risk C: Monitor therapy
PHENobarbital: LevETIRAcetam may enhance the CNS depressant effect of PHENobarbital. 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: LevETIRAcetam may enhance the CNS depressant effect of Primidone. Primidone may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy
Rivaroxaban: LevETIRAcetam may decrease the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
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
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
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
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: LevETIRAcetam may enhance the CNS depressant effect of Valproate Products. 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 may delay, but does not affect the extent of absorption. Management: Administer without regard to meals.
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 antiseizure drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiseizure 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/).
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 breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Maternal plasma concentrations should be monitored postpartum.
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 BP in children 1 month to <4 years; CBC (in patients who experience significant weakness, pyrexia, recurrent infections or coagulation disorders); signs and symptoms of hypersensitivity reaction or rash.
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)
The precise mechanism by which levetiracetam exerts its antiseizure 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.
Absorption: Oral: Rapid and almost complete.
Immediate release: Food decreases Cmax by 20% and delays time to Cmax (Tmax) by 1.5 hours.
Extended release: Intake of a high-fat, high-calorie breakfast before the administration results in a higher Cmax and longer median Tmax; the median Tmax is 2 hours longer in the fed state.
Distribution: Vd: 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 2006a).
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.
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: Cmax and AUC are higher in women.
Solution (Keppra Intravenous)
500 mg/5 mL (per mL): $14.44
Solution (Keppra Oral)
100 mg/mL (per mL): $2.06
Solution (levETIRAcetam in NaCl Intravenous)
500 mg/100 mL (per mL): $0.17 - $0.41
1000 mg/100 mL (per mL): $0.26 - $0.67
1500 mg/100 mL (per mL): $0.34 - $0.95
Solution (levETIRAcetam Intravenous)
500 mg/5 mL (per mL): $0.29 - $3.00
Solution (levETIRAcetam Oral)
100 mg/mL (per mL): $0.10 - $0.73
Tablet Disintegrating Soluble (Spritam Oral)
250 mg (per each): $11.13
500 mg (per each): $11.13
750 mg (per each): $11.13
1000 mg (per each): $11.13
Tablet, 24-hour (Elepsia XR Oral)
1000 mg (per each): $31.70
1500 mg (per each): $39.70
Tablet, 24-hour (Keppra XR Oral)
500 mg (per each): $9.71
750 mg (per each): $14.57
Tablet, 24-hour (levETIRAcetam ER Oral)
500 mg (per each): $4.41 - $4.47
750 mg (per each): $6.67 - $6.68
Tablets (Keppra Oral)
250 mg (per each): $8.76
500 mg (per each): $10.71
750 mg (per each): $14.50
1000 mg (per each): $21.41
Tablets (levETIRAcetam Oral)
250 mg (per each): $0.05 - $3.26
500 mg (per each): $0.08 - $3.52
750 mg (per each): $0.12 - $4.77
1000 mg (per each): $0.17 - $11.50
Tablets (Roweepra Oral)
500 mg (per each): $3.51
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