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LevETIRAcetam

Medically reviewed by Drugs.com. Last updated on Jul 25, 2020.

Pronunciation

(lee va tye RA se tam)

Index Terms

  • Elepsia XR

Dosage Forms

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

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)

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

Brand Names: U.S.

  • Keppra
  • Keppra XR
  • Roweepra
  • Roweepra XR
  • Spritam

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

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.

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: 0.63 ± 0.08 L/kg (Glauser 2007)

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

Adults: 0.5 to 0.7 L/kg

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

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: 1.57 mL/minute/kg (Glauser 2007).

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

Adults: 0.96 mL/minute/kg.

Onset of Action

Peak effect: Oral: 1 hour

Time to Peak

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.

Half-Life Elimination

Increased in patients with renal impairment

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

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

Adults: ~6 to 8 hours; extended release tablet: ~7 hours

Protein Binding

<10%

Special Populations: Renal Function Impairment

Clearance is decreased and half-life is increased.

Special Populations: Hepatic Function Impairment

Clearance is decreased in patients with severe (Child-Pugh class C) impairment

Special Populations: Elderly

Half-life is increased and clearance is decreased.

Special Populations: Gender

Cmax and AUC are higher in women.

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.

Off Label Uses

Craniotomy, seizure prophylaxis

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 [Pourzitaki 2016].

Status epilepticus

Data from a randomized, controlled trial [Kapur 2019] and meta-analyses [Brigo 2016], [Chu 2019] 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)

According to guidelines for the management of subarachnoid hemorrhage (SAH), prophylactic anticonvulsants may be considered following hemorrhage [AHA/ASA [Connolly 2012]]; however, data presented from 2 prospective trials present inconclusive results [Murphy-Human 2011], [Szaflarski 2010]. 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)

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 [Yang 2016].

Contraindications

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

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).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more 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: 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: Oral 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: 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 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 (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:

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.

Reconstitution

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).

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).

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.

Storage

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.

Drug Interactions

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

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

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

CarBAMazepine: LevETIRAcetam may enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of LevETIRAcetam. 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. Consider therapy modification

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

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

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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. 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. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. If anticonvulsants are being used for another indication, monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrexate: LevETIRAcetam may increase the serum concentration of Methotrexate. 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. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

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

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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 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. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

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

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.

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.

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).

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/).

Patient Education

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Diarrhea

• Stuffy nose

• Runny nose

• Trouble sleeping

• Abdominal pain

• Sore throat

• Nausea

• Vomiting

• Lack of appetite

• Flu-like symptoms

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.