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LevETIRAcetam

Pronunciation

Pronunciation

(lee va tye RA se tam)

Index Terms

  • Elepsia XR
  • Spritam

Dosage Forms

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/5 mL (5 mL)

Solution, Oral:

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

Generic: 100 mg/mL (5 mL, 118 mL [DSC], 473 mL, 500 mL)

Tablet, Oral:

Keppra: 250 mg [scored; contains fd&c blue #2 (indigotine)]

Keppra: 500 mg [scored]

Keppra: 750 mg [scored; contains fd&c yellow #6 (sunset yellow)]

Keppra: 1000 mg [scored]

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

Generic: 500 mg, 750 mg

Brand Names: U.S.

  • Keppra
  • Keppra 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 (Elepsia XR: 3 to 4.5 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 creatinine clearance; 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)

Onset of Action

Peak effect: Oral: 1 hour

Time to Peak

Oral solution: Fasting infants and children <4 years: 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: Children

Immediate release: Clearance was approximately 40% higher in children 6 to 12 y of age.

Special Populations: Gender

Cmax and AUC are higher in women.

Use: Labeled Indications

Myoclonic seizures:

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.

Partial-onset seizures:

Immediate-release tablets/oral solution/tablets for oral suspension: Adjunctive therapy in the treatment of partial-onset seizures in adults and children 1 month and older (Keppra) or 4 years and older and more than 20 kg (Spritam) with epilepsy.

Extended-release tablets: Adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents 12 years and older with epilepsy.

IV: Adjunctive therapy in the treatment of partial-onset seizures in adults and children 1 month and older with 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.

Contraindications

There are no contraindications listed in the U.S. manufacturer's labeling.

Canadian labeling: Hypersensitivity to levetiracetam or any component of the formulation

Dosing: Adult

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

Myoclonic seizures:

Oral: Immediate release (tablets, oral solution, tablets for oral suspension): Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1,500 mg twice daily. Efficacy of doses other than 3,000 mg/day has not been established.

IV: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1,500 mg twice daily. Efficacy of doses other than 3,000 mg/day has not been established.

Partial onset seizures:

Oral:

Immediate release (tablets, oral solution, tablets for oral suspension): Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the maximum recommended dose of 1,500 mg twice daily. Efficacy of doses >3,000 mg/day has not been established.

Extended release: Initial: 1,000 mg once daily; may increase every 2 weeks by 1,000 mg/day to a maximum of 3,000 mg once daily.

IV: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to a maximum of 1,500 mg twice daily. Doses >3,000 mg/day have been used in trials; however, there is no evidence of increased benefit.

Tonic-clonic seizures:

Oral: Immediate release (tablets, oral solution, tablets for oral suspension): Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1,500 mg twice daily. Efficacy of doses <3,000 mg/day has not been established.

IV: Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to the recommended dose of 1,500 mg twice daily. Efficacy of doses other than 3,000 mg/day has not been established.

Loading dose (off-label): Oral: Immediate release: Initial doses of 1,500 to 2,000 mg have been well-tolerated (Betts 2000; Koubeissi 2008), although the necessity of a loading dose has not been established

Status epilepticus (off-label use): IV: 1,000 to 3,000 mg administered at a rate of 2 to 5 mg/kg/minute (NCS [Brophy 2012])

Status epilepticus, refractory (off-label use): IV: 1,000 to 3,000 mg administered over 15 minutes (EFNS [Meierkord 2010]); 2,500 mg has been safely administered over 5 minutes in one report (Uges 2009). Note: Levetiracetam has not been well studied in comparison to other agents routinely used in this setting. EFNS recommends levetiracetam only for use in refractory complex partial status epilepticus; however, data suggests that levetiracetam may be beneficial in other forms of status epilepticus (EFNS [Meierkord 2010]; Knake 2008).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Use oral solution in children ≤20 kg; oral solution, immediate release tablets, and tablets for oral suspension may be used in children >20 kg. When switching from oral to IV formulations, the total daily dose should be the same.

Myoclonic seizures:

Oral: Immediate release (tablets, oral solution, tablets for oral suspension): Children ≥12 years and Adolescents: Refer to adult dosing.

IV: Children ≥12 years and Adolescents: Refer to adult dosing.

Partial onset seizures:

Oral:

Immediate release (tablets, oral solution):

Children 1 month to <6 months: Initial: 7 mg/kg/dose twice daily; may increase every 2 weeks by 7 mg/kg/dose to a recommended dose of 21 mg/kg/dose twice daily

Children 6 months to <4 years: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to a recommended dose of 25 mg/kg/dose twice daily

Children and Adolescents 4 to <16 years: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to a recommended dose of 30 mg/kg/dose twice daily (maximum daily dose: 3,000 mg/day)

Adolescents ≥16 years: Refer to adult dosing.

Alternate immediate-release fixed tablet dosing for partial onset seizures:

20 to 40 kg: Initial: 250 mg twice daily, increase every 2 weeks by 250 mg twice daily to the maximum recommended dose of 750 mg twice daily

>40 kg: Initial: 500 mg twice daily, increase every 2 weeks by 500 mg twice daily to the maximum recommended dose of 1,500 mg twice daily

Immediate release (tablets for oral suspension):

Children ≥4 years and weighing 20 kg to 40 kg: Initial: 250 mg twice daily; may increase every 2 weeks by 250 mg/dose to the maximum recommended dose of 750 mg twice daily.

Children ≥4 years (weighing >40 kg) and Adolescents: Refer to adult dosing.

Extended release: Children ≥12 years and Adolescents: Refer to adult dosing.

IV:

Children 1 month to < 6 months: Initial: 7 mg/kg twice daily; increase every 2 weeks by 7 mg/kg/dose to a recommended dose of 21 mg/kg twice daily. In clinical trials the average daily dose was 35 mg/kg/day. Efficacy of lower doses has not been established.

Children 6 months to <4 years: Initial: 10 mg/kg twice daily; increase every 2 weeks by 10 mg/kg/dose to a recommended dose of 25 mg/kg twice daily. If the patient cannot tolerate 50 mg/kg/day, reduce the daily dose. In clinical trials the average daily dose was 47 mg/kg/day.

Children and Adolescents 4 to <16 years: Initial: 10 mg/kg twice daily; increase every 2 weeks by 10 mg/kg/dose to the recommended dose of 30 mg/kg twice daily. If the patient cannot tolerate 60 mg/kg/day, reduce the daily dose. In clinical trials the average daily dose was 44 mg/kg/day and the maximum daily dose was 3,000 mg/day.

Adolescents ≥16 years: Refer to adult dosing.

Tonic-clonic seizures:

Oral:

Immediate release (tablets, oral solution):

Children and Adolescents 6 to <16 years: Initial: 10 mg/kg/dose twice daily; may increase every 2 weeks by 10 mg/kg/dose to the recommended dose of 30 mg/kg twice daily. Efficacy of doses other than 60 mg/kg/day has not been established.

Adolescents ≥16 years: Refer to adult dosing.

Immediate release (tablets for oral suspension):

Children ≥6 years and weighing 20 kg to 40 kg: Initial: 250 mg twice daily; may increase every 2 weeks by 250 mg/dose to the maximum recommended dose of 750 mg twice daily.

Children ≥6 years (weighing >40 kg) and Adolescents: Refer to adult dosing.

IV:

Children and Adolescents 6 to <16 years: Initial: 10 mg/kg twice daily; increase every 2 weeks by 10 mg/kg/dose to the recommended dose of 30 mg/kg twice daily. Efficacy of doses lower than 60 mg/kg/day has not been established.

Adolescents ≥16 years: Refer to adult dosing.

Status epilepticus (off-label use): Infants, Children, and Adolescents: IV: 20 to 60 mg/kg administered at a rate of 2 to 5 mg/kg/minute (NCS [Brophy 2012])

Dosing: Renal Impairment

Adults:

Immediate release and IV formulations:

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

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

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

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

End-stage renal disease (ESRD) requiring hemodialysis: 500 to 1,000 mg every 24 hours; supplemental dose of 250 to 500 mg is recommended posthemodialysis

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

Continuous renal replacement therapy (CRRT): 250 to 750 mg every 12 hours (Aronoff 2007)

Extended release tablets:

Elepsia XR:

CrCl >80 mL/minute/1.73 m2: 1,000 to 3,000 mg every 24 hours

CrCl 50 to 80 mL/minute/1.73 m2: 1,000 to 2,000 mg every 24 hours

CrCl <50 mL/minute/1.73 m2: Use not recommended.

Keppra XR and generic:

CrCl >80 mL/minute/1.73 m2: 1,000 to 3,000 mg every 24 hours

CrCl 50 to 80 mL/minute/1.73 m2: 1,000 to 2,000 mg every 24 hours

CrCl 30 to 50 mL/minute/1.73 m2: 500 to 1,500 mg every 24 hours

CrCl <30 mL/minute/1.73 m2: 500 to 1,000 mg every 24 hours

ESRD requiring hemodialysis: Use of immediate release formulation is recommended.

Dosing: Hepatic Impairment

US labeling: No dosage adjustment necessary

Canadian labeling:

Mild-to-moderate impairment: No dosage adjustment necessary

Severe impairment: Reduce maintenance dose by 50% in patients who also have CrCl <60 mL/minute/1.73 m2

Reconstitution

Vials for injection: Must dilute 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.

Administration

IV: For IV use only; infuse over 15 minutes

Oral: Administer without regard to meals.

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

Tablet (immediate release and extended release): Only administer as whole tablet; do not crush, break or chew.

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.

Compatibility

Stable in NS, LR, D5W

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 is stable for 24 hours in PVC bags kept at room temperature.

Drug Interactions

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

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

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

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

Brivaracetam: LevETIRAcetam may diminish the therapeutic effect of Brivaracetam. Consider therapy modification

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

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

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). 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 (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

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. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

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

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

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

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

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

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. 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

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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

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

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: 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

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%), drowsiness (8% to 15%; immediate release 4,000 mg/day, no titration: 45%; serious [patients hospitalized]: <1%), psychotic symptoms (infants and children: 17%; adults: 1%), irritability (infants, children and adolescents: 6% to12%), 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% (Limited to important or life-threatening): Agranulocytosis, decreased red blood cells, dyskinesia, DRESS syndrome, eczema, equilibrium disturbance, erythema multiforme, hepatic failure, hepatitis, hyperkinesia, hyponatremia, memory impairment, myalgia, myasthenia, pancreatitis, pancytopenia (with bone marrow suppression in some cases), panic attack, personality disorder, psychosis, Stevens-Johnson syndrome, suicidal tendencies, thrombocytopenia, toxic epidermal necrolysis

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 have been observed. Cases of eosinophilia, agranulocytosis, and lymphocytosis have also been reported.

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

• 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.

• 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. Elepsia XR is not recommended in patients with moderate or severe renal impairment (CrCl <50 mL/minute/1.73 m2).

Concurrent drug therapy issues:

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

Special populations:

• Pediatric: Children may have increased incidence of psychiatric symptoms; dose reduction or discontinuation may be required.

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

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 of age

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Levetiracetam crosses the placenta and can be detected in the newborn following delivery (Johannessen 2005; Lopez-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 (Hernandez-Diaz 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 and Meader 2009). Plasma concentrations of levetiracetam gradually decrease during pregnancy, especially during the third trimester, due to physiologic changes which occur; patients should be 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, rhinitis, rhinorrhea, insomnia, dyspepsia, pharyngitis, nausea, or lack of appetite. Have patient report immediately to prescriber hallucinations, considerable asthenia, severe dizziness, intolerable headache, syncope, change in balance, abnormal gait, significant fatigue, signs of infection, ecchymosis, hemorrhaging, suicidal ideation, depression, anxiety, akathisia, irritability, panic attacks, mood changes, behavioral changes, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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