Levetiracetam

Trade Names:
Keppra
- Tablets 250 mg
- Tablets 500 mg
- Tablets 750 mg
- Tablets 1,000 mg
- Solution, oral 100 mg/mL
- Injection, solution (concentrate) 100 mg/mL

Trade Names:
Keppra XR
- Tablets, extended-release 500 mg
- Tablets, extended-release 750 mg

Pharmacology

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Mechanism unknown; may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Pharmacokinetics

Absorption

T _max is 1 h. Oral bioavailability is 100%. Food does not affect the extent of absorption, but it can decrease C _max 20% and delay T _max 1.5 h. Steady state is achieved after 2 days of multiple, twice-daily dosing.

C _max is about 4 h. T _max is about 3 h longer with extended-release (ER) than with immediate-release tablets.

Distribution

Kinetics are linear over dose range of 500 to 5,000 mg. Less than 10% is protein bound.

Metabolism

Not extensively metabolized. Major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite ucb L057.

Elimination

Plasma half-life is approximately 7 h. It is eliminated from the systemic circulation by renal excretion as unchanged drug, which represents 66% of dose.

Special Populations

Total body Cl decreases 40% in patients with CrCl 50 to 80 mL/min, 50% in patients with CrCl 30 to 50 mL/min, and 60% in patients with CrCl less than 30 mL/min. Dosage reduction is recommended.

Total body Cl decreases 50%. No dosage adjustment is needed.

Total body Cl decreased 38%; half-life was 2.5 h longer.

Cl was approximately 40% higher (children 6 to 12 yr of age).

C _max and AUC are 20% higher in women.

C _max 21% to 30% higher and AUC 8% to 18% higher in women compared with men.

Pharmacokinetic studies have not been conducted.

Pharmacokinetics comparable between white and Asian patients.

Indications and Usage

Adjunctive therapy in partial-onset seizures in adults and children 4 yr of age and older with epilepsy; adjunctive therapy in myoclonic seizures in adults and adolescents 12 yr of age and older with juvenile myoclonic epilepsy; adjunctive treatment of primary generalized tonic-clonic seizures in adults and children 6 yr of age and older with idiopathic generalized epilepsy.

Adjunctive therapy in the treatment of partial-onset seizures in patients 16 yr of age and older with epilepsy.

Adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy; alternative route for patients when oral administration is not feasible. Adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy; adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.

Unlabeled Uses

Adjunctive therapy for bipolar disorder; monotherapy in new-onset pediatric epilepsy; prevention of migraine; tardive dyskinesia.

Contraindications

Standard considerations.

Dosage and Administration

Immediate-release tablets/solution/IV Initiate therapy with 500 mg twice daily; dosage may be increased by 1,000 mg/day every 2 wk (max, 3,000 mg/day).

Initiate therapy with 500 mg twice daily; dosage may be increased by 1,000 mg/day every 2 wk (max, 3,000 mg/day).

Start with 1,000 mg once daily. The dosage may be increased in increments of 1,000 mg/day at 2 wk intervals (max, 3,000 mg/day).

PO Initiate therapy with 10 mg/kg twice daily; dose may be increased by 20 mg/kg daily every 2 wk (max, 30 mg/kg twice daily).

IV Start with 500 mg twice daily. Dosage should be increased by 1,000 mg/day every 2 wk to the recommended dosage of 3,000 mg/day.

Immediate-release tablets/solution Start with 500 mg twice daily. Dosage should be increased by 1,000 mg/day every 2 wk to the recommended dosage of 3,000 mg/day.

Immediate-release tablets/solution Start with 10 mg/kg twice daily. Dose should be increased every 2 wk by increments of 20 mg/kg to the recommended dosage of 30 mg/kg twice daily.

For mild renal function impairment (CrCl 50 to 80 mL/min), give 500 to 1,000 mg every 12 h. For moderate impairment (CrCl 30 to 50 mL/min), give 250 to 750 mg every 12 h. For severe impairment (CrCl less than 30 mL/min), give 250 to 500 mg every 12 h. For patients on dialysis, give 500 to 1,000 mg every 24 h. Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For mild renal impairment (CrCl 50 to 80 mL/min), give 1,000 to 2,000 mg every 24 h. For moderate impairment (CrCl 30 to 50 mL/min), give 500 to 1,500 mg every 24 h. For severe impairment (CrCl less than 30), give 500 to 1,000 mg every 24 h.

General Advice

• May be administered without regard to meals. Administer with food if GI upset occurs.
• Administer tablets whole. Caution patient not to break, chew, or crush the ER tablet.
• Administer oral solution using dosing syringe, medicine dropper, or medicine cup.
• Administer IV levetiracetam as 15-min infusion following dilution in 100 mL of a compatible diluent.
• Injectable dose form is physically compatible and chemically stable when mixed with sodium chloride 0.9%, Ringer's lactate injection, or dextrose 5%, and lorazepam, diazepam, or valproate sodium.
• Patient may be switched from oral to IV administration at the equivalent dose and frequency.

Storage/Stability

Store tablets, oral solution, and undiluted IV injection at 59° to 86°F. Following dilution, IV solution is stable for at least 24 h when stored in polyvinyl chloride bags at 59° to 86°F.

Drug Interactions

Increased risk of carbamazepine toxicity, unrelated to elevated plasma concentrations, has been reported.

Although total body Cl of levetiracetam is increased about 22%, dosage adjustment is not recommended.

The C _max of the inactive metabolite of levetiracetam is approximately doubled.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Somnolence (23%); asthenia (15%); headache (14%); hostility (12%); fatigue, nervousness (10%); dizziness (9%); personality disorder (8%); irritability (7%); agitation, emotional lability (6%); depression, mood swings, vertigo (5%); anxiety, ataxia, seizures (3%); amnesia, confusion, depressed mood, hypersomnia, increased reflexes, insomnia, paresthesia (2%); aggression (1%); suicidal behavior (postmarketing).

Dermatologic

Pruritus, skin discoloration, vesiculobullous rash (2%); alopecia (postmarketing).

EENT

Nasopharyngitis (14%); rhinitis (13%); pharyngitis (10%); conjunctivitis (3%); amblyopia, diplopia, ear pain (2%).

GI

Vomiting (15%); anorexia (13%); diarrhea (8%); nausea (5%); gastroenteritis (4%); anorexia, constipation (3%); pancreatitis (postmarketing).

Genitourinary

Albuminuria (4%); urine abnormality (2%).

Hematologic-Lymphatic

Ecchymosis (4%); leukopenia, neutropenia, pancytopenia (with bone marrow suppression in some cases), thrombocytopenia (postmarketing).

Hepatic

Abnormal LFTs, hepatic failure, hepatitis (postmarketing).

Metabolic-Nutritional

Dehydration (2%); weight loss (postmarketing).

Musculoskeletal

Neck pain (8%).

Respiratory

Increased cough (11%); asthma, sinusitis (2%).

Miscellaneous

Accidental injury (17%); infection (13%); influenza (8%); pain (7%); flu syndrome (3%); face edema, viral infection (2%).

Precautions

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established in children younger than 4 yr of age.

Safety and efficacy not established in children younger than 16 yr of age.

Elderly

There were insufficient numbers of elderly subjects in clinical studies to adequately assess efficacy in elderly patients. No overall difference in safety was observed between subjects who were 65 yr of age and older compared with younger subjects.

Renal Function

Use reduced doses. Administer supplemental doses to dialysis patients because the drug is removed during treatment.

Laboratory Test Abnormalities

Infrequent abnormalities in hematologic parameters and liver function tests have been reported.

CNS effects

Treatment of partial-onset seizures was associated with behavioral abnormalities, coordination difficulties, and somnolence and fatigue.

Hematologic abnormalities

Decreases in RBC, hemoglobin, and hematocrit were seen.

Withdrawal seizures

Do not discontinue abruptly because of possible increased seizure frequency.

Overdosage

Symptoms

Aggression, agitation, coma, depressed level of consciousness, drowsiness, respiratory depression, somnolence.

Patient Information

• Advise patient to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient, family, or caregiver to continue to take/give other medications for seizures unless advised to do otherwise by health care provider.
• Instruct patient to take exactly as prescribed and not to change the dose or discontinue medication unless advised by health care provider.
• Advise patient that dose may be gradually increased no more often than every 2 wk until max benefit has been obtained.
• Advise patient to swallow tablets whole and not crush, chew, or break.
• Advise patient using oral solution to measure dose using dosing syringe, dosing dropper, or medicine cup. Caution patient not to measure dose using spoon.
• Advise patient that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
• Advise patient that the most common adverse reactions of therapy are dizziness, sleepiness, and weakness, which can occur at any time but are most common during the first 4 wk of treatment.
• Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of several weeks unless safety concerns (eg, rash) require a more rapid withdrawal.
• Caution patient that drug may cause coordination problems, dizziness, or drowsiness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
• Instruct patient to contact health care provider immediately if any of the following occur: coordination problems; extreme sleepiness, tiredness, and weakness; mood or behavior changes (eg, aggression, anger, depression, hallucinations, hostility, irritability, thoughts of suicide).
• Instruct patient to inform health care provider if seizures get worse or if new types of seizures occur.
• Advise patient to carry medical identification (eg, card, bracelet) indicating medication usage and epilepsy.
• Advise women who become pregnant or intend to become pregnant during therapy to notify health care provider.
• Advise patient that drug may cause changes in behavior (eg, aggression, agitation, anger, anxiety, hostility, irritability) and, in rare cases, psychotic symptoms and suicidal ideation.

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