Levetiracetam

Pronunciation

Pronunciation: LEE-ve-tye-RA-se-tam
Class: Anticonvulsant

Trade Names

Keppra
- Tablets, oral 250 mg
- Tablets, oral 500 mg
- Tablets, oral 750 mg
- Tablets, oral 1,000 mg
- Solution, oral 100 mg per mL
- Injection, solution 500 mg per 100 mL
- Injection, solution 1,000 mg per 100 mL
- Injection, solution 1,500 mg per 100 mL
- Injection, solution, concentrate 100 mg/mL

Keppra XR
- Tablets, ER, oral 500 mg
- Tablets, ER, oral 750 mg

Apo-Levetiracetam (Canada)
CO Levetiracetam (Canada)

Pharmacology

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

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Immediate-release tablets/oral solution

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

ER

T max is approximately 4 h. When administered with food, T max is approximately 2 h longer.

Distribution

Less than 10% is protein bound. Vd is close to the volume of intracellular and extracellular water.

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. Total body Cl is 0.96 mL/min/kg, and the renal Cl is 0.6 mL/min/kg.

Special Populations

Renal Function Impairment

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. In anuric (ESRD) patients, the total body Cl decreased by 70% compared with healthy subjects.

Hepatic Function Impairment

In patients with severe (Child-Pugh class C) impairment, total body Cl decreases 50%. In subjects with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged.

Elderly

Total body Cl decreased 38% and half-life was 2.5 h longer; this is likely because of decreased renal function.

Children

Cl was approximately 40% higher in children 6 to 12 y of age.

Gender
Immediate-release tablets/oral solution/injection

C max and AUC are 20% higher in women.

ER

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

Race

Pharmacokinetic differences because of race are not expected.

Indications and Usage

Immediate-release tablets/oral solution

Adjunctive therapy in the treatment of partial-onset seizures in adults and children 1 mo and older with epilepsy; adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 y and older with juvenile myoclonic epilepsy; adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 y and older with idiopathic generalized epilepsy.

ER

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

IV

Adjunctive therapy in the treatment of partial-onset seizures in adults (16 y and older) with epilepsy; adjunctive therapy in the treatment of myoclonic seizures in adults (16 y and older) with juvenile myoclonic epilepsy; adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults (16 y and older) with idiopathic generalized epilepsy.

Unlabeled Uses

Adjunctive therapy for bipolar disorder; prevention of migraine; tardive dyskinesia; in neonatal period as second-line therapy for seizures that have been refractory to phenobarbital and other anticonvulsants.

Contraindications

None well documented.

Dosage and Administration

Myoclonic Seizures
Adults and children 12 y and older

PO Initiate therapy with 500 mg twice daily; dosage may be increased by 500 mg twice daily every 2 wk to the recommended dosage of 1,500 mg twice daily.

Adults and children 16 y and older

IV Initiate therapy with 500 mg twice daily; dosage may be increased by 500 mg twice daily every 2 wk to the recommended dosage of 1,500 mg twice daily.

Partial-Onset Seizures
Adults and children 16 y and older Immediate-release tablets/oral solution/injection

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

ER

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

Children 4 y to younger than 16 y

PO Initiate therapy with 10 mg/kg twice daily (if using the tablets in these patients, administer 500 mg twice daily in patients more than 40 kg and 250 mg twice daily in patients 20 to 40 kg); dosage may be increased by 10 mg/kg twice daily every 2 wk to the recommended dosage of 30 mg/kg twice daily (max, 3,000 mg/day to patients weighing over 40 kg; 1,500 mg/day in patients weighing 20 to 40 kg).

Children 6 mo to younger than 4 y

PO Initiate therapy with 10 mg/kg twice daily. Dosage may be increased by 10 mg/kg twice daily every 2 wk to the recommended dosage of 25 mg/kg twice daily.

Children 1 mo to younger than 6 mo

PO Initiate therapy with 7 mg/kg twice daily. Dosage may be increased by 7 mg/kg twice daily every 2 wk to the recommended dosage of 21 mg/kg twice daily.

Primary Generalized Tonic-Clonic Seizures
Adults and children 16 y and older

IV/PO Initiate therapy with 500 mg twice daily; dosage may be increased by 500 mg twice daily every 2 wk to the recommended dosage of 1,500 mg twice daily.

Children 6 y to younger than 16 y

PO Start with 10 mg/kg twice daily. Dose should be increased every 2 wk by increments of 10 mg/kg twice daily to the recommended dosage of 30 mg/kg twice daily.

Renal Function Impairment
Immediate-release tablets/oral solution/injection

IV/PO For mild renal 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 with ESRD on dialysis, give 500 to 1,000 mg every 24 h. Following dialysis, a 250 to 500 mg supplemental dose is recommended.

ER

PO 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 mL/min), give 500 to 1,000 mg every 24 h. In patients with ESRD on dialysis, use immediate-release levetiracetam.

Discontinuation

PO/IV When discontinuing therapy, gradually withdraw drug.

General Advice

  • Oral
  • May be taken with or without food.
  • Administer tablets whole. Caution patient not to break, chew, or crush the tablet.
  • Administer oral solution using a calibrated measuring device.
  • Patient may be switched from oral to IV administration at the equivalent dose and frequency.
  • Dose children with a body weight of 20 kg or less with oral solution.
  • The following calculation should be used to determine the appropriate daily dose of oral solution: Total daily dosage (mL/day) = (daily dosage [mg/kg/day] × patient weight [kg]) ÷ 100 mg/mL.
  • Injection
  • Administer IV as a 15-min infusion.
  • Levetiracetam injection solution concentrate must be diluted in 100 mL of a compatible diluent prior to administration; levetiracetam in sodium chloride injection should not be further diluted.
  • Injectable doseform 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.
  • For doses (eg, 250 and 750 mg) not achievable with the available levetiracetam in sodium chloride injection product strengths, withdraw the appropriate dose from an intact commercial bag and place the measured dose in a separate empty, sterile infusion bag.
  • At the end of the IV treatment period, switch to oral levetiracetam at the equivalent daily dosage and frequency of the IV administration.
  • A product with particulate matter or discoloration should not be used.

Storage/Stability

Tablets/Oral solution

Store at 77°F; excursions are permitted between 59° and 86°F.

Injection

Store the injection concentrate between 59° and 86°F. Store levetiracetam in sodium chloride between 68° and 77°F. Physically compatible and chemically stable for at least 24 h when mixed with compatible diluents and antiepileptic drugs (AEDs) at 59° to 86°F. Any unused portion of the vial contents or bag should be discarded. Do not store or reuse.

Drug Interactions

Carbamazepine

Increased risk of carbamazepine toxicity, unrelated to elevated plasma concentrations, has been reported. Close clinical monitoring for signs of carbamazepine toxicity is warranted.

Probenecid

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

Adverse Reactions

CNS

Headache (19%); asthenia, somnolence (15%); irritability (12%); fatigue (11%); aggression (10%); dizziness (9%); abnormal behavior (7%); lethargy (6%); depression, insomnia, mood swings, vertigo (5%); agitation, nervousness (4%); altered mood, ataxia (3%); affect lability, amnesia, anxiety, confusion, emotional lability, hostility, paresthesia, sedation (2%); choreoathetosis, dyskinesia, suicidal behavior (including completed suicide), suicidal ideation, suicide attempt (postmarketing).

Dermatologic

Alopecia, erythema multiforme, Stevens-Johnson syndrome, TEN (postmarketing).

EENT

Nasopharyngitis (15%); nasal congestion (9%); pharyngitis, pharyngolaryngeal pain (7%); rhinitis (4%); conjunctivitis, diplopia, ear pain, sinusitis (2%).

GI

Vomiting (15%); upper abdominal pain (9%); decreased appetite, diarrhea (8%); nausea (5%); anorexia (4%); constipation (3%); gastroenteritis (2%); pancreatitis, weight loss (postmarketing).

Hematologic-Lymphatic

Leukopenia, neutropenia, pancytopenia (with bone marrow suppression in some cases), thrombocytopenia (postmarketing).

Hepatic

Abnormal LFTs, hepatic failure, hepatitis (postmarketing).

Musculoskeletal

Neck pain (8%); arthralgia, joint sprain (2%).

Respiratory

Cough (9%); increased cough (2%).

Miscellaneous

Infection (13%); influenza (8%); pain (7%); head injury (4%); contusion, fall (3%).

Precautions

Monitor

Monitor patients for CNS depression (eg, dizziness, somnolence), behavioral abnormalities (eg, psychosis, hallucinations), coordination difficulties (eg, ataxia, abnormal gait, incoordination), and/or other behavioral symptoms. Monitor patient for suicidality (eg, suicidal thoughts).


Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Immediate-release tablets/oral solution

Safety and efficacy not established in children younger than 1 mo.

Injection/ER

Safety and efficacy not established in children younger than 16 y.

Elderly

Because of age-related renal impairment, take care in dose selection and monitor renal function.

Renal Function

Use with caution in patients with renal impairment and in those undergoing hemodialysis.

Hazardous Tasks

May cause dizziness and somnolence, which may impair the ability to perform tasks, such as driving or operating machinery.

BP effects

Increased diastolic BP has been observed in children 1 mo to younger than 4 y.

CNS effects

Treatment was associated with psychotic and nonpsychotic symptoms, behavioral abnormalities, coordination difficulties, somnolence, asthenia, and fatigue.

Dermatological effects

Serious dermatological effects, including Stevens-Johnson syndrome and TEN, have been reported.

Hematologic abnormalities

Decreases in RBC, Hgb, Hct, neutrophil count, and WBC may occur.

Hepatic effects

Infrequent abnormalities in LFTs have been reported.

Suicidal behavior and ideation

May increase the risk of suicidal thoughts or behavior. This may occur as early as 1 wk after starting treatment and persist for the duration of treatment.

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 patients or caregivers to read the Medication Guide before starting therapy and to reread with each refill.
  • Advise patients to swallow tablets whole, and not to crush, chew, or break.
  • Advise patients using oral solution to measure their dose using a dosing syringe, dosing dropper, or medicine cup. Caution patients not to measure their dose using a spoon.
  • Advise patients that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
  • Advise patients that the most common adverse reactions are dizziness, sleepiness, and weakness, which can occur at any time but are most common during the first 4 wk of treatment.
  • Advise patients that if their 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 patients that levetiracetam 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 patients to contact their health care provider immediately if any of the following occur: coordination problems, extreme sleepiness, tiredness, and weakness.
  • Instruct patients to inform their health care provider if seizures get worse or if new types of seizures occur.
  • Advise women who become pregnant or intend to become pregnant during therapy to notify their health care provider. Also tell women to notify their health care provider if they are breast-feeding or intend to breast-feed during therapy.
  • Encourage women to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of AEDs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. In addition, the manufacturer has established the levetiracetam pregnancy registry. Either a health care provider or the patient can initiate enrollment in the levetiracetam pregnancy registry by calling 1-888-537-7734 (toll free).
  • Advise patients that levetiracetam may cause changes in behavior (eg, aggression, agitation, anger, anxiety, hostility, irritability) and, in rare cases, psychotic symptoms.
  • Counsel patients, their caregivers, and families that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior. Advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Tell patients, caregivers, and families to immediately report behaviors of concern to their health care providers.
  • Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their health care provider immediately if a rash develops.

Copyright © 2009 Wolters Kluwer Health.

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