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Levetiracetam

Pronunciation

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Molecular Formula: C8H14N2O2
CAS Number: 102767-28-2
Brands: Keppra

Introduction

Anticonvulsant; a pyrrolidine derivative.1 2 3 5 12 15 16 17 18

Uses for Levetiracetam

Seizure Disorders

Management (in combination with other anticonvulsants) of partial onset,1 2 3 15 16 17 18 myoclonic,1 and primary generalized tonic-clonic seizures.1

May be used IV in the management of such seizure disorders when oral therapy not feasible.12 18 19

Levetiracetam Dosage and Administration

General

  • Withdraw gradually (by reducing dosage by 1 g daily at 2-week intervals) to minimize potential for increased seizure frequency.1 2 5 12 (See Discontinuance of Therapy under Cautions.)

  • Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.10 11 21 22 (See Suicidality Risk under Cautions.)

Administration

Administer orally (as tablets or oral solution); may be administered by IV infusion in adults when oral therapy temporarily not feasible.1 12

Tablets are bioequivalent to both the oral solution and IV injection formulation.1 12 13 19 22

Oral Administration

Administer tablets and oral solution orally twice daily without regard to meals.1

Use a calibrated dosing device to measure and administer oral solution; household teaspoon or tablespoon not an adequate measuring device.1 22

IV Administration

Dilute appropriate dose in 100 mL of sodium chloride 0.9%, lactated Ringer’s, or dextrose 5% and administer by IV infusion over 15 minutes.12 Discard unused contents of vial after use.12

Dosage

When switching from oral to IV therapy, initial total daily IV dosage should be equivalent to daily dosage and frequency of oral therapy.12 At completion of the IV treatment period, may switch back to oral therapy at same daily dosage and frequency as IV therapy.12

Pediatric Patients

Seizure Disorders
Partial Seizures in Pediatric Patients 4 to <16 Years of Age
Oral

Usual initial dosage is 20 mg/kg daily (administered as 10 mg/kg twice daily).1 15

If response is inadequate, may increase by 20 mg/kg daily at 2-week intervals up to recommended dosage of 60 mg/kg daily (administered as 30 mg/kg twice daily).1 15

May reduce dosage if patient unable to tolerate a dosage of 60 mg/kg daily.1 In the clinical trial, mean daily dosage was 52 mg/kg.1

Children weighing ≤20 kg should receive the oral solution; children weighing >20 kg may receive either the tablets, administered whole (see Table 1), or the oral solution.1

Table 1. Levetiracetam Tablet Weight-based Dosing Guide for Children1

Daily Dosage

Patient Weight

20 mg/kg/day (twice-daily dosing)

40 mg/kg/day (twice-daily dosing)

60 mg/kg/day (twice-daily dosing)

20.1–40 kg

500 mg/day (1 x 250-mg tablet twice daily)

1000 mg/day (1 x 500-mg tablet twice daily)

1500 mg/day (1 x 750-mg tablet twice daily)

>40 kg

1000 mg/day (1 x 500-mg tablet twice daily)

2000 mg/day (2 x 500-mg tablets twice daily)

3000 mg/day (2 x 750-mg tablets twice daily)

Myoclonic Seizures in Pediatric Patients ≥12 Years of Age
Oral

Initially, 500 mg twice daily.1

If response is inadequate, may increase dosage in increments of 1 g daily at 2-week intervals up to recommended dosage of 3 g daily.1 Manufacturer of Keppra states that efficacy of dosages <3 g daily not established.1

Primary Generalized Tonic-Clonic Seizures in Pediatric Patients 6 to <16 Years of Age
Oral

Initially, 10 mg/kg twice daily.1

If response is inadequate, may increase by 20 mg/kg daily at 2-week intervals up to recommended dosage of 60 mg/kg daily.1 Manufacturer of Keppra states that efficacy of dosages <60 mg/kg daily not established.1

Children weighing ≤20 kg should receive the oral solution; children weighing >20 kg may receive either the tablets, administered whole (see Table 1), or the oral solution.1

Adults

May initiate therapy with either oral or IV administration.12

Seizure Disorders
Partial Seizures in Adults ≥16 Years of Age
Oral/IV

Initially, 500 mg twice daily.1 2 3 12 17

If response is inadequate, may increase dosage by 1 g daily at 2-week intervals up to maximum of 3 g daily.1 2 12 17 21 22

Some clinicians reportedly initiate therapy with dosages of 2–4 g daily.3

Dosages >3 g daily may not be associated with increased therapeutic benefit.1 2 12 21 22

Myoclonic Seizures in Adults ≥16 Years of Age
Oral/IV

Initially, 500 mg twice daily.1 12

If response is inadequate, may increase dosage in increments of 1 g daily at 2-week intervals up to recommended dosage of 3 g daily.1 12 Manufacturer of Keppra states that efficacy of dosages <3 g daily not established.1 12

Primary Generalized Tonic-Clonic Seizures in Adults ≥16 Years of Age
Oral/IV

Initially, 500 mg twice daily.1 12

If response is inadequate, may increase by 1 g daily at 2-week intervals up to recommended dosage of 3 g daily.1 12 Manufacturer of Keppra states that efficacy of dosages <3 g daily not established.1 12

Prescribing Limits

Adults

Seizure Disorders
Partial Seizures
Oral/IV

Maximum 3 g daily recommended by the manufacturer.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with hepatic impairment.1 2 12

Renal Impairment

Modify dosage according to the degree of impairment based on patient’s measured or estimated Clcr.1 2 (See Table 2.)

Table 2. Recommended Dosage Based on Clcr1

Renal Function

Clcr (mL/minute)

Dosage

Normal

>80

500–1500 mg every 12 hours

Mild

50–80

500–1000 mg every 12 hours

Moderate

30–50

250–750 mg every 12 hours

Severe

<30

250–500 mg every 12 hours

ESRD patients using dialysis

500–1000 mg every 24 hours; following dialysis, a 250- to 500-mg supplemental dose is recommended

Geriatric Patients

Select dosage carefully1 2 12 and consider monitoring renal function during therapy.1

Cautions for Levetiracetam

Contraindications

  • Known hypersensitivity to levetiracetam or any ingredient in the formulation.1 2

Warnings/Precautions

Warnings

Nervous System Effects

Possible adverse neuropsychiatric effects are classified into 3 categories: somnolence and fatigue; coordination difficulties; behavioral changes.1 2 12

Somnolence, asthenia, and coordination difficulties occur most frequently within first 4 weeks of treatment.1 2 12

Psychotic manifestations and hallucinations reported rarely.1 2 12

Possible behavioral symptoms (e.g., agitation, hostility, anxiety, apathy, emotional lability, depersonalization, depression, aggression, anger, irritability).1 12

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).10 11 21 22 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.10 11 22 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.10 22

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.10 11 21 22 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.10

Balance risk of suicidality with risk of untreated illness.10 22 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.21 22 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.21 22 (See Advice to Patients.)

Discontinuance of Therapy

Abrupt withdrawal may result in increased seizure frequency or status epilepticus.1 2 12 (See General under Dosage and Administration.)

General Precautions

Hematologic Effects

Minor decreases in total mean erythrocyte count, mean hemoglobin, and mean hematocrit possible.1 12

Possible leukopenia, neutropenia, pancytopenia with myelosuppression in some cases, and thrombocytopenia.1 12

Hepatic Effects

No meaningful changes in liver function test results in controlled studies.1 12

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Keppra (levetiracetam) and Kaletra (fixed combination of lopinavir and ritonavir, both antiretroviral agents) may result in errors.7

Specific Populations

Pregnancy

Category C.1

Keppra Pregnancy Registry at 888-537-7734 or North American Antiepileptic Drug Pregnancy Registry at 888-233-2334.1

Lactation

Distributed into milk.1 12 Discontinue nursing or the drug because of potential risk in nursing infant.1 12

Pediatric Use

Safety and efficacy of tablets and oral solution not established in children <4 years of age.1

Safety and efficacy of IV formulation not established in children <16 years of age.12

Geriatric Use

No substantial differences in safety relative to younger adults; insufficient experience in patients ≥65 years of age to determine whether efficacy is similar.1 2 12

Hepatic Impairment

Safety and efficacy demonstrated in a limited number of epileptic patients with chronic liver disease.20 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustment recommended for patients with decreased Clcr.1 2 12 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis.1 2

Interactions for Levetiracetam

Not a high-affinity substrate for or inhibitor of CYP isoenzymes.1 2

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1 2 12

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1 2 12

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid)

Pharmacokinetic interaction unlikely1 2 12

Digoxin

Pharmacokinetic interaction unlikely1 2 12

Oral contraceptives

Pharmacokinetic interaction unlikely1 2 12

Probenecid

No effect on levetiracetam pharmacokinetics, but steady-state plasma concentrations of principal inactive metabolite of levetiracetam approximately doubled because of 60% reduction in renal clearance1 2 12

Clinically unimportant5

Warfarin

Pharmacokinetic interaction unlikely1 2 12

Levetiracetam Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed (nearly 100% bioavailable) following oral administration, with peak plasma concentrations attained in approximately 1 hour.1

Commercially available tablets and oral solution are bioequivalent.1

Food

Food does not affect bioavailability but delays time to peak plasma concentration by 1.5 hours and decreases peak plasma concentration by 20%.1

Distribution

Extent

Distributed into milk.1

Plasma Protein Binding

<10%.1

Elimination

Metabolism

Not extensively metabolized.1 About 24% of an administered dose is metabolized to an inactive metabolite by hydrolysis of the acetamide group; metabolism is not dependent on CYP isoenzymes.1

Elimination Route

Excreted principally as unchanged drug (66%) in urine.1

Clearance is correlated with Clcr.1

Half-life

6–8 hours.1

Special Populations

In patients with renal impairment, clearance is reduced by 40, 50, and 60% in patients with mild, moderate, and severe renal impairment, respectively.1 In patients with end-stage renal disease, clearance is reduced by about 70%; hemodialysis removes about 50% of body stores of levetiracetam.1 (See Renal Impairment under Dosage and Administration.)

In patients with severe hepatic impairment (Child Pugh class C), total body clearance is reduced by 50%, principally due to decreased renal clearance; pharmacokinetics unchanged in patients with mild (Child Pugh class A) to moderate (Child Pugh class B) hepatic impairment.1

In geriatric patients with Clcr of 30–74 mL/minute, total body clearance is reduced by 38% and half-life increased by 2.5 hours, but no pharmacokinetic differences related solely to age observed.1 2

In pediatric patients 6–12 years of age, body weight-adjusted apparent clearance is approximately 40% higher than in adults.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Solution

25°C (may be exposed to 15–30°C).1

Parenteral

Injection

25°C (may be exposed to 15–30°C).12

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Ringer's injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Diazepam

Lorazepam

Valproate sodium

Actions

  • Structurally unrelated to other currently available anticonvulsants.1 2 3 5 12

  • Mechanism of anticonvulsant action is not known.1 2 4 12

  • Protection observed against secondarily generalized activity from focal seizures induced by 2 chemoconvulsants known to induce seizures that mimic some features of human complex partial seizures with secondary generalization.1 2 12

  • Demonstrated inhibitory properties in the kindling model in rats, another model of human complex partial seizures.1 2 4 12

Advice to Patients

  • Provide copy of manufacturer’s patient information.1

  • Risk of adverse neuropsychiatric effects (e.g., somnolence, fatigue, dizziness, coordination difficulties, behavioral changes), especially during the initial weeks of therapy.1 2

  • Risk of drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.1 2 5

  • Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).10 21 22 Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).10 22

  • Importance of adhering to prescribed directions for use.1

  • Importance of not abruptly discontinuing therapy.1 2

  • Use in combination with other anticonvulsants, not as monotherapy.1 2

  • Importance of informing patients who are taking levetiracetam oral solution not to use a household teaspoon or tablespoon to measure the dose; a calibrated measuring device (such as a medicine dropper, spoon, cup, or syringe) should be obtained and used when administering the oral solution.1 22

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Importance of clinicians informing women about existence of and encouraging enrollment in pregnancy registries.1 12 22 (See Pregnancy under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illness (e.g., renal disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

levETIRAcetam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

100 mg/mL

Levetiracetam Oral Solution

Keppra Oral Solution

UCB Pharma

Tablets, film-coated

250 mg

Levetiracetam Tablets

Keppra (scored)

UCB Pharma

500 mg

Levetiracetam Tablets

Keppra (scored)

UCB Pharma

750 mg

Levetiracetam Tablets

Keppra (scored)

UCB Pharma

1 g*

Levetiracetam Tablets

Keppra (scored)

UCB Pharma

Parenteral

For IV use

100 mg/mL

Keppra (available as single-use vials in a kit containing water for injection and sodium chloride)

UCB Pharma

AHFS DI Essentials. © Copyright 2017, Selected Revisions May 1, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. UCB Pharma, Inc. Keppra (levetiracetam) tablets and oral solution prescribing information. Smyrna, GA; 2008 Feb.

2. UCB Pharma. Keppra (levetiracetam) tablets product monograph. Smyrna, GA; 2002.

3. Anon. Two new drugs for epilepsy. Med Lett Drugs Ther. 2000; 42:33-5. [PubMed 10803174]

4. Haria M, Balfour JA. Levetiracetam. CNS Drugs. 1997; 7:159-64. [PubMed 23338133]

5. UCB Pharma, Smyrna, GA: Personal communication.

6. Krakow K, Walker M, Otoul C et al. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology. 2001; 56:1772-4. [PubMed 11425954]

7. Magnus L. Dear healthcare professional letter: Dispensing error alert. Smyrna, GA: UCB Pharma, Inc; 2003 Sep.

8. Institute for Safe Medication Practices. What’s in a name? Ways to prevent dispensing errors linked to name confusion. ISMP Medication Safety Alert!. Huntingdon Valley, PA; 2002 Jun 12.

10. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

11. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

12. UCB, Inc. Keppra (levetiracetam) injection for intravenous use prescribing information. Smyrna, GA; 2008 Feb.

13. Ramael S, Daoust A, Otoul C et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006; 47:128-35.

14. Otoul C, De Smedt H, Stockis A et al. Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. Epilepsia. 2007; 48:2111-5. [PubMed 17651416]

15. Glauser TA, Ayala R, Elterman RD et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006; 66:1654-60. [PubMed 16641323]

16. Chaisewikul R, Privitera MD, Hutton JL et al. Levetiracetam add-on for drug-resistant localization related (partial) epilepsy. Cochrane Database Syst Rev. 2001; Issue 1:Article no. CD001901.

17. Steinhoff BJ, Somerville ER, Van Paesschen W et al. The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. Epilepsy Res. 2007; 76:6-14. [PubMed 17681453]

18. Baulac M, Brodie MJ, Elger CE et al. Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures. Epilepsia. 2007; 48:589-92. [PubMed 17326794]

19. Ramael S, De Smedt F, Toublanc N et al. Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects. Clin Ther. 2006; 28:734-44. [PubMed 16861095]

20. Bilo L, Meo R, de Leva MF et al. Levetiracetam in patients with epilepsy and chronic liver disease: observations in a case series. Clin Neuropharmacol. 2008; 31:221-5. [PubMed 18670245]

21. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

22. UCB, Inc. Keppra (levetiracetam) tablets and oral solution prescribing information. Smyrna, GA; 2009 Apr.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013. Electronic Update.

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