Generic Name: Levetiracetam
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Molecular Formula: C8H14N2O2
CAS Number: 102767-28-2

Warning(s)

Special Alerts:

[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

For more information visit the FDA website at: and .

[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.

For more information visit the FDA website at: and .

[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for levetiracetam to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a pyrrolidine derivative.1 2 3 5

Uses for Keppra

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Slideshow: Flashback: FDA Drug Approvals 2013

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults with epilepsy.1 2 3

Keppra Dosage and Administration

Administration

Oral Administration

Administer orally twice daily without regard to meals.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adults

Seizure Disorders
Partial Seizures
Oral

Initially, 500 mg twice daily.1 2 3

If response is inadequate, dosage may be increased by 1 g daily at 2-week intervals.1 2

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

Do not discontinue abruptly;1 withdraw gradually by reducing dosage by 1 g daily at 2-week intervals.5 (See Discontinuance of Levetiracetam under Cautions.)

Prescribing Limits

Adults

Seizure Disorders
Partial Seizures
Oral

Maximum 3 g daily recommended by the manufacturer.1

Special Populations

Renal Impairment

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

Table 1. 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 and consider monitoring renal function during therapy.1

Cautions for Keppra

Contraindications

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

Warnings/Precautions

Warnings

Nervous System Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

Psychotic manifestations and hallucinations reported rarely.1 2

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

Discontinuance of Levetiracetam

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

General Precautions

Hematologic Effects

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

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

Hepatic Effects

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

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 Discontinue nursing or the drug because of potential risk in nursing infant.1

Pediatric Use

Safety and efficacy not established in children <16 years of age.1 2

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

Renal Impairment

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

Common Adverse Effects

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

Interactions for Keppra

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

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1 2

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1 2

Specific Drugs

Drug

Interaction

Comments

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

Pharmacokinetic interaction unlikely1 2

Digoxin

Pharmacokinetic interaction unlikely1 2

Oral contraceptives

Pharmacokinetic interaction unlikely1 2

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

Clinically unimportant5

Warfarin

Pharmacokinetic interaction unlikely1 2

Keppra 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

Actions

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

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

  • 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

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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

  • 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 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. (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.

Levetiracetam

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

100 mg/mL

Keppra Oral Solution (dye-free; with glycerin and parabens)

UCB Pharma

Tablets, film-coated

250 mg

Keppra (scored)

UCB Pharma

500 mg

Keppra (scored)

UCB Pharma

750 mg

Keppra (scored)

UCB Pharma

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Keppra 100MG/ML Solution (UCB PHARMA): 473/$437.98 or 1419/$1,306.04

Keppra 1000MG Tablets (UCB PHARMA): 60/$643.02 or 180/$1,906.88

Keppra 250MG Tablets (UCB PHARMA): 10/$56.99 or 30/$144.97

Keppra 500MG Tablets (UCB PHARMA): 30/$162.99 or 90/$469.95

Keppra 750MG Tablets (UCB PHARMA): 30/$215.00 or 90/$623.99

Keppra XR 500MG 24-hr Tablets (UCB PHARMA): 60/$263.98 or 180/$752.00

Keppra XR 750MG 24-hr Tablets (UCB PHARMA): 60/$410.97 or 180/$1,199.93

Levetiracetam 100MG/ML Solution (ROXANE): 473/$259.99 or 1419/$719.96

Levetiracetam 1000MG Tablets (LUPIN PHARMACEUTICALS): 60/$243.99 or 180/$699.97

Levetiracetam 250MG Tablets (LUPIN PHARMACEUTICALS): 60/$23.99 or 120/$37.97

LevETIRAcetam 500MG 24-hr Tablets (WATSON LABS): 60/$65.99 or 180/$179.96

Levetiracetam 500MG Tablets (LUPIN PHARMACEUTICALS): 30/$29.99 or 90/$59.97

Levetiracetam 750MG Tablets (LUPIN PHARMACEUTICALS): 60/$61.99 or 120/$111.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. UCB Pharma, Inc. Keppra (levetiracetam) tablets and oral solution prescribing information. Smyrna, GA; 2004 Nov.

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. [IDIS 466256] [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.

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