Drug Criteria & Outcomes

Levetiracetam (Keppra) for treatment of partial seizures

By John Fowler, PharmD candidate
Medical University of South Carolina
Charleston

Indication:

Levetiracetam (Keppra), by UCB Pharma, is approved by the Food and Drug Administration (FDA) for supplemental therapy in the treatment of partial seizures in adult patients with epilepsy.1

Pharmacology:

The antiepileptic activity of levetiracetam is thought to occur via a novel pathway that does not appear to affect known mechanisms of inhibitory and excitatory neurotransmission.1 EEG recordings of hippocampal epileptiform activity have shown that levetiracetam appears to prevent seizure propagation by stabilizing neuronal cell membrane potentials without causing hyperpolarization.1

Pharmacokinetics:

Absorption: The bioavailability of levetiracetam approaches 100% and is unaffected by food, antacids, or the size of the dose. Peak drug concentrations (Cmax) and area under the curve (AUC) concentrations display linear kinetics in healthy volunteers.1,2

Distribution: Plasma protein binding of levetiracetam and its major inactive metabolite is less than 10%. The average volume of distribution in a 70 kg human is between 35 and 49 liters, indicating that levetiracetam is distributed into extracellular fluids.1,2

Metabolism: Approximately 35% of each dose of levetiracetam is metabolized via cytochrome P450 independent enzymatic hydrolysis to an inactive carboxylic acid metabolite. Therefore, levetiracetam is not subject to induction or inhibition by other drugs. Two other inactive metabolites account for less than 3% of the administered dose. Neither the primary metabolite of levetiracetam nor levetiracetam undergoes enantiomeric interconversion.1,2

Elimination: Levetiracetam is primarily eliminated in the urine as the parent drug (~66%) via first-order elimination. Renal and total clearance of levetiracetam and its carboxylic acid metabolite are directly proportional to creatinine clearance and both are readily removed by hemodialysis. Renal elimination of the carboxylic acid metabolite of levetiracetam is decreased by coadministration of probenecid.1,2 Elimination of levetiracetam and its metabolites in feces is negligible.2 The half-life of levetiracetam is approximately seven hours in adults who have normal renal function.1 It is unknown if levetiracetam is excreted in human breast milk.1

Selected clinical trials:

Patients were eligible for the three pivotal trials3,4,5 if they were 16 years of age or older, experienced a minimum of one seizure per week despite a stable regimen of one or two antiepileptic drugs (AEDs), and if they had at least a two-year history of partial seizures. Study exclusion criteria included the following: current use of medications with central nervous system (CNS) activity (concomitant use of one or two antiepileptic drugs was mandatory for study inclusion); a history of drug or alcohol abuse; weight less than 50 kg; clusters of partial seizures during the baseline period; the display of either suicidal tendencies or psychiatric illness that required treatment; or lack of general good health. The only differences among the three studies with regard to inclusion and exclusion criteria were as follows: in the studies by Cereghino and Ben-Menachem, patients who exhibited clusters of partial seizures three months or five years prior to entry, respectively, were excluded; in the study by Ben-Menachem, the use of only one other concomitant antiepileptic drug was allowed; in the study by Ben-Menachem, the required baseline seizure rate was one-half of the baseline seizure rate in the studies by Cereghino and Shorvon. Therefore, patients in the studies by Cereghino and Shorvon were generally more resistant to current therapy.3,4,5

The primary measure of effectiveness in all three studies was the mean or median percent reduction in weekly partial seizure frequency during the titration and maintenance periods. The number of patients with > 50% reduction from their baseline seizure frequency was the secondary endpoint.3,4,5

Trials compare levetiracetam to placebo

Cereghino and colleagues3 conducted a multicenter, parallel-group, double-blind, randomized, controlled trial that was designed to compare the difference in efficacy of levetiracetam to placebo in the treatment of adult patients who had partial seizures that were refractory to the use of one or two other antiepileptic drugs. On average, patients were 38 years old and had had epilepsy for 24.2 years. A total of 294 patients, 62% of whom took two antiepileptic drugs, were randomized to one of three treatment arms after a prospective 12-week baseline period. The treatment arms included the following: levetiracetam, 500 mg, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 98); levetiracetam, 1,500 mg, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 101); or placebo, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 95). A four-week titration period ensued, after which patients were followed for 14 weeks. Both primary and secondary outcome measures included the titration and maintenance periods.3

Shorvon and colleagues4 conducted a randomized, double-blind, multicenter trial with a cross-over design to assess the effectiveness of levetiracetam vs. placebo in the treatment of adult patients who experienced partial seizures that were resistant to the use of one or two other antiepileptic drugs. The average patient age was 37 years, with most patients having had epilepsy for 23.6 years. Three hundred twenty-four patients participated in this trial. Two hundred forty-seven (76%) were also taking two antiepileptic drugs. The patients were randomized to one of three treatment arms after an eight- to 12-week prospective baseline period. The treatment arms were: levetiracetam, 500 mg, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 106); levetiracetam, 1,000 mg, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 106); or placebo, given orally, twice daily, plus a maximum of two concomitant antiepileptic drugs (n = 112). After a four-week titration period, the patients were followed for 12 weeks. Both primary and secondary outcome measures included the titration and maintenance periods.4

Ben-Menachem and colleagues5 conducted a randomized, double-blind, parallel, multicenter trial that evaluated the efficacy of levetiracetam vs. placebo in the treatment of partial seizures in adult patients that were resistant to the use of one other antiepileptic drug. On average, patients were 36 years old and had had epilepsy for 19 years. A total of 286 patients were randomized to one of two treatments after a prospective 12-week baseline period. The treatment arms were: levetiracetam, 1,500 mg, given orally, twice daily, plus one concomitant antiepileptic drug (n = 181); or placebo, given orally, twice daily, plus one concomitant antiepileptic drug (n = 105). A 4-week titration period ensued after which patients were followed for 12 weeks. Both primary and secondary outcome measures were included in the titration and maintenance periods.5

Adverse reactions:

In clinical trials, levetiracetam has been studied in 769 patients as adjunctive therapy for partial seizures. During these trials, patients received either one or two concomitant AEDs. Adverse effects reported at a frequency of > 2% when compared to placebo included somnolence (7%), asthenia (6%), dizziness (5%), infection (5%), ataxia (2%), depression (2%), emotional lability (2%), nervousness (2%), pharyngitis (2%), and vertigo (2%).1,3,4,5 Asthenia, somnolence, and dizziness appeared to occur predominantly during the first four weeks of treatment. Slow upward titration of the levetiracetam dose may help decrease the incidence of somnolence. Laboratory changes that occurred during clinical trials at a frequency of > 1% when compared to placebo included the following: leukopenia (1.4%) and neutropenia (1%).1

Pregnancy/lactation:

Levetiracetam is rated as a pregnancy category C, based on the presence of teratogenic or embryocidal activity during animal studies.1,5 Levetiracetam has not been studied in pregnant women and has a pregnancy category C rating based solely on animal data. It is not known whether levetiracetam is excreted in human breast milk. The use of levetiracetam during pregnancy or while nursing should be reserved for the adjunctive treatment of partial seizures only if the potential benefit justifies the potential risk to the fetus or nursing infant.1

Contraindications:

Levetiracetam is contraindicated in individuals with a prior history of a hypersensitivity reaction to levetiracetam or any of the inactive ingredients in levetiracetam tablets.1

Warnings:

In controlled clinical trials, patients treated with levetiracetam developed psychotic symptoms, psychotic depression, or attempted suicide at an increased frequency of 0.5% over placebo-treated patients. One of these cases resulted in suicide. Levetiracetam-induced psychosis was seen during the first week of treatment and abated following treatment discontinuation.

The reported cases of hallucination, psychotic depression, or attempted suicide either resolved or were not attempted again despite continued treatment. All of these cases occurred within the first six months of therapy.1

Dosage and administration:

A definitive dose-response relationship has not been established in clinical trials. The recommended dose of levetiracetam as adjunctive therapy for partial seizures in adults is 1,000 mg, by mouth, per day, given as two divided doses. If an incomplete response is seen after two weeks, the daily dose can be increased by 1,000 mg at two-week intervals until the maximum daily dose of 3,000 mg is obtained.

Levetiracetam is only available as a tablet for oral administration. The dose of levetiracetam should be adjusted in patients with renal dysfunction according to the product labeling and is adjusted according to patient creatinine clearance (ClCr). Patients with normal renal function (ClCr > 80 mL/min) should be dosed 500 to 1,500 mg every 12 hours. Those with mild renal impairment (ClCr 50 to 80 mL/min) may be dosed 500 to 1,000 mg every 12 hours. Moderate renal dysfunction (ClCr 30 to 50 mL/min) requires an adjustment down to 250 to 750 mg every 12 hours. For severe renal impairment (ClCr < 30 mL/min), the recommended dose is 250 to 500 mg every 12 hours, and for patients with end stage renal disease requiring dialysis, the recommended dose is 500 to 1,000 mg every 24 hours. Approximately 50% of the total body stores of levetiracetam are removed during a four-hour hemodialysis session. Therefore, a 250 mg to 500 mg supplemental dose should be given at the end of each dialysis session. There is no need to adjust the dose of levetiracetam in patients with hepatic dysfunction.1

Drug interactions:

The pharmacokinetics of levetiracetam were studied in humans when levetiracetam was coadministered with digoxin, warfarin, oral contraceptives, probenecid, and other antiepileptic drugs, including the following: carbamazepine; gabapentin; lamotrigine; phenobarbital; phenytoin; primidone; and valproic acid. No interactions of clinical significance were reported.1,2

Drug-food interactions:

Administration of levetiracetam with food decreases peak serum concentrations but not the bioavailability. Levetiracetam can be administered without regard to food.1

Dosage forms available:

Levetiracetam is supplied as 250 mg, 500 mg and 750 mg tablets.1

Potential for medication errors:

Levetiracetam 250 mg and 500 mg tablets could be confused for Levaquin 250 mg and 500 mg tablets. However, Levaquin is dosed once daily and levetiracetam is dosed twice daily.

Discussion:

Levetiracetam is FDA-approved for the adjunctive treatment of partial seizures in adults and has been studied in 769 patients at daily doses ranging from 1,000 mg to 3,000 mg administered orally in two divided doses.1 The most frequently reported adverse effects were somnolence (7%), asthenia (6%), dizziness (5%), infection (5%), ataxia (2%), depression (2%), emotional lability (2%), nervousness (2%), pharyngitis (2%), and vertigo (2%).1 During these trials, patients treated with levetiracetam experienced either psychotic symptoms, psychotic depression, or attempted suicide at an increased frequency of 0.5% over placebo-treated patients. Four of these patients attempted suicide, whereas, no placebo-treated patients attempted suicide. One of these cases resulted in death.1 Patients were excluded from these trials if they were taking drugs with CNS activity (with the exception of other antiepileptic drugs) or displayed either suicidal tendencies or psychiatric illness that required treatment.3,4,5

Drug interaction unlikely

Levetiracetam has a low potential for drug interactions because it is not a cytochrome P450 substrate or inhibitor and is < 10 % bound to plasma proteins.1,2 The primary route of levetiracetam elimination is via the kidneys and it exhibits predictable first-order kinetics.1,2 Levetiracetam has a FDA pregnancy category C rating.1 Because the safety and efficacy of levetiracetam has not been compared to other antiepileptic drugs in the adjunctive treatment of partial seizures, direct comparisons cannot be made.

Causes of Seizures
High fevers in children, also known as a fever fit. A temperature higher than 102 F can set off a fever fit. High fevers are the most common cause of seizures in children ages 6 months to 4 years. These seizures are generally harmless.
Epilepsy; seizure is the most common symptom of epilepsy
Brain injury, tumor, or stroke
Electric shock
Heat stroke
Poisons
Infections
Reactions or overdoses to medicines or drugs
Reye’s syndrome
Snakebites
Vaccinations
Breath-holding
Sometimes the cause is unknown
Source: The American Institute for Preventive Medicine at www.healthy.net/asp/templates/book.asp?PageType=Book&ID=815.


Drugs Commonly Used for Epilepsy Prevention

• Carbamazepine (Tegretol, Tegretol XR, Carbatrol)

• Clonazepam (Klonopin)

• Ethosuximide (Zarontin)

• Phenobarbital

• Phenytoin (Dilantin)

• Primidone (Mysoline)

• Valproic acid (Depakene)

• Divalproex sodium (Depakote)

• Felbamate (Felbatol)

• Gabapentin (Neurontin)

• Lamotrigine (Lamictal)

• Levetiracetam (Keppra)

• Oxcarbazepine (Trileptal)

• Tiagabine (Gabitril)

• Topiramate (Topamax)

• Zonisamide (Zonagran)

• Others in development

 

Source: The Epilepsy Foundation of America, www.efa.org/answerplace/treatment/treatment.html


References

1. Keppra package insert. Smyrna, GA: UCB Pharma; December 1999.

2. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85(2):77-85.

3. Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology July 2000; (2 of 2):236-42.

4. Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000; 41(9):1179-86.

5. Ben-Menachem E, Falter U, et al. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000; 41(10):1276-83.

6. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins; 1998. 

Useful Web Sites

• Epilepsy Foundation of America at www.efa.org/

• Epilepsy USA, the Epilepsy Foundation’s magazine at www.efa.org/epusa/index.html