EPIXX

Levetiracetam is a drug within the pyrrolidine class that is used to treat various types of seizures stemming from epileptic disorders.

It was first approved for use in the United States in and is structurally and mechanistically unrelated to other anti-epileptic drugs (AEDs). 11, 13, 15 Levetiracetam possesses a wide therapeutic index 15, 9 and little-to-no potential to produce, or be subject to, pharmacokinetic interactions 11, 13, 15.

• these characteristics make it a desirable choice over other AEDs, a class of drugs notorious for having generally narrow therapeutic indexes and a propensity for involvement in drug interactions.

Levetiracetam is indicated as an adjunctive therapy in the treatment of partial onset seizures in epileptic patients who are one month of age and older.

Additionally, it is indicated as an adjunct in the treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy who are 12 years of age and older, and in primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy who are 6 years of age and older.

Levetiracetam is also available as an

Oral dissolvable tablet that is indicated as an adjunct in the treatment of partial onset seizures in patients with epilepsy who are 4 years of age and older and weigh more than 20 kg.

Levetiracetam appears to prevent seizure activity via the selective inhibition of hypersynchronized epileptiform burst firing without affecting normal neuronal transmission, though the exact mechanism through which this occurs is unclear. 11, 15 The therapeutic index of levetiracetam is wide, 15, 9 making it relatively unique amongst other anti-epileptic medications.

Anti-epileptic drugs, including levetiracetam, may increase the risk of suicidal ideation or behaviour.

• patients taking levetiracetam should be monitored for the emergence or worsening of depressive symptoms, suicidal ideation, and behavioural abnormalities. 11, 13, 15.

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Levetiracetam is rapidly and nearly completely absorbed following oral administration, with a reported absolute oral bioavailability of essentially 100%. 15, 11, 13 T max is approximately 1.3 hours after dosing, and C max is 31 μg/mL following a single 1000 mg dose and 43 μg/mL following repeated dosing. 13, 15 Co-administration of levetiracetam with food delays T max by approximately 1.5 hours and decreases C max by 20%. 11, 13.

The volume of distribution of levetiracetam is approximately 0.5-0.7 L/kg. 13, 15.

Levetiracetam is minimally metabolized within the body.

• the major metabolic pathway appears to be the enzymatic hydrolysis of its acetamide group which produces an inactive carboxylic acid metabolite, L057, which accounts for approximately 24% of the total administered dose. 11, 13 The specific enzyme(s) responsible for this reaction are unclear, but this pathway is known to be independent of hepatic CYP enzymes and has been proposed to be driven primarily by type B esterases in the blood and other tissues.

Two minor metabolites involving modifications to the pyrrolidone ring have been identified, one involving hydroxylation of the ring (constituting 1.6% of the total dose) and the other involving opening of the ring structure (constituting 0.9% of the total dose). 15, 11, 13 Hover over products below to view reaction partners Levetiracetam Levetiracetam carboxylic acid metabolite (L057).

Approximately 66% of the administered dose of levetiracetam is excreted in the urine as unchanged drug, 11, 13 while only 0.3% of the total dose is excreted via the feces.

The primary inactive metabolite of levetiracetam, L057, is also found in the urine as approximately 24% of the administered dose.

The plasma half-life of levetiracetam is 6-8 hours and is not affected by dose or repeat administration.

Half-life is increased in the elderly (by about 40%) 15 and those with renal impairment. 11, 13.

The total plasma clearance of levetiracetam is 0.96 mL/min/kg, with renal clearance comprising 0.6 mL/min/kg.

The primary inactive metabolite of levetiracetam, L057, has a renal clearance of 4 mL/min/kg. Given the relatively high proportion of drug undergoing renal clearance, overall clearance of levetiracetam is reduced in patients with renal impairment. 11, 13.

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The oral

TDLO of levetiracetam in humans is 10 mg/kg.

Symptoms of levetiracetam overdose are consistent with its adverse effect profile and may include agitation, aggression, somnolence, decreased level of consciousness, respiratory depression, or coma. 11, 13 There is no antidote for levetiracetam overdose, therefore management should involve general supportive measures and symptomatic treatment.

Hemodialysis results in significant clearance of plasma levetiracetam (approximately 50% within 4 hours) and should be considered in cases of overdose as indicated by the patient's status. 11, 13.

Levetiracetam tablets are contraindicated in patients with a hypersensitivity to levetiracetam.

Reactions have included anaphylaxis and angioedema.

Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred.

Use the oral solution for pediatric patients with body weight ≤ 20 kg For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) Partial-Onset Seizures (monotherapy or adjunctive therapy) 1 Month to < 6 Months: 7 mg/kg twice daily; increase by 7 mg/kg twice daily every 2 weeks to recommended dose of 21 mg/kg twice daily 6 Months to < 4 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 25 mg/kg twice daily 4 Years to < 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to a recommended dose of 1500 mg twice daily Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily Primary Generalized Tonic-Clonic Seizures 6 Years to < 16 Years: 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily Adults 16 Years and Older: 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient’s estimated creatinine clearance 2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food.

The levetiracetam dosing regimen depends on the indication, , dosage form (tablets or oral solution), and renal function.

Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon).

Levetiracetam tablets should be swallowed whole.

Levetiracetam tablets should not be chewed or crushed. 2.2 Dosing for Partial-Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.

Adults 16 Years of Age and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Patients 1 Month to < 6 Months Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).

In the clinical trial, the mean daily dose was 35 mg/kg in this.

Months to < 4 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 47 mg/kg in this.

Years to < 16 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day. For levetiracetam tablet dosing in pediatric patients weighing to 40 kg, initiate treatment with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily).

Increase the daily dose every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily).

For levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, initiate treatment with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily).

Increase the daily dose every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily).

Levetiracetam Oral Solution Weight-Based Dosing Calculation For Pediatric Patients The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients: Daily dose (mg/kg/day) X patient weight (kg) Total daily dose (mL/day) = -----------------------------------------------------

• 100 mg/mL 2.3 Dosing for Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied. 2.4 Dosing for Primary Generalized Tonic-Clonic Seizures Adults 16 Years of Age and Older Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

Patients to <16 Years of Age Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

Patients with body weight ≤20 kg should be dosed with oral solution.

Patients with body weight above 20 kg can be dosed with either tablets or oral solution.

Only whole tablets should be administered. 2.5 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam tablet dosing must be individualized according to the patient’s renal function status.

Recommended dosage adjustments for adults are shown in Table 1.

In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.

To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: [140-age (years)] x weight (kg) CLcr = ----------------------------------------------(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min) CLcr (mL/min/1.73 m 2 ) = -------------------------

• x 1.73 BSA subject (m 2 ) Table 1: Dosing Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73 m 2 ) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild to 80 500 to 1,000 Every 12 hours Moderate to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ---

• 500 to 1,000 Every 24 hours * Following dialysis, a to 500 mg supplemental dose is recommended. 2.6 Discontinuation of Levetiracetam Tablets Avoid abrupt withdrawal from levetiracetam tablets in order to reduce the risk of increased seizure frequency and status epilepticus.

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There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam, during pregnancy.

Encourage women who are taking levetiracetam during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting Risk Summary Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades.

In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Levetiracetam blood levels may decrease during pregnancy.

Physiological changes during pregnancy may affect levetiracetam concentration.

Decrease in levetiracetam plasma concentrations has been observed during pregnancy.

This decrease is more pronounced during the third trimester.

Dose adjustments may be necessary to maintain clinical response.

While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage.

When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested.

There was no evidence of maternal toxicity.

The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis.

Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity.

The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested.

The no-effect dose for adverse effects on pre.

• and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).

The safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established.

The dosing recommendation in these pediatric patients varies according to and is weight-based.

The safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established.

The safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established.

Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam N=64, placebo N=34) pediatric patients, ages to 16 years old, with partial seizures that were inadequately controlled.

The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention.

Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo.

Checklist (CBCL/6 to 18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study.

An analysis of the

CBCL/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores.

Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development.

There were 347 subjects in clinical studies of levetiracetam that were and over.

No overall differences in safety were observed between these subjects and younger subjects.

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients.

Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.