Levetiracetam

Brand names: Elepsia XR, KEPPRA, Keppra, LEVERTIRACETAM, LEVETIRACETAM Extended-release, Levetiracetam Extended-Release, Levetiracetam extended-release, Levetiractam, ROWEEPRA, ROWEEPRA XR, Spritam, Levetiracetam, LEVETIRACETAM, ELEPSIA XR 1000 MG, Levetiracetam in Sodium Chloride, Levetiracetam Levetiracetam, LEVETIRACETAM solution, Roweepra, Levetiracetam ER, levetiracetam, Keppra XR, ELEPSIA XR 1500 MG

Warnings

No boxed warning. Levetiracetam is contraindicated in patients who have "previously exhibited hypersensitivity to levetiracetam." Major warnings include behavioral abnormalities and neuropsychiatric adverse reactions (such as "aggression, agitation, anger, anxiety...depression, emotional lability, hostility, irritability"), the class-wide warning that "antiepileptic drugs increase the risk of suicidal thoughts or behavior," withdrawal seizures if the drug is discontinued abruptly (it "should be withdrawn gradually"), and hematologic abnormalities along with coordination difficulties and somnolence/fatigue that can affect the ability to perform tasks requiring mental alertness.

Contraindications

4 CONTRAINDICATIONS Levetiracetam tablets are contraindicated in patients with a hypersensitivity to levetiracetam . Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4) ] . Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred (4, 5.4 )

Overdose

10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.

Drug interactions

Drug Interactions In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients. Phenytoin Levetiracetam (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin. Valproate Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Other Antiepileptic Drugs Potential drug interactions between levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam. Oral Contraceptives Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam. Digoxin Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam. Warfarin Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam. Probenecid Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. C ss max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of levetiracetam on probenecid was not studied.

Uses

Levetiracetam tablets are indicated as adjunctive therapy for: - "Partial onset seizures" in adults and children 4 years of age and older - "Myoclonic seizures" in adults and adolescents 12 years and older with juvenile myoclonic epilepsy - "Primary generalized tonic-clonic seizures" in adults and children 6 years and older with idiopathic generalized epilepsy

Dosage forms & strengths

C61005 Tablet Tablet, Extended Release Tablet, Film Coated Tablet, Film Coated, Extended Release SOLUTION TABLET INJECTION, SOLUTION, CONCENTRATE INJECTION TABLET, EXTENDED RELEASE TABLET, FILM COATED POWDER TABLET, FILM COATED, EXTENDED RELEASE TABLET, FOR SUSPENSION INJECTION, SOLUTION

LEVETIRACETAM 1000 mg LEVETIRACETAM 1500 mg LEVETIRACETAM 250 mg LEVETIRACETAM 500 mg LEVETIRACETAM 750 mg Levetiracetam 1000 mg Levetiracetam 250 mg Levetiracetam 500 mg Levetiracetam 750 mg levetiracetam 1000 mg levetiracetam 250 mg levetiracetam 500 mg levetiracetam 750 mg LEVETIRACETAM 100 mg/mL LEVETIRACETAM 1000 mg/1 LEVETIRACETAM 500 mg/5mL LEVETIRACETAM 250 mg/1 LEVETIRACETAM 750 mg/1 LEVETIRACETAM 500 mg/1 LEVETIRACETAM 1 kg/kg LEVETIRACETAM 25 kg/25kg LEVETIRACETAM 15 mg/mL LEVETIRACETAM 1 g/g LEVETIRACETAM 5 mg/mL LEVETIRACETAM 10 mg/mL LEVETIRACETAM 1000 mg/10mL LEVETIRACETAM 50 kg/50kg LEVETIRACETAM 1500 mg/1 LEVETIRACETAM 1500 mg/15mL

2 DOSAGE AND ADMINISTRATION Use the oral solution for pediatric patients with body weight ≤ 20 kg (2.1) For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) (2.1) 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 (2.2) 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 (2.2) 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 (2.2) 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 (2.2) 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 (2.3) 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 (2.4) 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 (2.4) Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient’s estimated creatinine clearance (2.5, 8.6) 2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food. The levetiracetam dosing regimen depends on the indication, age group, 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. Pediatric 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 age group. 6 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 age group. 4 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 20 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: Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 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. Pediatric Patients 6 to <16 Years of Age 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). 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 [see Dosage and Administration (2.1) ]. Only whole tablets should be administered. 2.5 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam 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: CLcr= [140-age (years)] x weight (kg) (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/1.73 m 2 ) = CLcr (mL/min) x 1.73 BSA subject (m 2 ) Table 1: Dosing Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73m 2 ) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 ─ 80 500 to 1,000 Every 12 hours Moderate 30 ─ 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis --- 500 to 1,000 1 Every 24 hours 1 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. 2.6 Discontinuation of Levetiracetam Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.8) ].