Levetiracetam

LEVETIRACETAM — levetiracetam injection, solution, concentrate
Jubilant Cadista Pharmaceuticals Inc.

figure1figure2figure3figure4figure5figure6structural figcartonlabel

1 INDICATIONS AND USAGE

1.1 Partial Onset Seizures

Levetiracetam injection, USP is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 1 month of age and older with epilepsy. Levetiracetam injection, USP is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Levetiracetam injection, USP is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. Levetiracetam injection, USP is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

1.3 Primary Generalized Tonic-Clonic Seizures

Levetiracetam injection, USP is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy. Levetiracetam injection, USP is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing for Partial Onset Seizures

Adults 16 Years 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. The effectiveness of lower doses has not been studied.

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.

2.2 Dosing for Myoclonic Seizures in Patients 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.

2.3 Dosing for Primary Generalized Tonic-Clonic Seizures

Adults 16 Years 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 Ages6 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 (10 mg/kg twice daily) 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.

2.4 Switching from Oral Dosing

When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

2.5 Switching to Oral Dosing

At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

2.6 Preparation and Administration Instructions

Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration. If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution. Consideration should also be given to the total daily fluid intake of the patient. Levetiracetam injection should be administered as a 15-minute IV infusion. One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

Levetiracetam injection may be mixed with the following diluents and antiepileptic drugs and may be stored in polyvinyl chloride (PVC) bags. The diluted solution should not be stored for more than 4 hours at controlled room temperature [15⁰C to 30⁰C (59⁰F to 86⁰F)].

Diluents:
Sodium chloride (0.9%) injection, USP
Lactated Ringer’s injection
Dextrose 5% injection, USP
Other Antiepileptic Drugs:
Lorazepam
Diazepam
Valproate sodium
There are no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.
Any unused portion of the levetiracetam injection vial contents should be discarded.

Adults
See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.Table 1: Preparation and Administration of Levetiracetam Injection for Adults

Dose	Withdraw Volume	Volume of Diluent	Infusion Time
500 mg	5 mL (5 mL vial)	100 mL	15 minutes
1000 mg	10 mL (two 5 mL vials)	100 mL	15 minutes
1500 mg	15 mL (three 5 mL vials)	100 mL	15 minutes

For example, to prepare a 1000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

Pediatric Patients
When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).
The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:
Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg)
100 mg/mL

2.7 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 with renal impairment are shown in Table 2. Information is unavailable for dosage adjustments in pediatric patients with renal impairment. In order to calculate the dose recommended for adult 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/1.73m²) = CLcr (mL/min) x 1.73
BSA subject (m²)Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment

Group	Creatinine Clearance (mL/min/1.73m2)	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 1,0001	1 Every 24 hours

¹ Following dialysis, a 250 to 500 mg supplemental dose is recommended.