Levetiracetam

Warnings and Precautions (

Levetiracetam in Sodium Chloride Injection is indicated for adjunct therapy in adults (≥16 years of age) with the following seizure types when oral administration is temporarily not feasible:

• Partial-onset seizures (
  1.1 Partial-Onset Seizures

  Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy.
  )
• Myoclonic seizures in patients with juvenile myoclonic epilepsy (
  1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy.
  )
• Primary generalized tonic-clonic seizures (
  1.3 Primary Generalized Tonic-Clonic Seizures

  Levetiracetam in Sodium Chloride Injection is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy.
  )

• For intravenous infusion only (
  2.1 General Information – Administration

  Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg/mL], 1000 mg [10 mg/mL], or 1500 mg [15 mg/mL]).

  A single-dose bag should be administered intravenously over a 15-minute IV infusion period.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
  
  Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.
  )
• Do not dilute prior to its use (
  2.1 General Information – Administration

  Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg/mL], 1000 mg [10 mg/mL], or 1500 mg [15 mg/mL]).

  A single-dose bag should be administered intravenously over a 15-minute IV infusion period.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
  
  Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.
  )
• Administer dose-specific bag intravenously over 15-minutes (
  2.1 General Information – Administration

  Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL bags, each containing a different total dosage of levetiracetam (500 mg [5 mg/mL], 1000 mg [10 mg/mL], or 1500 mg [15 mg/mL]).

  A single-dose bag should be administered intravenously over a 15-minute IV infusion period.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
  
  Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.
  )

•  
  Partial-Onset Seizures:
  Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1500 mg twice daily (
  2.2 Initial Exposure to Levetiracetam

  Levetiracetam can be initiated with either intravenous or oral administration.
  
  
  
  

  Partial-Onset Seizures

  
  
  In clinical trials of oral levetiracetam, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose

  [see Clinical Studies (14.1)],

  a consistent increase in response with increased dose has not been shown.

  
  
  

  Treatment should be initiated 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. Doses greater than 3000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

  
  
  

  Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  
  
  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  

  Primary Generalized Tonic-Clonic Seizures

  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  
  ).
• Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy:
  Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1500 mg twice daily. (
  2.2 Initial Exposure to Levetiracetam

  Levetiracetam can be initiated with either intravenous or oral administration.
  
  
  
  

  Partial-Onset Seizures

  
  
  In clinical trials of oral levetiracetam, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose

  [see Clinical Studies (14.1)],

  a consistent increase in response with increased dose has not been shown.

  
  
  

  Treatment should be initiated 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. Doses greater than 3000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

  
  
  

  Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  
  
  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  

  Primary Generalized Tonic-Clonic Seizures

  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  
  ).
• Primary Generalized Tonic-Clonic Seizures:
  Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1500 mg twice daily. (
  2.2 Initial Exposure to Levetiracetam

  Levetiracetam can be initiated with either intravenous or oral administration.
  
  
  
  

  Partial-Onset Seizures

  
  
  In clinical trials of oral levetiracetam, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose

  [see Clinical Studies (14.1)],

  a consistent increase in response with increased dose has not been shown.

  
  
  

  Treatment should be initiated 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. Doses greater than 3000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

  
  
  

  Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  
  
  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  

  Primary Generalized Tonic-Clonic Seizures

  Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased 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.

  
  
  
  ).

Injection: Levetiracetam in Sodium Chloride Injection is a clear, colorless solution packaged in a single-dose bag and available in three strengths:

• 500 mg/100 mL
  (5 mg/mL): 500 mg levetiracetam in 0.82 % sodium chloride
• 1000 mg/100 mL
  (10 mg/mL): 1000 mg levetiracetam in 0.75 % sodium chloride
• 1500 mg/100 mL
  (15 mg/mL): 1500 mg levetiracetam in 0.54% sodium chloride

• Pregnancy: Plasma levels of levetiracetam may be decreased ;monitor closely during pregnancy. Based on animal data, may cause fetal harm. (
  5.9 Seizure Control During Pregnancy

  Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.
  ,
  8.1 Pregnancy

  Pregnancy Exposure Registry

  
  
  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 injection during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

  
  
  

  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

  [see Human Data].

  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

  [see Animal Data].

  
  
  

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  
  
  
  
  

  Clinical Considerations

  
  
  Levetiracetam blood levels may decrease during pregnancy

  [see Warnings and Precautions (5.9)].

  
  
  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.
  
  
  
  

  Data

  
  
  
  
  Human Data
  
  
  
  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.
  
  
  
  Animal Data
  
  
  
  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 development 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/m²) 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/m²basis.

  
  
  

  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. There was no evidence of maternal toxicity. 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/m²basis.

  
  
  

  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/m²basis).
  )