Levetiracetam (injection)

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Levetiracetam (injection)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Disclaimer

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Overview

Levetiracetam (injection) is an anticonvulsant that is FDA approved for the treatment of partial onset seizures, myoclonic seizures and primary generalized tonic-clonic seizures. Common adverse reactions include somnolence, asthenia, infection, dizziness,fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Partial Onset Seizures

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

Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  • KEPPRA 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. KEPPRA injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

Primary Generalized Tonic-Clonic Seizures

  • KEPPRA 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. KEPPRA injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

Dosage

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.

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.

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.

Switching from Oral Dosing

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

Switching to Oral Dosing

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

Preparation and Administration Instructions

  • KEPPRA 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. KEPPRA injection should be administered as a 15-minute IV infusion. One vial of KEPPRA injection contains 500 mg levetiracetam (500 mg/5 mL).
  • 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 KEPPRA injection vial contents should be discarded.
  • See TABLE 1 for the recommended preparation and administration of KEPPRA injection for adults to achieve a dose of 500 mg, 1000 mg, or 1500 mg.
This image is provided by the National Library of Medicine.
  • For example, to prepare a 1000 mg dose, dilute 10 mL of KEPPRA injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

Dosage Adjustments in Adult Patients with Renal Impairment

  • KEPPRA 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:
This image is provided by the National Library of Medicine.

Then CLcr is adjusted for body surface area (BSA) as follows:

This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.

DOSAGE FORMS AND STRENGTHS

  • One vial of KEPPRA injection contains 500 mg levetiracetam (500 mg/5 mL).

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Levetiracetam (injection) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Levetiracetam (injection) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Levetiracetam (injection) in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Levetiracetam (injection) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Levetiracetam (injection) in pediatric patients.

Contraindications

  • None

Warnings

Behavioral Abnormalities and Psychotic Symptoms

  • KEPPRA may cause behavioral abnormalities and psychotic symptoms. Patients treated with KEPPRA should be monitored for psychiatric signs and symptoms.

Behavioral abnormalities

  • In clinical studies using an oral formulation of KEPPRA, 13% of adult KEPPRA-treated patients and 38% of pediatric KEPPRA-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).
  • A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of an oral formulation of KEPPRA as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in KEPPRA-treated patients on aggressive behavior (one of eight behavior dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
  • In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the KEPPRA-treated patients compared to 0% of placebo-treated patients.
  • In clinical studies, 1.7% of adult KEPPRA-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult KEPPRA-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of KEPPRA-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.

Psychotic symptoms

  • In clinical studies using an oral formulation of KEPPRA, 1% of KEPPRA-treated adult patients, 2% of KEPPRA-treated pediatric patients 4 to 16 years of age, and 17% of KEPPRA-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of KEPPRA in pediatric patients 4 to 16 years of age, 1.6% of KEPPRA-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of KEPPRA-treated patients experienced confusional state, compared to 0% of placebo-treated patients.
  • In clinical studies, two (0.3%) KEPPRA-treated adult patients were hospitalized, and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug- and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.

Somnolence and Fatigue

  • KEPPRA may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their ability to drive or operate machinery.

Somnolence

  • In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 15% of KEPPRA-treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving KEPPRA 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of KEPPRA-treated patients, compared to 0% in the placebo group. About 3% of KEPPRA-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of KEPPRA-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the KEPPRA-treated patients were hospitalized due to somnolence.

Asthenia

  • In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 15% of KEPPRA-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of KEPPRA-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of KEPPRA-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.
  • Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.

Serious Dermatological Reactions

  • Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with KEPPRA. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with KEPPRA has also been reported. KEPPRA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

Coordination Difficulties

  • KEPPRA may cause coordination difficulties.
  • In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 3.4% of KEPPRA-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled clinical studies discontinued KEPPRA treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of KEPPRA-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.
  • Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it could adversely affect their ability to drive or operate machinery.

Withdrawal Seizures

  • Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.

'Hematologic Abnormalities

  • KEPPRA can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in red blood cells count (RBC), hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cells count (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.

Partial Onset Seizures

Adults

  • In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 × 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in KEPPRA-treated patients.
  • A total of 3.2% of KEPPRA-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 × 109/L) decreased WBC, and 2.4% of KEPPRA-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 × 109/L) decreased neutrophil count. Of the KEPPRA-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Pediatric Patients 4 Years to < 16 Years

  • In a controlled study in pediatric patients age 4 years to <16 years, statistically significant decreases in WBC and neutrophil counts were seen in KEPPRA-treated patients, as compared to placebo. The mean decreases from baseline in the KEPPRA-treated group were -0.4 × 109/L and -0.3 × 109/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in KEPPRA-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant).
  • More KEPPRA-treated patients had a possibly clinically significant abnormally low WBC value (3% of KEPPRA-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% on KEPPRA versus 4.2% on placebo). No patient was discontinued because of low WBC or neutrophil count.
  • In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of KEPPRA as adjunctive therapy in pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the KEPPRA-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7×109/L).

Increase in Blood Pressure

  • In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of KEPPRA, a significantly higher risk of increased diastolic blood pressure was observed in the KEPPRA-treated patients (17%), compared to placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the KEPPRA and placebo treatment groups was not observed in the studies of older children or in adults.
  • Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.

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.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Levetiracetam (injection) in the drug label.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Levetiracetam (injection) in the drug label.

Drug Interactions

There is limited information regarding Levetiracetam (injection) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levetiracetam (injection) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Levetiracetam (injection) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Levetiracetam (injection) with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Levetiracetam (injection) with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Levetiracetam (injection) with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Levetiracetam (injection) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Levetiracetam (injection) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Levetiracetam (injection) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Levetiracetam (injection) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Levetiracetam (injection) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Levetiracetam (injection) in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

There is limited information regarding Monitoring of Levetiracetam (injection) in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Levetiracetam (injection) in the drug label.

Overdosage

There is limited information regarding Chronic Overdose of Levetiracetam (injection) in the drug label.

Pharmacology

There is limited information regarding Levetiracetam (injection) Pharmacology in the drug label.

Mechanism of Action

Structure

File:Levetiracetam (injection)01.png
This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Levetiracetam (injection) in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Levetiracetam (injection) in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Levetiracetam (injection) in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Levetiracetam (injection) in the drug label.

How Supplied

Storage

There is limited information regarding Levetiracetam (injection) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Levetiracetam (injection) in the drug label.

Precautions with Alcohol

  • Alcohol-Levetiracetam (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ "levetiracetam injection, solution, concentrate".
  2. ↑ "http://www.ismp.org". External link in |title= (help)

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