Levetiracetam (injection)

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

• The following adverse reactions are discussed in more details in other sections of labeling:

• Behavioral Abnormalities and Psychotic Symptoms
• Somnolence and Fatigue
• Serious Dermatological Reactions
• Coordination Difficulties
• Hematologic Abnormalities
• Increase in Blood Pressure

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• The adverse reactions that result from KEPPRA injection use include all of those reported for KEPPRA tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.

Partial Onset Seizures

Adults

• In controlled clinical studies using KEPPRA tablets in adults with partial onset seizures, the most common adverse reactions in adult patients receiving KEPPRA in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Of the most common adverse reactions in adults experiencing partial onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with KEPPRA.

• Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving KEPPRA tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent AED therapy.

This image is provided by the National Library of Medicine.

• In controlled adult clinical studies using KEPPRA tablets, 15% of patients receiving KEPPRA and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in KEPPRA-treated patients than in placebo-treated patients.

This image is provided by the National Library of Medicine.

Pediatric Patients 4 Years to <16 Years

• The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies using an oral formulation in pediatric patients 4 to 16 years of age with partial onset seizures. The most common adverse reactions in pediatric patients receiving KEPPRA in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

• Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that occurred in at least 2% of pediatric KEPPRA-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent AED therapy.

This image is provided by the National Library of Medicine.

• In the controlled pooled pediatric clinical studies in patients 4-16 years of age, 7% of patients receiving KEPPRA and 9% receiving placebo discontinued as a result of an adverse reaction.

Pediatric Patients 1 Month to < 4 Years

• In the 7-day controlled pediatric clinical study using an oral formulation of KEPPRA in children 1 month to less than 4 years of age with partial onset seizures, the most common adverse reactions in patients receiving KEPPRA in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability. Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients. Therefore, other controlled pediatric data, presented above, should also be considered to apply to this age group.

• Table 6 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with KEPPRA in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy.

This image is provided by the National Library of Medicine.

• In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving KEPPRA and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. There was no adverse reaction that resulted in discontinuation for more than one patient.

Myoclonic Seizures

• Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

• In the controlled clinical study using KEPPRA tablets in patients with myoclonic seizures, the most common adverse reactions in patients receiving KEPPRA in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

• Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with KEPPRA tablets and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy.

This image is provided by the National Library of Medicine.

• In the placebo-controlled study using KEPPRA tablets in patients with JME, 8% of patients receiving KEPPRA and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in KEPPRA-treated patients than in placebo-treated patients are presented in Table 8.

This image is provided by the National Library of Medicine.

Primary Generalized Tonic-Clonic Seizures

• Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures.

• In the controlled clinical study that included patients 4 years of age and older with PGTC seizures, the most common adverse reaction in patients receiving KEPPRA oral formulation in combination with other AEDs, for events with rates greater than placebo was nasopharyngitis.

Table 9 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy.

This image is provided by the National Library of Medicine.

• In the placebo-controlled study, 5% of patients receiving KEPPRA and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.

• This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see TABLES 4 and 8).

• In addition, the following adverse reactions were seen in other controlled adult studies of KEPPRA: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision.

Comparison of Gender, Age and Race

• The overall adverse reaction profile of KEPPRA was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race.

Postmarketing Experience

• The following adverse reactions have been identified during postapproval use of KEPPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• The following adverse reactions have been reported in patients receiving KEPPRA worldwide. The listing is alphabetized: abnormal liver function test, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with KEPPRA use; recovery was observed in majority of cases where KEPPRA was discontinued.

Drug Interactions

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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Levetiracetam blood levels may decrease during pregnancy.

Pregnancy Category C

• There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. KEPPRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study.

• Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day.

• When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.

• Treatment of rats during the last third 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/m2 basis).

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

• The effect of KEPPRA on labor and delivery in humans is unknown.

Nursing Mothers

• Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

• The safety and effectiveness of KEPPRA in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established. The dosing recommendation in these pediatric patients varies according to age group and is weight-based.

• The safety and effectiveness of KEPPRA as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established.

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

• A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of KEPPRA as adjunctive therapy in 98 (KEPPRA N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, 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. The Achenbach Child Behavior Checklist (CBCL/6-18), 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/6-18 indicated, on average, a worsening in KEPPRA-treated patients in aggressive behavior, one of the eight syndrome scores.

• Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not indicate a potential for age-specific toxicity.

Geriatic Use

• There were 347 subjects in clinical studies of levetiracetam that were 65 years old 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 KEPPRA 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.

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

• Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis.

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

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

Structure

File:Levetiracetam (injection)01.png

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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

• KEPPRA®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

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

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