levETIRAcetam 500 MG in 5 ML Injection
Generic Name: LEVETIRACETAM
Brand Name: Levetiracetam
- Substance Name(s):
- LEVETIRACETAM
OVERDOSAGE
10 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral 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.
DESCRIPTION
11 Levetiracetam Injection is an antiepileptic drug available as a clear, colorless, sterile solution (100 mg/mL) for intravenous administration.
The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O 2 and its molecular weight is 170.21.
Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).
It has the following structural formula: Levetiracetam, USP is a white to off-white crystalline powder with a faint odor and a bitter taste.
It is very soluble in water (104.0 g/100 mL).
It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane.
(Solubility limits are expressed as g/100 mL solvent.) Levetiracetam Injection contains 100 mg of levetiracetam per mL.
It is supplied in single-dose 5 mL vials containing 500 mg levetiracetam, water for injection, 45 mg sodium chloride, and buffered at approximately pH 5.5 with glacial acetic acid and 8.2 mg sodium acetate trihydrate.
Levetiracetam Injection must be diluted prior to intravenous infusion [see Dosage and Administration ( 2.6 ) ].
chemical structure
CLINICAL STUDIES
14 All clinical studies supporting the efficacy of Levetiracetam Injection utilized oral formulations.
The finding of efficacy of Levetiracetam Injection is based on the results of studies using an oral formulation of Levetiracetam, and on the demonstration of comparable bioavailability of the oral and parenteral formulations [see Clinical Pharmacology ( 12.3 ) ].
14.1 Partial Onset Seizures Effectiveness in Partial-Onset Seizures in Adults The effectiveness of Levetiracetam for the treatment of partial-onset seizures in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization.
The tablet formulation was used in all these studies.
In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day.
Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs.
Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED.
At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs.
During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.
Study 1 Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing Levetiracetam 1000 mg/day (N=97), Levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily.
After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described above.
The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
The results of the analysis of Study 1 are displayed in Table 10.
Table 10: Reduction In Mean Over Placebo In Weekly Frequency of Partial-Onset Seizures in Study 1 Placebo (N=95) Levetiracetam 1000 mg/day (N=97) Levetiracetam 3000 mg/day (N=101) Percent reduction in partial seizure frequency over placebo – 26.1% statistically significant versus placebo 30.1% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.
Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1 * statistically significant versus placebo Study 2 Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing Levetiracetam 1000 mg/day (N=106), Levetiracetam 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily.
The first period of the study (Period A) was designed to be analyzed as a parallel-group study.
After a prospective baseline period of up to 12 weeks, patients were randomized to one of the three treatment groups described above.
The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
The results of the analysis of Period A are displayed in Table 11.
Table 11: Reduction In Mean Over Placebo In Weekly Frequency ofPartial- Onset Seizures in Study 2: Period A Placebo (N=111) Levetiracetam 1000 mg/day (N=106) Levetiracetam 2000 mg/day (N=105) Percent reduction in partial seizure frequency over placebo – 17.1% statistically significant versus placebo 21.4% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.
Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A * statistically significant versus placebo The comparison of Levetiracetam 2000 mg/day to Levetiracetam 1000 mg/day for responder rate was statistically significant ( P =0.02).
Analysis of the trial as a cross-over yielded similar results.
Study 3 Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing Levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED.
Study drug was given in two divided doses.
After a prospective baseline period of 12 weeks, patients were randomized to one of two treatment groups described above.
The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
Table 12 displays the results of the analysis of Study 3.
Table 12: Reduction in Mean Over Placebo in Weekly Frequency of Partial-Onset Seizures in Study 3 Placebo (N=104) Levetiracetam 3000 mg/day (N=180) Percent reduction in partial seizure frequency over placebo – 23.0% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3.
Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3 * statistically significant versus placebo Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years of Age Study 4 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs).
Study 4 was conducted at 60 sites in North America.
The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period.
Eligible patients who still experienced, on a stable dose of 1 to 2 AEDs, at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either Levetiracetam or placebo.
Dosing was initiated at a dose of 20 mg/kg/day in two divided doses.
During the treatment period, Levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day.
The primary measure of efficacy was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week).
The enrolled population included 198 patients (Levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized.
Table 13 displays the results of Study 4.
Table 13: Reduction in Mean Over Placebo in Weekly Frequency of Partial-Onset Seizures in Study 4 Placebo (N=97) Levetiracetam (N=101) Percent reduction in partial seizure frequency over placebo – 26.8% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.
Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4 *statistically significant versus placebo Effectiveness in Partial Onset Seizures in Pediatric Patients 1 Month to <4 Years of Age Study 5 was a multicenter, randomized double-blind, placebo-controlled study, in pediatric patients 1 month to less than 4 years of age with partial seizures, uncontrolled by standard epileptic drugs (AEDs).
Study 5 was conducted at 62 sites in North America, South America, and Europe.
Study 5 consisted of a 5-day evaluation period, which included a 1-day titration period followed by a 4-day maintenance period.
Eligible patients who experienced, on a stable dose of 1-2 AEDs, at least 2 partial onset seizures during the 48-hour baseline video EEG were randomized to receive either Levetiracetam or placebo.
Randomization was stratified by age range as follows: 1 month to less than 6 months of age (N=4 treated with Levetiracetam), 6 months to less than 1 year of age (N=8 treated with Levetiracetam), 1 year to less than 2 years of age (N=20 treated with Levetiracetam), and 2 years to less than 4 years of age (N=28 treated with Levetiracetam).
Levetiracetam dosing was determined by age and weight as follows: children 1 month to less than 6 months old were randomized to a target dose of 40 mg/kg/day, and children 6 months to less than 4 years old were randomized to a target dose of 50 mg/kg/day.
The primary measure of efficacy was the responder rate (percent of patients with ≥ 50% reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG performed during the last two days of the 4-day maintenance period.
The enrolled population included 116 patients (Levetiracetam N=60, placebo N=56) with refractory partial onset seizures, whether or not secondarily generalized.
A total of 109 patients were included in the efficacy analysis.
A statistically significant difference between Levetiracetam and placebo was observed in Study 5 (see Figure 5).
The treatment effect associated with Levetiracetam was consistent across age groups.
Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5 *statistically significant versus placebo Figure 1: Responder Rate (≥50% Reduction from Baseline) in Study 1 Figure 2: Responder Rate (≥50% Reduction from Baseline) in Study 2: Period A Figure 3: Responder Rate (≥50% Reduction from Baseline) in Study 3 Figure 4: Responder Rate (≥ 50% Reduction from Baseline) in Study 4 Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5 14.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy The effectiveness of Levetiracetam as adjunctive therapy in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (study 6), conducted at 37 sites in 14 countries.
Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either Levetiracetam or placebo (Levetiracetam N=60, placebo N=60).
Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period).
Study drug was given in 2 divided doses.
The primary measure of efficacy was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline.
Table 14 displays the results for the 113 patients with JME in this study.
Table 14: Responder Rate (≥50% Reduction from Baseline) In Myoclonic Seizure Days per Week in Study 6 Placebo (N=59) Levetiracetam (N=54) Percentage of responders 23.7% 60.4% statistically significant versus placebo 14.3 Primary Generalized Tonic-Clonic Seizures The effectiveness of Levetiracetam as adjunctive therapy in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (study 7), conducted at 50 sites in 8 countries.
Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomized to either Levetiracetam or placebo.
The 8-week combined baseline period is referred to as “baseline” in the remainder of this section.
Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period).
Study drug was given in 2 equally divided doses per day.
The primary measure of efficacy was the percent reduction from baseline in weekly PGTC seizure frequency for Levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods).
The population included 164 patients (Levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures.
Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population.
There was a statistically significant decrease from baseline in PGTC frequency in the Levetiracetam-treated patients compared to the placebo-treated patients in Study 7 (see Table 15).
Table 15: Median Percent Reduction from Baseline in PGTC Seizure Frequency per Week in Study 7 Placebo (N=84) Levetiracetam (N=78) Percentage reduction in PGTC seizure frequency 44.6% 77.6% statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 6.
Figure 6: Responder Rate ( ≥ 50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7 * statistically significant versus placebo Figure 6: Responder Rate (≥50% Reduction from Baseline) in PGTC Seizure Frequency per Week in Study 7
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Levetiracetam Injection 500 mg/5 mL injection is a clear, colorless, sterile solution.
It is supplied in single-dose 5 mL vials, available in cartons of 25 vials (NDC 0143-9574-25).
16.2 Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].
GERIATRIC USE
8.5 Geriatric 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 Levetiracetam Injection 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 [see Clinical Pharmacology ( 12.3 ) ].
DOSAGE FORMS AND STRENGTHS
3 One vial of Levetiracetam Injection contains 500 mg levetiracetam (500 mg/5 mL) as a clear, colorless solution..
Injection: 500 mg/5 mL single dose vial ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.
A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam.
Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis.
Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice.
These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.
INDICATIONS AND USAGE
1 Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) • Levetiracetam Injection is indicated for adjunctive therapy for the treatment of: Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3 ) • Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible ( 1.4 ) 1.1 Partial-Onset Seizures Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.
1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam Injection is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.
1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam Injection is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.
1.4 Limitations of Use Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of Levetiracetam Injection for the treatment of partial onset seizures in patients 1 month to 16 years of age have been established [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 ) ].
The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and Administration ( 2.6 ) ].
The safety and effectiveness of Levetiracetam Injection as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see Clinical Studies ( 14.2 ) ].
The safety and effectiveness of Levetiracetam Injection as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see Clinical Studies ( 14.3 ) ].
Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established.
A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam Injection as adjunctive therapy in 98 (Levetiracetam Injection 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 Levetiracetam Injection-treated patients in aggressive behavior, one of the eight syndrome scores [see Warnings and Precautions ( 5.1 ) ].
Juvenile Animal Toxicity Data Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) 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/m 2 basis) did not demonstrate adverse effects on postnatal development.
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 Injection, 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 Injection 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 developmental 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/m 2 ) 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/m 2 basis.
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/m 2 basis.
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/m 2 basis).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms ( 5.1 ) Monitor for somnolence and fatigue; advise patients not to drive or operate machinery until they have sufficient experience on Levetiracetam Injection ( 5.2 ) Serious Dermatological Reactions: Discontinue Levetiracetam Injection at the first sign of rash unless clearly not drug related ( 5.4 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.5 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination ( 5.6 ) Withdrawal Seizures: Levetiracetam Injection must be gradually withdrawn.
( 5.7 ) 5.1 Behavioral Abnormalities and Psychotic Symptoms Levetiracetam Injection may cause behavioral abnormalities and psychotic symptoms.
Patients treated with Levetiracetam Injection should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced nonpsychotic 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 Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age).
The results from an exploratory analysis indicated a worsening in Levetiracetam-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 Levetiracetam-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult Levetiracetam-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 Levetiracetam-treated patients and in 0.5% of placebo-treated patients.
Overall, 11% of Levetiracetam-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 Levetiracetam, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of levetiracetam-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 Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients.
In the same study, 3.1% of Levetiracetam-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use in Specific Populations ( 8.4 ) ].
In clinical studies, two (0.3%) Levetiracetam-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.
5.2 Somnolence and Fatigue Levetiracetam Injection 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 Levetiracetam Injection to gauge whether it adversely affects their ability to drive or operate machinery.
Somnolence In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, 15% of Levetiracetam-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 levetiracetam 4000 mg/day reported somnolence.
The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group.
About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients.
In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.
Asthenia In controlled clinical studies using an oral formulation of levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients.
Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients.
In 0.5% of Levetiracetam-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.
5.3 Anaphylaxis and Angioedema Levetiracetam Injection can cause anaphylaxis or angioedema after the first dose or at any time during treatment.
Signs and symptoms in cases reported in the postmarketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet.
In some reported cases, reactions were life-threatening and required emergency treatment.
If a patient develops signs or symptoms of anaphylaxis or angioedema, Levetiracetam Injection should be discontinued and the patient should seek immediate medical attention.
Levetiracetam Injection should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ].
5.4 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 Levetiracetam Injection.
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 Levetiracetam Injection has also been reported.
Levetiracetam Injection 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.
5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Levetiracetam Injection.
These events can be fatal or life- threatening, particularly if diagnosis and treatment do not occur as early as possible.
Levetiracetam Injection typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Eosinophilia is often present.
Because this disorder is variable in its expression, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately.
Levetiracetam Injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4) ].
5.6 Coordination Difficulties Levetiracetam Injection may cause coordination difficulties.
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, 3.4% of Levetiracetam-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 Levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients.
In 0.7% of Levetiracetam-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 Levetiracetam Injection to gauge whether it could adversely affect their ability to drive or operate machinery.
5.7 Withdrawal Seizures As with most antiepileptic drugs, Levetiracetam Injection should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.
But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.
5.8 Hematologic Abnormalities Levetiracetam Injection can cause hematologic abnormalities.
Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cells counts (RBC); decreases in hemoglobin and hematocrit; and increases in eosinophil counts.
Cases of agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the postmarketing setting.
A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.
Partial-Onset Seizures Adults In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial-onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 x 10 6 /mm 3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients.
A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 10 9 /L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 10 9 /L) decreased neutrophil count.
Of the Levetiracetam-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 Levetiracetam-treated patients, as compared to placebo.
The mean decreases from baseline in the Levetiracetam-treated group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group.
Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant).
More Levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% of Levetiracetam-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% on Levetiracetam 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 Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X10 9 /L).
5.9 Increase in Blood Pressure In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-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 Levetiracetam 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.
5.10 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Psychiatric Reactions and Changes in Behavior Advise patients and their caregivers that Levetiracetam Injection may cause changes in behavior (e.g.
aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms [see Warnings and Precautions (5.1) ].
Effects on Driving or Operating Machinery Inform patients that Levetiracetam Injection may cause dizziness and somnolence.
Inform patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam Injection to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.2) ].
Anaphylaxis and Angioedema Advise patients to discontinue Levetiracetam Injection and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.3) ].
Dermatological Adverse Reactions Advise patients that serious dermatological adverse reactions have occurred in patients treated with Levetiracetam Injection and instruct them to call their physician immediately if a rash develops [see Warnings and Precautions (5.4) ].
DRESS/Multiorgan Hypersensitivity Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.
Levetiracetam Injection should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.5) ].
Withdrawal of Levetiracetam Injection Advise patients and caregivers not to discontinue use of Levetiracetam Injection without consulting with their healthcare provider.
Levetiracetam Injection should normally be gradually withdrawn to reduce the potential of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7) ].
Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Levetiracetam Injection therapy.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant [see Use In Specific Populations (8.1) ].
Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL) S.A.
Estrada do Rio da Mó, nº8, 8A and 8B – Fervença 2705-906 Terrugem SNT PORTUGAL Distributed by: Hikma Pharmaceuticals USA Inc.
Berkeley Heights, NJ 07922 Novaplus is a registered trademark of Vizient, Inc.
PIN370-NOV/9 Revised: April 2024
DOSAGE AND ADMINISTRATION
2 Levetiracetam Injection is for intravenous use only ( 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 ( 2.1 ) 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 ( 2.1 ) 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 ( 2.1 ) 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 ( 2.1 ) 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 ( 2.2 ) Primary Generalized Tonic-Clonic Seizures 6 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 ( 2.3 ) 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 ( 2.3 ) Switching From or To Oral Levetiracetam When switching from or to oral Levetiracetam, the total daily dosage/frequency of Levetiracetam Injection should be equivalent to those of oral Levetiracetam.
( 2.4 , 2.5 ) See full prescribing information for preparation and administration instructions ( 2.6 ) and dosage adjustment in adults with renal impairment ( 2.7 ) 2.1 Dosing for Partial Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same as outlined below.
There is no clinical study experience with administration of intravenous levetiracetam for a period longer than 4 days.
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.
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 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 (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 [15-30⁰C (59-86⁰F)].
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 Injection 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/1.73m 2 ) = CLcr (mL/min) x 1.73 BSA subject (m 2 ) Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73 m 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 1,0001 Following dialysis, a 250 to 500 mg supplemental dose is recommended.
Every 24 hours 2.8 Discontinuation of Levetiracetam Injection Avoid abrupt withdrawal from Levetiracetam Injection in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.6 ) ].