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1.1 Partial-Onset Seizures
Levetiracetam Oral Solution USP 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 Oral Solution USP 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 Oral Solution USP 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.
2.1 Important Administration Instructions
Levetiracetam Oral Solution USP is given orally with or without food. The Levetiracetam Oral Solution USP dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function.Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg.When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon).
2.2 Dosing For Partial-Onset Seizures
The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.
2.3 Dosing For Myoclonic Seizures In Patients 12 Years Of Age And Older 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.
2.5 Dosage Adjustments In Adult Patients With Renal Impairment
Levetiracetam Oral Solution USP dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for 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)] × weight (kg)
(× 0.85 for female patients)72 × serum creatinine (mg/dL)Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min/1.73m
× 1.73BSA subject (m
Table 1: Dosing Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance
Dosage (mg) FrequencyNormal>80500 to 1,500Every 12 hoursMild50 – 80500 to 1,000Every 12 hoursModerate30 – 50250 to 750Every 12 hoursSevere< 30250 to 500Every 12 hoursESRD patients using dialysis-----500 to 1,000
Following dialysis, a 250 to 500 mg supplemental dose is recommended.Every 24 hours
2.6 Discontinuation Of Levetiracetam
Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [
Warnings and Precautions (5.7)]
3 Dosage Forms And Strengths
- Levetiracetam Oral Solution USP100 mg/mL: a clear, colorless, grape-flavored liquid16 fl oz (473 mL) bottles - NDC 0121-0799-165 mL Unit Dose Cups packaged in trays of 10 - NDC 0121-4799-0510 mL Unit Dose Cups packaged in trays of 10 - NDC 0121-1598-1015 mL Unit Dose Cups packaged in trays of 10 - NDC 0121-2397-15
Levetiracetam Oral Solution USP is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [
Warnings and Precautions (5.4)].
5.1 Behavioral Abnormalities And Psychotic Symptoms
Levetiracetam may cause behavioral abnormalities and psychotic symptoms. Patients treated with levetiracetam should be monitored for psychiatric signs and symptoms.
5.2 Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including levetiracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 PatientsEpilepsy1.03.43.52.4Psychiatric18.104.22.168.9Other1.01.81.90.9Total22.214.171.124.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.Anyone considering prescribing levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
5.3 Somnolence And Fatigue
Levetiracetam may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
5.4 Anaphylaxis And Angioedema
Levetiracetam 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 should be discontinued and the patient should seek immediate medical attention. Levetiracetam should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [
5.5 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. 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 has also been reported. Levetiracetam 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.
5.6 Coordination Difficulties
Levetiracetam may cause coordination difficulties. In controlled clinical studies in adult patients with partial-onset seizure studies, 3.4% of adult levetiracetam-treated patients experienced coordination difficulties, (reported as either 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 levetiracetam-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 these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery.
5.7 Withdrawal Seizures
As with most antiepileptic drugs, levetiracetam should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.
5.8 Hematologic Abnormalities
Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cell (RBC) counts; 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.
5.9 Increase In Blood Pressure
In a randomized, placebo-controlled study in patients 1 month to < 4 years of age, a significantly higher risk of increased diastolic blood pressure was observed in the levetiracetam-treated patients (17%), compared to the 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.
6 Adverse Reactions
- The following adverse reactions are discussed in more details in other sections of labeling:Behavior Abnormalities and Psychotic Symptoms [
- Warnings and Precautions (5.1)]
- Suicidal Behavior and Ideation [
- Warnings and Precautions (5.2)]
- Somnolence and Fatigue [
- Warnings and Precautions (5.3)]
- Anaphylaxis and Angioedema [
- Warnings and Precautions (5.4)]
- Serious Dermatological Reactions [
- Warnings and Precautions (5.5)]
- Coordination Difficulties [
- Warnings and Precautions (5.6)]
- Hematologic Abnormalities [
- Warnings and Precautions (5.8)]
- Increase in Blood Pressure [
- Warnings and Precautions (5.9)]
6.1 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.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of levetiracetam. 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 marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, 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, weight loss and worsening of seizures. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.
8.4 Pediatric Use
The safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [
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 [
Dosage and Administration (2.2)].
The safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [
Clinical Studies (14.2)].
The safety and effectiveness of levetiracetam 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 [
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 as adjunctive therapy in 98 (levetiracetam N=64, placebo N=34) pediatric patients, ages 4 to 16 years old, 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-treated patients in aggressive behavior, one of the eight syndrome scores [
Warnings and Precautions (5.1)].
8.5 Geriatric Use
There were 347 subjects in clinical studies of levetiracetam that were 65 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 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 [
Clinical Pharmacology (12.3)].
8.6 Renal Impairment
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [
Clinical Pharmacology (12.3)]. Dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [
Dosage and Administration (2.5)].
10.1 Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans
The highest known dose of 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.
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.
Levetiracetam Oral Solution USP is an antiepileptic drug available as a clear, colorless, grape-flavored liquid (100 mg/mL) for oral administration.The chemical name of levetiracetam, a single enantiomer, is (–)–(S)–α–ethyl–2–oxo–1-pyrrolidine acetamide, its molecular formula is C
2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:
Levetiracetam 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 Oral Solution USP contains 100 mg of levetiracetam per mL. Inactive ingredients: acesulfame potassium, artificial grape flavor, citric acid, glycerin, maltitol solution, methylparaben, propylparaben, purified water, and sodium citrate.
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 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.
The pharmacokinetics of levetiracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.
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 effectiveness 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. Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. 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 for Patients with JME in Study 6 Placebo
Percentage of responders23.7%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 effectiveness 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.Table 15: Median Percent Reduction from Baseline in PGTC Seizure Frequency per Week in Study 7 Placebo
Percent reduction in PGTC seizure frequency44.6%77.6%
statistically significant versus placeboThe 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
16.1 How Supplied
Levetiracetam Oral Solution USP 100 mg/mL is a clear, colorless, grape-flavored liquid. It is supplied in the following oral dosage forms:NDC 0121-0799-16:16 fl oz (473 mL) bottleNDC 0121-4799-05:5 mL unit dose cup, in a tray of ten cups.NDC 0121-1598-10: 10 mL unit dose cup, in a tray of ten cups.NDC 0121-2397-15:15 mL unit dose cup, in a tray of ten cups.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure.
17 Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
* Please review the disclaimer below.