Levetiracetam Tablets (Manufacturer may vary)

DESCRIPTION

Levetiracetam is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (orange), and 1000 mg (white) tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 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 (1040 mg/mL). It is freely soluble in chloroform (653 mg/mL) and in methanol (536 mg/mL), soluble in ethanol (165 mg/mL), sparingly soluble in acetonitrile (57 mg/mL) and practically insoluble in n-hexane. (Solubility limits are expressed as mg/mL solvent.)

Levetiracetam tablets contain the labeled amount of levetiracetam. Inactive ingredients: corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, talc, magnesium stearate and additional agents listed below:

250 mg tablets: opadry II blue (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2/indigo carmine aluminum lake)

500 mg tablets: opadry II yellow (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow)

750 mg tablets:  opadry II orange (polyvinyl alcohol, titanium dioxide,  polyethylene glycol 3350, talc, FD&C yellow # 6/sunset yellow FCF aluminum lake, iron oxide red)

1000 mg tablets: opadry II white (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc)

CLINICAL PHARMACOLOGY

CLINICAL STUDIES

In the following studies, statistical significance versus placebo indicates a p value <0.05.

Effectiveness In Partial Onset Seizures In Adults With Epilepsy

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) 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 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 2.

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 3 displays the results of the analysis of Study 3.

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 With Epilepsy

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs). Eligible patients on a stable dose of 1 to 2 AEDs, who still experienced 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. The enrolled population included 198 patients (levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized. The study consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. 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 effectiveness 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).   Table 4 displays the results of this study.

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)

*statistically significant versus placebo

Effectiveness In Myoclonic Seizures In Patients ≥12 Years Of Age With Juvenile Myoclonic Epilepsy (JME)

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) 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, conducted at 37 sites in 14 countries. Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME. 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. Table 5 displays the results for the 113 patients with JME in this study.

Effectiveness For Primary Generalized Tonic-Clonic Seizures In Patients ≥6 Years Of Age

The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) 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, 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. 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. 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). There was a statistically significant decrease from baseline in PGTC frequency in the levetiracetam-treated patients compared to the placebo-treated patients.

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 5.

Figure 5: Responder Rate (≥50% Reduction From Baseline) In PGTC Seizure Frequency Per Week

*statistically significant versus placebo

INDICATIONS AND USAGE

Levetiracetam Tablet is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.

Levetiracetam Tablet 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.

Levetiracetam Tablet 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.

CONTRAINDICATIONS

This product should not be administered to patients who have previously exhibited hypersensitivity to levetiracetam or any of the inactive ingredients in levetiracetam tablets.

WARNINGS

PRECAUTIONS

Hematologic Abnormalities

Partial Onset Seizures

Adults

Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials.

A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the 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

Minor, but 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 × 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 levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).

In the well-controlled trial, more levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3.0% levetiracetam-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% levetiracetam-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.

Juvenile Myoclonic Epilepsy

Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.

Hepatic Abnormalities

There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

ADVERSE REACTIONS

The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Partial Onset Seizures

In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age with partial onset seizures, the adverse events most frequently reported with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia.

Table 8 lists treatment-emergent adverse events that occurred in at least 1% of adult epilepsy patients treated with levetiracetam participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. Table 9 lists treatment-emergent adverse events that occurred in at least 2% of pediatric epilepsy patients (ages 4 to 16 years) treated with levetiracetam participating in the placebo-controlled study and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.

Table 8: Incidence (%) Of Treatment-Emergent Adverse Events In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 1% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

Other events reported by at least 1% of adult levetiracetam-treated patients but as or more frequent in the placebo group were the following: abdominal pain, accidental injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary tract infection, vomiting and weight gain.

Table 9: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 2% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

Other events occurring in at least 2% of pediatric levetiracetam-treated patients but as or more frequent in the placebo group were the following: abdominal pain, allergic reaction, ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea, otitis media, rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor, and urinary incontinence.

Myoclonic Seizures

Although the pattern of adverse events 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 event pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.

Table 10 lists treatment-emergent adverse events that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.

Table 10: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older With Myoclonic Seizures By Body System (Adverse Events Occurred In At Least 5% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

Other events occurring in at least 5% of levetiracetam-treated patients with myoclonic seizures but as or more frequent in the placebo group were the following: fatigue and headache.

Primary Generalized Tonic-Clonic Seizures

Although the pattern of adverse events 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 event pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures.

In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse event associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.

Table 11 lists treatment-emergent adverse events that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.

Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 4 Years Of Age And Older With PGTC Seizures By MedDRA System Organ Class (Adverse Events Occurred In At Least 5% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

Other events occurring in at least 5% of levetiracetam-treated patients with PGTC seizures but as or more frequent in the placebo group were the following: dizziness, headache, influenza, and somnolence.

Time Course Of Onset Of Adverse Events For Partial Onset Seizures

Of the most frequently reported adverse events in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with levetiracetam.

Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies

Partial Onset Seizures

In well-controlled adult clinical studies, 15.0% of patients receiving levetiracetam and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 12 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction.

Table 12: Adverse Events That Most Commonly Resulted In Discontinuation Or Dose Reduction In Placebo-Controlled Studies In Adult Patients Experiencing Partial Onset Seizures

In the well-controlled pediatric clinical study, 16.8% of patients receiving levetiracetam and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events most commonly associated (≥3% in patients receiving levetiracetam) with discontinuation or dose reduction in the well-controlled study are presented in Table 13.

Table 13: Adverse Events Most Commonly Associated With Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures

Myoclonic Seizures

In the placebo-controlled study, 8.3% of patients receiving levetiracetam and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events that led to discontinuation or dose reduction in the well-controlled study are presented in Table 14.

Table 14: Adverse Events That Resulted In Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Patients With Juvenile Myoclonic Epilepsy

Primary Generalized Tonic-Clonic Seizures

In the placebo-controlled study, 5.1% of patients receiving levetiracetam and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment-emergent adverse event.

This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials.

Comparison Of Gender, Age And Race

The overall adverse experience profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.

Postmarketing Experience

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

In addition to the adverse experiences listed above, the following have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, and weight loss. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of levetiracetam has not been evaluated in human studies.

OVERDOSAGE

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 events 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.

Treatment Or 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.

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.

DOSAGE AND ADMINISTRATION

Levetiracetam Tablet is indicated as adjunctive treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.

Levetiracetam Tablet 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.

Levetiracetam Tablet 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.

Partial Onset Seizures

Adults 16 Years And Older

In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose, a consistent increase in response with increased dose has not been shown.

Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Pediatric Patients Ages 4 To <16 Years

Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). 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 52 mg/kg. Patients with body weight ≤ 20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution. Table 15 below provides a guideline for tablet dosing based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered.

Levetiracetam is given orally with or without food.

Table 15: Levetiracetam Tablet Weight-Based Dosing Guide For Children

The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients based on a daily dose of 20 mg/kg/day, 40 mg/kg/day or 60 mg/kg/day:

A household teaspoon or tablespoon is not an adequate measuring device. It is recommended that a calibrated measuring device be obtained and used. Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and provide instructions for measuring the dosage.

Myoclonic Seizures In Patients 12 Years Of Age And Older With Juvenile Myoclonic Epilepsy

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

Primary Generalized Tonic-Clonic Seizures

Adults 16 Years And Older

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

Pediatric Patients Ages 6 To <16 Years

Treatment should be initiated with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg BID). The daily dose should be increased every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg BID). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied. Patients with body weight ≤ 20 kg should be dosed with oral solution. Patients with body weight above 20 kg can be dosed with either tablets or oral solution. See Table 14 for tablet dosing based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered.

Adult Patients With Impaired Renal Function

Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 16. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:

HOW SUPPLIED

Levetiracetam tablets, 250 mg are blue coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘87’ on other side. They are supplied in containers of

30 tablets (NDC 31722-536-30)
60 tablets (NDC 31722-536-60)
120 tablets (NDC 31722-536-12)
500 tablets (NDC 31722-536-05)
1000 tablets (NDC 31722-536-10)

Levetiracetam tablets, 500 mg are yellow coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘88’ on other side. They are supplied in containers of

30 tablets (NDC 31722-537-30)
60 tablets (NDC 31722-537-60)
120 tablets (NDC 31722-537-12)
500 tablets (NDC 31722-537-05)
1000 tablets (NDC 31722-537-10)

Levetiracetam tablets, 750 mg are orange coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘90’ on other side. They are supplied in containers of

30 tablets (NDC 31722-538-30)
60 tablets (NDC 31722-538-60)
120 tablets (NDC 31722-538-12)
500 tablets (NDC 31722-538-05)

Levetiracetam tablets, 1000 mg are white coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘91’ on other side. They are supplied in containers of

30 tablets (NDC 31722-539-30)
60 tablets (NDC 31722-539-60)
120 tablets (NDC 31722-539-12)
500 tablets (NDC 31722-539-05)

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.

Manufactured for:
Camber Pharmaceuticals, Inc.                                    2007436-00
Piscataway, NJ 08854

By: Hetero Drugs Limited
Jeedimetla, Hyderabad – 500 055, India.

MEDICATION GUIDE

Levetiracetam Tablets
Rx Only

Read this Medication Guide before you start taking levetiracetam and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about levetiracetam?

Like other antiepileptic drugs, levetiracetam may cause suicidal thoughts or actions in a very small number of people, about 1 in 500 people taking it.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

Do not stop levetiracetam without first talking to a healthcare provider.

• Stopping levetiracetam suddenly can cause serious problems. Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus).
• Suicidal thoughts or actions can be caused by things other than medicines.  If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What is levetiracetam?

Levetiracetam is a prescription medicine taken by mouth that is used with other medicines to treat:

• partial onset seizures in people 4 years of age and older with epilepsy
• myoclonic seizures in people 12 years of age and older with juvenile myoclonic epilepsy
• primary generalized tonic-clonic seizures in people 6 years of age and older with certain types of generalized epilepsy.

It is not known if levetiracetam is safe or effective in children under 4 years of age.

Before taking your medicine, make sure you have received the correct medicine. Compare the name above with the name on your bottle and the appearance of your medicine with the description of levetiracetam provided below. Contact your pharmacist immediately if you believe a dispensing error may have occurred.

Levetiracetam tablets, 250 mg are blue coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘87’ on other side.

Levetiracetam tablets, 500 mg are yellow coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘88’ on other side.

Levetiracetam tablets, 750 mg are orange coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘90’ on other side.

Levetiracetam tablets, 1000 mg are white coloured, oblong shaped, scored, film coated tablets debossed with ‘H’ on one side and ‘91’ on other side.

What should I tell my healthcare provider before starting levetiracetam?

• Before taking levetiracetam, tell your healthcare provider about all of your medical conditions, including if you:
• have or have had depression, mood problems or suicidal thoughts or behavior
• have kidney problems
• are pregnant or planning to become pregnant.  It is not known if levetiracetam will harm your unborn baby. You and your healthcare provider will have to decide if you should take levetiracetam while you are pregnant.  If you become pregnant while taking levetiracetam, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry.  You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of levetiracetam and other antiepileptic medicine during the pregnancy.
• are breast feeding. Levetiracetam can pass into your milk and may harm your baby. You and your healthcare provider should discuss whether you should take levetiracetam or breast- feed; you should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.  Do not start a new medicine without first talking with your healthcare provider.

Know the medicines you take.  Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I take levetiracetam?

Take levetiracetam exactly as prescribed.

• Your healthcare provider will tell you how much levetiracetam to take and when to take it. Levetiracetam is usually taken twice a day.  Take levetiracetam at the same times each day.
• Your healthcare provider may change your dose.  Do not change your dose without talking to your healthcare provider.
• Take levetiracetam with or without food.
• Swallow the tablets whole. Do not chew or crush tablets.
• If you miss a dose of levetiracetam, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time.  Do not take two doses at the same time.
• If you take too much levetiracetam, call your local Poison Control Center or go to the nearest emergency room right away.

What should I avoid while taking levetiracetam?

Do not drive, operate machinery or do other dangerous activities until you know how levetiracetam affects you. Levetiracetam may make you dizzy or sleepy.

What are the possible side effects of levetiracetam?

• See “What is the most important information I should know about levetiracetam?”

  Levetiracetam can cause serious side effects.

  Call your healthcare provider right away if you have any of these symptoms:

• mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability.  A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs) and unusual behavior.
• extreme sleepiness, tiredness, and weakness
• problems with muscle coordination (problems walking and moving)

The most common side effects seen in people who take levetiracetam include:

• sleepiness
• weakness
• dizziness
• infection

The most common side effects seen in children who take levetiracetam include, in addition to those listed above:

• accidental injury
• irritability
• hostility

These side effects can happen at any time but happen more often within the first 4 weeks of treatment except for infection.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of levetiracetam.  For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store levetiracetam?

• Store levetiracetam at room temperature, 20°C to 25°C (68°F to 77°F) away from heat and light.
• Keep levetiracetam and all medicines out of the reach of children.

General information about levetiracetam.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.  Do not use levetiracetam for a condition for which it was not prescribed. Do not give levetiracetam to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about levetiracetam. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about levetiracetam that is written for health professionals.

What are the ingredients of levetiracetam?

Levetiracetam tablet active ingredient: levetiracetam

Inactive ingredients: corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, talc, magnesium stearate and additional agents listed below:

250 mg tablets: opadry II blue (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2/indigo carmine aluminum lake)

500 mg tablets: opadry II yellow (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow)

750 mg tablets:  opadry II orange (polyvinyl alcohol, titanium dioxide,  polyethylene glycol 3350, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide red)

1000 mg tablets: opadry II white (polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc)

Levetiracetam does not contain lactose or gluten.

Manufactured for:
Camber Pharmaceuticals, Inc.
Piscataway, NJ 08854

By: Hetero Drugs Limited
Jeedimetla, Hyderabad – 500 055, India.