Mechanism of Action

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain.

In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Levetiracetam at concentrations of up to 10 µM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.

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.

Pharmacokinetics

The pharmacokinetics of levetiracetam have been studied in healthy adult subjects, adults and pediatric patients with epilepsy, elderly subjects and subjects with renal and hepatic impairment.

Overview

Levetiracetam is rapidly and almost completely absorbed after oral administration. Levetiracetam tablets and oral solution are bioequivalent. The pharmacokinetics are linear and time-invariant, with low intra- and inter-subject variability. The extent of bioavailability of levetiracetam is not affected by food. Levetiracetam is not significantly protein bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6 to 8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.

Absorption and Distribution

Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of levetiracetam but it decreases Cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500 mg to 5000 mg. Steady-state is achieved after 2 days of multiple twice-daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

Metabolism

Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the 2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

Elimination

Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug which represents 66% of administered dose. The total body clearance is 0.96 mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with impaired renal function (see Special Populations: Renal Impairment and DOSAGE AND ADMINISTRATION: Adult Patients with Impaired Renal Function).

Pharmacokinetic Interactions

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients (see PRECAUTIONS: Drug Interactions).

Special Populations

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 2 years and had taken two or more classical AEDs. Patients enrolled in Study 3 had refractory partial onset seizures for at least one 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

Figure 1: Responder Rate (≥ 50% Reduction From Baseline) in Study 1

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

Figure 2: Responder Rate (≥ 50% Reduction From Baseline) in Study 2: Period A

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

Figure 3: Responder Rate (≥ 50% Reduction From Baseline) in Study 3

Effectiveness in Partial Onset Seizures in Pediatric Patients with Epilepsy

The effectiveness of levetiracetam tablets 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 one to two AEDs, who still experienced at least four partial onset seizures during the 4 weeks prior to screening, as well as at least four partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either levetiracetam tablets or placebo. The enrolled population included 198 patients (levetiracetam tablets 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 tablets 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)

Figure 4: Responder Rate (≥ 50% Reduction From Baseline)

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 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 to 100 years) in the clinical trials analyzed. Table 5 shows absolute and relative risk by indication for all evaluated AEDs.

The 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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Neuropsychiatric Adverse Events

Withdrawal Seizures

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

Hematologic Abnormalities

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 one (0.07%) adult epilepsy patient receiving open treatment.

Information for Patients

Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking levetiracetam. The Medication Guide may also be found by calling 1-877-446-3679 (1-877-4-INFO-RX). Patients should be instructed to take levetiracetam only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that levetiracetam may cause changes in behavior (e.g., aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.

Patients should be advised that levetiracetam may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their performance of these activities.

Laboratory Tests

Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

Drug Interactions

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

Other Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Pregnancy Registry

To provide information regarding the effects of in utero exposure to levetiracetam, physicians are advised to recommend that pregnant patients taking levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Labor and Delivery

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

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in patients below 4 years of age have not been established.

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

Geriatric Use

Of the total number of subjects in clinical studies of levetiracetam, 347 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.

A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone.

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.

Use in Patients with Impaired Renal Function

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION: Adult Patients with Impaired Renal Function).

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 6 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 7 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.

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.

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.

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

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.

Post-Marketing Experience

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.

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 post-marketing 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.

Partial Onset Seizures

Pediatric Patients Ages 4 to < 16 Years

Treatment should be initiated with a daily dose of 20 mg/kg in two 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 10 below provides a guideline for tablet dosing based on weight during titration to 60 mg/kg/day. Only whole tablets should be administered.

Levetiracetam tablets are given orally with or without food.

Table 10: Levetiracetam Tablet Weight-Based Dosing Guide for Children

Daily Dose
Patient Weight	20 mg/kg/day (BID dosing)	40 mg/kg/day (BID dosing)	60 mg/kg/day (BID dosing)
20.1 to 40 kg	500 mg/day (1 x 250 mg tablet BID)	1000 mg/day (1 x 500 mg tablet BID)	1500 mg/day  (1 x 750 mg tablet BID)
> 40 kg	1000 mg/day (1 x 500 mg tablet BID)	2000 mg/day (2 x 500 mg tablets BID)	3000 mg/day (2 x 750 mg tablets BID)

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.

Adult Patients with Impaired Renal Function

Levetiracetam tablets dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 11. 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:

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

Like other antiepileptic drugs, levetiracetam tablets 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:

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thoughts about suicide or dying

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attempts to commit suicide

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new or worse depression

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new or worse anxiety

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feeling agitated or restless

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panic attacks

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trouble sleeping (insomnia)

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new or worse irritability

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acting aggressive, being angry, or violent

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acting on dangerous impulses

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an extreme increase in activity and talking (mania)

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other unusual changes in behavior or mood

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

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Stopping levetiracetam tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus).

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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.

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Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What are levetiracetam tablets?

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

•

partial onset seizures in people 4 years of age and older with epilepsy

It is not known if levetiracetam tablets are 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 tablets provided below. Contact your pharmacist immediately if you believe a dispensing error may have occurred.

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250 mg levetiracetam tablets are white, film-coated, round tablets debossed with M above the score and 613 below the score on one side of the tablet and blank on the other side.

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500 mg levetiracetam tablets are white, film-coated, modified capsule-shaped tablets debossed with M to the left of the score and 615 to the right of the score on one side of the tablet and blank on the other side.

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750 mg levetiracetam tablets are white, film-coated, modified capsule-shaped tablets debossed with M to the left of the score and 617 to the right of the score on one side of the tablet and blank on the other side.

What should I tell my healthcare provider before starting levetiracetam tablets?

Before taking levetiracetam tablets, tell your healthcare provider about all of your medical conditions, including if you:

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have or have had depression, mood problems or suicidal thoughts or behavior

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have kidney problems

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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 tablets while you are pregnant. If you become pregnant while taking levetiracetam tablets, 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 tablets and other antiepileptic medicine during 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 tablets 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 tablets?

Take levetiracetam tablets exactly as prescribed.

•

Your healthcare provider will tell you how much levetiracetam to take and when to take it. Levetiracetam tablets are usually taken twice a day. Take levetiracetam tablets at the same times each day.

•

Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.

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Take levetiracetam tablets with or without food.

•

Swallow the tablets whole. Do not chew or crush tablets. Ask your healthcare provider for levetiracetam oral solution if you cannot swallow tablets.

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If your healthcare provider has prescribed levetiracetam oral solution, be sure to ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of levetiracetam oral solution. Do not use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.

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If you miss a dose of levetiracetam tablets, 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 tablets?

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

What are the possible side effects of levetiracetam tablets?

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

Levetiracetam tablets can cause serious side effects.

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

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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.

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extreme sleepiness, tiredness, and weakness

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problems with muscle coordination (problems walking and moving)

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

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sleepiness

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weakness

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dizziness

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infection

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

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accidental injury

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irritability

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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 tablets. 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 tablets?

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Store levetiracetam tablets at room temperature away from heat and light.

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Keep levetiracetam tablets and all medicines out of the reach of children.

General information about levetiracetam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levetiracetam tablets for a condition for which they were not prescribed. Do not give levetiracetam tablets 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 tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about levetiracetam tablets that is written for health professionals. You can also call 1-877-446-3679 (1-877-4-INFO-RX) for more information.

What are the ingredients of levetiracetam tablets?

Levetiracetam tablets active ingredient: levetiracetam.

Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, titanium dioxide and triacetin.

Levetiracetam tablets do not contain lactose or gluten.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED AUGUST 2009
MG:LVTC:R2

Levetiracetam tablets 500 mg and 750 mg are available from Cardinal Health in

unit dose cartons of 30.

Cardinal Health

Zanesville, OH 43701

OI83850910