Levetiracetam Information
Levetiracetam () Description
Levetiracetam () is an antiepileptic drug available as 250 mg, 500 mg or 750 mg 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 CHNO 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 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 () tablets contain the labeled amount of 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 () Clinical Pharmacology
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.
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, 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.
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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 ).
Levetiracetam () Clinical Studies
In the following studies, statistical significance versus placebo indicates a p value 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.
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.
The comparison of Levetiracetam () 2000 mg/day to Levetiracetam () 1000 mg/day for responder rate was statistically significant (= 0.02). Analysis of the trial as a cross-over yielded similar results.
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.
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.
Levetiracetam () Indications And Usage
Levetiracetam () tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.
Levetiracetam () 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 or oral solution.
Levetiracetam () Warnings
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.
Levetiracetam () Precautions
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.
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Levetiracetam () circulates largely unbound (
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.
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/m basis) did not indicate a potential for age-specific toxicity.
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.
Levetiracetam () 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.
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.
Levetiracetam () Drug Abuse And Dependence
The abuse and dependence potential of Levetiracetam () has not been evaluated in human studies.
Levetiracetam () Dosage And Administration
Levetiracetam () tablets are indicated as adjunctive treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.
Levetiracetam () How Supplied
Levetiracetam () Tablets are available containing 250 mg, 500 mg or 750 mg of Levetiracetam () .
The 250 mg tablets are white, film-coated, round tablets debossed with above the score and below the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-5613-78bottles of 120 tablets
NDC 0378-5613-05bottles of 500 tablets
The 500 mg tablets are white, film-coated, modified capsule-shaped tablets debossed with to the left of the score and to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-5615-78bottles of 120 tablets
NDC 0378-5615-05bottles of 500 tablets
The 750 mg tablets are white, film-coated, modified capsule-shaped tablets debossed with to the left of the score and to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-5617-78bottles of 120 tablets
NDC 0378-5617-05bottles of 500 tablets
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Mylan Pharmaceuticals Inc.Morgantown, WV 26505
REVISED AUGUST 2009LVTC:R5mpbmt
Levetiracetam () Medication Guidelevetiracetam Tablets
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.
Levetiracetam ()
Levetiracetam () Carton
Levetiracetam ()
Tablets
500 mg
QTY 30
Levetiracetam ()
Levetiracetam () Carton
Levetiracetam ()
Tablets
750 mg
QTY 30
