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These highlights do not include all the information needed to use levetiracetam extended-release tablets safely and effectively. See full prescribing information for levetiracetam extended-release tablets.LEVETIRACETAM extended-release tablets for oral u | Levetiracetam

05:56 EDT 27th August 2014 | BioPortfolio
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Levetiracetam extended-release tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥ 16 years of age with epilepsy.

Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg.

Levetiracetam extended-release tablet dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the patient's creatinine clearance (CL) in mL/min is needed. CL in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:

IMAGE aa3d7428-41d2-4a29-9622-34dcd69fd742-01.jpg
Table 1: Dosing Adjustment Regimen For Adult Patients With Impaired Renal Function
Group Creatinine Clearance (mL/min/1.73 m2) Dosage (mg) Frequency
Normal > 80 1000 to 3000 Every 24 h
Mild 50 to 80 1000 to 2000 Every 24 h
Moderate 30 to 50 500 to 1500 Every 24 h
Severe < 30 500 to 1000 Every 24 h

Levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release tablets imprinted with “TV/7795” with black ink on one side and plain on the other and contain 500 mg levetiracetam.

Levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release tablets imprinted with “TV/7796” with black ink on one side and plain on the other and contain 750 mg levetiracetam.

None

Antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 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 extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior 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.

Table 2 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

L evetiracetam Extended-Release Tablets

In some patients experiencing partial onset seizures, levetiracetam extended-release tablets cause somnolence, dizziness, and behavioral abnormalities.

In the levetiracetam extended-release tablet double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of levetiracetam extended-release tablet-treated patients experienced somnolence compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of levetiracetam extended-release tablet-treated patients compared to 2.5% of placebo-treated patients.

A total of 6.5% of levetiracetam extended-release tablet-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of levetiracetam extended-release tablet-treated patients. Aggression was reported in 1.3% of levetiracetam extended-release tablet-treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablet controlled trials may also occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release L evetiracetam Tablets

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, immediate-release levetiracetam tablets cause the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of immediate-release levetiracetam tablet-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients.

A total of 3.4% of immediate-release levetiracetam tablet-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients.

Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-release levetiracetam tablet-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient.

A total of 13.3% of immediate-release levetiracetam tablet patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.

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

Although there were no obvious hematologic abnormalities observed in treated patients in the levetiracetam extended-release tablet controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release levetiracetam tablet controlled studies should be considered to be relevant for levetiracetam extended-release tablet-treated patients.

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10/mm), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam tablet-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤ 2.8 x 10/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤ 1.0 x 10/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.

There were no meaningful changes in mean liver function tests (LFT) in the levetiracetam extended-release tablet controlled trial. No patients were discontinued from the controlled trial for LFT abnormalities.

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

Although effects on laboratory tests were not clinically significant with levetiracetam extended-release tablet treatment, it is expected that the data from immediate-release levetiracetam tablets controlled studies would be considered relevant for levetiracetam extended-release tablet-treated patients.

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The prescriber should be aware that the adverse reaction incidence figures in the following table, obtained when levetiracetam extended-release tablets were 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 reaction incidences in the population studied.

Levetiracetam Extended-Release Tablets

In the well-controlled clinical study using levetiracetam extended-release tablets in patients with partial onset seizures, the most frequently reported adverse reactions in patients receiving levetiracetam extended-release tablets in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were irritability and somnolence.

Table 3 lists treatment-emergent adverse reactions that occurred in at least 5% of epilepsy patients treated with levetiracetam extended-release tablets participating in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either levetiracetam extended-release tablets or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Discontinuation Or Dose Reduction In The Levetiracetam Extended-Release Tablets Well-Controlled Clinical Study

In the well-controlled clinical study using levetiracetam extended-release tablets, 5.2% of patients receiving levetiracetam extended-release tablets and 2.5% receiving placebo discontinued as a result of an adverse event. The adverse reactions that resulted in discontinuation and that occurred more frequently in levetiracetam extended-release tablet-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash and respiratory failure. Each of these adverse reactions led to discontinuation in a levetiracetam extended-release tablet-treated patient and no placebo-treated patients.

Comparison Of Gender, Age And Race

There are insufficient data for levetiracetam extended-release tablets to support a statement regarding the distribution of adverse experience reports by gender, age and race.

Table 4 lists the adverse reactions seen in the well-controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the levetiracetam extended-release tablet study seems somewhat different from that seen in partial onset seizure well-controlled studies for immediate-release levetiracetam tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for levetiracetam extended-release tablets are expected to be similar to those seen with immediate-release levetiracetam tablets.

Immediate-Release Levetiracetam Tablets

In well-controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most frequently reported adverse reactions, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness.

Table 4 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with immediate-release levetiracetam tablets participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

In addition, the following adverse reactions were seen in other well-controlled studies of immediate-release levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and vision blurred.

Table 3: Incidence (%) of Treatment-Emergent Adverse Reactions in the Placebo-Controlled, Add-on Study by Body System (Adverse Reactions Occurred in at Least 5% of Levetiracetam Extended-Release Tablet-Treated Patients and Occurred More Frequently Than Placebo-Treated Patients)
Body System/ Adverse Reaction Levetiracetam E xtended-Release Tablets (N = 77) % Placebo (N = 79) %
Gastrointestinal Disorders    
Nausea 5 3
Infections and Infestations    
Influenza 8 4
Nasopharyngitis 7 5
Nervous System Disorders    
Somnolence 8 3
Dizziness 5 3
Psychiatric Disorders    
Irritability 7 0
Table 4: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-on Studies in Adults Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in at Least 1% of Immediate-Release Levetiracetam Tablet-Treated Patients and Occurred More Frequently Than Placebo-Treated Patients)
Body System/ Adverse Reaction Immediate-Release Levetiracetam Tablets (N = 769) % Placebo (N = 439) %
Body as a Whole    
Asthenia 15 9
Headache 14 13
Infection 13 8
Pain 7 6
Digestive System    
Anorexia 3 2
Nervous System    
Somnolence 15 8
Dizziness 9 4
Depression 4 2
Nervousness 4 2
Ataxia 3 1
Vertigo 3 1
Amnesia 2 1
Anxiety 2 1
Hostility 2 1
Paresthesia 2 1
Emotional Lability 2 0
Respiratory System    
Pharyngitis 6 4
Rhinitis 4 3
Cough Increased 2 1
Sinusitis 2 1
Special Senses    
Diplopia 2 1

In addition to the adverse reactions listed above for immediate-release levetiracetam tablets [see Adverse Reactions (6.1)], the following adverse events have been identified during postapproval use of immediate-release levetiracetam tablets. 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 causal relationship to drug exposure. 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 immediate-release levetiracetam tablet use; recovery was observed in majority of cases where immediate-release levetiracetam tablets were discontinued.

In vitro data on metabolic interactions indicate that levetiracetam extended-release tablets are unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C 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 with immediate-release levetiracetam tablets in the placebo-controlled clinical studies in epilepsy patients. The following are the results of these studies. The potential for drug interactions for levetiracetam extended-release tablets is expected to be essentially the same as that with immediate-release levetiracetam tablets.

Immediate-release levetiracetam tablets (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.

Immediate-release levetiracetam tablets (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.

Potential drug interactions between immediate-release levetiracetam tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.

Immediate-release levetiracetam tablets (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.

Immediate-release levetiracetam tablets (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Immediate-release levetiracetam tablets (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. C of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of immediate-release levetiracetam tablets on probenecid was not studied.

Teratogenic Effects

Pregnancy category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥ 350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m basis). There was no overt maternal toxicity at the doses used in this study.

Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥ 600 mg/kg/day (approximately 4 times MRHD on a mg/m basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m basis). Maternal toxicity was also observed at 1800 mg/kg/day.

When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.

Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at oral doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m basis).

Pregnancy Registry

To provide information regarding the effects of in utero exposure to levetiracetam extended-release tablets, physicians are advised to recommend that pregnant patients taking levetiracetam extended-release tablets 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/.

The effect of levetiracetam extended-release tablets on labor and delivery in humans is unknown.

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

Safety and effectiveness of levetiracetam extended-release tablets in patients below the age of 16 years have not been established.

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam extended-release tablets in these patients. It is expected that the safety of levetiracetam extended-release tablets in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release levetiracetam tablets.

Of the total number of subjects in clinical studies of immediate-release levetiracetam tablets, 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 immediate-release levetiracetam tablets 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 of immediate-release levetiracetam tablets 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.

The effect of levetiracetam extended-release tablets on renally impaired patients was not assessed in the well-controlled study. However, it is expected that the effect on levetiracetam extended-release tablet-treated patients would be similar to the effect seen in well-controlled studies of immediate-release levetiracetam tablets. 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 extended-release tablets [see Clinical Pharmacology (12.3) and Dosage and Administration (2.1)].

Clearance of immediate-release levetiracetam tablets is decreased in patients with renal impairment and is correlated with creatinine clearance.

The abuse and dependence potential of levetiracetam extended-release tablets has not been evaluated in human studies.

Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans

The signs and symptoms for levetiracetam extended-release tablet overdose are expected to be similar to those seen with immediate-release levetiracetam tablets.

The highest known dose of oral immediate-release levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release levetiracetam tablet overdoses in postmarketing use.

Treatment Or Management Of Overdose

There is no specific antidote for overdose with levetiracetam extended-release tablets. 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 extended-release tablets.

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.

Levetiracetam extended-release tablets are an antiepileptic drug available as 500 mg and 750 mg (white) extended-release tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:

CHNO M.W. 170.21

Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.)

Levetiracetam extended-release tablets contain the labeled amount of levetiracetam. Inactive ingredients: dibutyl sebacate, ethylcellulose, hydrogenated castor oil powder, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide. The imprinting ink contains iron oxide black and shellac glaze.

IMAGE aa3d7428-41d2-4a29-9622-34dcd69fd742-02.jpg

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.

Overview

Bioavailability of levetiracetam extended-release tablets is similar to that of the levetiracetam immediate-release tablets. The pharmacokinetics (AUC and C) were shown to be dose proportional after single dose administration of 1000 mg, 2000 mg, and 3000 mg extended-release levetiracetam. Plasma half-life of extended-release levetiracetam is approximately 7 hours.

Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra- and inter-subject variability. 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. The half-life is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment.

Absorption and Distribution

Extended-release levetiracetam peak plasma concentrations occur in about 4 hours. The time to peak plasma concentrations is about 3 hours longer with extended-release levetiracetam than with immediate-release tablets.

Single administration of two 500 mg extended-release levetiracetam tablets once daily produced comparable maximal plasma concentrations and area under the plasma concentration versus time as did the administration of one 500 mg immediate-release tablet twice daily in fasting conditions. After multiple dose extended-release levetiracetam tablets intake, extent of exposure (AUC) was similar to extent of exposure after multiple dose immediate-release tablets intake. C and C were lower by 17% and 26% after multiple dose extended-release levetiracetam tablets intake in comparison to multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the administration of extended-release levetiracetam tablets resulted in a higher peak concentration, and longer median time to peak. The median time to peak (T) was 2 hours longer in the fed state.

Two 750 mg extended-release levetiracetam tablets were bioequivalent to a single administration of three 500 mg extended-release levetiracetam tablets.

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 Use in Specific Populations (8.6) and Dosage and Administration (2.1)].

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 C 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. The pharmacokinetics of immediate-release levetir

Manufacturer

Physicians Total Care, Inc.

Active Ingredients

Source

Drugs and Medications [78 Associated Drugs and Medications listed on BioPortfolio]

Levetiracetam [Mutual Pharmaceutical Company, Inc.]

These highlights do not include all the information needed to use extended-release levetiracetam tablets safely and effectively. See full prescribing information for extended-release levetiracetam tab...

Levetiracetam [Lupin Pharmaceuticals, Inc]

Levetiracetam Tablets 1000 mg

Levetiracetam [Actavis Mid Atlantic LLC]

Levetiracetam Oral Solution 100 mg/mL

Levetiracetam [American Health Packaging]

Levetiracetam Tablets 1000 mg

Levetiracetam [VistaPharm, Inc]

LEVETIRACETAM ORAL SOLUTION 100 mg/mL

Clinical Trials [116 Associated Clinical Trials listed on BioPortfolio]

Levetiracetam for Treatment of Pain Associated With Fibromyalgia

The purpose of this study is to assess the safety and effectiveness of levetiracetam in reducing the pain of fibromyalgia when compared to placebo. Levetiracetam, an anti-seizure drug, is...

Safety Study Of Intravenous Levetiracetam

The test article for this study is levetiracetam (Keppra, which is commercially available. Keppra is indicated for use as adjunctive therapy in the treatment of partial onset seizure disor...

Follow up Trial for Keppra (Levetiracetam) as Monotherapy in Patients With Newly Diagnosed Epilepsy Coming From N01175 (NCT00175903).

For ethical reasons to give opportunity for adult subjects (≥16 or 18 years) suffering from newly diagnosed epilepsy who completed the therapeutic confirmatory, open-label trial N01175 (...

Safety and Tolerability Study of Levetiracetam to Treat Patients With Status Epilepticus

The purpose of this study is to determine whether levetiracetam is safe and well tolerated by patients while suffering a status epilepticus. Levetiracetam is added to the standard treatmen...

A Bioequivalence Study of Levetiracetam Versus Keppra

The purpose of this study is to assess the bioequivalence of Levetiracetam versus Keppra administered under fasting conditions to healthy adult subjects.

PubMed Articles [41 Associated PubMed Articles listed on BioPortfolio]

Levetiracetam Versus Phenytoin for Seizure Prophylaxis Following Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Seizure following traumatic brain injury (TBI) constitutes a common complication that requires effective prevention to improve the outcome of TBI. Phenytoin has been the only recommended antiepileptic...

Levetiracetam and Valproate Retention Rate in Juvenile Myoclonic Epilepsy.

Valproic acid (VPA) is an effective treatment in juvenile myoclonic epilepsy (JME), but concerns on its use during pregnancy are remarkable. Levetiracetam (LEV) is approved as second-line therapy, and...

The efficacy, tolerability and safety of levetiracetam therapy in a pediatric population.

The purpose of this study was to assess the efficacy and safety of levetiracetam monotherapy in a pediatric population.

Levetiracetam for seizure prevention in brain tumor patients: a systematic review.

Seizures are common complications for patients with brain tumors. No clear evidence exists regarding the use of antiepileptic agents for prophylactic use yet newer agents are being favoured in many cl...

A New SV2A Ligand for Epilepsy.

Since the 1970s, racetams have been in use as cognitive enhancers. Levetiracetam was discovered to have antiseizure activity in animal models and was then found to bind to SV2A in synaptic and endocri...

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Epilepsy
Epilepsy is defined as a disorder of brain function characterized by recurrent seizures that have a sudden onset.  (Oxford Medical Dictionary).  A seizure is caused by a sudden burst of excess electrical activity in the brain, causing a tempora...


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