Kepreptol

Levetiracetam.

Each film-coated tablet contains: Levetiracetam (USP) 500 mg.

Pharmacology: Pharmacodynamics: Effects on QTc Interval: The effect of levetiracetam on QTc (corrected Q-T interval) prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of Levetiracetam (1000 mg or 5000 mg) in 52 healthy subjects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 milliseconds. Therefore, there was no evidence of significant QTc prolongation in this study.
Pharmacokinetics: 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 (maximum peak concentration) by 205 and delays Tmax (maximum peak time) by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500 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 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-pyrroliding 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 secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with renal impairment [see Patients with Impaired Renal Function under Dosage & Administration].
Specific Populations: Elderly: Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age 61 to 88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.
Pediatric Patients: Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6 to 12 years) after single dose (20 mg/kg). The body weight adjusted apparent clearance of levetiracetam was approximately 40% higher than in adults. A repeat dose pharmacokinetic study was conducted in pediatric patients (age 4 to 12 years) at doses of 20 mg/kg/day, 40 mg/kg/day, and 60 mg/kg/day. The evaluation of the pharmacokinetic profile of levetiracetam and its metabolite (ucb L057) in 14 pediatric patients demonstrated rapid absorption of levetiracetam at all doses with a Tmax of about 1 hour and a t 1/2 of 5 hours across the three dosing levels. The pharmacokinetics of levetiracetam in children was linear between 20 to 60 mg/kg/day. The potential interaction of levetiracetam with other AEDs was also evaluated in these patients. Levetiracetam had no significant effect on the plasma concentrations of carbamazepine, valproic acid, topiramate or lamotrigine. However, there was about a 22% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing AED (e.g. carbamazepine).
Following single dose administration (20 mg/kg) of a 10% oral solution to children with epilepsy (1 month to < 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 mL/min/kg) than for adults (0.96 mL/min/kg). Population pharmacokinetic analysis showed that body weight was significantly correlated to the clearance of levetiracetam in pediatric patients; clearance increased with an increase in body weight.
Pregnancy: Levetiracetam levels may decrease during pregnancy.
Gender: Levetiracetam Cmax and AUC were 20% higher in women (N=11) compared to men (N=12). However, clearances adjusted for body weight were comparable.
Race: Formal pharmacokinetic studies of the effects of race have not been conducted. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of levetiracetam were comparable between the two races. Because levetiracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.
Renal Impairment: The disposition of levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal function by 40% in the mild group (CLcr = 50 to 80 mL/min), 50% in the moderate group (CLcr = 30 to 50 mL/min) and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is correlated with creatinine clearance. In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure [see DOSAGE & ADMINISTRATION].
Hepatic Impairment: In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment.
Toxicology: In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses. Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥ 350 mg/kg/day and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day. There was no overt maternal toxicity at the doses used in this study. Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥ 600 mg/kg/day and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day. The developmental no effect dose was 200 mg/kg/day. Maternal toxicity was also observed at 1800 mg/kg/day. When pregnant rats were treated 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. 1200 mg/kg/day was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day.
Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on an mg/m basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on an mg/m or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on an mg/m or exposure basis).

Levetiracetam is indicated as monotherapy in the treatment of: partial onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
Levetiracetam is indicated as adjunctive therapy in the treatment of: partial onset seizures with or without secondary generalization in adults and children from 4 years of age with epilepsy; myoclonic seizures in adults, adolescents and children from 12 years of age with juvenile myoclonic epilepsy; and primary generalized tonic-clonic seizures in adults and adolescents from 4 years of age with idiopathic generalized epilepsy.
Levetiracetam concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.

The film-coated tablets must be taken orally, swallowed with a sufficient quantity of water and may be taken with or without food. The daily dose is administered in 2 equally divided doses. Levetiracetam treatment can be started by oral administration. In case that the route of administration is changed from intravenous to oral or inversely, it can be directly administered without dose titration, but total daily dose and dose frequency should be kept.
Monotherapy: Adults and Adolescents (16 years and older): Recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after 2 weeks. The dose can be further increased by 500 mg a day [250 mg, twice daily] every 2 weeks depending upon the clinical response. The maximum dose is 3000 mg [1500 mg twice daily].
Add-on Therapy: Partial seizures: Adults (≥18 year) and Adolescents (12-17 years) of ≥50 kg: The initial therapeutic dose is 500 mg, twice daily. Depending upon the clinical response and tolerance, the daily dose can be increased up to 3000 mg/day. Dose changes can be made in 1000 mg/day increments or decrements every 2-4 weeks.
Adolescents (12-17 years) and Children (4-11 years) of <50 kg: Initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 60 mg/kg/day [30 mg/kg twice daily]. Dose changes should not exceed increments or decrements of 10 mg/kg twice daily every 2 weeks. The lowest effective dose should be used, Dosage in children ≥50 kg is the same as in adults. (See Table 1.)

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Myoclonic Seizures In Pediatric Patients (12 Years of age and older): Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.
Primary generalized tonic-clonic seizures (12 Years of age and older): Adults (≥18 years) and adolescents (12-17 years) weighing more than 50 kg or more: Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg BID). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg [1,500 mg, BID]. The effectiveness of doses lower than 3000 mg/day has not been studied.
Adolescents (12-17 years) of <50 kg: Treatment should be initiated with a daily dose of 20 mg/kg, given as twice-daily dosing (10 mg/kg, BID). Additional dosing increments may be given at 20 mg/kg/day (10 mg/kg, BID) additional every 2 weeks to a maximum recommended daily dose of 60 mg/kg [30 mg/kg, BID]. The effectiveness of doses lower than 60 mg/day has not been studied.
Patients with Impaired Renal Function: Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in the following table. 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. (See Equation 1 and Table 2.)

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The CLcr in mL/min/1.73 m² may be estimated from serum creatinine (mg/dL) determination, for young adolescents, children and infants, using the following formula: See Equation 2.

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Ks = 0.45 in Term infants to 1 year old; ks = 0.55 in Children to less than 13 years and in adolescent female; ks = 0.7 in adolescent male. (See Table 3.)

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Patients with Hepatic Impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the CrCl may underestimate the renal insufficiency. Therefore, a 50% reduction of the daily maintenance dose is recommended when the CrCl is <60 mL/min/1.73 m².
Children: The safety and efficacy of oral Levetiracetam product has not been thoroughly assessed in infants aged less than 1 year. The tablet formulation is not adapted for use in children under the age of 4 years and a Levetiracetam oral solution is used in infants older than 1 month of age. Because safety and efficacy of Levetiracetam injection in children below 16 years of age, it is not recommended.
Elderly (from 65 years old): Adjustment of the dose is recommended in the elderly patients with compromised renal function.

Signs, Symptoms And Laboratory Findings of Acute Overdose age In Humans: Somnolence, agitation, aggression, and depressed level of consciousness, respiratory depression and coma were observed with Levetiracetam overdoses.
Treatment or Management of Overdose: After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for Levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60% for Levetiracetam and 74% for the primary metabolite.

Patients who have previously exhibited hypersensitivity to levetiracetam or any of the inactive ingredients.
This drug contains lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including this drug, 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. 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.
Psychiatric Reactions: Partial onset seizure: Adults: In adults experiencing partial onset seizures, levetiracetam use is associated with the occurrence of central nervous system adverse events that can be classified into the following categories 1) Somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.
Pediatric Patients: In pediatric patients experiencing partial onset seizures, Levetiracetam is associated with somnolence, fatigue, and behavioral abnormalities.
Primary generalized tonic-clonic seizures: This drug is associated with behavioral disorders in patients 6 years of age and older with primary generalized tonic-clonic seizures.
Discontinuation: To minimize increasing the seizure onset frequency, if Antiepileptic drugs (AEDs), including this drug, has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg:500 mg decreases twice daily every two to four weeks; in children, dose decrease should not exceed 10 mg/kg twice daily every two weeks).

Caution is exercised in the following patients: Suicide, suicide attempt and suicidal ideation have been reported in patients treated with levetiracetam. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.
The administration of Levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see Dosage & Administration).
This drug contains Yellow No.5 (Sunset yellow FCF). This drug should be carefully used to patients who have a hypersensitivity to the component or history of allergy.
General Caution: 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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, eg. Driving vehicles or operating machinery.
Use in Children: Safety and effectiveness of oral preparation in patients below 1 month of age have not been established. The tablet formulation is not adapted for use in infants and children under the age of 4 years and the liquid formulation should be used in children older than 1 month of age. Safety and effectiveness of injection in patients below 16 years of age have not been established.
Use in the Elderly: 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 61-88 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.

Pregnancy: Post marketing data from several prospective pregnancy registries have documented outcomes in over 1000 women exposed to levetiracetam monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk for major congenital malformations, although a teratogenic risk cannot be completely excluded. Therapy with multiple antiepileptic medicinal products is associated with a higher risk of congenital malformations than monotherapy and therefore monotherapy should be considered. Studies in animals have shown Reproductive toxicity.
Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary. As with other antiepileptic medicinal products, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the fetus.
Lactation: Levetiracetam is excreted in human breast milk. Therefore, breast feeding is not recommended. However, if levetiracetam treatment is needed during breast feeding, the benefit/risk of the treatment should be weighed considering the importance of breast feeding.

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 of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Neuropsychiatric Adverse Events: Partial Onset Seizures: Adults: Somnolence and fatigue: In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of 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 a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of Levetiracetam tablet-treated patients discontinued treatment due to somnolence and 1.4% of treated patients reduced the dose. (0.7% and 0.9% in the placebo patients, respectively) 0.3% of Levetiracetam tablet treated patients were hospitalized due to somnolence. In non-comparative, phase 3 clinical trials of patients with epilepsy experiencing uncontrolled partial onset seizures (n=100), incidence of somnolence was 36.0 % (36/100), that was incidence (18.8%) in the same designed foreign non-comparative, clinical trial (n=1541). 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. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced.
Coordination difficulties: A total of 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of preexisting ataxia.
Behavioral abnormalities: In controlled trials of patients with epilepsy experiencing psychotic symptoms, 5 (0.7%) of Levetiracetam tablet treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) Levetiracetam tablet-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1-5 months and resolved within 2-7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of Levetiracetam tablet patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) (6.2% of placebo patients). Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events and the treatment dose was reduced in 0.8% of treated patients (0.2% and 0.5% of placebo patients, respectively). A total of 0.8% of treated patient behavioral event (0.2% of placebo patients) and were had a serious behavioral event (0.2% of placebo patients) hospitalized. 4 (0.5%) of Levetiracetam tablet treated patients experienced suicidal attempt (0% of placebo patients). One patient committed suicide. The other 3 patients didn't discontinue therapy or didn't reduce the dose, due to adverse reaction. Such adverse reaction occurred after treatment during 4 weeks~6 months.
Pediatric Patients: Somnolence and fatigue: In the double-blind, controlled trial in children with epilepsy experiencing partial onset seizures, 22.8 % of Levetiracetam-treated patients experienced somnolence, compared to 11.3% of placebo patients. The design of the study prevented accurately assessing dose-response effects. No patients discontinued treatment for somnolence. In about 3.0% of Levetiracetam-treated patients and in 3.1% of placebo patients the dose was reduced as a result of somnolence.
Asthenia: Asthenia was reported in 8.9% of Levetiracetam-treated patients, compared to 3.1% of placebo patients. No patient discontinued treatment for asthenia, but asthenia led to a dose reduction in 3.0% of Levetiracetam treated patients compared to 0% of placebo patients.
Behavioral abnormalities: A total of 37.6% of the Levetiracetam-treated patients experienced behavioral symptoms (reported as agitation, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesia, nervousness, neurosis, and personality disorder) (18.6% of placebo patients). One Levetiracetam-treated patients experienced suicidal ideation. (See Table 4.)

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A total of 3.0% of Levetiracetam-treated patients discontinued treatment due to psychotic and nonpsychotic adverse events, compared to 4.1% of placebo patients. Overall, 10.9% of Levetiracetam-treated patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients.
Primary Generalized Tonic-Clonic Seizures: Primary generalized Tonic: In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of Levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the Levetiracetam-treated patients compared to 3.6% of placebo patients. Of the Levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (including anger, apathy, depression, mood altered, mood swings, negativism, and tearfulness) occurred in 12.7% of Levetiracetam-treated patients compared to 8.3% of placebo patients. No Levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One Levetiracetam-treated patients experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of Levetiracetam.
In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to Levetiracetam discontinuation. The other case was described as worsening of preexistent schizophrenia and did not lead to drug discontinuation.
Adverse reactions from controlled clinical studies: Levetiracetam has been administered to >3000 subjects and patients. One thousand and twenty three (1,023) patients with epilepsy participated in controlled clinical studies.
Pooled safety data from these studies conducted in adult patients showed that 46.4% and 42.2% of the patients experienced adverse reactions in the Levetiracetam and placebo groups, respectively, and that 2.4% and 2% of the patients experienced serious adverse reactions in the Levetiracetam and placebo groups, respectively. The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no evidence of dose-response relationship but incidence and severity of the CNS-related adverse reactions decreased over time.
In monotherapy, 49.8% of the subjects experienced at least 1 adverse reaction. The most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in pediatric patients (4-16 years) showed that 55.4% of the patients in the Levetiracetam group and 40.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in 0% of the patients in the Levetiracetam group and 1% of the patients in the placebo group. The most commonly reported adverse reactions were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the pediatric population. Safety results in pediatric patients were consistent with the safety profile of Levetiracetam in adults except for behavioral and psychiatric adverse reactions which were more common in children than in adults (38.6% vs 18.6%). However, the relative risk was similar in children as compared to adults.
A study conducted in pediatric patients (1 month to <4 years) with partial onset seizures showed that 21.7% of the patients in the LEV group and 7.1% of the patients in the placebo group experienced adverse reactions. No serious adverse reactions were experienced in patients in the LEV or placebo group. During the long-term follow-up study N01148, the most frequent adverse reactions in the 1-month to <4-year group were irritability (7.9%), convulsion (7.2%), somnolence (6.6%), psychomotor hyperactivity (3.3%), sleep disorder (3.3%), and aggression (3.3%). Safety results in pediatric patients were consistent with the safety profile of Levetiracetam in older children 4-16 years.
A study conducted in adults and adolescents with myoclonic seizures (12-65 years) showed that 33.3% of the patients in the Levetiracetam group (30% of the patients in the placebo group) experienced adverse reactions. The most commonly reported adverse reactions were headache and somnolence. The incidence of adverse reactions in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% vs 46.4%).
A study conducted in adults and children (4-65 years) with idiopathic generalized epilepsy with primary generalized tonic-clonic seizures showed that 39.2% of the patients in the Levetiracetam group and 29.8% of the patients in the placebo group experienced adverse reactions. The most commonly reported adverse reaction was fatigue.
The most commonly reported adverse reactions with LEV IV solution were headache and dizziness.
Adverse reactions reported in clinical studies (adults and children) are listed in the following table per System Organ Class and per frequency. The frequency is defined as follows: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000) and very rare (<1/10,000). (See Table 5.)

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Adverse reactions from domestic post marketing surveillance in post marketing surveillance, adverse reactions of Nervous system disorders and Psychiatric disorders have been most frequently reported. The following adverse reactions have been additionally reported in post marketing surveillance. (See Table 6.)

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Domestic post marketing surveillance of Levetiracetam tablet and liquid products. In domestic post marketing surveillance for 4,896 patients over 6 years for re-evaluation, onset of AEs was 7.76% (n: 380/4896, 438 cases), with or without causality. Major AE was somnolence 2.23% (n: 109/4896, 110 cases), convulsion 1.21% (n: 59/4896, 59 cases), dizziness 1.04% (n: 51/4896, 52 cases), and headache 0.59% (n: 29/4896, 30 cases). Most of AEs were mild or moderate.
Onset of ADE whose causality with this drug cannot be excluded was 7.25% (n: 355/4896, 406 cases), major ADR was somnolence 2.23% (n: 109/4896, 110 cases), convulsion 1.06% (n: 52/4896, 52 cases), dizziness 0.98% (n: 48/4896, 49 cases), headache and hypersensitivity, 0.49% respectively (n: 24/4896, 25 cases).
As serious ADE, suicide attempt and sepsis have been reported one case respectively. Onset of ADE whose causality with this drug cannot be excluded was suicide attempt that has been reported one case.
Onset of unexpected AE was 0.39% (n: 19/4896, 20 cases), including constipation, palpitation, aphasia, dyskinesia, impulsive act, psychomotor retardation, edema, cheilitis, abdominal distension, GI disorder, salivation, urticaria, sepsis, Musculoskeletal stiffness, neck pain, urinary frequency and dyspnea have been reported.

Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown. 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.
Other Antiepileptic Drugs: Potential drug interactions between Levetiracetam and other AEDs (phenytoin, carbamazepine, valproate, phenobarbital, lamotrigine, gabapentin and primidone) 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.
Oral Contraceptives: Levetiracetam (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. Co-administration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.
Digoxin: Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Co-administration of digoxin did not influence the pharmacokinetics of levetiracetam.
Warfarin: Levetiracetam (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Co-administration of warfarin did not affect the pharmacokinetics of levetiracetam.
Probenecid: 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. Cssmax 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.
DRURenal 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 levetiracetam on probenecid was not studied.
Pharmacokinetics of levetiracetam in pediatric patients: As in adults, there is no evidence of clinically significant medicinal product interactions in pediatric patients receiving up to 60 mg/kg/day levetiracetam. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 22% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
Others: No data on the influence of antacids on the absorption of levetiracetam are available. The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

Cautions on Application: To prevent accidental use and to keep the drug quality, keep in the original container.

Store at temperatures not exceeding 30°C.
Shelf-Life: 36 months from manufacturing date.

Anticonvulsants

N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.

Rx