VETRAM

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

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O and its molecular weight is 170.21.

Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).

It has the following structural formula

Levetiracetam USP 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 USP contain the labeled amount of levetiracetam.

Inactive ingredients: corn starch, colloidal silicon dioxide, povidone, talc, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and purified water.

In addition 250 mg contains FD&C Blue #2/indigo carmine aluminum lake, 500 mg contains iron oxide yellow, and 750 mg contains FD&C Yellow #6/sunset yellow FCF aluminum lake, FD&C Blue #2/indigo carmine aluminum lake, and iron oxide red.

USP dissolution test 2.

The drug of

Lefeteracitam alone is used to treat partial seizures in adults aged and over, especially in the newly diagnosed epilepsy.

Partial seizures mean that they start from a specific area of the brain, and may later remain in place or spread to the side of the brain, so their symptoms vary according to the infected area of the brain.

The doctor may also describe them with other medications for the following cases: rapid seizures in adults and children aged and above.

Before starting using this drug, the doctor reported all the details of your health status, especially in the following cases: kidney problems; because this drug is given through urine, so the dose must be adjusted for the kidney patient.

Depressantity; Liviteractam drug affects mental health and may increase suicidal thoughts.

Pregnancy; Liviteractam is given to the pregnant woman only after consultation with the doctor, and only when the intended benefit is greater than the risk to the baby.

Breastfeeding; it is transmitted through mother milk in a large amount, which poses a risk to the infant's health.

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

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 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. 12.2 Pharmacodynamics Effects on QTc Interval The effect of levetiracetam on QTc 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. 12.3 Pharmacokinetics The pharmacokinetics of levetiracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

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 C max by 20% and delays T max by 1.5 hours.

The pharmacokinetics of levetiracetam are linear over the dose range of to 5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing.

Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

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.

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 renal impairment.

Pharmacokinetics of levetiracetam were evaluated in 16 elderly subjects (age to 88 years) with creatinine clearance ranging from 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.

Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 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 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 T max 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 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.

Pediatric Patients with Obesity A population

PK analysis of levetiracetam was conducted in 164 obese and non-obese pediatric patients to <18 years of age with median (range) weight 39.2 (11.3 to 134) kg to evaluate the potential impact of obesity on plasma levetiracetam exposures.

Obesity was defined as

BMI ≥95th percentile for age and sex based on CDC 2000 growth chart recommendations.

Simulations were conducted for obese and non-obese pediatric patients ages to <16 years.

When the recommended tablet dose is administered to pediatric patients weighing < 40 kg, obese pediatric patients have 27% higher median C max,ss and 19% higher median C min,ss compared to non-obese patients.

When the recommended tablet dose is administered to pediatric patients weighing ≥ 40 kg, obese pediatric patients have to 11% lower median C max,ss and 2% lower median C min,ss compared to non-obese patients.

When the recommended oral solution dose is administered to pediatric patients across the full weight range, obese pediatric patients have 25% higher median C max,ss and 41% higher median C min,ss compared to non-obese pediatric patients.

However, differences in exposures between obese and non-obese pediatric patients are not expected to be clinically meaningful because the recommended dose titration at initiation of levetiracetam therapy would establish an appropriate dose for each individual patient.

Levetiracetam levels may decrease during pregnancy.

Gender Levetiracetam C max and

AUC were 20% higher in women (N=11) compared to men (N=12).

However, clearances adjusted for body weight were comparable.

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.

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.

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.

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 max levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes.

In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

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

Levetiracetam (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.

Levetiracetam (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 levetiracetam 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.

There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with enzyme-inducing AEDs.

Dose adjustment is not recommended.

Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

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.

Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.

Levetiracetam (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.

Levetiracetam (1000 m.

Levetiracetam is an anti-epulsion anti-epulsion, used alone or with other drugs to treat certain types of seizures, caused by the brain's electrical activity disorder.

Leveteracetam is associated with the

SV2A protein on the surface of neurons, and this protein is responsible for regulating the release of the chemical (neurotransmitters) that allow neurotransmitters to communicate with each other, thus helping to stabilize the seizures and reduce their frequency, so you must not stop taking them without consulting a doctor, even if you feel better; the seizures may reappear once treatment has ceased.

Do you have questions relevant to this subject?

The following adverse reactions are discussed in more details in other sections of labeling: Behavior Abnormalities and Psychotic Symptoms Suicidal Behavior and Ideation Somnolence and Fatigue Anaphylaxis and Angioedema Serious Dermatological Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Coordination Difficulties Hematologic Abnormalities Increase in Blood Pressure Most common adverse reactions (incidence ≥ 5% more than placebo) include: Adult patients: somnolence, asthenia, infection and dizziness Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience 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.

In controlled clinical studies in adults with partial-onset seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness.

Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam in placebo-controlled studies and were numerically more common than in patients treated with placebo.

In these studies, either levetiracetam or placebo was added to concurrent AED therapy.

Table 3: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults Experiencing Partial-Onset Seizures Levetiracetam (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients.

Table 4: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo-Controlled Studies in Adult Patients Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Pediatric Patients 4 Years to <16 Years The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies in pediatric patients to 16 years of age with partial-onset seizures.

The most common adverse reactions in pediatric patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients Ages to 16 Years Experiencing Partial-Onset Seizures Levetiracetam (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Cough 9 5 Nasal Congestion 9 2 Upper Abdominal Pain 9 8 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Altered Mood 3 1 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In the controlled pooled pediatric clinical studies in patients to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction.

Patients 1 Month to < 4 Years In the 7-day, controlled pediatric clinical study in children 1 month to less than 4 years of age with partial-onset seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability.

Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients.

Therefore, other controlled pediatric data, presented above, should also be considered to apply to this.

Table 6 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with levetiracetam in the placebo-controlled study and were numerically more common than in patients treated with placebo.

In this study, either levetiracetam or placebo was added to concurrent AED therapy.

Table 6: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Pediatric Patients Ages 1 Month to < 4 Years Experiencing Partial-Onset Seizures Levetiracetam (N=60) % Placebo (N=56) % Somnolence 13 2 Irritability 12 0 In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

There was no adverse reaction that resulted in discontinuation for more than one patient.

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies.

The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical study in patients 12 years of age and older with myoclonic seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo.

Table 7: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Patients 12 Years of Age and Older with Myoclonic Seizures Levetiracetam (N=60) % Placebo (N=60) % Somnolence 12 2 Neck pain 8 2 Pharyngitis 7 0 Depression 5 2 Influenza 5 2 Vertigo 5 3 In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 8.

Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies.

The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical study that included patients 4 years of age and older with PGTC seizures, the most common adverse reaction in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 9 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo.

Table 9: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Patients 4 Years of Age and Older with PGTC Seizures Levetiracetam (N=79) % Placebo (N=84) % Nasopharyngitis 14 5 Fatigue 10 8 Diarrhea 8 7 Irritability 6 2 Mood swings 5 1 In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.

This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population.

It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials.

In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision.

Comparison of

Gender, Age and Race The overall adverse reaction profile of levetiracetam was similar between females and males.

There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levetiracetam.

Because these reactions 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 following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide.

The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures.

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse 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 levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam.

If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway.

General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status.

Center should be contacted for up to date information on the management of overdose with levetiracetam. 10.3 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 tablets are contraindicated in patients with a hypersensitivity to levetiracetam.

Reactions have included anaphylaxis and angioedema.

Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred.

Use the oral solution for pediatric patients with body weight ≤ 20 kg For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) Partial-Onset Seizures (monotherapy or adjunctive therapy) 1 Month to < 6 Months: 7 mg/kg twice daily; increase by 7 mg/kg twice daily every 2 weeks to recommended dose of 21 mg/kg twice daily 6 Months to < 4 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 25 mg/kg twice daily 4 Years to < 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to a recommended dose of 1500 mg twice daily Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily Primary Generalized Tonic-Clonic Seizures 6 Years to < 16 Years: 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily Adults 16 Years and Older: 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient’s estimated creatinine clearance 2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food.

The levetiracetam dosing regimen depends on the indication, , dosage form (tablets or oral solution), and renal function.

Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon).

Levetiracetam tablets should be swallowed whole.

Levetiracetam tablets should not be chewed or crushed. 2.2 Dosing for Partial-Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.

Adults 16 Years of Age and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Patients 1 Month to < 6 Months Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).

In the clinical trial, the mean daily dose was 35 mg/kg in this.

Months to < 4 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 47 mg/kg in this.

Years to < 16 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.

In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day. For levetiracetam tablet dosing in pediatric patients weighing to 40 kg, initiate treatment with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily).

Increase the daily dose every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily).

For levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, initiate treatment with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily).

Increase the daily dose every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily).

Levetiracetam Oral Solution Weight-Based Dosing Calculation For Pediatric Patients The following calculation should be used to determine the appropriate daily dose of oral solution for pediatric patients: Daily dose (mg/kg/day) X patient weight (kg) Total daily dose (mL/day) = -----------------------------------------------------

• 100 mg/mL 2.3 Dosing for Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase the dosage 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. 2.4 Dosing for Primary Generalized Tonic-Clonic Seizures Adults 16 Years of Age and Older Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

Patients to <16 Years of Age Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

Patients with body weight ≤20 kg should be dosed with oral solution.

Patients with body weight above 20 kg can be dosed with either tablets or oral solution.

Only whole tablets should be administered. 2.5 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam tablet dosing must be individualized according to the patient’s renal function status.

Recommended dosage adjustments for adults are shown in Table 1.

In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.

To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: [140-age (years)] x weight (kg) CLcr = ----------------------------------------------(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min) CLcr (mL/min/1.73 m 2 ) = -------------------------

• x 1.73 BSA subject (m 2 ) Table 1: Dosing Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73 m 2 ) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild to 80 500 to 1,000 Every 12 hours Moderate to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ---

• 500 to 1,000 Every 24 hours * Following dialysis, a to 500 mg supplemental dose is recommended. 2.6 Discontinuation of Levetiracetam Tablets Avoid abrupt withdrawal from levetiracetam tablets in order to reduce the risk of increased seizure frequency and status epilepticus.

50090-7774 NDC: 50090-7774-0 120 TABLET, FILM COATED in a BOTTLE NDC: 50090-7774-1 500 TABLET, FILM COATED in a BOTTLE.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam, during pregnancy.

Encourage women who are taking levetiracetam during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting Risk Summary Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades.

In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Levetiracetam blood levels may decrease during pregnancy.

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.

Dose adjustments may be necessary to maintain clinical response.

While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage.

When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested.

There was no evidence of maternal toxicity.

The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis.

Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity.

The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested.

The no-effect dose for adverse effects on pre.

• and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).

The safety and effectiveness of levetiracetam for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established.

The dosing recommendation in these pediatric patients varies according to and is weight-based.

The safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established.

The safety and effectiveness of levetiracetam as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established.

Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of levetiracetam as adjunctive therapy in 98 (levetiracetam N=64, placebo N=34) pediatric patients, ages to 16 years old, with partial seizures that were inadequately controlled.

The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention.

Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo.

Checklist (CBCL/6 to 18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study.

An analysis of the

CBCL/6 to 18 indicated on average a worsening in levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores.

Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development.

There were 347 subjects in clinical studies of levetiracetam that were 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.

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.