Levetiracetam

Sun Pharma Global FZE

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use levetiracetam safely and effectively. See full prescribing information for levetiracetam extended-release tablets. Levetiracetam Extended-Release Tablets, for oral useInitial U.S. Approval: 1999 RECENT MAJOR CHANGESDosage and Administration, Partial Onset Seizures (2.1)              [07/2013] Warnings and Precautions (5.1, 5.3, 5.4, 5.5, 5.8)            [07/2013]INDICATIONS AND USAGELevetiracetam is an antiepileptic drug indicated for adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy (1)DOSAGE AND ADMINISTRATIONTreatment should be initiated with a dose of 1,000 mg once daily. The daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg (2). See full prescribing information for use in patients with impaired renal function (2.1).DOSAGE FORMS AND STRENGTHS 500 mg blue and white to off-white colored biconvex, bilayer, film-coated extended-release tablet (3) 750 mg blue and white to off-white colored biconvex, bilayer, film-coated extended-release tablet (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Psychiatric Reactions: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms (5.1) Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior (5.2) Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam extended-release tablets (5.3) Withdrawal Seizures: Levetiracetam extended-release tablets must be gradually withdrawn (5.6) Side Effects Most common adverse reactions (incidence in levetiracetam extended-release tablets-treated patients is ≥5% more than in placebo-treated patients) include: somnolence and irritability (6.1). To report SUSPECTED ADVERSE REACTIONS, contact CARACO Pharmaceutical Laboratories Ltd. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Pregnancy: Plasma levels of levetiracetam may be decreased and therefore need to be monitored closely during pregnancy. Based on animal data, may cause fetal harm (5.8, 8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 LEVETIRACETAM INDICATIONS AND USAGE
• 2 LEVETIRACETAM DOSAGE AND ADMINISTRATION
  • 2.1 Adult Patients with Impaired Renal Function
• 3 DOSAGE FORMS AND STRENGTHS
• 4 LEVETIRACETAM CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Psychiatric Reactions
  • 5.2 Suicidal Behavior and Ideation
  • 5.3 Somnolence and Fatigue
  • 5.4 Serious Dermatological Reactions
  • 5.5 Coordination Difficulties
  • 5.6 Withdrawal Seizures
  • 5.7 Hematologic Abnormalities
  • 5.8 Seizure Control During Pregnancy
• 6 LEVETIRACETAM ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Use in Patients with Impaired Renal Function
• 10 OVERDOSAGE
  • 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans
  • 10.2 Management of Overdose
  • 10.3 Hemodialysis
• 11 LEVETIRACETAM DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDE
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 500MG
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 750MG

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Levetiracetam extended-release tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy.

2 DOSAGE AND ADMINISTRATION

Treatment should be initiated with a dose of 1,000 mg once daily. The daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg.

2.1 Adult Patients with Impaired Renal Function

Levetiracetam extended-release tablets dosing must be individualized according to the patient’s renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient’s creatinine clearance (CL_cr) in mL/min must first be calculated using the following formula:

Then CL_cr is adjusted for body surface area (BSA) as follows:

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “573” with black ink on one side and plain on other side.
 
Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “576” with black ink on one side and plain on other side.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Psychiatric Reactions

Levetiracetam Extended-Release Tablets

In some patients levetiracetam extended-release tablets cause behavioral abnormalities.

A total of 6.5% of levetiracetam extended-release tablets-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 tablets-treated patients. Aggression was reported in 1.3% of levetiracetam extended-release tablets-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 tablets controlled trials will likely occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

A total of 13.3% of adult levetiracetam tablets-treated patients compared to 6.2% of placebo patients experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, and nervousness).

A total of 1.7% of adult levetiracetam tablets-treated patients discontinued treatment due to behavioral adverse events compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult levetiracetam tablets-treated patients and in 0.5% of placebo patients.

One percent of adult levetiracetam tablets-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients.

Two (0.3%) adult levetiracetam tablets-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

The above psychiatric signs and symptoms should be monitored.

5.2 Suicidal Behavior and Ideation

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

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

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

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs 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.

5.3 Somnolence and Fatigue

Levetiracetam Extended-Release Tablets

In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of levetiracetam extended-release tablets-treated patients experienced somnolence compared to 2.5% of placebo-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 tablets controlled trials will likely occur in patients receiving levetiracetam extended-release tablets.                               

Immediate-Release Levetiracetam Tablets

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam tablets-treated patients reported somnolence, compared to 8.4% of placebo patients.

There was no clear dose response up to 3,000 mg/day. In a study where there was no titration, about 45% of patients receiving 4,000 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 tablets-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of levetiracetam tablets-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia 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 due to asthenia.

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

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam tablets to gauge whether it adversely affects their ability to drive or operate machinery.

5.4 Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. Levetiracetam extended-release tablets should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

5.5 Coordination Difficulties

Coordination difficulties were not observed in the levetiracetam extended-release tablets controlled trial, however, 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. However, adverse reactions observed in the immediate-release levetiracetam tablets controlled trials may also occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

A total of 3.4% of adult levetiracetam tablets-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 tablets 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. These events occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam tablets to gauge whether it could adversely affect their ability to drive or operate machinery.

5.6 Withdrawal Seizures

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

5.7 Hematologic Abnormalities

Although there were no obvious hematologic abnormalities observed in treated patients in the levetiracetam extended-release tablets controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release levetiracetam tablets controlled studies should be considered to be relevant for levetiracetam extended-release tablets-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 10⁶/mm³), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam tablets-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 10⁹/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1 x 10⁹/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.

5.8 Seizure Control During Pregnancy

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more details in other sections of labeling:

• Psychiatric Reactions [see Warnings and Precautions (5.1)]
• Suicidal Behavior And Ideation [see Warnings and Precautions (5.2)]
• Somnolence And Fatigue [see Warnings and Precautions (5.3)]
• Serious Dermatological Reactions [see Warnings and Precautions (5.4)]
• Coordination Difficulties [see Warnings and Precautions (5.5)]
• Withdrawal Seizures [see Warnings and Precautions (5.6)]
• Hematologic Abnormalities [see Warnings and Precautions (5.7)]
• Seizure Control During Pregnancy [see Warnings and Precautions (5.8)]

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.

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 reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical trials. 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 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, for events with rates greater than placebo, were irritability and somnolence.

Table 3 lists 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 Controlled Clinical Study

In the 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 reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in levetiracetam extended-release tablets-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 tablets-treated patient and no placebo-treated patients.


Table 4 lists the adverse reactions seen in the 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 tablets study seems somewhat different from that seen in partial onset seizure 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 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, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness.

Table 4 lists 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.

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.

6.2 Postmarketing Experience

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 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 listing is alphabetized: abnormal liver function test, choreoathetosis, dyskinesia, erythema multiforme, 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 tablets use; recovery was observed in majority of cases where immediate-release levetiracetam tablets were discontinued.

7 DRUG INTERACTIONS

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications via human liver cytochrome P450 isoforms, epoxide hydrolase, UDP-glucuronidation enzymes, P-glycoprotein, or renal tubular secretion [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Levetiracetam extended-release tablets levels may decrease during pregnancy [see Warnings and Precautions (5.8)].
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 (equivalent to the maximum recommended human dose of 3,000 mg [MRHD] on a mg/m² basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1,800 mg/kg/day (6 times the MRHD on a mg/m² basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m² 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 (4 times MRHD on a mg/m² basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1,800 mg/kg/day (12 times the MRHD on a mg/m² basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m² basis). Maternal toxicity was also observed at 1,800 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 3,600 mg/kg/day (12 times the MRHD). 1,200 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 1,800 mg/kg/day (6 times the MRHD on a mg/m² 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/.

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Levetiracetam is excreted in human 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.

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

There were 347 subjects in clinical studies of immediate-release levetiracetam that 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.

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 [see Clinical Pharmacology (12.3)].

8.6 Use in Patients with Impaired Renal Function

The effect of levetiracetam extended-release tablets on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on levetiracetam extended-release tablets-treated patients would be similar to the effect seen in controlled studies of immediate-release levetiracetam tablets. Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology (12.3)]. Dose adjustment is recommended for patients with impaired renal function [see Dosage and Administration (2.1)].

10 OVERDOSAGE

10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

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

The highest known dose of oral immediate-release levetiracetam tablets received in the clinical development program was 6,000 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 tablets overdoses in postmarketing use.

10.2 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.

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.

11 DESCRIPTION

Levetiracetam is an antiepileptic drug available as 500 mg and 750 mg (blue and white to off-white) extended-release 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 C₈H₁₄N₂O₂ 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 extended-release tablets contain the labeled amount of levetiracetam. Inactive ingredients: povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide, magnesium stearate, talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, FD&C Blue #1 aluminum lake, ethyl cellulose aqueous dispersion, dibutyl sebacate, triethyl citrate, polysorbate 20, polyvinyl alcohol, polyethylene glycol, and polysorbate 80. The imprinting ink contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

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

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

12.2 Pharmacodynamics

Effects on QTc Interval

The effects of levetiracetam extended-release tablets on QTc prolongation is expected to be the same as that of immediate-release levetiracetam tablets. The effect of immediate-release levetiracetam tablets on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin 400 mg) and placebo-controlled crossover study of levetiracetam tablets (1,000 mg or 5,000 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

Overview

Bioavailability of levetiracetam extended-release tablets is similar to that of the levetiracetam tablets. The pharmacokinetics (AUC and C_max) were shown to be dose proportional after single dose administration of 1,000 mg, 2,000 mg, and 3,000 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_0-24) was similar to extent of exposure after multiple dose immediate-release tablets intake. C_max and C_min 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_max) 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)].


Special Populations

Elderly
 
There are insufficient pharmacokinetic data to specifically address the use of extended-release levetiracetam in the elderly population.

Pharmacokinetics of immediate-release 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

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

Pregnancy

Levetiracetam extended-release tablets levels may decrease during pregnancy.

Gender 
Extended-release levetiracetam C_max was 21 to 30% higher and AUC was 8 to 18% higher in women (N=12) 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 with extended-release or immediate-release levetiracetam. Cross study comparisons involving Caucasians (N=12) and Asians (N=12), however, show that pharmacokinetics of immediate-release 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 effect of levetiracetam extended-release tablets on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on levetiracetam extended-release tablets-treated patients would be similar to that seen in controlled studies of immediate-release levetiracetam tablets. In patients with end stage renal disease on dialysis, it is recommended that immediate-release levetiracetam tablets be used instead of levetiracetam extended-release tablets.

The disposition of immediate-release 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 (CL_cr = 50 to 80 mL/min), 50% in the moderate group (CL_cr = 30 to 50 mL/min) and 60% in the severe renal impairment group (CL_cr <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 (CL_cr >80mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4- hour hemodialysis procedure.

Dosage should be reduced in patients with impaired renal function receiving levetiracetam; immediate-release levetiracetam should be given to patients on dialysis [see Dosage and Administration (2.1)].

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.

Drug Interactions:

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

Phenytoin

Immediate-release levetiracetam tablets (3,000 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.

Valproate

Immediate-release levetiracetam tablets (1,500 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.

Other Antiepileptic Drugs

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.

Oral Contraceptives

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.

Digoxin

Immediate-release levetiracetam tablets (1,000 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.

Warfarin

Immediate-release levetiracetam tablets (1,000 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

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 1,000 mg twice daily. C^ss _max 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1,800 mg/kg/day. The highest dose is 6 times the maximum recommended daily human dose (MRHD) of 3,000 mg on a mg/m² basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. In mice, oral administration of levetiracetam for 80 weeks (doses up to 960 mg/kg/day) or 2 years (doses up to 4,000 mg/kg/day, lowered to 3,000 mg/kg/day after 45 weeks due to intolerability) was not associated with an increase in tumors. The highest dose tested in mice for 2 years (3,000 mg/kg/day) is approximately 5 times the MRHD on a mg/m² basis.

Mutagenesis

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.

Impairment of Fertility

No adverse effects on male or female fertility or reproductive performance were observed in rats at oral doses up to 1,800 mg/kg/day (6 times the maximum recommended human dose on a mg/m² or systemic exposure [AUC] basis).

14 CLINICAL STUDIES

The effectiveness of the immediate-release formulation of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo controlled clinical studies in 904 patients who had refractory partial onset seizures with or without secondary generalization for at least two years and had taken two or more classical AEDs.

The effectiveness of levetiracetam extended-release tablets as adjunctive therapy (added to other antiepileptic drugs) was established in one multicenter, randomized, double-blind, placebo-controlled clinical study across 7 countries in patients who had refractory partial onset seizures with or without secondary generalization. Patients enrolled had at least eight partial seizures with or without secondary generalization during the 8-week baseline period and at least two partial seizures in each 4-week interval of the baseline period. Patients were taking a stable dose regimen of at least one and could take a maximum of three AEDs. After a prospective baseline period of 8 weeks, 158 patients were randomized to placebo (N=79) or levetiracetam extended-release tablets (2×500 mg tablets) (N=79) given once daily over a 12-week treatment period.

The primary efficacy endpoint was the percent reduction over placebo in mean weekly frequency of partial onset seizures. The median percent reduction in weekly partial onset seizure frequency from baseline over the treatment period was 46.1% in the levetiracetam extended-release tablets 1,000 mg treatment group (N=74) and 33.4% in the placebo group (N=78). The estimated percent reduction over placebo in weekly partial onset seizure frequency over the treatment period was 14.4% (statistically significant).

The relationship between the effectiveness of the same daily dose of levetiracetam extended-release tablets and immediate-release levetiracetam tablets has not been studied and is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “573” with black ink on one side and plain on other side. They are supplied as follows:

Bottles of 60’s with Child Resistant Cap…................... NDC 47335-573-86
Bottles of 100’s with Child Resistant Cap…................. NDC 47335-573-88
Bottles of 500’s with Non Child Resistant Cap………. NDC 47335-573-13
 
Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “576” with black ink on one side and plain on other side. They are supplied as follows:
 
Bottles of 60’s with Child Resistant Cap…................... NDC 47335-576-86
Bottles of 100’s with Child Resistant Cap…................. NDC 47335-576-88
Bottles of 500’s with Non Child Resistant Cap………. NDC 47335-576-13

16.2 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling (Medication Guide).

Counsel patients on the benefits and risks of receiving levetiracetam extended-release tablets. Provide the Medication Guide to patients and/or caregivers, and instruct them to read the Medication Guide prior to taking levetiracetam extended-release tablets. Instruct patients to take levetiracetam extended-release tablets only as prescribed.

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider.

Psychiatric Reactions and Changes in Behavior

Advise patients that levetiracetam extended-release tablets may cause changes in behavior (e.g. irritability and aggression). In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of levetiracetam, which include agitation, anger, anxiety, apathy, depression, hostility, and, in rare cases, psychotic symptoms.

Effects on Driving or Operating Machinery

Inform patients that levetiracetam extended-release tablets may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam extended-release tablets to gauge whether it adversely affects their ability to drive or operate machinery.

Dermatological Adverse Reactions

Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their physician immediately if a rash develops.

Dosing and Administration

Patients should be instructed to only take levetiracetam extended-release tablets as prescribed and to swallow the tablets whole. They should not be chewed, broken, or crushed.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during levetiracetam extended-release tablets therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334. [see Use In Specific Populations (8.1)]. 

MEDICATION GUIDE

Levetiracetam Extended-Release Tablets


Read this Medication Guide before you start taking levetiracetam extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

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

Like other antiepileptic drugs, levetiracetam extended-release tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500 people taking it.
 
Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

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

• Stopping levetiracetam extended-release tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly can cause seizures that will not stop (status epilepticus).
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What are levetiracetam extended-release tablets?

Levetiracetam extended-release tablets are prescription medicines taken by mouth that is used with other medicines to treat partial onset seizures in people 16 years of age and older with epilepsy.

It is not known if levetiracetam extended-release tablets are safe or effective in people under 16 years of age.

Before taking your medicine, make sure you have received the correct medicine. Compare the name above with the name on your bottle and the appearance of your medicine with the description of levetiracetam extended-release tablets provided below. Tell your pharmacist immediately if you think you have been given the wrong medicine.
 
500 mg levetiracetam extended-release tablets are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “573” with black ink on one side and plain on other side.
 
750 mg levetiracetam extended-release tablets are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “576” with black ink on one side and plain on other side.
 
What should I tell my healthcare provider before starting levetiracetam extended-release tablets?

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

• have or have had depression, mood problems or suicidal thoughts or behavior
• have kidney problems
• are pregnant or planning to become pregnant. It is not known if levetiracetam extended-release tablets will harm your unborn baby. You and your healthcare provider will have to decide if you should take levetiracetam extended-release tablets while you are pregnant. If you become pregnant while taking levetiracetam extended-release tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of levetiracetam extended-release tablets and other antiepileptic medicine during pregnancy.
• are breast feeding. Levetiracetam can pass into your milk and may harm your baby. You and your healthcare provider should discuss whether you should take levetiracetam extended-release tablets or breast feed; you should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Do not start a new medicine without first talking with your healthcare provider.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I take levetiracetam extended-release tablets?

Take levetiracetam extended-release tablets exactly as prescribed.

• Your healthcare provider will tell you how many levetiracetam extended-release tablets to take and when to take it. Levetiracetam extended-release tablets are usually taken once a day. Take levetiracetam extended-release tablets at the same time each day.
• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
• Take levetiracetam extended-release tablets with or without food.
• Swallow the tablets whole. Do not chew, break, or crush tablets.
• If you miss a dose of levetiracetam extended-release tablets, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
• If you take too many levetiracetam extended-release tablets, call your local Poison Control Center or go to the nearest emergency room right away.

What should I avoid while taking levetiracetam extended-release tablets?

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

What are the possible side effects of levetiracetam extended-release tablets?

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

Levetiracetam extended-release tablets can cause serious side effects.

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

• mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability. A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs) and unusual behavior.
• extreme sleepiness, tiredness, and weakness
• problems with muscle coordination (problems walking and moving)
• a skin rash. Serious skin rashes can happen after you start taking levetiracetam extended-release tablets. There is no way to tell if a mild rash will become a serious reaction

Common side effects seen in people who take levetiracetam extended-release tablets and other formulations of levetiracetam include:

• sleepiness
• weakness
• infection
• dizziness

These side effects can happen at any time but happen more often within the first 4 weeks of treatment except for infection.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of levetiracetam extended-release tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may also report side effects to FDA at 1-800-­FDA-1088.

How should I store levetiracetam extended-release tablets?

• Store levetiracetam extended-release tablets at room temperature, at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) away from heat and light.
• Keep levetiracetam extended-release tablets and all medicines out of the reach of children.

General information about levetiracetam extended-release tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levetiracetam extended-release tablets for a condition for which it was not prescribed. Do not give levetiracetam extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about levetiracetam extended-release tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about levetiracetam extended-release tablets that is written for health professionals. You can also call Caraco Pharmaceutical Laboratories Ltd. at 1-800-818-4555.

What are the ingredients of levetiracetam extended-release tablets?

Levetiracetam extended-release tablets
active ingredient: levetiracetam
Inactive ingredients: povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide, magnesium stearate, talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, FD&C Blue #1 aluminum lake, ethyl cellulose aqueous dispersion, dibutyl sebacate, triethyl citrate, polysorbate 20, polyvinyl alcohol, polyethylene glycol, and polysorbate 80. The imprinting ink contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

Levetiracetam extended-release tablets do not contain lactose or gluten.
 
This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:
Caraco Pharmaceutical Laboratories, Ltd.
1150 Elijah McCoy Drive, Detroit, MI 48202

Manufactured by:
Sun Pharmaceutical Ind. Ltd.
Halol-Baroda Highway,
Halol-389 350, Gujarat, India.

PJPI0321B
ISS. 08/2013

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 500MG

NDC 47335-573-86
Once Daily Dosing
Levetiracetam Extended-Release Tablets
500 mg
PHARMACIST: Please dispense with medication guide provided separately to each patient.
Rx only
60 TABLETS
SUN PHARMA 

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 750MG

NDC 47335-576-86
Once Daily Dosing
Levetiracetam Extended-Release Tablets
750 mg
PHARMACIST: Please dispense with medication guide provided separately to each patient.
Rx only
60 TABLETS
SUN PHARMA 

Levetiracetam Levetiracetam TABLET, FILM COATED, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:47335-573 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVETIRACETAM LEVETIRACETAM 500 mg Inactive Ingredients Ingredient Name Strength POVIDONE K90 HYPROMELLOSE 2208 (15000 MPA.S) DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER SILICON DIOXIDE MAGNESIUM STEARATE talc CROSPOVIDONE SODIUM LAURYL SULFATE FD&C BLUE NO. 1 ETHYLCELLULOSES DIBUTYL SEBACATE TRIETHYL CITRATE POLYSORBATE 20 POLYVINYL ALCOHOL POLYETHYLENE GLYCOL 3350 polysorbate 80 Product Characteristics Color Size Imprint Code Shape WHITE (white to off-white) 16 mm 573 OVAL Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:47335-573-86 60 in 1 BOTTLE 2 NDC:47335-573-88 100 in 1 BOTTLE 3 NDC:47335-573-13 500 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203059 2013-09-09

Levetiracetam Levetiracetam TABLET, FILM COATED, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:47335-576 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVETIRACETAM LEVETIRACETAM 750 mg Inactive Ingredients Ingredient Name Strength POVIDONE K90 HYPROMELLOSE 2208 (15000 MPA.S) DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER SILICON DIOXIDE MAGNESIUM STEARATE talc CROSPOVIDONE SODIUM LAURYL SULFATE FD&C BLUE NO. 1 ETHYLCELLULOSES DIBUTYL SEBACATE TRIETHYL CITRATE POLYSORBATE 20 POLYVINYL ALCOHOL POLYETHYLENE GLYCOL 3350 polysorbate 80 Product Characteristics Color Size Imprint Code Shape WHITE (white to off-white) 19 mm 576 OVAL Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:47335-576-86 60 in 1 BOTTLE 2 NDC:47335-576-88 100 in 1 BOTTLE 3 NDC:47335-576-13 500 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203059 2013-09-09