LEVETIRACETAM tablet, film coated, extended release

Levetiracetam by

Drug Labeling and Warnings

Levetiracetam by is a Prescription medication manufactured, distributed, or labeled by Florida Pharmaceutical Products, LLC., Zhejiang Huahai Pharmaceutical Co., Ltd., Dexcel Pharma Technologies Ltd.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Levetiracetam extended-release tablets USP are indicated as adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    Levetiracetam extended-release tablets are administered once daily.‎

    Initiate treatment with a dose of 1000 mg once daily. The once daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg/day.

    2.2 Dosage Adjustment in Adult Patients with Renal Impairment

    Levetiracetam extended-release tablets 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, creatine 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/1.73m2) = ----------------------------- x 1.73

          BSA subject (m2)

         

    Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment
    Group
    		Creatinine Clearance
    (mL/min/1.73m2)    		Dosage
    (mg)
    		Frequency
    Normal >801000 to 3000Every 24 hours
    Mild 50 – 801000 to 2000Every 24 hours
    Moderate 30 – 50500 to 1500Every 24 hours
    Severe < 30500 to 1000Every 24 hours
  • 3 DOSAGE FORMS AND STRENGTHS

    Levetiracetam extended-release tablets USP, 500 mg are white, oblong-shaped, film-coated extended-release tablets debossed with "500" on one side and contain 500 mg levetiracetam.

    Levetiracetam extended-release tablets USP, 750 mg are white, oblong-shaped, film-coated extended-release tablets debossed with "750" on one side and contain 750 mg levetiracetam.

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Behavioral Abnormalities and Psychotic Symptoms

    Levetiracetam extended release tablets may cause behavioral abnormalities and psychotic symptoms. Patients treated with ‎ levetiracetam extended-release should be monitored for psychiatric signs and symptoms.

    Behavioral abnormalities

    Levetiracetam Extended-release Tablets

    A total of 7% of levetiracetam extended-release-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 7% of levetiracetam extended-release-treated patients. Aggression was reported in 1% of levetiracetam extended-release-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 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 controlled trials will likely occur in patients receiving levetiracetam extended-release tablets.

    Immediate-Release Levetiracetam Tablets

    A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19% of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis suggested a worsening in aggressive behavior in patients treated with immediate-release levetiracetam tablets in that study [see Use in Specific Populations (8.4)]. 

    A total of 1.7% of adult patients treated with immediate-release levetiracetam discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult patients treated with immediate-release levetiracetam, compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with immediate-release levetiracetam experienced behavioral symptoms associated with ‎discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients.‎

    One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and placebo-treated pediatric patients. In the controlled study that assessed the neurocognitive and behavioral effects of immediate-release levetiracetam in pediatric patients 4 to 16 years of age, 1.6% levetiracetam-treated patient experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release levetiracetam who experienced confusional state, compared to no placebo-treated patients [see Use in Specific Populations (8.4)]. 

    Psychotic symptoms

    Immediate-Release Levetiracetam tablets

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

    Two (0.3%) levetiracetam-treated adult 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. There was no difference between drug and placebo-treated patients in the incidence of pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. 

    5.2 Suicidal Behavior and Ideation

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

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

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

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

    Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
    IndicationPlacebo Patients with Events Per 1000 PatientsDrug Patients with Events Per 1000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1000 Patients
    Epilepsy1.03.43.52.4
    Psychiatric5.78.51.52.9
    Other1.01.81.90.9
    Total2.44.31.81.9

    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 may cause somnolence and fatigue. 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 extended-release tablets to gauge whether it adversely affects their ability to drive or operate machinery.

    Somnolence

    Levetiracetam Extended-release Tablets

    In a levetiracetam extended-release double-blind, controlled trial in patients experiencing partial onset seizures, 8% of levetiracetam extended-release-treated patients experienced somnolence compared to 3% 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 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 controlled trials will likely occur in patients receiving levetiracetam extended-release. 

    Immediate-Release Levetiracetam Tablets

    In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 15% of levetiracetam treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of levetiracetam-treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of levetiracetam-treated patients and in 0.9% of placebo-treated patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

    Asthenia

    Immediate-Release Levetiracetam Tablets

    In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 15% of levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.

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

    5.4 Serious Dermatological Reactions

    Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults 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 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 a levetiracetam extended-release tablets controlled trial, however, the number of patients exposed to levetiracetam extended-release 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 controlled trials may also occur in patients receiving levetiracetam extended-release tablets.

    Immediate-Release Levetiracetam Tablets

    A total of 3.4% of adult levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled trials discontinued immediate-release levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the levetiracetam-treated patients was hospitalized due to worsening of pre-existing 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 to gauge whether it could adversely affect their ability to drive or operate machinery.‎

    5.6 Withdrawal Seizures

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

    5.7 Hematologic Abnormalities

    Levetiracetam extended-release can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in red blood cell (RBC) counts, hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cell (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.

    In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, minor, but statistically significant, decrease 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-treated patients.

    A total of 3.2% of levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of levetiracetam-treated and  1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the levetiracetam-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.

    In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release levetiracetam, as compared to placebo. The mean decreases from baseline in the immediate-release levetiracetam group were -0.4 × 109/L and -0.3 × 109/L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release levetiracetam compared to a decrease of 4% in patients on placebo.

    In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release levetiracetam, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts.

    In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release levetiracetam -treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X109/L).

    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:

    • Behavioral abnormalities and Psychotic Symptoms [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)]
    • Hematologic Abnormalities [see Warnings and Precautions (5.7)]

    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.

    Levetiracetam Extended-release Tablets

    In a controlled clinical study in patients with partial onset seizures, the most common adverse reactions in patients receiving levetiracetam extended-release 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 receiving levetiracetam extended-release in a placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either levetiracetam extended-release or placebo was added to concurrent AED therapy.

    Table 3: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients Experiencing Partial Onset Seizures
    Levetiracetam Extended-release Tablets
    (N=77)
    %    		Placebo
    (N=79)
    %
        Influenza84
        Somnolence83
        Irritability70
        Nasopharyngitis75
        Dizziness53
        Nausea53

    Discontinuation or Dose Reduction in a Levetiracetam Extended-release Controlled Clinical Study 

    In a controlled clinical study, 5% of patients receiving levetiracetam extended-release tablets and 3% 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-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-treated patient and no placebo-treated patients.

    Immediate-Release Levetiracetam Tablets

    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.

    Adults

    In controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most common 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 receiving immediate-release levetiracetam tablets 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.

    Table 4: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures
    Levetiracetam
    (N=769)
    %    		Placebo
    (N=439)
    %
        Asthenia159
        Somnolence158
        Headache1413
        Infection138
        Dizziness94
        Pain76
        Pharyngitis64
        Depression42
        Nervousness42
        Rhinitis43
        Anorexia32
        Ataxia31
        Vertigo31
        Amnesia21
        Anxiety21
        Cough Increased21
        Diplopia21
        Emotional Lability20
        Hostility21
        Paresthesia21
        Sinusitis21

    Pediatric Patients 4 Years to <16 Years

    In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial onset seizures, the adverse reactions most frequently reported with the use of immediate-release levetiracetam in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

    Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-release levetiracetam and were more common than in pediatric patients on placebo. In these studies, either immediate-release levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

    Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures
    Levetiracetam
    (N=165)
    %    		Placebo
    (N=131)
    %
    Headache1915
    Nasopharyngitis1512
    Vomiting1512
    Somnolence139
    Fatigue115
    Aggression105
    Abdominal Pain Upper98
    Cough95
    Nasal Congestion92
    Decreased Appetite82
    Abnormal Behavior74
    Dizziness75
    Irritability71
    Pharyngolaryngeal Pain74
    Diarrhea62
    Lethargy65
    Insomnia53
    Agitation41
    Anorexia43
    Head Injury40
    Constipation31
    Contusion31
    Depression31
    Fall32
    Influenza31
    Mood Altered31
    Affect Lability21
    Anxiety21
    Arthralgia20
    Confusional State20
    Conjunctivitis20
    Ear Pain21
    Gastroenteritis20
    Joint Sprain21
    Mood Swings21
    Neck Pain21
    Rhinitis20
    Sedation21

    In controlled pediatric clinical studies in patients 4-16 years of age, 7% of patients treated with immediate-release levetiracetam tablets and 9% of patients on placebo discontinued as a result of an adverse event.

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

    Comparison of Gender, Age and Race

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

    6.2 Postmarketing Experience

    The following adverse reactions 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, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with immediate-release levetiracetam use; recovery was observed in majority of cases where immediate-release levetiracetam was discontinued.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Levetiracetam extended-release 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 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/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 1800 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 1800 mg/kg/day.

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

    Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at oral doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/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 in pediatric patients 12 years of age and older has been established based on pharmacokinetic data in adults and adolescents using levetiracetam extended-release tablets and efficacy and safety data in controlled pediatric studies using immediate-release levetiracetam [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

    A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (levetiracetam N=64; placebo N=34). The target dose of immediate-release levetiracetam was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which assesses various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo- and levetiracetam-treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority between the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), 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/6-18 indicated a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with levetiracetam [see Warnings and Precautions (5.1)].

    Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not indicate a potential for age-specific toxicity.

    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 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 Renal Impairment

    The effect of levetiracetam extended-release tablets on renally impaired patients was not assessed in a controlled study. However, it is expected that the effect on levetiracetam extended-release-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 (2.2)].

  • 10 OVERDOSAGE

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

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

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

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

    The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, 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:

    The structural formula of Levetiracetam.

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

    Levetiracetam extended-release tablets USP contain the labeled amount of levetiracetam.  Inactive ingredients: cetostearyl alcohol, compressible sugar, copovidone, talc, polyvinyl alcohol-polyethylene glycol copolymer, magnesium stearate, colloidal silicon dioxide, titanium dioxide, kaolin, sodium lauryl sulfate, carnauba wax.

    USP Dissolution Test pending.

  • 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 on QTc prolongation is expected to be the same as that of immediate-release levetiracetam. The effect of immediate-release 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

    Overview

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

    Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra- and inter-subject variability. Levetiracetam is not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged. The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is approximately 6-8 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 (AUC0-24) was similar to extent of exposure after multiple dose immediate-release tablets intake. Cmax and Cmin 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 (Tmax) 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 Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

    Specific 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 61-88 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

    An open label, multicenter, parallel-group, two-arm study was conducted to evaluate the pharmacokinetics of levetiracetam extended-release tablets in pediatric patients (13 to 16 years old) and in adults (18 to 55 years old) with epilepsy. Levetiracetam extended-release oral tablets (1000 mg to 3000 mg) were administered once daily with a minimum of 4 days and a maximum of 7 days of treatment to 12 pediatric patients and 13 adults in the study. Dose-normalized steady-state exposure parameters, Cmax and AUC, were comparable between pediatric and adult patients.

    Pregnancy

    Levetiracetam extended-release levels may decrease during pregnancy.

    Gender

    Extended-release levetiracetam Cmax was 21-30% higher and AUC was 8-18% 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 on renally impaired patients was not assessed in a controlled study. However, it is expected that the effect on levetiracetam extended-release-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 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 (CLcr = 50-80 mL/min), 50% in the moderate group (CLcr = 30-50 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 >80mL/min). Approximately 50% of the pool of levetiracetam in the body is removed during a standard 4- hour hemodialysis procedure [see Dosage and Administration (2.2)].

    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 Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

    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 extended-release levetiracetam is expected to be essentially the same as that with immediate-release levetiracetam tablets.

    Phenytoin

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

    Valproate

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

    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 (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.

    Warfarin

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

    Probenecid

    Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. Cssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. 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 1800 mg/kg/day. The highest dose is 6 times the maximum recommended daily human dose (MRHD) of 3000 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 4000 mg/kg/day, lowered to 3000 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 (3000 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 1800 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 levetiracetam extended-release tablets as adjunctive therapy in partial onset seizures in adults was established in one multicenter, randomized, double-blind, placebo-controlled clinical study in patients who had refractory partial onset seizures with or without secondary generalization. This was supported by the demonstration of efficacy of immediate-release levetiracetam tablets (see below) in partial seizures in three multicenter, randomized, double-blind, placebo-controlled clinical studies in adults, as well as a demonstration of comparable bioavailability between the extended-release and immediate-release formulations [see Clinical Pharmacology (12.3)] in adults. The effectiveness for levetiracetam extended-release tablets as adjunctive therapy in partial onset seizures in pediatric patients, 12 years of age and older, was ‎based upon a single pharmacokinetic study showing comparable pharmacokinetics of levetiracetam extended-release in adults and adolescents ‎‎[see Clinical Pharmacology (12.3)]. All studies are described below.‎ ‎

    14.1 Levetiracetam Extended-release Tablets in Adults

    The effectiveness of levetiracetam extended-release 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 (Study 1).

    Study 1‎

    Patients enrolled in Study 1 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 AED, 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 1000 mg (two 500 mg tablets) of levetiracetam extended-release (N=79), given once daily over a 12-week treatment period.

    The primary efficacy endpoint in Study 1 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 1000 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.

    14.2 Immediate-release Levetiracetam in Adults

    The effectiveness of immediate-release levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization (Studies 2, 3, and 4). The tablet formulation was used in all three studies. In these studies, 904 patients were randomized to placebo, levetiracetam 1000 mg, levetiracetam 2000 mg, or levetiracetam 3000 mg/day. Patients enrolled in Study 2 or Study 3 had refractory partial onset seizures for at least two years, and had taken two or more AEDs. Patients enrolled in Study 4 had refractory partial onset seizures for at least 1 year and had taken one AED. At the time of the study, patients were taking a stable dose regimen of at least one AED, and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.

    Study 2

    Study 2 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States, comparing immediate-release levetiracetam 1000 mg/day (N=97), immediate-release levetiracetam 3000 mg/day (N=101), and placebo (N=95), given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients in Study 2 were randomized to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 2 was a between-group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of Study 2 are displayed in Table 6.

    Table 6: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 2
    Placebo
    (N=95)    		Immediate-release Levetiracetam
    1000 mg/day
    (N=97)    		Immediate-release Levetiracetam
    3000 mg/day
    (N=101)
    Percent reduction in partial seizure frequency over placebo–26.1%*30.1%*

    * statistically significant versus placebo

    The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 2 is presented in Figure 1.

    Figure 1: Responder Rate (≥50% Reduction From Baseline) in Study 2‎

    Figure 1: Responder Rate (≥50% Reduction From Baseline) in Study 2

    * statistically significant versus placebo

    Study 3

    Study 3 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe, comparing immediate-release levetiracetam 1000 mg/day (N=106), immediate-release levetiracetam 2000 mg/day (N=105), and placebo (N=111), given in equally divided doses twice daily.

    The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients in Study 3 were randomized to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 3 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). The results of the analysis of Period A are displayed in Table 7.

    Table 7: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 3: Period A
    Placebo
    (N=111)    		Immediate-release Levetiracetam
    1000 mg/day
    (N=106)    		Immediate-release
    Levetiracetam
    2000 mg/day
    (N=105)
    Percent reduction in partial seizure frequency over placebo–17.1%*21.4%*

    * statistically significant versus placebo

    The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 3 is presented in Figure 2.

    Figure 2: Responder Rate (≥50% Reduction From Baseline) in Study 3: Period A

    Figure 2: Responder Rate (≥50% Reduction From Baseline) in Study 3: Period A

    * statistically significant versus placebo

    The comparison of immediate-release levetiracetam 2000 mg/day to immediate-release levetiracetam 1000 mg/day for responder rate in Study 3 was statistically significant (P=0.02). Analysis of the trial as a cross-over study yielded similar results.

    Study 4

    Study 4 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing immediate-release levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients in Study 4 were randomized to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness in Study 4 was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency). Table 8 displays the results of Study 4.

    Table 8: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 4‎
    Placebo
    (N=104)    		Immediate-release Levetiracetam
    3000 mg/day
    (N=180)
    Percent reduction in partial seizure frequency over placebo–23.0%*

    * statistically significant versus placebo

    The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) in Study 4 is presented in Figure 3.

    Figure 3: Responder Rate (≥50% Reduction From Baseline) in Study 4‎

    Figure 3: Responder Rate (≥50% Reduction From Baseline) in Study 4‎

    * statistically significant versus placebo

    14.3 Immediate-release Levetiracetam in Pediatric Patients 4 Years to 16 Years

    The use of levetiracetam extended-release tablets in pediatric patients 12 years of age and older is supported by Study 5, which was conducted using immediate-release levetiracetam. Levetiracetam extended-release tablets are not indicated in children below 12 years of age.

    Study 5

    The effectiveness of immediate-release levetiracetam as adjunctive therapy in pediatric patients was established in a multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (Study 5). Eligible patients on a stable dose of 1-2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either immediate-release levetiracetam or placebo. The enrolled population included 198 patients (levetiracetam N=101; placebo N=97) with refractory partial onset seizures, with or without secondarily generalization. Study 5 consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, the immediate-release levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness in Study 5 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week). Table 9 displays the results of this study.

    Table 9: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 5
    Placebo
    (N=97)    		Immediate-release Levetiracetam
    (N=101)
    Percent reduction in partial seizure frequency over placebo–26.8%*

    *statistically significant versus placebo

    The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) in Study 5 is presented in Figure 4.

    Figure 4: Responder Rate (≥ 50% Reduction From Baseline) in Study 5‎

    Figure 4: Responder Rate (≥ 50% Reduction From Baseline) in Study 5‎

    * statistically significant versus placebo

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    Levetiracetam Extended-release Tablets USP, 500 mg are white, oblong-shaped, film-coated tablets debossed with "500" on one side. They are supplied in white HDPE bottles containing 60 tablets (NDC: 69076-500-60).

    Levetiracetam Extended-release Tablets USP, 750 mg are white, oblong-shaped, film-coated tablets debossed with "750" on one side. They are supplied in white HDPE bottles containing 60 tablets (NDC: 69076-750-60).

    16.2 Storage

    Store at 25°C (77°F); excursions permitted to 15⁰ to 30°C (59⁰ to 86°F) [see USP Controlled Room Temperature].

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved Patient Labeling (Medication Guide).

    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 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 once daily 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 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)].

    Dexcel Pharma Technologies Ltd
    10 Hakidma St.
    Yokneam 2069200,
    Israel

     

    Manufactured For:
    QUINN PHARMACEUTICALS, LLC
    WWW.QUINNRX.COM
    Ph: 844-477-8466
    Rev. 01/16 (5)

  • MEDICATION GUIDE

    Patient should be instructed to take extended-release levetiracetam tablets only as prescribed.

    Levetiracetam Extended-Release Tablets

    Read this Medication Guide before you start taking extended-release levetiracetam 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 extended-release levetiracetam tablets?

    Like other antiepileptic drugs, extended-release levetiracetam 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 extended-release levetiracetam tablets without first talking to a healthcare provider.

    Stopping extended-release levetiracetam 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 schedule

    Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

    What are extended-release levetiracetam tablets?

    Extended-release levetiracetam tablet is a prescription medicine 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 extended-release levetiracetam 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 extended-release levetiracetam tablets provided below.

    Tell your pharmacist immediately if you think you have been given the wrong medicine.

    500 mg levetiracetam extended-release tablets are white, oblong-shaped, film-coated extended-release tablets debossed with "500" on one side and plain on the other side.

    750 mg levetiracetam extended-release tablets are white, oblong-shaped, film-coated extended-release tablets debossed with "750" on one side and plain on the other side. 

    What should I tell my healthcare provider before starting extended-release levetiracetam tablets?

    Before taking extended-release levetiracetam 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 extended-release levetiracetam tablets will harm your unborn baby. You and your healthcare provider will have to decide if you should take extended-release levetiracetam tablets while you are pregnant. If you become pregnant while taking extended-release levetiracetam 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 the registry is to collect information about the safety of extended-release levetiracetam 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 extended-release levetiracetam 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 extended-release levetiracetam tablets?

    Take extended-release levetiracetam tablets exactly as prescribed.

    Your healthcare provider will tell you how much extended-release levetiracetam tablets to take and when to take it. Extended-release levetiracetam tablets are usually taken once a day. Take extended-release levetiracetam 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 extended-release levetiracetam tablets with or without food.

    Swallow the tablets whole. Do not chew, break, or crush tablets.

    If you miss a dose of extended-release levetiracetam 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 much extended-release levetiracetam tablets, call your local Poison Control Center or go to the nearest emergency room right away.

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

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

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

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

    Extended-release levetiracetam 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)

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

    • sleepiness
    • weakness
    • dizziness
    • infection

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

    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 extended-release levetiracetam 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 Quinn Pharmaceuticals at 1-844-477-8466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    How should I store extended-release levetiracetam tablets?

    • Store extended-release levetiracetam tablets at room temperature, 20 to 25ºC (68 to 77ºF) [see USP Controlled Room Temperature] away from heat and light.
    • Keep extended-release levetiracetam tablets and all medicines out of the reach of children.

    General information about extended-release levetiracetam tablets.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use extended-release levetiracetam tablets for a condition for which it was not prescribed. Do not give extended-release levetiracetam 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 extended-release levetiracetam tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about extended-release levetiracetam tablets that is written for health professionals.

    What are the ingredients of extended-release levetiracetam tablets?

    Levetiracetam extended-release tablet active ingredient: levetiracetam

    Inactive ingredients: cetostearyl alcohol, compressible sugar, copovidone, talc, polyvinyl alcohol-polyethylene glycol copolymer, magnesium stearate, colloidal silicon dioxide, titanium dioxide, kaolin, sodium lauryl sulfate, carnauba wax.

    USP Dissolution Test pending.

    This Medication Guide has been approved by the US Food and Drug Administration.

    Rx only

  • PRINCIPAL DISPLAY PANEL

    NDC 69076-500-60
    Once Daily Dosing
    Levetiracetam
    Extended-release Tablets USP
    500 mg

    PRINCIPAL DISPLAY PANEL NDC: <a href=/NDC/69076-500-60>69076-500-60</a> Once Daily Dosing Levetiracetam Extended-release Tablets USP 500 mg

  • PRINCIPAL DISPLAY PANEL

    NDC 69076-750-60
    Once Daily Dosing
    Levetiracetam
    Extended-release Tablets USP
    750 mg

    PRINCIPAL DISPLAY PANEL NDC: <a href=/NDC/69076-750-60>69076-750-60</a> Once Daily Dosing Levetiracetam Extended-release Tablets USP 750 mg

  • INGREDIENTS AND APPEARANCE
    LEVETIRACETAM 
    levetiracetam tablet, film coated, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69076-500
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LEVETIRACETAM (UNII: 44YRR34555) (LEVETIRACETAM - UNII:44YRR34555) LEVETIRACETAM500 mg
    Inactive Ingredients
    Ingredient NameStrength
    CETOSTEARYL ALCOHOL (UNII: 2DMT128M1S)  
    SUCROSE (UNII: C151H8M554)  
    COPOVIDONE (UNII: D9C330MD8B)  
    TALC (UNII: 7SEV7J4R1U)  
    POLYVINYL ALCOHOL GRAFT POLYETHYLENE GLYCOL COPOLYMER (3:1; 45000 MW) (UNII: 23ZQ42JZZH)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    KAOLIN (UNII: 24H4NWX5CO)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CARNAUBA WAX (UNII: R12CBM0EIZ)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeOVAL (oblong-shaped) Size19mm
    FlavorImprint Code 500
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69076-500-6060 in 1 BOTTLE; Type 0: Not a Combination Product06/01/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20216706/01/2016
    LEVETIRACETAM 
    levetiracetam tablet, film coated, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 69076-750
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LEVETIRACETAM (UNII: 44YRR34555) (LEVETIRACETAM - UNII:44YRR34555) LEVETIRACETAM750 mg
    Inactive Ingredients
    Ingredient NameStrength
    CETOSTEARYL ALCOHOL (UNII: 2DMT128M1S)  
    SUCROSE (UNII: C151H8M554)  
    COPOVIDONE (UNII: D9C330MD8B)  
    TALC (UNII: 7SEV7J4R1U)  
    POLYVINYL ALCOHOL GRAFT POLYETHYLENE GLYCOL COPOLYMER (3:1; 45000 MW) (UNII: 23ZQ42JZZH)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    KAOLIN (UNII: 24H4NWX5CO)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    CARNAUBA WAX (UNII: R12CBM0EIZ)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeOVAL (oblong-shaped) Size19mm
    FlavorImprint Code 750
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 69076-750-6060 in 1 BOTTLE; Type 0: Not a Combination Product06/01/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20216706/01/2016
    Labeler - Quinn Pharmaceuticals, LLC (079421782)
    Registrant - Dexcel Pharma Technologies Ltd. (600534200)
    Establishment
    NameAddressID/FEIBusiness Operations
    Dexcel Pharma Technologies Ltd.600534200ANALYSIS(69076-750, 69076-500) , LABEL(69076-750, 69076-500) , MANUFACTURE(69076-750, 69076-500) , PACK(69076-750, 69076-500)
    Establishment
    NameAddressID/FEIBusiness Operations
    Zhejiang Huahai Pharmaceutical Co., Ltd.421262001API MANUFACTURE(69076-750, 69076-500)
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