Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 18 December 2019

Indication(s)

1 INDICATIONS AND USAGE Extended-release levetiracetam tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy. Extended-release levetiracetam tablet is indicated for adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy (1)

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

EPNS 2019 Congress Highlights

EPNS 2019 Congress Highlights

The epgonline.org team is creating daily reports from the 13th European Paediatric Neurology Society (EPNS) Congress, held in Athens, Greece from 17th to 21st September 2019, to bring you coverage of cutting-edge science and advances in clinical care across all fields of paediatric neurology. 

Migraine Knowledge Centre

Migraine Knowledge Centre

The Migraine Knowledge Centre features latest research on the prevalence and impact of migraine, the proposed neurological basis of the condition (and how this is being translated into new and exciting drug therapies), as well as current patient care strategies collated from headache organisations worldwide.

Hereditary ATTR amyloidosis

Hereditary ATTR amyloidosis

Explore the pathophysiology, epidemiology and multi-system symptoms associated with hereditary ATTR amyloidosis, as well as how to achieve an early and accurate diagnosis.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS Extended-release levetiracetam tablets are contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4)]. Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 )
Adverse reactions
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)] Anaphylaxis and Angioedema [see Warnings and Precautions (5.4)] Serious Dermatological Reactions [see Warnings and Precautions (5.5)] Coordination Difficulties [see Warni ngs and Precautions (5.6)] Hematologic Abnormalities [see Warnings and Precautions (5.8)] Most common adverse reactions (incidence ≥5% more than placebo) include: somnolence and irritability (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Extended-Release Levetiracetam Tablets In the controlled clinical study in patients with partial onset seizures, the most common adverse reactions in patients receiving extended-release levetiracetam 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 receiving extended-release levetiracetam tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either extended-release levetiracetam tablets or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in the Placebo-Controlled, Add-On Study in Patients Experiencing Partial Onset Seizures Extended-Release Levetiracetam Tablets (N=77) % Placebo (N=79) % Influenza 8 4 Somnolence 8 3 Irritability 7 0 Nasopharyngitis 7 5 Dizziness 5 3 Nausea 5 3 Discontinuation or Dose Reduction in the Extended-Release Levetiracetam Tablets Controlled Clinical Study In the controlled clinical study, 5% of patients receiving extended-release levetiracetam 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 extended-release levetiracetam tablet-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash, and respiratory failure. Each of these adverse reactions led to discontinuation in a extended-release levetiracetam tablet-treated patient and no placebo-treated patients. Immediate-Release Levetiracetam Tablets Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the extended-release levetiracetam 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 extended-release levetiracetam 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 Immediate-Release Levetiracetam Tablets (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 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 tablets 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 tablets and were more common than in pediatric patients on 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. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures Immediate-Release Levetiracetam Tablets (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Abdominal Pain Upper 9 8 Cough 9 5 Nasal Congestion 9 2 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In 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 extended-release levetiracetam 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, acute kidney injury, anaphylaxis, angioedema, 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 tablets use; recovery was observed in majority of cases where immediate-release levetiracetam tablets were discontinued.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Initiate treatment with a dose of 1,000 mg once daily; increase by 1,000 mg every 2 weeks to a maximum recommended dose of 3,000 mg once daily (2) See full prescribing information for use in patients with impaired renal function (2.1) 2.1 Recommended Dosing Extended-release levetiracetam tablets are administered once daily. Initiate treatment with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg/day. 2.2 Dosage Adjustments in Adult Patients with Renal Impairment Extended-release levetiracetam 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, creatinine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: [140-age (years)] x weight (kg) (x0.85 for female patients) CLcr= --------------------------------------------------------------------------- 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 > 80 1000 to 3000 Every 24 hours Mild 50 to 80 1000 to 2000 Every 24 hours Moderate 30 to 50 500 to 1500 Every 24 hours Severe < 30 500 to 1000 Every 24 hours
Use in special populations
8 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 (5.9, 8.1) 8.1 Pregnancy Extended-release levetiracetam tablets levels may decrease during pregnancy [see Warnings and Precautions (5.9)]. 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. Extended-release levetiracetam 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 extended-release levetiracetam tablets, physicians are advised to recommend that pregnant patients taking extended-release levetiracetam 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 extended-release levetiracetam 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 extended-release levetiracetam 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 extended-release levetiracetam tablets and efficacy and safety data in controlled pediatric studies using immediate-release levetiracetam tablets [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 tablets as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (immediate-release levetiracetam tablets N=64; placebo N=34). The target dose of immediate-release levetiracetam tablets 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 immediate-release levetiracetam tablet-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 to 18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6 to 18 indicated a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with immediate-release levetiracetam tablets [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 extended-release levetiracetam tablets in these patients. It is expected that the safety of extended-release levetiracetam 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 Renal Impairment The effect of extended-release levetiracetam tablets on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on extended-release levetiracetam tablet-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) ].
Pregnancy and lactation
8.3 Nursing Mothers Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from extended-release levetiracetam 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.

More information

Category Value
Authorisation number ANDA091360
Agency product number 44YRR34555
Orphan designation No
Product NDC 10370-214,10370-195
Date Last Revised 04-12-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 807832
Marketing authorisation holder Par Pharmaceutical, Inc.