Included as part of the PRECAUTIONS section.

Neuropsychiatric Adverse Reactions

KEPPRA XR (levetiracetam extended-release tablets) Tablets

In some patients experiencing partial onset seizures, KEPPRA XR (levetiracetam extended-release tablets) causes somnolence, dizziness, and behavioral abnormalities.

In the KEPPRA XR (levetiracetam extended-release tablets) double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of KEPPRA XR (levetiracetam extended-release tablets) -treated patients experienced somnolence compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of KEPPRA XR-treated patients compared to 2.5% of placebo-treated patients.

A total of 6.5% of KEPPRA XR (levetiracetam extended-release tablets) -treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of KEPPRA XR (levetiracetam extended-release tablets) -treated patients. Aggression was reported in 1.3% of KEPPRA XR (levetiracetam extended-release tablets) -treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to KEPPRA XR (levetiracetam extended-release tablets) was considerably smaller than the number of patients exposed to immediate-release KEPPRA tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release KEPPRA controlled trials may also occur in patients receiving KEPPRA XR (levetiracetam extended-release tablets) .

Immediate-Release KEPPRA Tablets

In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, immediate-release KEPPRA causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of immediate-release KEPPRA-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients.

A total of 3.4% of immediate-release KEPPRA-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients.

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

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-release KEPPRA-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient.

A total of 13.3% of immediate-release KEPPRA patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.

In addition, 4 (0.5%) immediate-release KEPPRA-treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months.

Withdrawal Seizures

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

Hematologic Abnormalities

Although there were no obvious hematologic abnormalities observed in treated patients in the KEPPRA XR (levetiracetam extended-release tablets) controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release KEPPRA controlled studies should be considered to be relevant for KEPPRA XR (levetiracetam extended-release tablets) -treated patients.

In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10⁶/mm³), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release KEPPRA-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant ( ≤ 2.8 x 10⁹/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant ( ≤ 1.0 x 10⁹/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.

Hepatic Abnormalities

There were no meaningful changes in mean liver function tests (LFT) in the KEPPRA XR (levetiracetam extended-release tablets) controlled trial. No patients were discontinued from the controlled trial for LFT abnormalities.

There were no meaningful changes in mean liver function tests (LFT) in controlled trials of immediate-release KEPPRA tablets in adult patients; lesser LFT abnormalities were similar in drug and placebo-treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

Laboratory Tests

Although effects on laboratory tests were not clinically significant with KEPPRA XR treatment, it is expected that the data from immediate-release KEPPRA tablets controlled studies would be considered relevant for KEPPRA XR (levetiracetam extended-release tablets) -treated patients.

Although most laboratory tests are not systematically altered with immediate-release KEPPRA treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

Patient Counseling Information

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

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised that KEPPRA XR (levetiracetam extended-release tablets) may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate heavy machinery or engage in other hazardous activities until they have gained sufficient experience on KEPPRA XR (levetiracetam extended-release tablets) to gauge whether it adversely affects their performance of these activities.

Patients should be advised that KEPPRA XR (levetiracetam extended-release tablets) may cause irritability and aggression.

In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of KEPPRA, which include agitation, anger, anxiety, apathy, depression, hostility, irritability and, in rare cases, psychotic symptoms and/or suicidal ideation. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Physicians should advise patients and caregivers to read the PATIENT INFORMATION leaflet which appears as the last section of the labeling.

Nonclinical Toxicology

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 corresponds to 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. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m² or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.

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 (approximately 6 times the maximum recommended human dose on a mg/m²or exposure basis).

Animal Toxicology And/Or Pharmacology

In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses.

Use In Specific Populations

Pregnancy

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. KEPPRA XR (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 (approximately 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 (approximately 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 (1.3 times 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).

UCB AED Pregnancy Registry

UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with all UCB antiepileptic drugs including KEPPRA XR (levetiracetam extended-release tablets) . To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free). Patients may also enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).

Labor And Delivery

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

Nursing Mothers

Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA XR (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.

Pediatric Use

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

Geriatric Use

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of KEPPRA XR (levetiracetam extended-release tablets) in these patients. It is expected that the safety of KEPPRA XR (levetiracetam extended-release tablets) in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release KEPPRA tablets.

Of the total number of subjects in clinical studies of immediate-release levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release KEPPRA in these patients.

A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses of immediate-release KEPPRA tablets for 10 days showed no pharmacokinetic differences related to age alone.

Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Use In Patients With Impaired Renal Function

The effect of KEPPRA XR (levetiracetam extended-release tablets) on renally impaired patients was not assessed in the well-controlled study. However, it is expected that the effect on KEPPRA XR (levetiracetam extended-release tablets) -treated patients would be similar to the effect seen in well-controlled studies of immediate-release KEPPRA tablets. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving KEPPRA XR [see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION].

Clearance of immediate-release levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance.

Last reviewed on RxList: 3/16/2009
This monograph has been modified to include the generic and brand name in many instances.