"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.
Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...
Behavioral Abnormalities And Psychotic Symptoms
KEPPRA may cause behavioral abnormalities and psychotic symptoms. Patients treated with KEPPRA should be monitored for psychiatric signs and symptoms.
In clinical studies using an oral formulation of KEPPRA, 13% of adult KEPPRA-treated patients and 38% of pediatric KEPPRA-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).
A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of an oral formulation of KEPPRA as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in KEPPRA-treated patients on aggressive behavior (one of eight behavior dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the KEPPRA-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult KEPPRA-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult KEPPRA-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of KEPPRA-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.
In clinical studies using an oral formulation of KEPPRA, 1% of KEPPRA-treated adult patients, 2% of KEPPRA-treated pediatric patients 4 to 16 years of age, and 17% of KEPPRA-treated pediatric patients 1 month to < 4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of KEPPRA in pediatric patients 4 to 16 years of age, 1.6% of KEPPRA-treated patient experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of KEPPRA-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use In Specific Populations].
In clinical studies, two (0.3%) KEPPRA-treated adult patients were hospitalized, and their treatment was discontinued due to psychosis. Both events 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 the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.
Somnolence And Fatigue
KEPPRA may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their ability to drive or operate machinery.
In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 15% of KEPPRA-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 in which there was no titration, about 45% of patients on KEPPRA 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of KEPPRA-treated patients, compared to 0% in the placebo group. About 3% of KEPPRA-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of KEPPRA-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the KEPPRA-treated patients were hospitalized due to somnolence.
In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 15% of KEPPRA-treated patients reported asthenia, compared to 9.1% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of KEPPRA-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of KEPPRA-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. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.
Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with KEPPRA. 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 KEPPRA has also been reported. KEPPRA 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.
KEPPRA may cause coordination difficulties. Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it could adversely affect their ability to drive or operate machinery.
In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, 3.4% of KEPPRA-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled clinical studies discontinued KEPPRA treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of KEPPRA-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment.
Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.
In controlled clinical studies using an oral formulation of KEPPRA in adult patients with partial onset seizures, minor but statistically significant decreases (compared to placebo) in total mean RBC (0.03 x 106/mm³), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in KEPPRA-treated patients. A total of 3.2% of KEPPRA-treated versus 1.8% of placebo-treated patients had at least one possibly significant ( ≤ 2.8 x 109/L) decreased WBC, and 2.4% of KEPPRA-treated versus 1.4% of placebo-treated patients had at least one possibly significant ( ≤ 1.0 x 109/L) decreased neutrophil count. Of the KEPPRA-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 a controlled study in pediatric patients age 4 years to < 16 years, statistically significant decreases in WBC and neutrophil counts were seen in KEPPRA-treated patients, as compared to placebo. The mean decreases from baseline in the KEPPRA-treated group were -0.4 × 109/L and -0.3 × 109/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in KEPPRA-treated patients, compared to a decrease of 4% in placebo-treated patients. More KEPPRA-treated patients had a possibly clinically significant abnormally low WBC value (3% of KEPPRA-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% on KEPPRA versus 4.2% on placebo). No patient was discontinued because of low WBC or neutrophil count.
In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of KEPPRA as adjunctive therapy in pediatric patients (4 to 16 years of age), two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the KEPPRA-treated group had high eosinophil count values that were possibly clinically significant ( ≥ 10% or ≥ 0.7X109/L).
Increase In Blood Pressure
In a randomized, placebo-controlled study in patients 1 month to < 4 years of age using an oral formulation of KEPPRA, a significantly higher risk of increased diastolic blood pressure was observed in the KEPPRA-treated patients (17%), compared to placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the KEPPRA and placebo treatment groups was not observed in the studies of older children or in adults.
Monitor patients 1 month to < 4 years of age for increases in diastolic blood pressure.
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
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).
Use In Specific Populations
Levetiracetam blood levels may decrease during pregnancy [see WARNINGS AND PRECAUTIONS].
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 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 during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m² basis).
To provide information regarding the effects of in utero exposure to KEPPRA, physicians are advised to recommend that pregnant patients taking KEPPRA 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/. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including KEPPRA. 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 1-888-537-7734 (toll free).
Labor And Delivery
The effect of KEPPRA on labor and delivery in humans is unknown.
Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of KEPPRA in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established [see Clinical Studies]. The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see DOSAGE AND ADMINISTRATION].
The safety and effectiveness of KEPPRA as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see Clinical Studies].
The safety and effectiveness of KEPPRA as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see Clinical Studies].
A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of KEPPRA as adjunctive therapy in 98 (KEPPRA N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. 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, on average, a worsening in KEPPRA-treated patients in aggressive behavior, one of the eight syndrome scores [see WARNINGS AND PRECAUTIONS].
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.
There were 347 subjects in clinical studies of levetiracetam that were 65 years old 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 KEPPRA 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].
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see CLINICAL PHARMACOLOGY]. Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see DOSAGE AND ADMINISTRATION].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/13/2014
Additional Keppra Injection Information
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