"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"...
- Patient Information:
Details with Side Effects
In some patients KEPPRA causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult and pediatric partial onset seizure studies.
A total of 13.3% of adult KEPPRA-treated patients and 37.6% of pediatric KEPPRA-treated patients (4 to 16 years of age) compared to 6.2% and 18.6% of adult and pediatric placebo patients respectively, 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 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 pediatric patients 1 month to < 4 years of age, irritability was reported in 11.7% of the KEPPRA-treated patients compared to 0% of placebo patients.
A total of 1.7% of adult KEPPRA-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult KEPPRA-treated patients and in 0.5% of placebo patients. Overall, 10.9% of KEPPRA-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients.
One percent of adult KEPPRA-treated patients, 2% of children 4 to 16 years of age, and 17% of children 1 month to < 4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% respectively, in the placebo patients. In the controlled study that assessed the neurocognitive and behavioral effects of KEPPRA in pediatric patients 4 to 16 years of age, 1 (1.6%) KEPPRA-treated patient experienced paranoia compared to no placebo patients. There were 2 (3.1%) KEPPRA-treated patients that experienced confusional state compared to no placebo patients [see Use In Specific Populations].
Two (0.3%) adult KEPPRA-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. 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.
The above psychiatric signs and symptoms should be monitored.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including KEPPRA, 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
|Indication||Placebo Patients with Events Per 1000 Patients||Drug Patients with Events Per 1000 Patients||Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients||Risk Difference: Additional Drug Patients with Events Per 1000 Patients|
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 KEPPRA or any other AED must balance the risk of suicidal thoughts or behaviors 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.
Somnolence And Fatigue
In some patients, KEPPRA causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial onset seizure studies. 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 seizure studies were comparable to those of the adult partial onset seizure studies.
In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of KEPPRA-treated patients reported somnolence, compared to 8.4% of placebo 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 the 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 patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.
In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of KEPPRA-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced due to asthenia.
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their ability to drive or operate machinery.
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. 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.
Coordination difficulties were only observed in the adult partial onset seizure studies. A total of 3.4% of adult KEPPRA-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued KEPPRA treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of 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 KEPPRA to gauge whether it could adversely affect their ability to drive or operate machinery.
Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.
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 KEPPRA-treated patients in controlled trials.
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.
Pediatric Patients 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 patients (statistically significant).
In the controlled trial, more KEPPRA-treated patients had a possibly clinically significant abnormally low WBC value (3.0% KEPPRA-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% KEPPRA-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.
In the controlled cognitive and neuropsychological safety study, 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).
Juvenile Myoclonic Epilepsy
Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.
Blood Pressure Increases
In a randomized, placebo-controlled study in patients aged 1 month to < 4 years of age, a significantly higher risk of at least one measured increase in diastolic blood pressure was observed in the KEPPRA-treated patients (17%) compared to the 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.
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.
Patient Counseling Information
See FDA-approved Patient Labeling (Medication Guide).
Counsel patients on the benefits and risks of receiving KEPPRA. Provide the Medication Guide to patients and/or caregivers, and instruct them to read the Medication Guide prior to taking KEPPRA. Instruct patients to take KEPPRA only as prescribed.
Suicidal Behavior and Ideation
Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including KEPPRA, 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 KEPPRA may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases, psychotic symptoms have occurred.
Effects on Driving or Operating Machinery
Inform patients that KEPPRA may cause dizziness and somnolence. Inform patients 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.
Dermatological Adverse Reactions
Advise patients that serious dermatological adverse reactions have occurred in patients treated with KEPPRA and instruct them to call their physician immediately if a rash develops.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during KEPPRA 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. Additionally, inform patients they can enroll in the UCB AED Pregnancy Registry and they or their healthcare provider can call 1888-537-7734 (toll free) [see Use In Specific Populations].
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
Keppra 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 with levetiracetam 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 old 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 tonicclonic 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 to 16 years old, 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 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].
Use In Patients With Impaired Renal Function
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see CLINICAL PHARMACOLOGY]. Dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see DOSAGE AND ADMINISTRATION].
Last reviewed on RxList: 3/19/2014
This monograph has been modified to include the generic and brand name in many instances.
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