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Keppra XR

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Keppra XR

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Psychiatric Reactions

Patients on KEPPRA XR should be monitored for behavioral abnormalities.

KEPPRA XR Tablets

A total of 6.5% of patients treated with KEPPRA XR experienced non-psychotic behavioral disorders (reported as irritability and aggression), compared to no patients on placebo. Irritability was reported in 6.5% of patients treated with KEPPRA XR. Aggression was reported in 1.3% of patients treated with KEPPRA XR.

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

There is considerably less controlled clinical trial experience with KEPPRA XR than with immediate-release KEPPRA tablets, and some adverse reactions observed with immediate-release KEPPRA may not have been detected in KEPPRA XR clinical trials because of limited number of patients. These adverse reactions may however occur in patients receiving KEPPRA XR.

Immediate-Release KEPPRA Tablets

A total of 13.3% of adult patients and 37.6% of pediatric patients (4 to 16 years of age) treated with immediate-release KEPPRA 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 6.2% and 18.6% 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 KEPPRA 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 KEPPRA tablets in that study [see Use in Specific Populations].

A total of 1.7% of adult patients treated with immediate-release KEPPRA discontinued treatment due to behavioral adverse events, compared to 0.2% of patients on placebo. The treatment dose was reduced in 0.8% of adult patients treated with immediate-release KEPPRA, compared to 0.5% of patients on placebo. Overall, 10.9% of pediatric patients treated with immediate-release KEPPRA experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of pediatric patients on placebo.

One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release KEPPRA experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and pediatric patients on placebo. In the controlled study that assessed the neurocognitive and behavioral effects of immediate-release KEPPRA in pediatric patients 4 to 16 years of age, 1 (1.6%) patient treated with KEPPRA experienced paranoia, compared to no patients on placebo. There were 2 (3.1%) patients treated with immediate-release KEPPRA who experienced confusional state, compared to no patients on placebo [see Use in Specific Populations].

Two (0.3%) adult patients treated with immediate-release KEPPRA were hospitalized, and their treatment was discontinued due to psychosis. In both patients, the psychosis event 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.

Suicidal Behavior And Ideation

Antiepileptic drugs (AEDs), including KEPPRA XR, 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
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

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 KEPPRA XR 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.

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 XR to gauge whether it adversely affects their ability to drive or operate machinery. In clinical trials of immediate-release KEPPRA, somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.

KEPPRA XR Tablets

In the KEPPRA XR double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of patients treated with KEPPRA XR experienced somnolence, compared to 2.5% of patients on placebo.

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

There is considerably less controlled clinical trial experience with KEPPRA XR than with immediate-release KEPPRA tablets, and some adverse reactions observed with immediate-release KEPPRA may not have been detected in KEPPRA XR clinical trials because of limited number of patients. These adverse reactions may however occur in patients receiving KEPPRA XR.

Immediate-Release KEPPRA Tablets

In general, the incidences of somnolence and fatigue in the pediatric partial onset 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 patients treated with immediate-release KEPPRA reported somnolence, compared to 8.4% of patients on placebo. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of patients treated with immediate-release KEPPRA, compared to no patients on placebo. About 3% of patients treated with immediate-release KEPPRA discontinued treatment due to somnolence, compared to 0.7% of patients on placebo. The dose was reduced due to somnolence in 1.4% of patients treated with immediate-release KEPPRA and in 0.9% of patients on placebo, while 0.3% of the patients treated with immediate-release KEPPRA were hospitalized due to somnolence.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of patients treated with immediate-release KEPPRA reported asthenia, compared to 9.1% of patients on placebo. Treatment was discontinued due to asthenia in 0.8% of patients treated with immediate-release KEPPRA, compared to 0.5% of patients on placebo. The dose was reduced due to asthenia in 0.5% of patients treated with immediate-release KEPPRA and in 0.2% of patients on placebo.

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 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 XR 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

Patients should be monitored for coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA XR to gauge whether it could adversely affect their ability to drive or operate machinery.

A total of 3.4% of adult patients treated with immediate-release KEPPRA experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination), compared to 1.6% of patients on placebo. A total of 0.4% of patients in controlled trials discontinued immediate-release KEPPRA treatment due to ataxia, compared to no patients on placebo. In 0.7% of patients treated with immediate-release KEPPRA and in 0.2% of patients on placebo, 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.

Coordination difficulties were not observed in the KEPPRA XR controlled trial. There is considerably less controlled clinical trial experience with KEPPRA XR than with immediate-release KEPPRA tablets, and some adverse reactions observed with immediate-release KEPPRA may not have been detected in KEPPRA XR clinical trials because of limited number of patients. These adverse reactions may however occur in patients receiving KEPPRA XR

Withdrawal Seizures

Antiepileptic drugs, including KEPPRA XR, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalities

Although there were no obvious hematologic abnormalities observed in the KEPPRA XR controlled study, there is considerably less controlled clinical trial experience with KEPPRA XR than with immediate-release KEPPRA tablets, and some adverse reactions observed with immediate-release KEPPRA may not have been detected in KEPPRA XR clinical trials because of limited number of patients. These adverse reactions may however occur in patients receiving KEPPRA XR.

In controlled trials, a 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%), was seen in adult patients treated with immediate-release KEPPRA. A total of 3.2% of adult patients treated with immediate-release KEPPRA, and 1.8% of patients on placebo had at least one possibly significant ( ≤ 2.8 x 109/L) decreased WBC, and 2.4% of patients treated with immediate-release KEPPRA vs. 1.4% of patients on placebo had at least one possibly significant ( ≤ 1.0 x 109/L) decreased neutrophil count. Of the patients treated with immediate-release KEPPRA 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 KEPPRA, as compared to placebo. The mean decreases from baseline in the immediate-release KEPPRA 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 KEPPRA 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 KEPPRA, 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 KEPPRA-treated group had high eosinophil count values that were possibly clinically significant ( ≥ 10% or ≥ 0.7X109/L).

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

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

Counsel patients on the benefits and risks of receiving KEPPRA XR. Provide the Medication Guide to patients and/or caregivers, and instruct them to read the Medication Guide prior to taking KEPPRA XR. Instruct patients to take KEPPRA XR only as prescribed.

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including KEPPRA XR, 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 XR 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 KEPPRA, which include agitation, anger, anxiety, apathy, depression, hostility, and, in rare cases, psychotic symptoms.

Effects on Driving or Operating Machinery

Inform patients that KEPPRA XR may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on KEPPRA XR 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 KEPPRA XR 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 KEPPRA XR 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 1-888-537-7734 (toll free) [see Use In Specific Populations].

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 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).

Use In Specific Populations

Pregnancy

KEPPRA XR 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 XR 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 Registries

To provide information regarding the effects of in utero exposure to KEPPRA XR, physicians are advised to recommend that pregnant patients taking KEPPRA XR 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 in pregnant women being treated with all UCB antiepileptic drugs including KEPPRA XR. 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).

Labor And Delivery

The effect of KEPPRA XR on labor and delivery in humans is unknown.

Nursing Mothers

Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA XR, 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 in pediatric patients 12 years of age and older has been established based on pharmacokinetic data in adults and adolescents using KEPPRA XR and efficacy and safety data in controlled pediatric studies using immediate-release KEPPRA [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies].

Safety and effectiveness of KEPPRA XR in patients below the age of 12 years have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release KEPPRA as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (KEPPRA N=64; placebo N=34). The target dose of immediate-release KEPPRA 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 KEPPRA-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 KEPPRA [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.

Geriatric Use

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

The effect of KEPPRA XR on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on KEPPRA XR-treated patients would be similar to the effect seen in controlled studies of immediate-release KEPPRA tablets. 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 [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 8/15/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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