Included as part of the PRECAUTIONS section.
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, 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 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 KEPPRAtreated 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-treated 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
In clinical studies, 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 KEPPRA in pediatric patients 4 to 16 years of age,
1.6% of KEPPRA-treated patients 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, 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.
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
||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
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 selfharm. Behaviors
of concern should be reported immediately to healthcare providers.
Somnolence And Fatigue
KEPPRA may cause somnolence and fatigue. 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.
In controlled trials of adult patients with epilepsy
experiencing 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 where there was no titration, about 45%
of patients receiving 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 placebotreated 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
In controlled clinical studies of adult patients with
epilepsy experiencing partial onset seizures, 15% of KEPPRAtreated patients
reported asthenia, compared to 9% 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 KEPPRAtreated 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 seizure studies were
comparable to those of the adult partial onset seizure studies.
Anaphylaxis And Angioedema
KEPPRA can cause anaphylaxis or angioedema after the
first dose or at any time during treatment. Signs and symptoms in cases reported
in the postmarketing setting have included hypotension, hives, rash,
respiratory distress, and swelling of the face, lip, mouth, eye, tongue,
throat, and feet. In some reported cases, reactions were lifethreatening and
required emergency treatment. If a patient develops signs or symptoms of
anaphylaxis or angioedema, KEPPRA should be discontinued and the patient should
seek immediate medical attention. KEPPRA should be discontinued permanently if
a clear alternative etiology for the reaction cannot be established [see CONTRAINDICATIONS].
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.
In controlled clinical studies in adult patients with
partial onset seizure studies, 3.4% of adult KEPPRA-treated patients experienced
coordination difficulties, (reported as either 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 KEPPRA-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.
KEPPRA can cause hematologic abnormalities. Hematologic
abnormalities occurred in clinical trials and included decreases in white blood
cell (WBC), neutrophil, and red blood cell (RBC) counts; decreases in
hemoglobin and hematocrit; and increases in eosinophil counts. Cases of
agranulocytosis, pancytopenia, and thrombocytopenia have been reported in the
postmarketing setting. A complete blood count is recommended in patients
experiencing significant weakness, pyrexia, recurrent infections, or
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
A total of 3.2% of KEPPRA-treated and 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 and 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.
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 Ã 109/L and -0.3
Ã 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% 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% of KEPPRA-treated patients versus 4.2% of placebotreated patients).
No patient was discontinued secondary to low WBC or neutrophil counts.
In the controlled cognitive and neuropsychological safety
study, 5 patients (8.6%) in the KEPPRA-treated group and two patients (6.1%) in
the placebo-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, a significantly higher risk of increased 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.
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
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 psychotic symptoms [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS AND PRECAUTIONS].
Anaphylaxis And Angioedema
Advise patients to discontinue KEPPRA and seek medical
care if they develop signs and symptoms of anaphylaxis or angioedema [see WARNINGS
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 [see WARNINGS AND PRECAUTIONS].
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 [see Use In Specific
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 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
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
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/.
Labor And Delivery
The effect of KEPPRA on labor and delivery in humans is
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 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 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 KEPPRA
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].
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].