Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Withdrawal Seizures
(additions and/or
revisions are underlined)
As
with most
antiepileptic drugs, KEPPRA should generally be withdrawn gradually because
of the risk of increased seizure frequency and status
epilepticus. But if withdrawal is needed because of a serious adverse reaction,
rapid discontinuation can be considered.
6
Adverse Reactions
6.1 Clinical Trials Experience
(minor additions
and/or revisions throughout subsection; please refer to labeling for complete
information)
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and
Lactation Labeling Rule (PLLR) conversion)
Pregnancy
Exposure Registry
There
is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to antiepileptic drugs (AEDs), including KEPPRA, during pregnancy.
Encourage women who are taking KEPPRA during pregnancy to enroll in the North
American Antiepileptic Drug (NAAED) pregnancy registry by calling
1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
Risk
Summary
Prolonged
experience with KEPPRA in pregnant women has not identified a drug-associated
risk of major birth defects or miscarriage, based on published literature,
which includes data from pregnancy registries, and reflects experience over two
decades. In animal studies, levetiracetam produced developmental toxicity
(increased embryofetal and offspring mortality, increased incidences of fetal
structural abnormalities, decreased embryofetal and offspring growth,
neurobehavioral alterations in offspring) at doses similar to human therapeutic
doses.
In
the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively. The background risk of major birth defects and miscarriage
for the indicated population is unknown.
Clinical
Considerations
Levetiracetam
blood levels may decrease during pregnancy.
Physiological
changes during pregnancy may affect levetiracetam concentration. Decrease in
levetiracetam plasma concentrations has been observed during pregnancy. This
decrease is more pronounced during the third trimester. Dose adjustments may be
necessary to maintain clinical response.
Data
Human Data
While
available studies cannot definitively establish the absence of risk, data from
the published literature and pregnancy registries have not established an
association with levetiracetam use during pregnancy and major birth defects or
miscarriage.
Animal Data
When
levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to
pregnant rats during the period of organogenesis, reduced fetal weights and
increased incidence of fetal skeletal variations were observed at the highest
dose tested. There was no evidence of maternal toxicity. The no-effect dose for
adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is
approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a
body surface area (mg/m^2) basis.
Oral
administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant
rabbits during the period of organogenesis resulted in increased embryofetal
mortality and incidence of fetal skeletal variations at the mid and high dose
and decreased fetal weights and increased incidence of fetal malformations at
the high dose, which was associated with maternal toxicity. The no-effect dose
for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is
approximately equivalent to the MRHD on a mg/m^2 basis.
Oral
administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats
throughout pregnancy and lactation led to an increased incidence of fetal
skeletal variations, reduced fetal body weight, and decreased growth in
offspring at the mid and high doses and increased pup mortality and
neurobehavioral alterations in offspring at the highest dose tested. There was
no evidence of maternal toxicity. The no-effect dose for adverse effects on
pre- and postnatal development in rats (70 mg/kg/day) is less than the MRHD on
a mg/m^2 basis.
Oral
administration of levetiracetam to rats during the latter part 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/m^2 basis).
8.2 Lactation
(Pregnancy and
Lactation Labeling Rule (PLLR) conversion)
Risk
Summary
Levetiracetam
is excreted in human milk. There are no data on the effects of KEPPRA on the
breastfed infant, or the effects on milk production.
The
developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for KEPPRA and any potential adverse effects on
the breastfed infant from KEPPRA or from the underlying maternal condition.
8.4 Pediatric Use
(additions and/or
revisions are underlined)
The
safety and effectiveness of KEPPRA for the treatment of partial-onset
seizures in patients 1 month to 16 years of age have been established. The
dosing recommendation in these pediatric patients varies according to age group
and is weight-based.
The
safety and effectiveness of KEPPRA as adjunctive therapy for the
treatment of myoclonic seizures in adolescents 12 years of age and older with
juvenile myoclonic epilepsy have been established.
The
safety and effectiveness of KEPPRA as adjunctive therapy for the
treatment of primary generalized tonic-clonic seizures in pediatric patients 6
years of age and older with idiopathic generalized epilepsy have been
established.
Safety
and effectiveness for the treatment of partial-onset seizures in pediatric
patients below the age of 1 month; adjunctive therapy for the treatment of
myoclonic seizures in pediatric patients below the age of 12 years; and
adjunctive therapy for the treatment of primary generalized tonic-clonic
seizures in pediatric patients below the age of 6 years have not been
established.
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.
Juvenile
Animal Toxicity Data
Studies
of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52)
and dogs (dosed from postnatal weeks 3 through 7) 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/m^2 basis) did not demonstrate
adverse effects on postnatal development.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions and/or
revisions are underlined)
Psychiatric
Reactions and Changes in Behavior
Advise
patients and their caregivers that KEPPRA may cause changes in behavior (e.g., aggression,
agitation, anger, anxiety, apathy, depression, hostility, and irritability) and
psychotic symptoms.
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.
Anaphylaxis
and Angioedema
Advise
patients to discontinue KEPPRA and seek medical care if they develop signs and symptoms
of anaphylaxis or angioedema.
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.
Withdrawal
of KEPPRA
Advise
patients and caregivers not to discontinue use of KEPPRA without consulting with
their healthcare provider. KEPPRA should normally be gradually withdrawn to reduce
the potential of increased seizure frequency and status epilepticus.
Pregnancy
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.
Approved Drug Label (PDF)
4
Contraindications
Addition of the
following:
KEPPRA
is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions
have included anaphylaxis and angioedema.
5
Warnings and Precautions
5.4 Anaphylaxis and Angioedema
Addition of the following:
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 life- threatening 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.
6
Adverse Reactions
Additions and/or
revisions underlined:
The
following adverse reactions are discussed in more details in other sections of
labeling:
Anaphylaxis and Angioedema
6.2
Postmarketing Experience
The
following adverse reactions have been reported in patients receiving marketed
KEPPRA worldwide. The listing is alphabetized: abnormal liver function test,
acute kidney injury, anaphylaxis, angioedema, choreoathetosis …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Addition of the
following:
Who
should not take KEPPRA?
Do
not take KEPPRA if you are allergic to levetiracetam.
What
are the possible side effects of KEPPRA?
Call
your healthcare provider right away if you have any of these symptoms:
allergic
reactions such as swelling of the face, lips, eyes, tongue, and throat, trouble
swallowing or breathing, and hives.
PATIENT COUNSELING INFORMATION
Addition of the
following:
Anaphylaxis
and Angioedema
Advise
patients to discontinue KEPPRA and seek medical care if they develop signs and
symptoms of anaphylaxis or angioedema.
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