Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Multiorgan Hypersensitivity
Newly added
subsection:
Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as
multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs,
including levetiracetam. These
events can be fatal or life-threatening, particularly if diagnosis and
treatment do not occur as early as possible. DRESS typically, although not
exclusively, presents with fever, rash, lymphadenopathy, and/or facial
swelling, in association with other organ system involvement, such as
hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis,
sometimes resembling an acute viral infection. Eosinophilia is often present.
Because this disorder is variable in its expression, other organ systems not
noted here may be involved. It is important to note that early manifestations
of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is
not evident. If such signs or symptoms
are present, the patient should be evaluated immediately. SPRITAM
should be discontinued if an alternative etiology for the signs or symptoms
cannot be established [See Contraindication (4)].
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.2 Postmarketing
Experience
Additions and/or
revisions underlined:
The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
The
listing is alphabetized: abnormal liver function test, acute kidney injury,
agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with
eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic
failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive
disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression
identified in some of these cases), panic attack, thrombocytopenia, weight
loss, and worsening of seizures including in patients with SCN8A mutations.
Alopecia has been reported with levetiracetam use; recovery was observed in
majority of cases where levetiracetam was discontinued.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or
revisions underlined:
What are the possible side effects of SPRITAM?
…
a serious allergic reaction that may
affect your skin or other parts of your body such as your liver, kidneys, heart,
or blood cells. This allergic reaction
can be life-threatening and can cause death,
particularly if it is not treated as early
as possible. Call your healthcare provider right away if you have:
…
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
…
DRESS/Multiorgan Hypersensitivity
Instruct patients
and caregivers that a fever or rash associated with signs of other organ system
involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related
and should be reported to their healthcare provider immediately. SPRITAM should
be discontinued immediately if a serious
hypersensitivity reaction is suspected [see Warnings and Precautions
(5.6)].
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Withdrawal Seizures
(Additions and/or
revisions underlined)
As
with most antiepileptic
drugs, SPRITAM should generally be withdrawn gradually because of
the risk of increased seizure frequency and status epilepticus. If
withdrawal is needed because of a serious adverse reaction, rapid
discontinuation can be considered.
6
Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or
revisions underlined)
…
Table
3: Adverse Reactions in Pooled
Placebo-Controlled, Adjunctive Studies in Adults with Partial-Onset Seizures
…
Table
5: Adverse Reactions in Pooled
Placebo-Controlled, Adjunctive Studies in Pediatric Patients 4 to 16
Years of Age with Partial-Onset Seizures
…
Myoclonic
Seizures
Although
the pattern of adverse reactions in this study seems somewhat different from that
seen in patients with partial-onset seizures, this is likely due to the
much smaller number of patients in this study compared to partial seizure
studies. The adverse reaction pattern for patients with JME is expected to be
essentially the same as for patients with partial seizures.
…
Table
6: Adverse Reactions in a Placebo-Controlled,
Adjunctive Study in Patients 12 Years of Age and Older with Myoclonic Seizures
…
Primary
Generalized Tonic-Clonic Seizures
Although
the pattern of adverse reactions in this study seems somewhat different from
that seen in patients with partial-onset seizures, this is likely due to
the much smaller number of patients in this study compared to partial seizure
studies. The adverse reaction pattern for patients with primary generalized
tonic-clonic (PGTC) seizures is expected to be essentially the same as for
patients with partial seizures.
…
Table
8: Adverse Reactions in a
Placebo-Controlled, Adjunctive Study in Patients 4 Years of Age and
Older with PGTC Seizures
…
6.2 Postmarketing Experience
(Additions and/or
revisions underlined)
The
following adverse reactions have been identified during postapproval use of
levetiracetam. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
The
listing is alphabetized: abnormal liver function test, acute kidney injury,
agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with
eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme,
hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis,
pancytopenia (with bone marrow suppression identified in some of these cases),
panic attack, thrombocytopenia, weight loss, and worsening of seizures.
Alopecia has been reported with levetiracetam use; recovery was observed in
majority of cases where levetiracetam was discontinued.
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion)
Pregnancy
Exposure Registry
There
is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to antiepileptic drugs (AEDs), including SPRITAM, during pregnancy.
Encourage women who are taking SPRITAM 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 levetiracetam 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 [see Human
Data]. 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 [see Animal Data].
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 [see
Warnings and Precautions (5.10)].
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/m2) 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/m2 basis.
Oral
administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats
throughout pregnancy and lactation let 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/m2 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/m2 basis).
8.2 Lactation
(PLLR conversion)
Risk
Summary
Levetiracetam
is excreted in human milk. There are no data on the effects of levetiracetam 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 SPRITAM and any potential adverse effects
on the breastfed infant from SPRITAM or from the underlying maternal condition.
8.4 Pediatric Use
(Additions and/or
revisions underlined)
SPRITAM
is not recommended for pediatric patients that weigh 20 kg or less. The
following sections describe age appropriate indications.
Partial-Onset
Seizures
The
safety and effectiveness of SPRITAM have been established for the treatment
of partial- onset seizures in pediatric patients 4 years of age and older. Use
is based on controlled studies in adult patients and efficacy data in 198
pediatric patients 4 to 16 years of age treated with levetiracetam with partial-onset
seizures [see Clinical Pharmacology
(12.3) and Clinical Studies (14.1)].
Safety
and effectiveness for the treatment of partial-onset seizures in pediatric
patients below the age of 4 years have not been established.
A
3-month, randomized, double-blind, placebo-controlled study was conducted to
assess the neurocognitive and behavioral effects of levetiracetam as adjunctive
therapy in 98 (levetiracetam N=64, placebo N=34) pediatric patients, 4 to 16
years of age, 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 levetiracetam-treated
patients in aggressive behavior, one of the eight syndrome scores [see Warnings and Precautions (5.1)].
Myoclonic
Seizures
The
safety and effectiveness of SPRITAM have been established as adjunctive
treatment of myoclonic seizures in pediatric patients 12 years of age and older
with juvenile myoclonic epilepsy. Use is based on one controlled study that
included 113 adult and pediatric patients as young as 12 years of age treated
with levetiracetam with juvenile myoclonic epilepsy [see Clinical Studies (14.2)].
Safety
and effectiveness as adjunctive therapy for the treatment of myoclonic seizures
in pediatric patients below the age of 12 years have not been established.
Primary
Generalized Tonic-Clonic Seizures
The
safety and effectiveness of SPRITAM have been established 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. Use is
based on one controlled study that included 164 adult and pediatric patients
treated with levetiracetam with generalized tonic clonic seizures [see Clinical Studies (14.3)].
Safety
and effectiveness as adjunctive therapy for the treatment of primary
generalized tonic- clonic seizures in pediatric patients below the age of 6
years have not been established.
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/m2 basis) did not demonstrate
adverse effects on postnatal development.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Do not stop
SPRITAM without first talking to a healthcare provider.
- Suicidal thoughts or
actions can be caused by things other than medicines. If you have suicidal thoughts
or actions, your healthcare provider may check for other causes.
How can I watch
for early symptoms of suicidal thoughts and actions?
Pay attention to
any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up
visits with your healthcare provider as scheduled.
Call your healthcare
provider between visits as needed, especially if you are worried about symptoms.
What is SPRITAM?
SPRITAM
is a prescription medicine taken by mouth that is used to treat partial-onset
seizures in people 4 years of age and older weighing more than 20 kg (44
pounds).
SPRITAM
is a prescription medicine taken by mouth that is used with other medicines to treat:
- primary generalized
tonic-clonic seizures in people 6 years of age and older with certain types of generalized
epilepsy.
It
is not known if SPRITAM is safe or effective in children under:
- 6 years of age to
treat primary generalized tonic-clonic seizures
SPRITAM
is not recommended for children that weigh 20 kg (44 pounds) or less.
…
What should I tell
my healthcare provider before starting SPRITAM?
Before
taking SPRITAM, tell your healthcare provider about all of your medical
conditions, including if you:
have or have had
depression, mood problems or suicidal thoughts or behavior.
have kidney problems.
are pregnant or planning
to become pregnant. It is not known if SPRITAM will harm your unborn baby. You and
your healthcare provider will have to decide if you should take SPRITAM while you
are pregnant. If you become pregnant while
taking SPRITAM, talk to your healthcare provider about registering with the
North American Antiepileptic Drug Pregnancy Registry. You can enroll in this
registry by calling 1-888-233-2334 or go to http://www.aedpregnancyregistry.org.
The purpose of the registry is to collect information about the safety of
SPRITAM and other antiepileptic medicine during pregnancy.
- are breastfeeding or
plan to breastfeed. SPRITAM can pass into your breast milk. It is not known
if the SPRITAM that passes into your breast milk can harm your baby. Talk to
your doctor about the best way to feed your baby while you receive SPRITAM.
Tell
your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
Do not start a new medicine without first talking with your healthcare
provider.
…
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide). Psychiatric
Reactions and Changes in Behavior
Advise
patients that SPRITAM may cause changes in behavior (e.g. aggression,
agitation, anger, anxiety, apathy, depression, hostility, and irritability) and
psychotic symptoms [see Warnings and
Precautions (5.1)].
Suicidal
Behavior and Ideation
Counsel
patients, their caregivers, and/or families that antiepileptic drugs (AEDs),
including SPRITAM, 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
(5.2)].
Effects
on Driving or Operating Machinery
Inform
patients that SPRITAM may cause dizziness and somnolence. Inform patients not
to drive or operate machinery until they have gained sufficient experience on
SPRITAM to gauge whether it adversely affects their ability to drive or operate
machinery [see Warnings and Precautions
(5.3)].
Anaphylaxis
and Angioedema
Advise
patients to discontinue SPRITAM and seek medical care if they develop signs and
symptoms of anaphylaxis or angioedema [see
Warnings and Precautions (5.4)].
Dermatological
Adverse Reactions
Advise
patients that serious dermatological adverse reactions have occurred in
patients treated with SPRITAM and instruct them to call their physician
immediately if a rash develops [see Warnings
and Precautions (5.5)].
Withdrawal
of SPRITAM
Advise
patients and caregivers not to discontinue use of SPRITAM without consulting
with their healthcare provider. SPRITAM should normally be gradually withdrawn
to reduce the potential of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].
Pregnancy
Advise
patients to notify their healthcare provider if they become pregnant or intend
to become pregnant during SPRITAM therapy. Encourage patients to enroll in the
North American Antiepileptic Drug (NAAED) pregnancy registry if they become
pregnant [see Use in Specific Populations
(8.1)].
Administration
Information
Advise
patients that SPRITAM (levetiracetam) tablet(s) for oral suspension is intended
to disintegrate in the mouth when taken with a sip of liquid. As a primary
method of administration, place tablet on the tongue with a dry hand, follow
with a sip of liquid and swallow only after the
tablet
disintegrates. Advise patients not to swallow SPRITAM intact. Partial tablets
should not be administered [see Dosage
and Administration (2.1)].
Alternately,
add whole SPRITAM tablet(s) to a small volume of liquid in a cup (one
tablespoon or enough to cover the medicine). Allow the tablet(s) to disperse
prior to consuming the entire contents immediately. After administration of the
suspension, re-suspend any residue by adding an additional small volume of
liquid, and swallow the full amount.
No
attempts should be made to administer partial quantities of the dispersed
tablet(s) [see Dosage and Administration
(2.1)].
Instruct
patients to peel the foil from the blister by bending up and lifting the peel
tab around the blister seal.
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