Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
…
The studies described below were conducted with
AUSTEDO tablets; adverse reactions with AUSTEDO XR extended-release tablets are
expected to be similar to AUSTEDO tablets.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions and/or revisions underlined:
Administration
Instructions
Instruct
patients
to swallow AUSTEDO XR or AUSTEDO whole and not to chew, crush, or break AUSTEDO
XR or AUSTEDO [see Dosage and
Administration (2.1)].
AUSTEDO XR
Advise
patients to take AUSTEDO XR with or without food in once-daily doses.
AUSTEDO
Advise
patients to take AUSTEDO with food. Advise patients to take daily dosages of 12
mg or higher in two divided doses (twice daily).
…
Dispense
with Medication Guide available at: www.tevausa.com/medguides
MEDICATION GUIDE
Additions and/or revisions underlined:
…
The
most common side effects of AUSTEDO XR are expected to be similar to AUSTEDO in
people with Huntington’s disease or tardive dyskinesia.
…
How
should I store AUSTEDO XR and AUSTEDO?
…
Other
Updates to NDA 208082
(Austedo) to align with combined labeling for NDA 216354 (Austedo XR)
Approved Drug Label (PDF)
8
Use in Specific Populations
8.4 Pediatric Use
Additions
underlined
Tourette syndrome
The
safety and effectiveness of AUSTEDO have not been established in pediatric patients
for the treatment of Tourette syndrome.
Efficacy
was not demonstrated in two randomized, double-blind, placebo-controlled
studies in pediatric patients aged 6 to 16 years with Tourette syndrome. One
study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the
other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943).
The studies included a total of 274 pediatric patients who received at least
one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both
studies was the change from baseline to end-of-treatment on the Yale Global Tic
Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of
deutetrabenazine on the YGTSS-TTS was not statistically significantly different
from placebo in either study. The placebo subtracted least squares means
difference in YGTSS-TTS from baseline to end-of-treatment was -0.7 (95% CI:
-4.1, 2.8) in the flexible dose study and -0.8 (95% CI: -3.9, 2.3) for the
primary analysis in the fixed dose study.
The
following adverse reactions were reported in frequencies of at least 5% of
pediatric patients treated with AUSTEDO and with a greater incidence than in
pediatric patients receiving placebo (AUSTEDO vs placebo): headache (includes:
migraine, migraine with aura, and headache; 13% vs 9%), somnolence (includes:
sedation, hypersomnia, and somnolence; 11% vs 2%), fatigue (8% vs 3%),
increased appetite (5% vs <1%), and increased weight (5% vs <1%).
Chorea associated
with Huntington’s disease and Tardive dyskinesia
The
safety and effectiveness of AUSTEDO have not been established in pediatric
patients for the treatment of chorea associated with Huntington’s disease or
for the treatment of tardive dyskinesia.
Juvenile
Animal Toxicity Data
Deutetrabenazine
orally administered to juvenile rats from postnatal days 21 through 70 (at 2.5,
5, or 10 mg/kg/day) resulted in an increased incidence of tremor,
hyperactivity, and adverse increases in motor activity at greater than or equal
to 5 mg/kg/day, and reduced body weight and food consumption at 10 mg/kg/day.
There was no reproductive or early embryonic toxicity up to the highest dose.
All drug-related findings were reversible after a drug-free period. The no
observed adverse effect level (NOAEL) in juvenile rats was 2.5 mg/kg/day. These
drug-related findings were similar to those observed in adult rats; however,
the juvenile rats were more sensitive.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Parkinsonism
(additions
underlined)
AUSTEDO
may cause parkinsonism in patients with Huntington’s disease or tardive
dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors.
rigidity
can develop as part of the underlying disease process in Huntington’s disease,
it may be difficult to distinguish between potential drug-induced parkinsonism
and progression of underlying Huntington’s disease. Drug-induced
parkinsonism has the potential to cause more functional disability than untreated
chorea for some patients with Huntington’s disease.
Postmarketing
cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia
have been reported. Signs and symptoms in reported cases have included
bradykinesia, gait disturbances, which led to falls in some cases, and the
emergence or worsening of tremor. In most cases, the development of
parkinsonism occurred within the first two weeks after starting or increasing
the dose of AUSTEDO. In cases in which follow-up clinical information was
available, parkinsonism was reported to resolve following discontinuation of
AUSTEDO therapy.
If
a patient develops parkinsonism during treatment with AUSTEDO, the AUSTEDO dose
should be reduced; some patients may require discontinuation of therapy.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions
underlined)
…
What are the
possible side effects of AUSTEDO?
AUSTEDO can cause serious side effects,
including:
…
Parkinsonism. Symptoms of
parkinsonism include: slight shaking, body stiffness, trouble moving, trouble
keeping your balance, or falls.
…
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Parkinsonism
Inform
patients that AUSTEDO may cause Parkinson-like symptoms, which could be severe.
Advise patients to consult their healthcare provider if they experience slight
shaking, body stiffness, trouble moving, trouble keeping their balance, or
falls.
…
Approved Drug Label (PDF)
Boxed Warning
Additions and/or warnings underlined:
WARNING:
DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE
AUSTEDO can increase the risk
of
depression …
4
Contraindications
Additions and/or warnings underlined:
5
Warnings and Precautions
Additions and/or warnings underlined:
5.1 Depression and Suicidality in Patients with
Huntington’s Disease
Patients with
Huntington’s disease are at increased risk for depression, and suicidal ideation
or behaviors (suicidality) …
5.2 Clinical Worsening and Adverse Events in Patients
with Huntington’s Disease
Huntington’s
disease is a progressive disorder …
5.3 QTc Prolongation
Tetrabenazine, a
closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the
corrected QT (QTc) interval.
A clinically
relevant QT prolongation may occur …
For patients who
are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose
reduction may be necessary. The use of AUSTEDO in combination with other drugs
that are known to prolong QTc may result in clinically significant QT
prolongations.
For patients
requiring AUSTEDO doses greater than 24 mg per day who are using AUSTEDO with
other drugs known to prolong QTc, assess the QTc interval before and after
increasing the dose of AUSTEDO or other medications that are known to prolong
QTc.
AUSTEDO should
also be avoided in patients with congenital long QT syndrome …
5.5 Akathisia, Agitation, and Restlessness
AUSTEDO may
increase the risk of akathisia, agitation, and restlessness in patients with
Huntington’s disease and tardive dyskinesia.
In a 12-week,
double-blind, placebo-controlled trial in Huntington’s disease patients,
akathisia, agitation, or restlessness was reported by 4% of patients treated
with AUSTEDO, compared to 2% of patients on placebo; in patients with
tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on
placebo experienced these events …
5.6 Parkinsonism in Patients with Huntington’s
Disease
5.7 Sedation and Somnolence
… In a 12-week,
double-blind, placebo-controlled trial examining patients with Huntington’s
disease, 11% of AUSTEDO- treated patients …
6
Adverse Reactions
Additions and/or revisions underlined:
6.1 Clinical Trials Experience
Patients with
Huntington’s Disease
Study 1 was a
randomized, 12-week, placebo-controlled study …
Table 2: Adverse
Reactions in Patients with Huntington’s Disease (Study 1) Experienced by
at Least 4% of Patients on AUSTEDO and with a Greater Incidence than on Placebo
Addition of the following:
Patients with
Tardive Dyskinesia
The data described
below reflect 410 tardive dyskinesia patients participating in clinical trials.
AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed
dose, dose escalation). The population was 18 to 80 years of age, and had
tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or
schizophrenia/schizoaffective disorder (63%). In these studies, AUSTEDO was
administered in doses ranging from 12-48 mg per day. All patients continued on
previous stable regimens of antipsychotics; 71% and 14% respective atypical and
typical antipsychotic medications at study entry.
The most common
adverse reactions occurring in greater than 3% of AUSTEDO-treated patients and
greater than placebo were nasopharyngitis and insomnia. The adverse reactions
occurring in
>2% or more
patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo
patients in two double-blind, placebo-controlled studies in patients with
tardive dyskinesia (Study 1 and Study 2) are summarized in Table 3.
Table 3: Adverse
Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies (Study 1 and Study
2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and
Greater than Placebo Please see label for complete information.
One or more
adverse reactions resulted in a reduction of the dose of study medication in 4%
of AUSTEDO-treated patients and in 2% of placebo-treated patients.
7
Drug Interactions
7.3 Reserpine
Additions and/or revisions underlined:
… Prescribers
should wait for chorea or dyskinesia to reemerge …
7.7 Concomitant Tetrabenazine or Valbenazine
Additions and/or revisions underlined:
AUSTEDO is
contraindicated in patients currently taking tetrabenazine or valbenazine.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Risk of Depression
and Suicide in Patients with Huntington’s Disease
Addition of the following:
Prolongation of
the QTc Interval
Inform patients to
consult their physician immediately if they feel faint, lose consciousness, or
have heart palpitations. Advise patients to inform physicians that they are
taking AUSTEDO before any new drug is taken.
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