Austedo
Generic Name: deutetrabenazine
Dosage Form: tablet, coated
Medically reviewed by
Drugs.com. Last updated on Jul 1, 2019.
WARNING: DEPRESSION AND SUICIDALITY IN
PATIENTS WITH HUNTINGTON’S DISEASE
Austedo can increase the risk of depression
and suicidal thoughts and behavior (suicidality) in patients with Huntington’s
disease. Anyone considering the use of Austedo must balance the risks of
depression and suicidality with the clinical need for treatment of chorea.
Closely monitor patients for the emergence or worsening of depression,
suicidality, or unusual changes in behavior. Patients, their caregivers, and
families should be informed of the risk of depression and suicidality and
should be instructed to report behaviors of concern promptly to the treating
physician.
Particular caution should be exercised in
treating patients with a history of depression or prior suicide attempts or
ideation, which are increased in frequency in Huntington’s disease. Austedo is
contraindicated in patients who are suicidal, and in patients with untreated or
inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.1)].
Indications
and Usage for Austedo
Austedo® is indicated for
the treatment of:
chorea associated with
Huntington’s disease
[see Clinical Studies
(14.1)]tardive dyskinesia in
adults
[see Clinical Studies (14.2)]Austedo
Dosage and AdministrationDosing Information
The dose of Austedo is
determined individually for each patient based on reduction of chorea or
tardive dyskinesia and tolerability. When first prescribed to patients who are
not being switched from tetrabenazine (a related VMAT2 inhibitor), the
recommended starting dose of Austedo is 6 mg administered orally once daily for
patients with Huntington’s disease and 12 mg per day (6 mg twice daily) for
patients with tardive dyskinesia.
The dose of Austedo may be
increased at weekly intervals in increments of 6 mg per day to a maximum
recommended daily dosage of 48 mg.Administer total daily dosages
of 12 mg or above in two divided doses.Administer Austedo with
food
[see Clinical Pharmacology (12.3)].Swallow Austedo whole. Do not chew,
crush, or break tablets.For patients at risk for QT
prolongation, assess the QT interval before and after increasing total
Austedo dosage above 24 mg per day
[see Warnings
and Precautions (5.3) and
Drug Interactions (7.2)].Switching Patients from Tetrabenazine (XENAZINE
®) to Austedo
Discontinue tetrabenazine
(XENAZINE®) and initiate Austedo the following day. The recommended
initial dosing regimen of Austedo in patients switching from tetrabenazine
(XENAZINE®) to Austedo is shown in Table 1.
Table 1: Recommended Initial Dosing
Regimen when Switching from Tetrabenazine (XENAZINE®) to Austedo
|
|
Current tetrabenazine
daily dosage
|
Initial regimen of
Austedo
|
|
12.5 mg
|
6 mg once daily
|
|
25 mg
|
6 mg twice daily
|
|
37.5 mg
|
9 mg twice daily
|
|
50 mg
|
12 mg twice
daily
|
|
62.5 mg
|
15 mg twice
daily
|
|
75 mg
|
18 mg twice
daily
|
|
87.5 mg
|
21 mg twice
daily
|
|
100 mg
|
24 mg twice
daily
|
After patients are switched
to Austedo, the dose may be adjusted at weekly intervals [see Dosage and Administration (2.1)].
Dosage Adjustment with Strong CYP2D6 Inhibitors
In patients receiving strong
CYP2D6 inhibitors (e.g., quinidine, antidepressants such as paroxetine,
fluoxetine, and bupropion), the total daily dosage of Austedo should not exceed
36 mg (maximum single dose of 18 mg) [see Drug
Interactions (7.1) and Clinical
Pharmacology (12.3)].
Dosage Adjustment in Poor CYP2D6 Metabolizers
In patients who are poor
CYP2D6 metabolizers, the total daily dosage of Austedo should not exceed 36 mg
(maximum single dose of 18 mg) [see Use in Specific
Populations (8.7)].
Discontinuation and Interruption of Treatment
Treatment with Austedo can
be discontinued without tapering. Following treatment interruption of greater
than one week, Austedo therapy should be re-titrated when resumed. For
treatment interruption of less than one week, treatment can be resumed at the
previous maintenance dose without titration.
Dosage
Forms and Strengths
Austedo tablets are available
in the following strengths:
The 6 mg tablets are round,
purple-coated tablets, with “SD” over “6” printed in black ink on one
side.The 9 mg tablets are round,
blue-coated tablets, with “SD” over “9” printed in black ink on one side.The 12 mg tablets are round,
beige-coated tablets, with “SD” over “12” printed in black ink on one
side.Contraindications
Austedo is contraindicated
in patients:
With Huntington’s disease who
are suicidal, or have untreated or inadequately treated depression
[see Warnings and Precautions (5.1)].With hepatic impairment
[see Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].Taking reserpine. At least 20
days should elapse after stopping reserpine before starting Austedo
[see Drug Interactions (7.3)].Taking monoamine oxidase
inhibitors (MAOIs). Austedo should not be used in combination with an
MAOI, or within 14 days of discontinuing therapy with an MAOI
[see Drug Interactions (7.4)].Taking tetrabenazine (XENAZINE
®)
or valbenazine
[see Drug Interactions (7.7)].Warnings
and PrecautionsDepression 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). Austedo may increase the risk for suicidality in
patients with Huntington’s disease.
In a 12-week, double-blind,
placebo-controlled trial, suicidal ideation was reported by 2% of patients
treated with Austedo, compared to no patients on placebo; no suicide attempts
and no completed suicides were reported. Depression was reported by 4% of
patients treated with Austedo.
When considering the use of
Austedo, the risk of suicidality should be balanced against the need for
treatment of chorea. All patients treated with Austedo should be observed for
new or worsening depression or suicidality. If depression or suicidality does
not resolve, consider discontinuing treatment with Austedo.
Patients, their caregivers,
and families should be informed of the risks of depression, worsening
depression, and suicidality associated with Austedo, and should be instructed
to report behaviors of concern promptly to the treating physician. Patients
with Huntington’s disease who express suicidal ideation should be evaluated
immediately.
Clinical Worsening and Adverse Events in Patients with
Huntington’s Disease
Huntington’s disease is a
progressive disorder characterized by changes in mood, cognition, chorea,
rigidity, and functional capacity over time. VMAT2 inhibitors, including
Austedo, may cause a worsening in mood, cognition, rigidity, and functional
capacity.
Prescribers should
periodically re-evaluate the need for Austedo in their patients by assessing
the effect on chorea and possible adverse effects, including
sedation/somnolence, depression and suicidality, parkinsonism, akathisia,
restlessness, and cognitive decline. It may be difficult to distinguish between
adverse reactions and progression of the underlying disease; decreasing the
dose or stopping the drug may help the clinician to distinguish between the two
possibilities. In some patients, the underlying chorea itself may improve over
time, decreasing the need for Austedo.
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 in some patients treated with Austedo who are CYP2D6
poor metabolizers or are co-administered a strong CYP2D6 inhibitor [see Clinical Pharmacology (12.2, 12.3)].
For patients who are CYP2D6
poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may
be necessary [see Dosage and Administration (2.3, 2.4)]. The use of
Austedo in combination with other drugs that are known to prolong QTc may
result in clinically significant QT prolongations [see
Drug Interactions (7.2)].
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 and in patients with a
history of cardiac arrhythmias. Certain circumstances may increase the risk of
the occurrence of torsade de pointes and/or sudden death in association with
the use of drugs that prolong the QTc interval, including (1) bradycardia; (2)
hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong
the QTc interval; and (4) presence of congenital prolongation of the QT
interval.
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom
complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been
reported in association with drugs that reduce dopaminergic transmission. While
NMS has not been observed in patients receiving Austedo, it has been observed
in patients receiving tetrabenazine (a closely related VMAT2 inhibitor).
Clinicians should be alerted to the signs and symptoms associated with NMS.
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered
mental status, and evidence of autonomic instability (irregular pulse or blood
pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs
may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis,
and acute renal failure. The diagnosis of NMS can be complicated; other serious
medical illness (e.g., pneumonia, systemic infection) and untreated or
inadequately treated extrapyramidal disorders can present with similar signs
and symptoms. Other important considerations in the differential diagnosis
include central anticholinergic toxicity, heat stroke, drug fever, and primary
central nervous system pathology.
The management of NMS should
include (1) immediate discontinuation of Austedo; (2) intensive symptomatic
treatment and medical monitoring; and (3) treatment of any concomitant serious
medical problems for which specific treatments are available. There is no general
agreement about specific pharmacological treatment regimens for NMS.
Recurrence of NMS has been
reported with resumption of drug therapy. If treatment with Austedo is needed
after recovery from NMS, patients should be monitored for signs of recurrence.
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.
Patients receiving Austedo
should be monitored for signs and symptoms of restlessness and agitation, as
these may be indicators of developing akathisia. If a patient develops
akathisia during treatment with Austedo, the Austedo dose should be reduced;
some patients may require discontinuation of therapy.
Parkinsonism
Austedo may cause parkinsonism in
patients with Huntington’s disease or tardive dyskinesia. Parkinsonism
has also been observed with other VMAT2 inhibitors.
Because 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.
Sedation and Somnolence
Sedation is a common
dose-limiting adverse reaction of Austedo. In a 12-week, double-blind,
placebo-controlled trial examining patients with Huntington’s disease, 11% of
Austedo-treated patients reported somnolence compared with 4% of patients on
placebo and 9% of Austedo-treated patients reported fatigue compared with 4% of
placebo-treated patients.
Patients should not perform
activities requiring mental alertness to maintain the safety of themselves or
others, such as operating a motor vehicle or operating hazardous machinery,
until they are on a maintenance dose of Austedo and know how the drug affects
them.
Hyperprolactinemia
Serum prolactin levels were
not evaluated in the Austedo development program. Tetrabenazine, a closely
related VMAT2 inhibitor, elevates serum prolactin concentrations in humans.
Following administration of 25 mg of tetrabenazine to healthy volunteers, peak
plasma prolactin levels increased 4- to 5-fold.
Tissue culture experiments
indicate that approximately one-third of human breast cancers are
prolactin-dependent in vitro, a factor of
potential importance if Austedo is being considered for a patient with
previously detected breast cancer. Although amenorrhea, galactorrhea,
gynecomastia, and impotence can be caused by elevated serum prolactin
concentrations, the clinical significance of elevated serum prolactin
concentrations for most patients is unknown.
Chronic increase in serum
prolactin levels (although not evaluated in the Austedo or tetrabenazine
development programs) has been associated with low levels of estrogen and
increased risk of osteoporosis. If there is a clinical suspicion of symptomatic
hyperprolactinemia, appropriate laboratory testing should be done and
consideration should be given to discontinuation of Austedo.
Binding to Melanin-Containing Tissues
Since deutetrabenazine or
its metabolites bind to melanin-containing tissues, it could accumulate in
these tissues over time. This raises the possibility that Austedo may cause
toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic
examination of the eye has been conducted in the chronic toxicity studies in a
pigmented species such as dogs. Ophthalmologic monitoring in humans was
inadequate to exclude the possibility of injury occurring after long-term
exposure.
The clinical relevance of
deutetrabenazine’s binding to melanin-containing tissues is unknown. Although
there are no specific recommendations for periodic ophthalmologic monitoring,
prescribers should be aware of the possibility of long-term ophthalmologic
effects [see Clinical Pharmacology (12.2)].
Adverse
Reactions
The following serious
adverse reactions are discussed in greater detail in other sections of the
labeling:
Depression and Suicidality in
Patients with Huntington’s disease
[see Warnings
and Precautions (5.1)]QTc Prolongation
[see Warnings and Precautions (5.3)]Neuroleptic Malignant Syndrome
(NMS)
[see Warnings and Precautions (5.4)]Akathisia, Agitation, and
Restlessness
[see Warnings and Precautions (5.5)]Parkinsonism
[see Warnings and Precautions (5.6)]Sedation and Somnolence
[see Warnings and Precautions (5.7)]Hyperprolactinemia
[see Warnings and Precautions (5.8)]Binding to Melanin-Containing
Tissues
[see Warnings and Precautions (5.9)]Clinical Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Patients
with Huntington’s Disease
Study 1 was a randomized,
12-week, placebo-controlled study in patients with chorea associated with Huntington’s
disease. A total of 45 patients received Austedo, and 45 patients received
placebo. Patients ranged in age between 23 and 74 years (mean 54 years); 56%
were male, and 92% were Caucasian. The most common adverse reactions occurring
in greater than 8% of Austedo-treated patients were somnolence, diarrhea, dry
mouth, and fatigue. Adverse reactions occurring in 4% or more of patients
treated with Austedo, and with a greater incidence than in patients on placebo,
are summarized in Table 2.
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
|
|
Adverse Reaction
|
Austedo
(N = 45)
%
|
Placebo
(N = 45)
%
|
|
Somnolence
|
11
|
4
|
|
Diarrhea
|
9
|
0
|
|
Dry mouth
|
9
|
7
|
|
Fatigue
|
9
|
4
|
|
Urinary tract infection
|
7
|
2
|
|
Insomnia
|
7
|
4
|
|
Anxiety
|
4
|
2
|
|
Constipation
|
4
|
2
|
|
Contusion
|
4
|
2
|
One or more adverse
reactions resulted in a reduction of the dose of study medication in 7% of
patients in Study 1. The most common adverse reaction resulting in dose
reduction in patients receiving Austedo was dizziness (4%).
Agitation led to
discontinuation in 2% of patients treated with Austedo in Study 1.
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
|
|
Preferred Term
|
Austedo
(N=279)
(%)
|
Placebo
(N=131)
(%)
|
|
Nasopharyngitis
|
4
|
2
|
|
Insomnia
|
4
|
1
|
|
Depression/ Dysthymic disorder
|
2
|
1
|
|
Akathisia/Agitation/Restlessness
|
2
|
1
|
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.
Drug
InteractionsStrong CYP2D6 Inhibitors
A reduction in Austedo dose
may be necessary when adding a strong CYP2D6 inhibitor in patients maintained
on a stable dose of Austedo. Concomitant use of strong CYP2D6 inhibitors (e.g.,
paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the
systemic exposure to the active dihydro-metabolites of deutetrabenazine by
approximately 3-fold. The daily dose of Austedo should not exceed 36 mg per
day, and the maximum single dose of Austedo should not exceed 18 mg in patients
taking strong CYP2D6 inhibitors [see Dosage and
Administration (2.3) and Clinical
Pharmacology (12.3)].
Drugs that Cause QTc Prolongation
Tetrabenazine, a closely
related VMAT2 inhibitor, may cause an increase in the corrected QT (QTc)
interval. Clinically relevant QT prolongation may also occur with Austedo [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)].
For patients requiring
Austedo doses above 24 mg per day, who are using Austedo in combination 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. Drugs known to prolong QTc include antipsychotic medications (e.g.,
chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g.,
moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g.,
amiodarone, sotalol) antiarrhythmic medications.
Reserpine
Reserpine binds irreversibly
to VMAT2 and the duration of its effect is several days. Prescribers should
wait for chorea or dyskinesia to reemerge before administering Austedo to help
reduce the risk of overdosage and major depletion of serotonin and
norepinephrine in the central nervous system. At least 20 days should elapse
after stopping reserpine before starting Austedo. Austedo and reserpine should
not be used concomitantly [see Contraindications (4)].
Monoamine Oxidase Inhibitors (MAOIs)
Austedo is contraindicated
in patients taking MAOIs. Austedo should not be used in combination with an
MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications (4)].
Neuroleptic Drugs
The risk of parkinsonism,
NMS, and akathisia may be increased by concomitant use of Austedo and dopamine
antagonists or antipsychotics.
Alcohol or Other Sedating Drugs
Concomitant use of alcohol
or other sedating drugs may have additive effects and worsen sedation and
somnolence [see Warnings and Precautions (5.7)].
Concomitant Tetrabenazine or Valbenazine
Austedo is contraindicated
in patients currently taking tetrabenazine or valbenazine. Austedo may be
initiated the day following discontinuation of tetrabenazine [see Dosage and Administration (2.2)].
USE IN
SPECIFIC POPULATIONSPregnancy
Risk
Summary
There are no adequate data
on the developmental risk associated with the use of Austedo in pregnant women.
Administration of deutetrabenazine to rats during organogenesis produced no
clear adverse effect on embryofetal development. However, administration of
tetrabenazine to rats throughout pregnancy and lactation resulted in an
increase in stillbirths and postnatal offspring mortality [see 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.
Data
Animal
Data
Oral administration of
deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to
pregnant rats during organogenesis had no clear effect on embryofetal
development. The highest dose tested was 6 times the maximum recommended human
dose of 48 mg/day, on a body surface area (mg/m2) basis.
The effects of
deutetrabenazine when administered during organogenesis to rabbits or during
pregnancy and lactation to rats have not been assessed.
Tetrabenazine had no effects
on embryofetal development when administered to pregnant rabbits during the
period of organogenesis at oral doses up to 60 mg/kg/day. When tetrabenazine
was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the
beginning of organogenesis through the lactation period, an increase in
stillbirths and offspring postnatal mortality was observed at 15 and
30 mg/kg/day, and delayed pup maturation was observed at all doses.
Lactation
Risk
Summary
There are no data on the
presence of deutetrabenazine or its metabolites in human milk, the effects on
the breastfed infant, or the effects of the drug on milk production.
The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for Austedo and any potential adverse effects on the breastfed infant from
Austedo or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in
pediatric patients have not been established.
Geriatric Use
Clinical studies of Austedo
did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of hepatic, renal, and cardiac dysfunction, and of
concomitant disease or other drug therapy.
Hepatic Impairment
The effect of hepatic
impairment on the pharmacokinetics of deutetrabenazine and its primary
metabolites has not been studied; however, in a clinical study conducted with
tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in
exposure to tetrabenazine and its active metabolites in patients with hepatic
impairment. The clinical significance of this increased exposure has not been
assessed, but because of concerns for a greater risk for serious adverse
reactions, the use of Austedo in patients with hepatic impairment is
contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].
Poor CYP2D6 Metabolizers
Although the
pharmacokinetics of deutetrabenazine and its metabolites have not been
systematically evaluated in patients who do not express the drug metabolizing
enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased
similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In
patients who are CYP2D6 poor metabolizers, the daily dose of Austedo should not
exceed 36 mg (maximum single dose of 18 mg) [see
Dosage and Administration (2.4) and Clinical
Pharmacology (12.3)].
Overdosage
Overdoses ranging from 100
mg to 1 g have been reported in the literature with tetrabenazine, a closely
related VMAT2 inhibitor. The following adverse reactions occurred with
overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating,
sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
Treatment should consist of
those general measures employed in the management of overdosage with any
central nervous system-active drug. General supportive and symptomatic measures
are recommended. Cardiac rhythm and vital signs should be monitored. In
managing overdosage, the possibility of multiple drug involvement should always
be considered. The physician should consider contacting a poison control center
on the treatment of any overdose. Telephone numbers for certified poison
control centers are listed on the American Association of Poison Control
Centers website www.aapcc.org.
Austedo
Description
Austedo (deutetrabenazine)
is a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral
administration. The molecular weight of deutetrabenazine is 323.46; the pKa is
6.31. Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and
has the following chemical name: (RR, SS)-1, 3, 4,
6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.
The molecular formula for
deutetrabenazine is C19H21D6NO3. Deutetrabenazine is a racemic mixture containing the following
structures:
Deutetrabenazine is a white
to slightly yellow crystalline powder that is sparingly soluble in water and
soluble in ethanol.
Austedo tablets contain 6
mg, 9 mg, or 12 mg deutetrabenazine, and the following inactive ingredients:
ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated
hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol,
microcrystalline cellulose, polyethylene glycol, polyethylene oxide,
polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc,
titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain
FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake.
Austedo -
Clinical PharmacologyMechanism of Action
The precise mechanism by
which deutetrabenazine exerts its effects in the treatment of tardive
dyskinesia and chorea in patients with Huntington’s disease is unknown but is
believed to be related to its effect as a reversible depletor of monoamines
(such as dopamine, serotonin, norepinephrine, and histamine) from nerve
terminals. The major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and
β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in
decreased uptake of monoamines into synaptic vesicles and depletion of
monoamine stores.
Pharmacodynamics
Cardiac Electrophysiology
The effect of a single 12-mg
or 24-mg dose of Austedo on the QT interval was studied in a randomized,
double-blind, placebo-controlled crossover study in healthy male and female
subjects with moxifloxacin as a positive control. At 24 mg, Austedo caused an
approximately 4.5 msec mean increase in QTc (90% CI: 2.4, 6.5 msec). Effects at
higher exposures to Austedo or its metabolites have not been evaluated.
Melanin
Binding
Deutetrabenazine or its
metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in
pigmented rats. After a single oral dose of radiolabeled deutetrabenazine,
radioactivity was still detected in eye and fur at 35 days following
dosing [see Warnings and Precautions (5.9)].
Pharmacokinetics
After oral dosing up to 25
mg, plasma concentrations of deutetrabenazine are generally below the limit of
detection because of the extensive hepatic metabolism of deutetrabenazine to
the active deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ. Linear
dose dependence of Cmax and AUC was observed for the active metabolites following
single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice
daily to 22.5 mg twice daily).
Absorption
Following oral
administration of deutetrabenazine, the extent of absorption is at least 80%.
Plasma concentrations of
deutetrabenazine are generally below the limit of detection after oral dosing.
Peak plasma concentrations (Cmax) of deuterated α-HTBZ and β-HTBZ are reached within 3 to 4
hours after dosing.
Effect
of Food
The effects of food on the
bioavailability of Austedo were studied in subjects administered a single dose
with and without food. Food had no effect on the area under the plasma concentration-time
curve (AUC) of α-HTBZ or β-HTBZ, although Cmax was increased by
approximately 50% in the presence of food [see Dosage
and Administration (2.1)].
Distribution
The median volume of
distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of Austedo are
approximately 500 L and 730 L, respectively.
Results of PET-scan studies
in humans show that following intravenous injection of 11C-labeled tetrabenazine or
α-HTBZ, radioactivity is rapidly distributed to the brain, with the highest
binding in the striatum and lowest binding in the cortex.
The in vitro protein binding of tetrabenazine, α-HTBZ,
and β-HTBZ was examined in human plasma for concentrations ranging from 50 to
200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding
ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.
Elimination
Austedo is primarily renally
eliminated in the form of metabolites.
The half-life of total
(α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours.
The median clearance values
(CL/F) of the α-HTBZ, and the β-HTBZ metabolites of Austedo are approximately
47 L/hour and 70 L/hour, respectively, in the Huntington’s disease patient
population.
Metabolism
In
vitro experiments in human liver microsomes demonstrate that
deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase,
to its major active metabolites, α-HTBZ and β-HTBZ, which are subsequently
metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and
CYP3A4/5, to form several minor metabolites.
Excretion
In a mass balance study in 6
healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the
urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary
excretion of the α-HTBZ and β-HTBZ metabolites from deutetrabenazine each
accounted for less than 10% of the administered dose. Sulfate and glucuronide
conjugates of the α-HTBZ and β-HTBZ metabolites of deutetrabenazine, as well as
products of oxidative metabolism, accounted for the majority of metabolites in
the urine.
Specific
Populations
Male
and Female Patients
There is no apparent effect
of gender on the pharmacokinetics of α-HTBZ and β‑HTBZ of deutetrabenazine.
Patients
with Renal Impairment
No clinical studies have
been conducted to assess the effect of renal impairment on the PK of Austedo.
Patients
with Hepatic Impairment
The effect of hepatic
impairment on the pharmacokinetics of deutetrabenazine and its primary
metabolites has not been studied. However, in a clinical study conducted to
assess the effect of hepatic impairment on the pharmacokinetics of
tetrabenazine, a closely related VMAT2 inhibitor, the exposure to α-HTBZ and
β-HTBZ was up to 40% greater in patients with hepatic impairment, and the mean
tetrabenazine Cmax in patients with hepatic impairment was up to 190-fold
higher than in healthy subjects [see Contraindications
(4), Use in Specific Populations (8.6)].
Poor
CYP2D6 Metabolizers
Although the
pharmacokinetics of deutetrabenazine and its metabolites have not been
systematically evaluated in patients who do not express the drug metabolizing
enzyme CYP2D6, it is likely that the exposure to α-HTBZ and β-HTBZ would be
increased similarly to taking strong CYP2D6 inhibitors (approximately
3-fold) [see Dosage and Administration (2.4), Drug Interactions (7.1)].
Drug Interaction Studies
Deutetrabenazine, α-HTBZ,
and β-HTBZ have not been evaluated in in vitro studies
for induction or inhibition of CYP enzymes or interaction with P-glycoprotein.
The results of in vitro studies of
tetrabenazine do not suggest that tetrabenazine or its α-HTBZ or β-HTBZ
metabolites are likely to result in clinically significant inhibition of
CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine
nor its α-HTBZ or β-HTBZ metabolites are likely to result in clinically
significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
Neither tetrabenazine nor its α-HTBZ or β-HTBZ metabolites are likely to be a
substrate or inhibitor of P-glycoprotein at clinically relevant
concentrations in vivo.
The deutetrabenazine
metabolites, 2-methylpropanoic acid of β-HTBZ (M1) and monohydroxy
tetrabenazine (M4), have been evaluated in a panel of in
vitro drug-drug interaction studies; the results indicate that
M1/M4 are not expected to cause clinically relevant drug interactions.
CYP2D6
Inhibitors
In
vitro studies indicate that the α-HTBZ and β-HTBZ metabolites of
deutetrabenazine are substrates for CYP2D6. The effect of CYP2D6 inhibition on
the pharmacokinetics of deutetrabenazine and its metabolites was studied in 24
healthy subjects following a single 22.5 mg dose of deutetrabenazine given
after 8 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg
daily. In the presence of paroxetine, systemic exposure (AUCinf) of α-HTBZ was 1.9-fold
higher and β-HTBZ was 6.5-fold higher, resulting in approximately 3-fold
increase in AUCinf for total (α+β)-HTBZ. Paroxetine decreased the clearance
of α-HTBZ and β-HTBZ metabolites of Austedo with corresponding increases in
mean half-life of approximately 1.5-fold and 2.7-fold, respectively. In the
presence of paroxetine, Cmax of α-HTBZ and β-HTBZ were 1.2-fold and 2.2-fold higher,
respectively.
The effect of moderate or
weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or
sertraline on the exposure of deutetrabenazine and its metabolites has not been
evaluated.
Digoxin
Austedo was not evaluated
for interaction with digoxin. Digoxin is a substrate for P-glycoprotein. A
study in healthy subjects showed that tetrabenazine (25 mg twice daily for 3
days) did not affect the bioavailability of digoxin, suggesting that at this
dose, tetrabenazine does not affect P‑glycoprotein in the intestinal
tract. In vitro studies also do not
suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.
Nonclinical
ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
No carcinogenicity studies
were performed with deutetrabenazine.
No increase in tumors was
observed in p53+/– transgenic mice treated orally with tetrabenazine at doses
of 0, 5, 15, and 30 mg/kg/day for 26 weeks.
Mutagenesis
Deutetrabenazine and its
deuterated α-HTBZ and β-HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome
aberration in human peripheral blood lymphocytes) assays in the presence or
absence of metabolic activation and in the in vivo micronucleus
assay in mice.
Impairment
of Fertility
The effects of
deutetrabenazine on fertility have not been evaluated. Oral administration of
deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months
resulted in estrous cycle disruption at all doses; the lowest dose tested was
similar to the maximum recommended human dose (48 mg/day) on a body surface
area (mg/m2) basis.
Oral administration of
tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and
throughout mating, and continuing through day 7 of gestation, resulted in
disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on
mating and fertility indices or sperm parameters (motility, count, density)
were observed when males were treated orally with tetrabenazine at doses of 5,
15 or 30 mg/kg/day prior to and throughout mating with untreated females.
Clinical
StudiesChorea Associated with Huntington’s Disease
Double-Blind,
Placebo-Controlled Study
The efficacy of Austedo as a
treatment for chorea associated with Huntington's disease was established
primarily in Study 1, a randomized, double-blind, placebo-controlled,
multi-center trial conducted in 90 ambulatory patients with manifest chorea
associated with Huntington’s disease. The diagnosis of Huntington’s disease was
based on family history, neurological exam, and genetic testing. Treatment
duration was 12 weeks, including an 8-week dose titration period and a 4-week
maintenance period, followed by a 1-week washout. Patients were not blinded to
discontinuation. Austedo was started at 6 mg per day and titrated upward, at
weekly intervals, in 6 mg increments until satisfactory treatment of chorea was
achieved, intolerable side effects occurred, or until a maximal dose of 48 mg
per day was reached. The primary efficacy endpoint was the Total Maximal Chorea
Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On
this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7
different parts of the body. The total score ranges from 0 to 28.
Of the 90 patients enrolled,
87 patients completed the study. The mean age was 54 (range 23 to 74). Patients
were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per
day. Table 4 and Figure 1 summarize the effects of Austedo on chorea based on
the Total Maximal Chorea Score. Total Maximal Chorea Scores for patients
receiving Austedo improved by approximately 4.4 units from baseline to the
maintenance period (average of Week 9 and Week 12), compared to approximately
1.9 units in the placebo group. The treatment effect of -2.5 units was
statistically significant (p<0.0001). The Maintenance Endpoint is the mean
of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the
Week 13 follow-up visit (1 week after discontinuation of the study medication),
the Total Maximal Chorea Scores of patients who had received Austedo returned
to baseline (Figure 1).
Table 4: Change from Baseline to
Maintenance Therapy in Total Maximal Chorea (TMC)a Score in Patients with Huntington’s
Disease Treated with Austedo in Study 1
|
|
Motor Endpoint
|
Austedo
N = 45
|
Placebo
N = 45
|
p value
|
|
Change in Total Chorea Scorea from Baseline
to Maintenance Therapyb
|
-4.4
|
-1.9
|
<0.0001
|
a TMC is a subscale of the Unified Huntington's Disease
Rating Scale (UHDRS)
b Primary
efficacy endpoint
Figure
1: Total Maximal Chorea Score Over Time in Study 1
Figure
2: Distribution of the Change in Total Maximal Chorea Scores in Study 1
Figure 2 shows the
distribution of values for the change in Total Maximal Chorea Score in Study 1.
Negative values indicate a reduction in chorea and positive numbers indicate an
increase in chorea.
A patient-rated global
impression of change assessed how patients rated their overall Huntington’s
disease symptoms. Fifty-one percent of patients treated with Austedo rated
their symptoms as “Much Improved” or “Very Much Improved” at the end of
treatment, compared to 20% of placebo-treated patients.
In a physician-rated
clinical global impression of change, 42% percent of patients treated with
Austedo rated their symptoms as “Much Improved” or “Very Much Improved” at the
end of treatment compared to 13% of placebo-treated patients.
Tardive Dyskinesia
The efficacy of Austedo in
the treatment for tardive dyskinesia was established in two 12‑week,
randomized, double-blind, placebo-controlled, multi-center trials conducted in
335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine
receptor antagonists. Patients had a history of using a dopamine receptor
antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month
in patients 60 years of age and older). Concurrent diagnoses included
schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With
respect to concurrent antipsychotic use, 64% of patients were receiving
atypical antipsychotics, 12% were receiving typical or combination
antipsychotics, and 24% were not receiving antipsychotics.
The Abnormal Involuntary
Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive
dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the
severity of involuntary movements across body regions and these items were used
in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as:
0=not present; 1=minimal, may be extreme normal (abnormal movements occur
infrequently and/or are difficult to detect); 2=mild (abnormal movements occur
infrequently and are easy to detect); 3=moderate (abnormal movements occur
frequently and are easy to detect) or 4 =severe (abnormal movements occur
almost continuously and/or of extreme intensity). The AIMS total score (sum of
items 1 to 7) could thus range from 0 to 28, with a decrease in score
indicating improvement.
In Study 1, a 12-week,
placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were
randomized 1:1:1:1 to 12 mg Austedo, 24 mg Austedo, 36 mg Austedo, or placebo.
Treatment duration included a 4-week dose escalation period and an 8-week
maintenance period followed by a 1-week washout. The dose of Austedo was
started at 12 mg per day and increased at weekly intervals in 6 mg/day
increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population
(n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian.
In Study 1, the AIMS total score for patients receiving Austedo demonstrated
statistically significant improvement, from baseline to Week 12, of 3.3 and 3.2
units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in
placebo (Study 1 in Table 5). The improvements on the AIMS total score over the
course of the study are displayed in Figure 3. Data did not suggest substantial
differences in efficacy across various demographic groups. The treatment
response rate distribution, based on magnitude of AIMS total score from
baseline to week 12 is displayed in Figure 4.
The mean changes in the AIMS
total score by visit are shown in Figure 3.
In Study 2, a 12-week,
placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113)
received daily doses of placebo or Austedo, starting at 12 mg per day with
increases allowed in 6-mg increments at 1-week intervals until satisfactory
control of dyskinesia was achieved, until intolerable side effects occurred, or
until a maximal dose of 48 mg per day was reached. Treatment duration included
a 6-week dose titration period and a 6-week maintenance period followed by a
1-week washout. The population was 25 to 75 years old (mean 55 years), 48%
male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks.
The average dose of Austedo after treatment was 38.3 mg per day. There was no
evidence suggesting substantial differences in efficacy across various
demographic groups. In Study 2, AIMS total score for patients receiving Austedo
demonstrated statistically significant improvement by 3.0 units from baseline
to endpoint (Week 12), compared with 1.6 units in the placebo group with a
treatment effect of -1.4 units. Table 5 summarizes the effects of Austedo on
tardive dyskinesia based on the AIMS.
Table 5: Improvement in AIMS Total Score
in Patients Treated with Austedo in Study 1 and Study 2
|
|
|
Study
|
Treatment Group
|
Primary Efficacy Measure: AIMS Total Score
|
|
|
Mean Baseline Score (SD)
|
LS Mean Change from Baseline (SE)
|
Treatment Effect (95% CI)
|
|
|
Study 1
|
Austedo 36 mg*
(n= 55)
|
10.1 (3.21)
|
-3.3 (0.42)
|
-1.9 (-3.09, -0.79)
|
|
|
Austedo 24 mg
(n= 49)
|
9.4 (2.93)
|
-3.2 (0.45)
|
-1.8 (-3.00, -0.63)
|
|
|
Austedo 12 mg
(n= 60)
|
9.6 (2.40)
|
-2.1 (0.42)
|
-0.7 (-1.84, 0.42)
|
|
|
Placebo (n= 58)
|
9.5 (2.71)
|
-1.4 (0.41)
|
|
|
|
Study 2
|
Austedo
(12-48 mg/day)*
(n= 56)
|
9.7 (4.14)
|
-3.0 (0.45)
|
-1.4 (-2.6, -0.2)
|
|
|
Placebo (n= 57)
|
9.6 (3.78)
|
-1.6 (0.46)
|
|
|
*Dose that was statistically
significantly different from placebo after adjusting for multiplicity.
LS Mean = Least-squares
mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence
interval
Figure
3: Least Square Means of Change in AIMS Total Score from Baseline for Austedo
Compared to Placebo (Study 1)
SE = Standard error
Figure
4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement
at the End of Week 12 (Study 1)
How
Supplied/Storage and HandlingHow Supplied
Austedo tablets are
available in the following strengths and packages:
6 mg: round, purple-coated
tablets, with “SD” over “6” printed in black ink on one side.
Bottles of 60 tablets: NDC
68546-170-60.
9 mg: round, blue-coated
tablets, with “SD” over “9” printed in black ink on one side.
Bottles of 60 tablets: NDC
68546-171-60.
12 mg: round, beige-coated
tablets, with “SD” over “12” printed in black ink on one side.
Bottles of 60 tablets: NDC
68546-172-60.
Storage
Store at 25ºC (77ºF);
excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see
USP Controlled Room Temperature]. Protect from light and moisture.
Patient
Counseling Information
Advise the patient or caregiver
to read the FDA-approved patient labeling (Medication Guide).
Administration
Instructions
Advise patients to take
Austedo with food. Austedo tablets should be swallowed whole and not chewed,
crushed, or broken [see Dosage and Administration (2.1)].
Risk
of Depression and Suicide in Patients with Huntington’s Disease
Advise patients, their
caregivers, and families that Austedo may increase the risk of depression,
worsening depression, and suicidality, and to immediately report any symptoms
to a healthcare provider [see Contraindications (4), Warnings and Precautions
(5.2)].
Prolongation
of the QTc Interval
Inform patients to consult
their physician immediately if they feel faint, lose consciousness, or have
heart palpitations [see Warnings and Precautions (5.3)]. Advise
patients to inform physicians that they are taking Austedo before any new drug
is taken.
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 [see Warnings and Precautions (5.6)].
Risk
of Sedation and Somnolence
Advise patients that Austedo
may cause sedation and somnolence and may impair the ability to perform tasks
that require complex motor and mental skills. Until they learn how they respond
to a stable dose of Austedo, patients should be careful doing activities that
require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.7)].
Interaction
with Alcohol or Other Sedating Drugs
Advise patients that alcohol
or other drugs that cause sleepiness will worsen somnolence [see Drug Interactions (7.6)].
Concomitant
Medications
Advise patients to notify
their physician of all medications they are taking and to consult with their
healthcare provider before starting any new medications because of a potential
for interactions [see Contraindications (4) and Drug Interactions (7.1, 7.5)].
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
AUS-003
U.S. Patent Nos: 8,524,733;
9,233,959; 9,296,739; 9,550,780
XENAZINE® is a trademark of
Valeant Pharmaceuticals Luxembourg S.A.R.L.
MEDICATION
GUIDE
|
MEDICATION GUIDE
Austedo® (aw-STED-oh)
(deutetrabenazine)
tablets, for oral use
|
|
What
is the most important information I should know about Austedo?
Austedo
can cause serious side effects in people with Huntington’s disease,
including:depressionsuicidal
thoughtssuicidal
actionsDo not
start taking Austedo if you have Huntington’s disease and are depressed
(have untreated depression or depression that is not well controlled by
medicine) or have suicidal
thoughts.Pay
close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is especially important when
Austedo is started and when the dose is changed.
Call your
healthcare provider right away if you become depressed or have any of the
following symptoms, especially if they are new, worse, or worry you:
feel
sad or have crying spellslose
interest in seeing your friends or doing things you used to enjoysleep a
lot more or a lot less than usualfeel
unimportantfeel
guiltyfeel
hopeless or helplessfeel
more irritable, angry, or aggressive than usualfeel
more or less hungry than usual or notice a big change in your body
weighthave
trouble paying attentionfeel
tired or sleepy all the timehave thoughts about hurting yourself or ending
your life
|
|
What
is Austedo?
Austedo is a prescription
medicine that is used to treat:
the
involuntary movements (chorea) of Huntington’s disease. Austedo does not
cure the cause of the involuntary movements, and it does not treat other
symptoms of Huntington’s disease, such as problems with thinking or
emotions.movements
in the face, tongue, or other body parts that cannot be controlled
(tardive dyskinesia).
It is not known if Austedo is
safe and effective in children.
|
|
Who
should not take Austedo?
Do not take
Austedo if you:
have
Huntington’s disease and are depressed or have thoughts of suicide. See
“What is the most important information I should know about Austedo?”have
liver problems.are
taking a monoamine oxidase inhibitor (MAOI) medicine. Do not take an MAOI within 14 days after
you stop taking Austedo. Do not start
Austedo if you stopped taking an MAOI in the last 14 days. Ask your
healthcare provider or pharmacist if you are not sure.are
taking reserpine. Do not take
medicines that contain reserpine (such as Serpalan and Renese-R) with
Austedo. If your healthcare provider plans to switch you from taking
reserpine to Austedo, you must wait at least 20 days after your last
dose of reserpine before you start taking Austedo.are
taking tetrabenazine (Xenazine). If your healthcare provider plans to
switch you from tetrabenazine (Xenazine) to Austedo, take your first
dose of Austedo on the day after your last dose of tetrabenazine
(Xenazine).are taking valbenazine (Ingrezza).
|
|
Before
taking Austedo, tell your healthcare provider about all of your medical
conditions, including if you:
have
emotional or mental problems (for example, depression, nervousness,
anxiety, anger, agitation, psychosis, previous suicidal thoughts or
suicide attempts).have
liver disease.have an
irregular heart rhythm or heartbeat (QT prolongation, cardiac
arrhythmia) or a heart problem called congenital long QT syndrome.have
low levels of potassium or magnesium in your blood (hypokalemia or
hypomagnesemia).have
breast cancer or a history of breast cancer.are
pregnant or plan to become pregnant. It is not known if Austedo can harm
your unborn baby.are
breastfeeding or plan to breastfeed. It is not known if Austedo passes
into breast milk.
Tell your
healthcare provider about all of the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Taking Austedo with certain
other medicines may cause side effects. Do not start any new medicines while
taking Austedo without talking to your healthcare provider first.
|
|
How
should I take Austedo?
Take
Austedo exactly as your healthcare provider tells you to take it.Take
Austedo by mouth and with food.Swallow
Austedo tablets whole with water. Do not chew, crush, or break Austedo
tablets before swallowing. If you cannot swallow Austedo tablets whole,
tell your healthcare provider. You may need a different medicine.If your
dose of Austedo is 12 mg or more each day, take Austedo tablets 2 times
a day in equal doses with food.Your
healthcare provider will increase your dose of Austedo each week for
several weeks, until you and your healthcare provider find the right dose
for you.Tell your healthcare provider if you stop
taking Austedo for more than 1 week. Do not take another dose until you
talk to your healthcare provider.
|
|
What
should I avoid while taking Austedo?
Sleepiness (sedation) is a
common side effect of Austedo. While taking Austedo, do not drive a car or
operate dangerous machinery until you know how Austedo affects you. Drinking
alcohol and taking other drugs that may also cause sleepiness while you are
taking Austedo may increase any sleepiness caused by Austedo.
|
|
What
are the possible side effects of Austedo?
Austedo can
cause serious side effects, including:
Depression and suicidal thoughts or actions in
people with Huntington’s disease. See “What is the most important
information I should know about Austedo?”Irregular heartbeat (QT prolongation). Austedo increases your chance of
having certain changes in the electrical activity in your heart. These
changes can lead to a dangerous abnormal heartbeat. Taking Austedo with
certain medicines may increase this chance.If you
are at risk of QT prolongation, your healthcare provider should check
your heart before and after increasing your Austedo dose above 24 mg a
day.Neuroleptic Malignant Syndrome (NMS). Call your healthcare provider right
away and go to the nearest emergency room if you develop these signs and
symptoms that do not have another obvious cause:high
fever problems
thinkingincreased
sweatingstiff
musclesvery
fast or uneven heartbeatRestlessness. You may get a condition where you
feel a strong urge to move. This is called akathisia.Parkinsonism. Symptoms of parkinsonism include:
slight shaking, body stiffness, trouble moving, trouble keeping
your balance, or falls.
The most
common side effects of Austedo in people with Huntington’s disease include:
sleepiness
(sedation)diarrheatirednessdry
mouth
The most
common side effects of Austedo in people with tardive dyskinesia include:
inflammation
of the nose and throat (nasopharyngitis)problems
sleeping (insomnia)
These are not all the possible
side effects of Austedo. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
|
|
How
should I store Austedo?
Store
Austedo tablets at room temperature, between 68°F to 77°F (20°C to
25°C).Keep the
bottle tightly closed to protect Austedo from light and moisture.
Keep Austedo
tablets and all medications out of reach of children.
|
|
General
information about the safe and effective use of Austedo.
Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide. Do not
use Austedo for a condition for which it was not prescribed. Do not give
Austedo to other people, even if they have the same symptoms you have. It may
harm them. You can ask your pharmacist or healthcare provider for information
about Austedo that is written for health professionals.
|
|
What
are the ingredients in Austedo?
Active
ingredient: deutetrabenazine
Inactive
ingredients: ammonium
hydroxide, black iron oxide, n‑butyl alcohol, butylated hydroxyanisole,
butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline
cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl
alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and
FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake.
The 12 mg tablets also contain FD&C yellow #6 lake.
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
AUSMG-003
For more information, go to
www.Austedo.com or call 1-888-483-8279.
|
|
This
Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: July 2019
|
Package/Label
Display Panel
NDC 68546-170-60
Austedo™ (deutetrabenazine) tablets
6 mg
60 tablets
Medication Guide Required: Each time
Austedo is dispensed, give the patient a Medication Guide.
Package/Label
Display Panel
NDC 68546-171-60
Austedo™ (deutetrabenazine) tablets
9 mg
60 tablets
Medication Guide Required: Each time
Austedo is dispensed, give the patient a Medication Guide.
Package/Label
Display Panel
NDC 68546-172-60
Austedo™ (deutetrabenazine) tablets
12 mg
60 tablets
Medication Guide Required: Each time
Austedo is dispensed, give the patient a Medication Guide.
|
Austedo
deutetrabenazine tablet, coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:68546-170
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DEUTETRABENAZINE (DEUTETRABENAZINE)
|
DEUTETRABENAZINE
|
6 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
AMMONIA
|
|
|
FERROSOFERRIC
OXIDE
|
|
|
BUTYL
ALCOHOL
|
|
|
BUTYLATED
HYDROXYANISOLE
|
|
|
BUTYLATED
HYDROXYTOLUENE
|
|
|
MAGNESIUM
STEARATE
|
|
|
MANNITOL
|
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
POLYETHYLENE
GLYCOL, UNSPECIFIED
|
|
|
POLYSORBATE
80
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
POVIDONE,
UNSPECIFIED
|
|
|
PROPYLENE
GLYCOL
|
|
|
SHELLAC
|
|
|
TALC
|
|
|
TITANIUM
DIOXIDE
|
|
|
FD&C
BLUE NO. 2
|
|
|
FD&C
RED NO. 40
|
|
|
POLYETHYLENE
GLYCOL 2000000
|
|
|
|
Product
Characteristics
|
|
Color
|
PURPLE
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
SD;6
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68546-170-60
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
2
|
NDC:68546-170-66
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208082
|
04/12/2017
|
|
|
|
Austedo
deutetrabenazine tablet, coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:68546-171
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DEUTETRABENAZINE (DEUTETRABENAZINE)
|
DEUTETRABENAZINE
|
9 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
AMMONIA
|
|
|
FERROSOFERRIC
OXIDE
|
|
|
BUTYL
ALCOHOL
|
|
|
BUTYLATED
HYDROXYANISOLE
|
|
|
BUTYLATED
HYDROXYTOLUENE
|
|
|
MAGNESIUM
STEARATE
|
|
|
MANNITOL
|
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
POLYETHYLENE
GLYCOL, UNSPECIFIED
|
|
|
POLYSORBATE
80
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
POVIDONE,
UNSPECIFIED
|
|
|
PROPYLENE
GLYCOL
|
|
|
SHELLAC
|
|
|
TALC
|
|
|
TITANIUM
DIOXIDE
|
|
|
FD&C
BLUE NO. 2
|
|
|
POLYETHYLENE
GLYCOL 2000000
|
|
|
|
Product
Characteristics
|
|
Color
|
BLUE
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint
Code
|
SD;9
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68546-171-60
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
2
|
NDC:68546-171-66
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208082
|
04/12/2017
|
|
|
|
Austedo
deutetrabenazine tablet, coated
|
|
Product
Information
|
|
Product
Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:68546-172
|
|
Route of
Administration
|
ORAL
|
DEA
Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DEUTETRABENAZINE (DEUTETRABENAZINE)
|
DEUTETRABENAZINE
|
12 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
AMMONIA
|
|
|
FERROSOFERRIC
OXIDE
|
|
|
BUTYL
ALCOHOL
|
|
|
BUTYLATED
HYDROXYANISOLE
|
|
|
BUTYLATED
HYDROXYTOLUENE
|
|
|
MAGNESIUM
STEARATE
|
|
|
MANNITOL
|
|
|
MICROCRYSTALLINE
CELLULOSE
|
|
|
POLYETHYLENE
GLYCOL, UNSPECIFIED
|
|
|
POLYSORBATE
80
|
|
|
POLYVINYL
ALCOHOL, UNSPECIFIED
|
|
|
POVIDONE,
UNSPECIFIED
|
|
|
PROPYLENE
GLYCOL
|
|
|
SHELLAC
|
|
|
TALC
|
|
|
TITANIUM
DIOXIDE
|
|
|
FD&C
BLUE NO. 2
|
|
|
FD&C
YELLOW NO. 6
|
|
|
POLYETHYLENE
GLYCOL 2000000
|
|
|
|
Product
Characteristics
|
|
Color
|
BROWN (beige)
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
10mm
|
|
Flavor
|
|
Imprint
Code
|
SD;12
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68546-172-60
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
2
|
NDC:68546-172-66
|
60 TABLET,
COATED in 1 BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208082
|
04/12/2017
|
|
|
|
Labeler - Teva Neuroscience, Inc. (009906397)
|
Teva Neuroscience,
Inc.
