Deutetrabenazine- Austedo-@-(Mar 2017)- Neurological disorders
Drug Name:Deutetrabenazine- Austedo-@-(Mar 2017)- Neurological disorders
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
Concomitant use of strong CYP2D6 inhibitors: Maximum recommended
dose of AUSTEDO is 36 mg per day (18 mg twice daily)
Alcohol or other sedating drugs: May have additive sedation and
somnolence
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 13
Name of the Drug- Austerdo
Active Ingredient- Deuterabenazine Pharmacological Classification-
For the treatment of chorea associated with Huntingtons
disease
Date of Approval- 04-03-2017
(Ref- FDA approved List 2017) HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AUSTEDO safely and effectively. See full prescribing information for
AUSTEDO.
AUSTEDO (deutetrabenazine) tablets, for oral use
Initial U.S. Approval: 2017
WARNING: DEPRESSION AND SUICIDALITY
See full prescribing information for complete boxed warning.
Increases the risk of depression and suicidal thoughts and behavior
(suicidality) in patients with Huntington’s disease
Balance risks of depression and suicidality with the clinical need for
treatment of chorea when considering the use of AUSTEDO
Monitor patients for the emergence or worsening of depression, suicidality,
or unusual changes in behavior
Inform patients, caregivers and families of the risk of depression and
suicidality and instruct to report behaviors of concern promptly to the
treating physician
Exercise caution when treating patients with a history of depression or prior
suicide attempts or ideation
AUSTEDO is contraindicated in patients who are suicidal, and in patients
with untreated or inadequately treated depression
INDICATIONS AND USAGE
AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor
indicated for the treatment of chorea associated with Huntington disease
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (>8% of AUSTEDO-treated patients and
greater than placebo) were: somnolence, diarrhea, dry mouth, and fatigue
Contra-Indications:
CONTRAINDICATIONS
Suicidal, or untreated/inadequately treated depression
Hepatic impairment
Taking MAOIs, reserpine, or tetrabenazine (XENAZINE®
WARNINGS AND PRECAUTIONS
Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs
Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or
discontinue if this occurs
Sedation/somnolence: May impair the patient’s ability to drive or
operate complex machinery
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor
indicated for the treatment of chorea associated with Huntington disease
DOSAGE AND ADMINISTRATION
The starting dose is 6 mg once daily. Titrate up at weekly intervals by
6 mg per day to a tolerated dose that reduces chorea, up to a maximum
recommended daily dosage of 48 mg (24 mg twice daily)
Administer total daily dosages of 12 mg or above in two divided doses
Administer with food
Swallow tablets whole; do not chew, crush, or break .
If switching patients from tetrabenazine, discontinue tetrabenazine and
initiate AUSTEDO the following day. See full prescribing information
for recommended conversion table.
Maximum recommended dosage of AUSTEDO in poor CYP2D6
metabolizers is 36 mg per day (i.e., 18 mg twice daily)
DOSAGE FORMS AND STRENGTHS
Tablets: 6 mg, 9 mg, and 12 mg (3)
Patient Information:
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.
Risk of Depression and Suicide
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
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 .
Interaction with Alcohol or Other Sedating Drugs
Advise patients that alcohol or other drugs that cause sleepiness
will worsen somnolence
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
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
AUSTEDOTM is a trademark
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
The precise mechanism by which AUSTEDO (deutetrabenazine) exerts
its anti-chorea effects 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 (a-dihydrotetrabenazine [HTBZ]
and ß-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2,
resulting in decreased uptake of monoamines into synaptic vesicles
and depletion of monoamine stores.
2. 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.
The effect of a single 25-mg or 50-mg dose of tetrabenazine, a closely
related VMAT2 inhibitor, 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 50 mg,
tetrabenazine caused an approximately 8 msec mean increase in
QTc (90% CI: 5.0, 10.4 msec).
Effects at higher exposures to either tetrabenazine 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.
3. 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), a-HTBZ and ß-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 a-HTBZ and ß-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 a-HTBZ or ß-HTBZ, although
Cmax was increased by approximately 50% in the presence of food..
Distribution
The median volume of distribution (Vc/F) of the a-HTBZ, and the ß-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 a-HTBZ, radioactivity is rapidly
distributed to the brain, with the highest binding in the striatum and lowest
binding in the cortex.
Elimination
AUSTEDO is primarily renally eliminated in the form of metabolites.
The half-life of total (a+ß)-HTBZ from deutetrabenazine is approximately
9 to 10 hours.
The median clearance values (CL/F) of the a-HTBZ, and the ß-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, a-HTBZ and ß- 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 a-HTBZ and ß-HTBZ metabolites from
deutetrabenazine each accounted for less than 10% of the
administered dose.
Sulfate and glucuronide conjugates of the a-HTBZ and ß-HTBZ
metabolites of deutetrabenazine, as well as products of oxidative
metabolism, accounted for the majority of metabolites in the urine.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1.Pregancy
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.
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.
2. 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.
3.Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
4.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.
5. Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine
and its primarymetabolites 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.
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.