Valbenazine - Ingrezza-@- (2017)- Neuromuscular disorders
Drug Name:Valbenazine - Ingrezza-@- (2017)- Neuromuscular 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
Dose adjustments due to drug interactions :
Factors Dose Adjustments for INGREZZA
Use of MAOIs with INGREZZA Avoid concomitant use with MAOIs.
Use of strong CYP3A4 inducers with INGREZZA
Concomitant use is not recommended.
Use of strong CYP3A4 inhibitors with INGREZZA
Reduce dose to 40 mg.
Use of strong CYP2D6 inhibitors with INGREZZA
Consider dose reduction based on tolerability.
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 14
Name of the Drug- Ingrezza
Active Ingredient- Valbenazine Pharmacological Classification-
To treat adults with tardive dyskinesia
disease
(Ref- FDA approved List 2017) HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INGREZZA safely and effectively. See full prescribing information for
INGREZZA.
INGREZZATM (valbenazine) capsules, for oral use
Initial U.S. Approval: 2017
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reaction (=5% and twice the rate of placebo):
somnolence.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Somnolence:
May impair patient’s ability to drive or operate hazardous machinery.
QT Prolongation:
May cause an increase in QT interval.
Avoid use in patients with congenital long QT syndrome or with
arrhythmias associated with a prolonged QT interval.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
INGREZZA is a vesicular monoamine transporter 2 (VMAT2) inhibitor
indicated for the treatment of adults with tardive dyskinesia.
DOSAGE AND ADMINISTRATION
The initial dose is 40 mg once daily. After one week, increase the dose to
the recommended dose of 80 mg once daily.
Can be taken with or without food.
The recommended dose for patients with moderate or severe hepatic
impairment is 40 mg once daily.
Consider dose reduction based on tolerability in known CYP2D6 poor
metabolizers.
DOSAGE FORMS AND STRENGTHS
Capsules: 40 mg.
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling
(Patient Information).
Somnolence
Inform patients that INGREZZA may cause somnolence and may impair
the ability to perform tasks that require complex motor and mental skills.
Advise patients that until they learn how they respond to INGREZZA, they
should be careful or avoid doing activities that require them to be alert,
such as driving a car or operating machinery.
Prolongation of the QT 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 INGREZZA
before any new drug is taken.
Pregnancy
Advise a pregnant patient of the potential risk to a fetus.
Lactation
Advise a woman not to breastfeed during treatment with INGREZZA
and for 5 days after the final dose .
Distributed by:
Neurocrine Biosciences, Inc.
San Diego, CA 92130
INGREZZA is a trademark of Neurocrine Biosciences, Inc.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
The mechanism of action of valbenazine in the treatment of tardive dyskinesia
is unknown, but is thought to be mediated through the reversible inhibition
of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates
monoamine uptake from the cytoplasm to the synaptic vesicle for storage
and release.
2. Pharmacodynamics
Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable
binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active
metabolite [+]-a-dihydrotetrabenazine ([+]-a-HTBZ). [+]- a-HTBZ also binds
with relatively high affinity to human VMAT2 (Ki ~ 3 nM).
Valbenazine and [+]-a-HTBZ have no appreciable binding affinity (Ki > 5000 nM) for
dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic,
histaminergic or muscarinic receptors.
Cardiac Electrophysiology
INGREZZA may cause an increase in the corrected QT interval in patients
who are CYP2D6 poor metabolizers or who are taking a strong CYP2D6
or CYP3A4 inhibitor. An exposure-response analysis of clinical data from
two healthy volunteer studies revealed increased QTc interval with higher
plasma concentrations of the active metabolite.
Based on this model, patients taking an INGREZZA 80 mg dose with
increased exposure to the metabolite (e.g., being a CYP2D6 poor
metabolizer) may have a mean QT prolongation of 11.7 msec
(14.7 msec upper bound of double-sided 90% CI) as compared to
otherwise healthy volunteers given
INGREZZA, who had a mean QT prolongation of 6.7 msec (8.4 msec)..
3. Pharmacokinetics
Valbenazine and its active metabolite ([+]-a-HTBZ) demonstrate
approximate proportional increases for the area under the plasma
concentration versus time curve (AUC) and maximum plasma
concentration (Cmax) after single oral doses from 40 mg to 300 mg
(i.e., 50% to 375% of the recommended treatment dose).
Absorption
Following oral administration, the time to reach maximum valbenazine
plasma concentration (tmax) ranges from 0.5 to 1.0 hours.
Valbenazine reaches steady state plasma concentrations within 1 week.
The absolute oral bioavailability of valbenazine is approximately
49%. [+]-a-HTBZ gradually forms and reaches Cmax 4 to 8 hours
after administration of INGREZZA.
Ingestion of a high-fat meal decreases valbenazine Cmax by
approximately 47% and AUC by approximately 13%. [+]-a-HTBZ
Cmax and AUC are unaffected.
Distribution
The plasma protein binding of valbenazine and [+]-a-HTBZ are greater than
99% and approximately 64%,respectively. The mean steady state volume
of distribution of valbenazine is 92 L.
Nonclinical data in Long-Evans rats show that valbenazine can bind to
melanin-containing structures of the eye such as the uveal tract.
The relevance of this observation to clinical use of INGREZZA is unknown.
Elimination
Valbenazine has a mean total plasma systemic clearance value of
7.2 L/hr. Valbenazine and [+]-a-HTBZ have half-lives of 15 to 22 hours.
Metabolism
Valbenazine is extensively metabolized after oral administration by
hydrolysis of the valine ester to form the active metabolite ([+]-a-HTBZ)
and by oxidative metabolism, primarily by CYP3A4/5, to form
monooxidized valbenazine and other minor metabolites. [+]-a-HTBZ
appears to be further metabolized in part by CYP2D6.
Excretion
Following the administration of a single 50-mg oral dose of radiolabeled
C-valbenazine (i.e., ~63% of the recommended treatment dose),
approximately 60% and 30% of the administered radioactivity was recovered
in the urine and feces, respectively. Less than 2% was excreted as
unchanged valbenazine or [+]-a-HTBZ in either urine or feces.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
The limited available data on INGREZZA use in pregnant women are
insufficient to inform a drug-associated risk.
In animal reproductive studies, no malformations were observed when
valbenazine was administered orally to rats and rabbits during the period
of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum
recommended human dose (MRHD) of 80 mg/day based on mg/m2
body surface area.
However,administration of valbenazine to pregnant rats during
organogenesis through lactation produced an increase in the number
of stillborn pups and postnatal pup mortalities at doses <1 times the
MRHD based on mg/m2.
Advise a pregnant woman of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage
for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes.
The background risk of major birth defects and miscarriage in the U.S.
general population is 2-4% and 15-20% of clinically recognized pregnancies,
respectively.
2. Lactation
Risk Summary
There is no information regarding the presence of valbenazine or its metabolites
in human milk, the effects on the breastfed infant, or the effects on milk production.
Valbenazine and its metabolites have been detected in rat milk at concentrations
higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2
times the MRHD based on mg/m2
Based on animal findings of increased perinatal mortality in exposed fetuses
and pups, advise a woman not to breastfeed during treatment with INGREZZA
and for 5 days after the final dose.
3. Pediatric Use
Safety and effectiveness of INGREZZA have not been established in pediatric
patients.
4. Geriatric Use
No dose adjustment is required for elderly patients. In 3 randomized,
placebo-controlled studies of INGREZZA, 16% were 65 years and older.
The safety and effectiveness were similar in patients older than 65
years compared to younger patients.
5. CYP2D6 Poor Metabolizers
Consider reducing INGREZZA dose based on tolerability for known CYP2D6
poor metabolizers.
Increased exposure (Cmax and AUC) to valbenazine’s active metabolite
is anticipated in CYP2D6 poor metabolizers.
Increased exposure of active metabolite may increase the risk of
exposure-related adverse reactions..
6. Hepatic Impairment
Dosage reduction of INGREZZA is recommended for patients with
moderate or severe hepatic impairment .
Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to
15) had higher exposure of valbenazine and its active metabolite than
patients with normal hepatic function .
7. Renal Impairment
Dosage adjustment is not necessary for patients with mild to moderate
renal impairment (creatinine clearance 30 to 90 mL/min).
INGREZZA does not undergo primary renal clearance.
INGREZZA is not recommended in patients with severe renal impairment
(creatinine clearance <30 mL/min).
OVERDOSAGE
1. Human Experience
The pre-marketing clinical trials involving INGREZZA in approximately 850
subjects do not provide information regarding symptoms with overdose.
2. Management of Overdosage
No specific antidotes for INGREZZA are known. In managing overdose,
provide supportive care, including close medical supervision and monitoring,
and consider the possibility of multiple drug involvement
