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
-----------------------------INDICATIONS
AND USAGE--------------------------
INGREZZA is a vesicular monoamine transporter 2
(VMAT2) inhibitor indicated for the treatment of adults with tardive
dyskinesia. (1)
------------------------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. (2.1)
Can be taken with or without food. (2.1)
The recommended dose for patients with moderate or severe
hepatic impairment is 40 mg once daily. (2.2)
Consider dose reduction based on tolerability in known
CYP2D6 poor metabolizers. (2.2)
---------------------DOSAGE FORMS AND
STRENGTHS---------------------- Capsules:
40 mg. (3)
-------------------------------CONTRAINDICATIONS------------------------------
None. (4)
----------------------WARNINGS
AND PRECAUTIONS----------------------
Somnolence: May impair patient’s ability to drive or
operate hazardous machinery. (5.1)
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. (5.2)
-------------------------------ADVERSE
REACTIONS------------------------------
Most common adverse reaction (≥5% and twice the rate
of placebo):
somnolence. (6.1)
To report SUSPECTED
ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 or FDA
at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG
INTERACTIONS-------------------------------
Dose adjustments due to drug interactions (2.3, 7):
|
Factors
|
Dose Adjustments for
|
|
|
INGREZZA
|
|
Use of MAOIs with INGREZZA
|
Avoid concomitant use with
|
|
|
MAOIs.
|
|
Use of strong CYP3A4 inducers
|
Concomitant use is not
|
|
with
INGREZZA
|
recommended.
|
|
Use of strong CYP3A4 inhibitors
|
Reduce dose to 40 mg.
|
|
with
INGREZZA
|
|
|
Use of strong CYP2D6 inhibitors
|
Consider dose reduction based on
|
|
with
INGREZZA
|
tolerability.
|
--------------------------USE
IN SPECIFIC POPULATIONS---------------------
Pregnancy: May cause fetal harm. (8.1)
Lactation: Advise not to breastfeed. (8.2)
Renal Impairment: No dosage adjustment is necessary
for patients with mild to moderate renal impairment. Use is not recommended in
patients with severe renal impairment. (8.8)
See 17 for PATIENT
COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 04/2017
FULL PRESCRIBING
INFORMATION: CONTENTS*
1
INDICATIONS
AND USAGE
2
DOSAGE
AND ADMINISTRATION
2.1 Dosing and Administration Information
2.2 Dosage
Recommendations for Patients with Hepatic Impairment
2.3 Dosage
Recommendations for Known CYP2D6 Poor Metabolizers
2.4 Dosage Recommendations for Concomitant
Use with Strong CYP3A4 Inducers and Strong CYP3A4 or CYP2D6 Inhibitors
3
DOSAGE
FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS
AND PRECAUTIONS 5.1 Somnolence
5.2 QT Prolongation
6
ADVERSE
REACTIONS
6.1 Clinical Trials Experience
7
DRUG
INTERACTIONS
7.1 Drugs
Having Clinically Important Interactions with INGREZZA
7.2 Drugs
Having No Clinically Important Interactions with
INGREZZA
8
USE
IN SPECIFIC POPULATIONS 8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 CYP2D6 Poor Metabolizers
8.7 Hepatic Impairment
8.8 Renal Impairment
10 OVERDOSAGE
10.1
Human Experience
10.2
Management of Overdosage
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY 12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
Sections or
subsections omitted from the full prescribing information are not listed.
1
Reference ID: 4083041
1 INDICATIONS AND USAGE
INGREZZA is indicated for the treatment of adults with
tardive dyskinesia [see Clinical Studies
(14)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosing and Administration Information
The initial dose for INGREZZA is 40 mg once daily.
After one week, increase the dose to the recommended dose of 80 mg once daily.
Continuation of 40 mg once daily may be considered for some patients.
Administer INGREZZA orally with or without food [see Clinical Pharmacology (12.3)].
2.2 Dosage Recommendations for Patients with Hepatic Impairment
The recommended dose for patients with moderate or
severe hepatic impairment (Child-Pugh score 7 to 15) is INGREZZA 40 mg once
daily [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
2.3 Dosage Recommendations for Known CYP2D6 Poor Metabolizers
Consider reducing INGREZZA dose based on tolerability
for known CYP2D6 poor metabolizers [see
Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].
2.4 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inducers
and Strong CYP3A4 or CYP2D6 Inhibitors
Coadministration
with Strong CYP3A4 Inducers
Concomitant
use of strong CYP3A4 inducers with INGREZZA is not recommended [see Drug Interactions (7.1)].
Coadministration
with Strong CYP3A4 Inhibitors
Reduce
INGREZZA dose to 40 mg once daily when INGREZZA is coadministered with a strong
CYP3A4 inhibitor [see Drug Interactions (7.1)].
Coadministration
with Strong CYP2D6 Inhibitors
Consider
reducing INGREZZA dose based on tolerability when INGREZZA is coadministered
with a strong CYP2D6 inhibitor [see Drug
Interactions (7.1)].
3 DOSAGE FORMS AND STRENGTHS
INGREZZA
is available as 40 mg capsules. The white opaque body and purple cap capsule is
printed with ‘VBZ’ and ‘40’ in black ink.
4 CONTRAINDICATIONS
None.
Reference ID: 4083041
5.1 Somnolence
INGREZZA
can cause somnolence. Patients should not perform activities requiring mental
alertness such as operating a motor vehicle or operating hazardous machinery
until they know how they will be affected by INGREZZA [see Adverse Reactions (6.1)].
5.2 QT Prolongation
INGREZZA
may prolong the QT interval, although the degree of QT prolongation is not
clinically significant at concentrations expected with recommended dosing. In
patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor
metabolizers, INGREZZA concentrations may be higher and QT prolongation
clinically significant [see Clinical
Pharmacology (12.2)]. For patients who are
CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose
reduction may be necessary. For patients taking a strong CYP3A4 inhibitor,
reduce the dose of INGREZZA to 40 mg once daily [see Dosage and Administration (2.3,
2.4)].
INGREZZA should be avoided in patients with congenital long QT syndrome or with
arrhythmias associated with a prolonged QT interval. For patients at increased
risk of a prolonged QT interval, assess the QT interval before increasing the
dosage.
6 ADVERSE REACTIONS
The
following adverse reactions are discussed in more detail in other sections of
the labeling:
Somnolence
[see Warnings and Precautions (5.1)]
QT
Prolongation [see Warnings and
Precautions (5.2)]
6.1 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.
Variable
and Fixed Dose Placebo-Controlled Trial Experience
The
safety of INGREZZA was evaluated in 3 placebo-controlled studies, each 6 weeks
in duration (fixed dose, dose escalation, dose reduction), including 445
patients. Patients were 26 to 84 years of age with moderate to severe tardive
dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/
schizoaffective disorder (72%). The mean age was 56 years. Patients were 57%
Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28%
were Hispanic or Latino. All subjects continued previous stable regimens of
antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and
typical antipsychotic medications at study entry.
Adverse Reactions Leading to Discontinuation
of Treatment
A
total of 3% of INGREZZA treated patients and 2% of placebo-treated patients discontinued
because of adverse reactions.
Common Adverse Reactions
Adverse
reactions that occurred in the 3 placebo-controlled studies at an incidence of ≥2%
and greater than placebo are presented in Table 1.
Reference ID: 4083041
Table
1: Adverse Reactions in 3 Placebo-Controlled
Studies of 6-week Treatment Duration Reported at ≥2% and >Placebo
|
Adverse Reaction1
|
INGREZZA
|
Placebo
|
|
|
(n=262) (%)
|
(n=183) (%)
|
|
General Disorders
|
|
|
|
Somnolence
|
10.9%
|
4.2%
|
|
(somnolence,
fatigue, sedation)
|
|
|
|
Nervous System Disorders
|
|
|
|
Anticholinergic
effects
|
5.4%
|
4.9%
|
|
(dry
mouth, constipation, disturbance in attention, vision
|
|
|
|
blurred,
urinary retention)
|
|
|
|
Balance
disorders/fall
|
4.1%
|
2.2%
|
|
(fall,
gait disturbance, dizziness, balance disorder)
|
|
|
|
Headache
|
3.4%
|
2.7%
|
|
Akathisia
|
2.7%
|
0.5%
|
|
(akathisia,
restlessness)
|
|
|
|
Gastrointestinal Disorders
|
|
|
|
Vomiting
|
2.6%
|
0.6%
|
|
Nausea
|
2.3%
|
2.1%
|
|
Musculoskeletal Disorders
|
|
|
|
Arthralgia
|
2.3%
|
0.5%
|
1
Within each adverse reaction category, the
observed adverse reactions are listed in order of decreasing frequency.
Other Adverse Reactions Observed During the
Premarketing Evaluation of INGREZZA
Other
adverse reactions of ≥1% incidence and greater than placebo are shown below.
The following list does not include adverse reactions: 1) already listed in
previous tables or elsewhere in the labeling, 2) for which a drug cause was
remote, 3) which were so general as to be uninformative, 4) which were not
considered to have clinically significant implications, or 5) which occurred at
a rate equal to or less than placebo.
Endocrine Disorders: blood
glucose increased
General Disorders: weight
increased
Infectious Disorders: respiratory
infections
Neurologic Disorders: drooling,
dyskinesia, extrapyramidal symptoms (non-akathisia)
Psychiatric Disorders: anxiety,
insomnia
During
controlled trials, there was a dose-related increase in prolactin.
Additionally, there was a dose-related increase in alkaline phosphatase and
bilirubin, suggesting a potential risk for cholestasis.
Reference ID: 4083041
7.1 Drugs Having Clinically Important Interactions with INGREZZA
Table
2: Clinically Significant Drug Interactions
with INGREZZA
Monoamine Oxidase Inhibitors (MAOIs)
|
Clinical Implication:
|
Concomitant
use of INGREZZA with MAOIs may increase the
|
|
|
concentration
of monoamine neurotransmitters in synapses, potentially
|
|
|
leading
to increased risk of adverse reactions such as serotonin syndrome,
|
|
|
or
attenuated treatment effect of INGREZZA.
|
|
Prevention or Management:
|
Avoid
concomitant use of INGREZZA with MAOIs.
|
|
Examples:
|
isocarboxazid,
phenelzine, selegiline
|
|
Strong CYP3A4 Inhibitors
|
|
|
|
|
|
Clinical Implication:
|
Concomitant use of INGREZZA with strong CYP3A4 inhibitors
increased
|
|
|
the exposure (Cmax and AUC) to valbenazine and its
active metabolite
|
|
|
compared
with the use of INGREZZA alone [see
Clinical Pharmacology
|
|
|
(12.3)]. Increased
exposure of valbenazine and its active metabolite may
|
|
|
increase
the risk of exposure-related adverse reactions [see Warnings and
|
|
|
Precautions (5.2)].
|
|
Prevention or Management:
|
Reduce INGREZZA dose when INGREZZA is coadministered with a
|
|
|
strong
CYP3A4 inhibitor [see Dosage and
Administration (2.3)].
|
|
Examples:
|
itraconazole,
ketoconazole, clarithromycin
|
|
Strong CYP2D6 Inhibitors
|
|
|
|
|
|
Clinical Implication:
|
Concomitant use of INGREZZA with strong CYP2D6 inhibitors may
|
|
|
increase the exposure (Cmax and AUC) to valbenazine’s
active metabolite
|
|
|
compared
with the use of INGREZZA alone [see
Clinical Pharmacology
|
|
|
(12.3)].
Increased exposure of active metabolite may increase the risk of
|
|
|
exposure-related
adverse reactions [see Warnings and
Precautions (5.2)].
|
|
Prevention or Management:
|
Consider reducing INGREZZA dose based on tolerability when
|
|
|
INGREZZA
is coadministered with a strong CYP2D6 inhibitor [see
|
|
|
Dosage and Administration (2.3)].
|
|
Examples:
|
paroxetine,
fluoxetine, quinidine
|
|
Strong CYP3A4 Inducers
|
|
|
|
|
|
Clinical Implication:
|
Concomitant use of INGREZZA with a strong CYP3A4 inducer
decreased
|
|
|
the
exposure of valbenazine and its active metabolite compared to the use
|
|
|
of INGREZZA alone. Reduced exposure of valbenazine and its
active
|
|
|
metabolite
may reduce efficacy [see Clinical
Pharmacology (12.3)].
|
|
Prevention or Management:
|
Concomitant use of strong CYP3A4 inducers with INGREZZA is not
|
|
|
recommended
[see Dosage and Administration (2.3)].
|
|
Examples:
|
rifampin, carbamazepine, phenytoin, St. John’s wort1
|
|
Digoxin
|
|
|
|
|
|
Clinical Implication:
|
Concomitant use of INGREZZA with digoxin increased digoxin
levels
|
|
|
because
of inhibition of intestinal P-glycoprotein (P-gp) [see Clinical
|
|
|
Pharmacology (12.3)].
|
|
Prevention or Management:
|
Digoxin concentrations should be monitored when co-administering
|
|
|
INGREZZA
with digoxin. Increased digoxin exposure may increase the
|
|
|
risk
of exposure related adverse reactions. Dosage adjustment of digoxin
|
|
|
may
be necessary.
|
1
The induction potency of St. John’s wort may
vary widely based on preparation.
Reference ID: 4083041
7.2 Drugs Having No Clinically Important Interactions with INGREZZA
Dosage
adjustment for INGREZZA is not necessary when used in combination with
substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5
based on in vitro study results.
8 USE IN SPECIFIC POPULATIONS
8.1 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 based="" m="" mg="" mrhd="" on="" sup="" the="" times="">2
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.
Data
Animal Data
Valbenazine
was administered orally to pregnant rats during the period of organogenesis at
1, 5, and
15
mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day
based on mg/m2 body surface area. Valbenazine produced a significant
decrease in maternal body weight gain at 0.6 and 2 times the MRHD of 80 mg/day
based on mg/m2. No adverse embryo fetal effects were produced when
valbenazine was administered at doses up to 2 times the MRHD of 80 mg/day based
on mg/m2.
Valbenazine
was administered orally to pregnant rabbits during the period of organogenesis
at 20, 50, and 100 mg/kg/day, which are approximately 5, 12, and 24 times the
MRHD of 80 mg/day based on mg/m2. No malformations were observed at
doses up to 24 times the MRHD of 80 mg/day based on mg/m2. However,
valbenazine produced a delay in fetal development (decreased fetal weights and
delayed ossification) at 24 times the MRHD of 80 mg/day based on mg/m2,
likely secondary to maternal toxicity (decreased food intake and loss in body
weight).
Valbenazine
was administered orally to pregnant rats during the period of organogenesis
through lactation (day 7 of gestation through day 20 postpartum) at 1, 3, and
10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2 times the MRHD of 80
mg/day based on mg/m2. Valbenazine produced an increase in the
incidence of stillbirths and postnatal pup mortality at 0.4 and 1.2 times the
MRHD of 80 mg/day based on mg/m2. Valbenazine did not affect
neurobehavioral function including learning and memory and had no effect on
sexual maturation at doses <1 80="" based="" day="" m="" mg="" mrhd="" of="" on="" sup="" the="" times="">2
(because of death in the majority of the high dose group (1.2 times the MRHD),
these parameters were not assessed in this group).
Reference ID: 4083041
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.
8.4 Pediatric Use
Safety
and effectiveness of INGREZZA have not been established in pediatric patients.
8.5 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.
8.6 CYP2D6 Poor Metabolizers
Consider
reducing INGREZZA dose based on tolerability for known CYP2D6 poor metabolizers
[see Dosage and Administration (2.2)].
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 [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Dosage
reduction of INGREZZA is recommended for patients with moderate or severe
hepatic impairment [see Dosage and Administration (2.3)]. 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 [see Clinical
Pharmacology (12.3)].
8.8 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 min="" ml="" o:p="">
10 OVERDOSAGE
10.1 Human Experience
The
pre-marketing clinical trials involving INGREZZA in approximately 850 subjects
do not provide information regarding symptoms with overdose.
10.2 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. If an overdose occurs,
consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).
Reference ID: 4083041
INGREZZA
contains valbenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor,
present as valbenazine tosylate salt, with the chemical name, L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy -3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester, 4-methylbenzenesulfonate (1:2).
Valbenazine tosylate is slightly soluble in water. Its molecular formula is C38H54N2O10S2,
and its molecular weight is
762.97
g/mol (ditosylate salt) with the following structure:
The
molecular formula of valbenazine free base is C24H38N2O4 and its molecular
weight is 418.57.
INGREZZA
capsules are intended for oral administration only. Each capsule contains 73 mg
of valbenazine tosylate, which is equivalent to 40 mg of valbenazine free base.
It also contains the following inactive ingredients: mannitol, partially
pregelatinized starch, fumed silica, and magnesium stearate. The capsule shell
contains gelatin, candurin silver fine, FD&C Red#40, and FD&C Blue#1.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 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 [+]-α-dihydrotetrabenazine
([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human
VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-α-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) [see Warnings and Precautions (5.2)].
Reference ID: 4083041
Valbenazine
and its active metabolite ([+]-α-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%. [+]-α-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%. [+]-α-HTBZ Cmax and AUC are unaffected.
Distribution
The
plasma protein binding of valbenazine and [+]-α-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
[+]-α-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 ([+]-α-HTBZ) and by oxidative
metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other
minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by
CYP2D6.
The
results of in vitro studies suggest
that valbenazine and [+]-α-HTBZ are unlikely to inhibit CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5, or induce CYP1A2, CYP2B6 or CYP3A4/5 at
clinically relevant concentrations.
The
results of in vitro studies suggest
that valbenazine and [+]-α-HTBZ are unlikely to inhibit the transporters (BCRP,
OAT1, OAT3, OCT2, OATP1B1, or OATP1B3) at clinically relevant concentrations.
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 [+]-α-HTBZ
in either urine or feces.
Studies
in Specific Populations
Exposures
of valbenazine in patients with hepatic impairment are summarized in Figure 1.
Reference ID: 4083041
AUCinf=area under the plasma concentration versus time
curve from 0 hours extrapolated to infinity
[+]-α-HTBZ=[+]-α-dihydrotetrabenazine (active metabolite)
Drug
Interaction Studies
The
effects of ketoconazole and rifampin on the exposure of valbenazine are
summarized in Figure 2.
Figure
2: Effects of Strong CYP3A4 Inducers and
Inhibitors on Valbenazine Pharmacokinetics
Fold Change and 90% confidence intervals
Strong CYP3A4 Inducer:
Rifampin
Cmax
Valbenazine AUCinf
[+]- -HTBZ Cmax
AUCinf
Strong CYP3A4 Inhibitor:
Ketoconazole
Cmax
Valbenazine AUCinf
[+]- -HTBZ Cmax
AUCinf
0.25 0.5 1 2
Change relative to reference (without interacting drug)
AUCinf=area under the plasma concentration versus time
curve from 0 hours extrapolated to infinity
[+]-α-HTBZ=[+]-α-dihydrotetrabenazine (active metabolite)
The
effects of valbenazine on the exposure of other coadministered drugs are
summarized in Figure 3.
Reference ID: 4083041
AUCinf=area
under the plasma concentration versus time curve from 0 hours extrapolated to
infinity
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valbenazine
did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day.
These doses are <1 0.1="" 0.24="" 80="" and="" based="" day="" m="" mg="" mrhd="" of="" on="" respectively="" sup="" the="" times="">2
Valbenazine
did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks
at 10, 30 and 75 mg/kg/day, which are 0.6, 1.9 and 4.6 times the MRHD of 80
mg/day based on mg/m2.
Mutagenesis
Valbenazine
was not mutagenic in the in vitro
bacterial reverse mutation test (Ames) or clastogenic in the in vitro
mammalian chromosomal aberrations assay in human peripheral blood
lymphocytes or in the in vivo rat bone marrow micronucleus assay.
Impairment
of Fertility
In
a fertility study, rats were treated orally with valbenazine at 1, 3, and 10
mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males)
or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2
times the MRHD of 80 mg/day based on mg/m2, respectively.
Valbenazine delayed mating in both sexes, which led to lower number of
pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the
MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on
sperm parameters (motility, count, density) or on uterine parameters (corpora
lutea, number of implants, viable implants, pre-implantation loss, early
resorptions and post-implantation loss) at any dose.
Reference ID: 4083041
A
randomized, double-blind, placebo-controlled
trial of INGREZZA was conducted in patients with moderate to severe tardive
dyskinesia as determined by clinical observation. Patients had underlying
schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at
significant risk for suicidal or violent behavior and individuals with unstable
psychiatric symptoms were excluded.
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=no dyskinesia; 1=low amplitude, present during some but
not most of the exam; 2=low amplitude and present during most of the exam (or
moderate amplitude and present during some of the exam); 3=moderate amplitude
and present during most of exam; or 4=maximal amplitude and present during most
of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could thus range
from 0 to 28, with a decrease in score indicating improvement. The AIMS was
scored by central raters who interpreted the videos blinded to subject
identification, treatment assignment, and visit number.
The
primary efficacy endpoint was the mean change from baseline in the AIMS
dyskinesia total score at the end of Week 6. The change from baseline for two
fixed doses of INGREZZA (40 mg or 80 mg) was compared to placebo. At the end of
Week 6, subjects initially assigned to placebo were re- randomized to receive
INGREZZA 40 mg or 80 mg. Subjects originally randomized to INGREZZA continued
INGREZZA at their randomized dose. Follow-up was continued through Week 48 on
the assigned drug, followed by a 4-week period off-drug (subjects were not
blind to withdrawal).
A
total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to
completion of the placebo-controlled period. Mean age was 56 (range 26 to 84).
Patients were 54% male and 46% female. Patients were 57% Caucasian, 38%
African-American, and 5% other. Concurrent diagnoses included
schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With
respect to concurrent antipsychotic use, 70% of subjects were receiving
atypical antipsychotics, 14% were receiving typical or combination
antipsychotics, and 16% were not receiving antipsychotics.
Results
are presented in Table 3, with the distribution
of responses shown in Figure 4. The change from
baseline in the AIMS total dyskinesia score in the 80 mg INGREZZA group was
statistically significantly different from the change in the placebo group.
Subgroup analyses by gender, age, racial subgroup, underlying psychiatric
diagnostic category, and concomitant antipsychotic medication did not suggest
any clear evidence of differential responsiveness.
The
mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at
the end of the 48-week treatment (N=123 [52.6%]), following discontinuation of
INGREZZA, the mean AIMS dyskinesia total score appeared to return toward
baseline (there was no formal hypothesis testing for the change following
discontinuation).
Reference ID: 4083041
Table
3: Primary Efficacy Endpoint – Severity of
Tardive Dyskinesia at Baseline and the End of Week 6
|
Endpoint
|
Treatment Group
|
Mean Baseline
|
LS Mean Change
|
Placebo-subtracted
|
|
|
|
|
Score (SD)
|
from Baseline
|
Difference (95% CI)
|
|
|
|
|
|
(SEM)**
|
|
|
|
AIMS Dyskinesia
|
INGREZZA
40 mg
|
9.8 (4.1)
|
-1.9 (0.4)
|
-1.8 (-3.0, -0.7)
|
|
|
Total Score
|
|
|
|
|
|
|
INGREZZA
80 mg*
|
10.4 (3.6)
|
-3.2 (0.4)
|
-3.1 (-4.2, -2.0)
|
||
|
|
|||||
|
|
|
|
|
|
|
|
|
Placebo
|
9.9 (4.3)
|
-0.1 (0.4)
|
|
LS
Mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean;
CI=2-sided 95% confidence interval *Dose that was statistically significantly
different from placebo after adjusting for multiplicity.
**A
negative change from baseline indicates improvement.
Figure
4: Percent of Patients with Specified
Magnitude of AIMS Total Score Improvement at the End of Week 6
ITT=Intent
to Treat; This analysis set includes all randomized patients who had a baseline
and at least one post-baseline AIMS dyskinesia total score value reported.
Reference ID: 4083041
Figure
5: AIMS Dyskinesia Total Score Mean Change
from Baseline – Entire Study Duration (Arithmetic Mean)
DB=Double- Blind; After Week 6, subjects initially
receiving placebo were re -randomized to receive INGREZZA 40 mg or 80 mg until
the end of Week 48. Error bars represent ±1 Standard Error of the
Mean (SEM).
16 HOW SUPPLIED/STORAGE AND HANDLING
INGREZZA (valbenazine) capsules are available as:
40 mg Capsule: White opaque body with a purple cap, printed with ‘VBZ’
and ‘40’ in black ink.
Bottle of 30: NDC 70370-1040-1
Bottle of 90: NDC 70370-1040-2
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions
permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.
Reference ID: 4083041
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 [see Warnings and
Precautions (5.1)].
Prolongation
of the QT Interval
Inform
patients to consult their physician immediately if they feel faint, lose
consciousness, or have heart palpitations [see
Warnings and Precautions (5.2)]. 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 [see Use in Specific Populations (8.1)].
Lactation
Advise
a woman not to breastfeed during treatment with INGREZZA and for 5 days after
the final dose [see Use in Specific Populations (8.2)].
For
further information on INGREZZA, call 84-INGREZZA (844-647-3992).
Distributed
by:
Neurocrine
Biosciences, Inc.
San
Diego, CA 92130
INGREZZA
is a trademark of Neurocrine Biosciences, Inc.
Reference ID: 4083041
INGREZZA™ (in
greh' zah)
(valbenazine)
capsules
What is INGREZZA?
INGREZZA is a
prescription medicine used to treat adults with movements in the face, tongue,
or other body parts that cannot be controlled (tardive dyskinesia).
It is not known
if INGREZZA is safe and effective in children.
Before taking INGREZZA, tell your healthcare provider about all of
your medical conditions including if you:
have liver
problems
have heart
disease that is not stable, have heart failure or recently had a heart attack
have an irregular heart rhythm or heartbeat (QT prolongation, heart arrhythmia)
are pregnant or
plan to become pregnant. INGREZZA may harm your unborn baby.
are
breastfeeding or plan to breastfeed. It is not known if INGREZZA passes into
your breast milk. Do not breastfeed during treatment with INGREZZA and for 5
days after the final dose. Talk to your healthcare provider about the best way
to feed your baby during treatment with INGREZZA.
Tell your
healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins and herbal supplements.
Taking INGREZZA
with certain other medicines may cause serious side effects. Do not start any new medicines while taking INGREZZA without talking to your
healthcare provider first.
How should I take INGREZZA?
Take INGREZZA
exactly as your healthcare provider tells you to. Your healthcare provider will
tell you how much INGREZZA to take and when to take it.
Do not stop
taking INGREZZA without talking to your healthcare provider first. INGREZZA can
be taken with or without food.
If you take too
much INGREZZA, call your poison control center at 1-800-222-1222.
What are the possible side effects of INGREZZA?
INGREZZA may cause serious side effects, including:
Sleepiness (somnolence). Do not drive, operate heavy machinery, or do other dangerous
activities until you know how INGREZZA
affects you.
Heart rhythm problems (QT prolongation). INGREZZA may
cause a heart problem known as QT prolongation.
Symptoms of QT prolongation may include:
o fast, slow, or
irregular heartbeat o shortness of breath
o
dizziness or fainting
Tell your
healthcare provider right away if you have a change in your heartbeat (a fast
or irregular heartbeat), or if you faint.
The most common side effect of INGREZZA is sleepiness
(somnolence).
Other common side effects include:
|
|
changes in
balance (balance problems,
|
|
headache
|
|
feelings of restlessness
|
|
|
dizziness) or
an increased risk of falls
|
|
constipation
|
|
blurred
vision
|
|
dry mouth
|
|
|
These are not
all of the possible side effects of INGREZZA. 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 INGREZZA?
Store INGREZZA
at room temperature between 68°F to 77°F (20°C to 25°C).
Keep INGREZZA and all medicines out of the reach of children.
General information about the safe and effective use of INGREZZA
Medicines are
sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. Do not use INGREZZA for a condition for which it was not
prescribed. Do not give INGREZZA to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your pharmacist or
healthcare provider for information about INGREZZA that is written for
healthcare professionals.
What are the ingredients in INGREZZA?
Active ingredient: valbenazine
Inactive ingredients: mannitol, partially pregelatinized starch, fumed silica, and
magnesium stearate. The capsule shell contains gelatin, candurin silver fine, FD&C Red#40, and FD&C
Blue#1.
Distributed by:
Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A
For more
information, go to www.INGREZZA.com or call 84-INGREZZA (844-647-3992).
This
Patient Information has been approved by the U.S. Food and Drug Administration Approved:
4/2017
Reference ID: 4083041