-------------------------------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
`Avoid concomitant use with
`MAOIs.
`Concomitant use is not
`recommended.
`Reduce dose to 40 mg.
`
`Use of MAOIs with INGREZZA
`
`Use of strong CYP3A4 inducers
`with INGREZZA
`Use of strong CYP3A4 inhibitors
`with INGREZZA
`Use of strong CYP2D6 inhibitors
`with INGREZZA
`
`Consider dose reduction based on
`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
`
`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.
`
`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
`
`-----------------------------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)
`
`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
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Somnolence
`5.2 QT Prolongation
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 Drugs Having Clinically Important Interactions with INGREZZA
`7.2 Drugs Having No Clinically Important Interactions with
`INGREZZA
`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
`
`6
`
`7
`
`8
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`
`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`INGREZZA is indicated for the treatment of adults with tardive dyskinesia [see Clinical Studies (14)].
`
`DOSAGE AND ADMINISTRATION
`
`2
`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.
`
`CONTRAINDICATIONS
`
`4
`None.
`
`
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`WARNINGS AND PRECAUTIONS
`
`
`5
`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.
`
`
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`Table 1:
`
`Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment Duration
`Reported at ≥2% and >Placebo
`Adverse Reaction1
`
`INGREZZA
`(n=262) (%)
`
`Placebo
`(n=183) (%)
`
`10.9%
`
`4.2%
`
`5.4%
`
`4.1%
`
`3.4%
`2.7%
`
`2.6%
`2.3%
`
`4.9%
`
`2.2%
`
`2.7%
`0.5%
`
`0.6%
`2.1%
`
`General Disorders
`Somnolence
`
`(somnolence, fatigue, sedation)
`Nervous System Disorders
`Anticholinergic effects
`(dry mouth, constipation, disturbance in attention, vision
`blurred, urinary retention)
`Balance disorders/fall
`(fall, gait disturbance, dizziness, balance disorder)
`Headache
`Akathisia
`(akathisia, restlessness)
`Gastrointestinal Disorders
`Vomiting
`Nausea
`Musculoskeletal Disorders
`0.5%
`2.3%
`Arthralgia
`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.
`
`
`
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`DRUG INTERACTIONS
`
`
`7
`7.1
`Drugs Having Clinically Important Interactions with INGREZZA
`Clinically Significant Drug Interactions with INGREZZA
`Table 2:
`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.
`Avoid concomitant use of INGREZZA with MAOIs.
`isocarboxazid, phenelzine, selegiline
`
`Prevention or Management:
`Examples:
`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)].
`Reduce INGREZZA dose when INGREZZA is coadministered with a
`strong CYP3A4 inhibitor [see Dosage and Administration (2.3)].
`itraconazole, ketoconazole, clarithromycin
`
`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)].
`Consider reducing INGREZZA dose based on tolerability when
`INGREZZA is coadministered with a strong CYP2D6 inhibitor [see
`Dosage and Administration (2.3)].
`paroxetine, fluoxetine, quinidine
`
`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)].
`Concomitant use of strong CYP3A4 inducers with INGREZZA is not
`recommended [see Dosage and Administration (2.3)].
`rifampin, carbamazepine, phenytoin, St. John’s wort1
`
`Prevention or Management:
`
`Examples:
`Strong CYP2D6 Inhibitors
`Clinical Implication:
`
`Prevention or Management:
`
`Examples:
`Strong CYP3A4 Inducers
`Clinical Implication:
`
`Prevention or Management:
`
`Examples:
`Digoxin
`Clinical Implication:
`
`Prevention or Management:
`
`
`Concomitant use of INGREZZA with digoxin increased digoxin levels
`because of inhibition of intestinal P-glycoprotein (P-gp) [see Clinical
`Pharmacology (12.3)].
`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.
`
`
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`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.
`
`USE IN SPECIFIC POPULATIONS
`
`8
`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 times the MRHD based on mg/m2 [see
`Data]. 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.
`
`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 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of the
`high dose group (1.2 times the MRHD), these parameters were not assessed in this group).
`
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`8.2
`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.
`
` Pediatric Use
`8.4
`Safety and effectiveness of INGREZZA have not been established in pediatric patients.
`
` Geriatric Use
`8.5
`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.
`
` CYP2D6 Poor Metabolizers
`8.6
`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)].
`
` Hepatic Impairment
`8.7
`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)].
`
` Renal Impairment
`8.8
`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
`
`10
`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).
`
`
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`11
`DESCRIPTION
`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)].
`
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`12.3
`Pharmacokinetics
`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.
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`Figure 1:
`
`Effects of Hepatic Impairment on Valbenazine Pharmacokinetics
`
`
`
`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
`
`Valbenazine
`
`Cmax
`AUCinf
`
`[+]--HTBZ
`
`Cmax
`AUCinf
`
`Strong CYP3A4 Inhibitor:
`Ketoconazole
`
`Valbenazine
`
`[+]--HTBZ
`
`Cmax
`AUCinf
`
`Cmax
`AUCinf
`
`2
`1
`0.5
`0.25
`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
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`Figure 3:
`
`Effects of Valbenazine on Pharmacokinetics of Other Drugs
`
`
`AUCinf=area under the plasma concentration versus time curve from 0 hours extrapolated to infinity
`
`
`
`
`
`NONCLINICAL TOXICOLOGY
`
`13
`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 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.
`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
`
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`14
`CLINICAL STUDIES
`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).
`
`
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`Reference ID: 4083041
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`Table 3:
`
`Endpoint
`
`Primary Efficacy Endpoint – Severity of Tardive Dyskinesia at Baseline and the End of
`Week 6
`Treatment Group
`
`Placebo-subtracted
`Difference (95% CI)
`
`Mean Baseline
`Score (SD)
`
`LS Mean Change
`from Baseline
`(SEM)**
`-1.8 (-3.0, -0.7)
`-1.9 (0.4)
`9.8 (4.1)
`INGREZZA 40 mg
`-3.1 (-4.2, -2.0)
`-3.2 (0.4)
`10.4 (3.6)
`INGREZZA 80 mg*
`-0.1 (0.4)
`9.9 (4.3)
`
`Placebo
`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:
`
`AIMS Dyskinesia
`Total Score
`
`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 r