2.1 Dosing and Administration Information

The initial dosage for INGREZZA is 40 mg once daily. After one week, increase the dose to the recommended dosage of 80 mg once daily. A dosage of 40 mg or 60 mg once daily may be considered depending on response and tolerability.

Administer INGREZZA orally with or without food [see Clinical Pharmacology (12.3)].

2.2 Dosage Recommendations for Patients with Hepatic Impairment

The recommended dosage 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

The recommended dosage for known CYP2D6 poor metabolizers is INGREZZA 40 mg once daily [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

The recommended dosage for patients receiving strong CYP3A4 inhibitors is INGREZZA 40 mg once daily [see Drug Interactions (7.1)].

Coadministration with Strong CYP2D6 Inhibitors

The recommended dosage for patients receiving strong CYP2D6 inhibitors is INGREZZA 40 mg once daily [see Drug Interactions (7.1)].

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.

5.3 Parkinsonism

INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. In the 3 placebo-controlled clinical studies in patients with tardive dyskinesia, the incidence of parkinson-like adverse events was 3% of patients treated with INGREZZA and <1% of placebo-treated patients. Postmarketing safety reports have described parkinson-like symptoms, some of which were severe and required hospitalization. In most cases, severe parkinsonism occurred within the first two weeks after starting or increasing the dose of INGREZZA. Associated symptoms have included falls, gait disturbances, tremor, drooling and hypokinesia. In cases in which follow-up clinical information was available, parkinson-like symptoms were reported to resolve following discontinuation of INGREZZA therapy. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-like signs or symptoms.

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.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of INGREZZA that are not included in other sections of labeling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: hypersensitivity reactions (including allergic dermatitis, angioedema, pruritis, and urticaria)

Skin and Subcutaneous Tissue Disorders: rash

7.1 Drugs Having Clinically Important Interactions with INGREZZA

Table 2: Clinically Significant Drug Interactions with INGREZZA

1. The induction potency of St. John’s wort may vary widely based on preparation.

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.

8.1 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 to 4% and 15 to 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).

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.

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

Dosage reduction of INGREZZA is recommended for known CYP2D6 poor metabolizers [see Dosage and Administration (2.3)]. 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 (2.2)]. 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, moderate, or severe renal impairment. INGREZZA does not undergo primary renal clearance.[see Clinical Pharmacology (12.3)].

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).

12.1 Mechanism of Action

The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unclear, 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 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given INGREZZA, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec [see Warnings and Precautions (5.2)].

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 and severe renal impairment are summarized in Figure 1.

Figure 1: Effects of Hepatic and Severe Renal 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 paroxetine, ketoconazole and rifampin on the exposure of valbenazine are summarized in Figure 2.

Figure 2: Effects of Strong CYP2D6 and CYP3A4 Inhibitors and CYP3A4 Inducers on Valbenazine Pharmacokinetics

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.

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

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.