Ingrezza

Generic Name: Valbenazine Tosylate
Class: Central Nervous System Agents, Miscellaneous
Chemical Name: [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate
Molecular Formula: C₂₄H₃₈N₂O₄
CAS Number: 1025504-45-3

Introduction

Valbenazine tosylate is a central nervous system agent.

Uses for Ingrezza

Valbenazine tosylate has the following uses:

Valbenazine tosylate is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia.¹

Ingrezza Dosage and Administration

General

Valbenazine tosylate is available in the following dosage form(s) and strength(s):

Capsules: 40 mg (of valbenazine).¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• The initial dose is 40 mg once daily.¹

• After one week, increase the dose to the recommended dose of 80 mg once daily.¹ Continuation of a dose of 40 mg once daily may be considered for some patients.¹

• Can be taken with or without food.¹

• The recommended dose for patients with moderate or severe hepatic impairment is 40 mg once daily.¹

• Reduce dose to 40 mg once daily when given with strong CYP3A4 inhibitors.¹ (See Interactions.)

• Consider dose reduction based on tolerability in known CYP2D6 poor metabolizers or with concomitant strong CYP2D6 inhibitor therapy.¹

Cautions for Ingrezza

Contraindications

None.¹

Warnings/Precautions

Somnolence

Valbenazine tosylate 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 valbenazine tosylate.¹

QT Prolongation

Valbenazine tosylate 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, valbenazine tosylate concentrations may be higher and QT prolongation clinically significant. 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 valbenazine to 40 mg once daily. Valbenazine tosylate 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.¹

Specific Populations

Pregnancy

The limited available data on valbenazine tosylate 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.¹

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).¹

Lactation

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 valbenazine tosylate and for 5 days after the final dose. ¹

Pediatric Use

Safety and effectiveness of valbenazine tosylate have not been established in pediatric patients. ¹

Geriatric Use

No dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies of valbenazine tosylate, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients. ¹

CYP2D6 Poor Metabolizers

Consider reducing valbenazine tosylate dose based on tolerability for known CYP2D6 poor metabolizers. Increased exposure (C_max 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.¹

Hepatic Impairment

Dosage reduction of valbenazine tosylate 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. ¹

Renal Impairment

Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30 to 90 mL/min). Valbenazine tosylate does not undergo primary renal clearance. Valbenazine tosylate is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).¹

Common Adverse Effects

Most common adverse reaction (≥5% and twice the rate of placebo): somnolence.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Dose adjustments due to drug interactions:

Actions

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. ¹

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling.¹

Inform patients that valbenazine tosylate 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 valbenazine tosylate, they should be careful or avoid doing activities that require them to be alert, such as driving a car or operating machinery. ¹

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 valbenazine tosylate before any new drug is taken.¹

Advise a pregnant patient of the potential risk to a fetus. ¹

Advise a woman not to breastfeed during treatment with valbenazine tosylate and for 5 days after the final dose.¹

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.