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Valbenazine (Monograph)

Brand name: Ingrezza
Drug class: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors
Chemical name: [(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl] (2S)-2-amino-3-methylbutanoate
Molecular formula: C24H38N2O4C24H38N2O4•2C7H8O3S
CAS number: 1025504-45-3

Medically reviewed by Drugs.com on May 25, 2023. Written by ASHP.

Introduction

A monoamine-depleting agent; vesicular monoamine transporter 2 (VMAT2) inhibitor.

Uses for Valbenazine

Tardive Dyskinesia

Treatment of tardive dyskinesia.

Tardive dyskinesia is a hyperkinetic movement disorder associated with prolonged use of antipsychotic agents or other antidopaminergic drugs (e.g., metoclopramide).

The American Psychiatric Association (APA) recommends use of a VMAT2 inhibitor such as valbenazine, for treating moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy. Treatment may also be considered for patients with mild tardive dyskinesia.

Valbenazine Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Administration

Oral Administration

Administer orally once daily without regard to meals.

In the main clinical study, patients continued to receive the antipsychotic treatment regimen they had been stabilized on during valbenazine therapy.

Dosage

Available as valbenazine tosylate; dosage expressed in terms of valbenazine.

Adults

Tardive Dyskinesia
Oral

Initially, 40 mg once daily. After 1 week, increase to recommended dosage of 80 mg once daily. May consider continuing at a dosage of 40 or 60 mg once daily depending on response and tolerability.

Continued therapy appears to be necessary; tardive dyskinesia symptoms recur following drug discontinuance.

Special Populations

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh score of 7–15): Recommended dosage is 40 mg once daily.

Mild hepatic impairment: No specific dosage recommendations.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Poor CYP2D6 Metabolizer Phenotype

For dosage adjustments related to CYP-mediated interactions in populations other than patients with poor CYP2D6 metabolizer phenotype, see Interactions.

Known poor CYP2D6 metabolizers: Recommended dosage is 40 mg once daily.

Cautions for Valbenazine

Contraindications

Warnings/Precautions

Somnolence

Somnolence, fatigue, or sedation can occur. May impair cognitive and/or physical abilities required to perform potentially hazardous tasks such as driving or operating machinery. Do not perform such tasks until drug effect is known.

Prolongation of QT Interval

QT-interval prolongation may occur, although degree of prolongation not clinically important at drug concentrations expected with recommended dosing. Higher than expected plasma concentrations of valbenazine and/or its active metabolite and clinically important QT-interval prolongation may occur in poor CYP2D6 metabolizers and in patients concurrently receiving a strong CYP2D6 or CYP3A4 inhibitor.

In poor CYP2D6 metabolizers or patients concurrently receiving a potent CYP2D6 inhibitor, reduce dosage to 40 mg once daily.

In patients concurrently receiving a strong CYP3A4 inhibitor, reduce valbenazine dosage to 40 mg once daily.

Avoid use in patients with congenital long QT syndrome or with cardiac arrhythmias associated with a prolonged QT interval.

Assess QT interval prior to increasing valbenazine dosage in patients at increased risk of QT-interval prolongation.

Parkinsonism

Parkinsonism can occur, including severe cases requiring hospitalization. Incidence in clinical trials was 3% and <1% in patients receiving valbenazine and placebo, respectively. Severe parkinsonism usually occurs within the first 2 weeks after starting or increasing the dose of valbenazine. Symptoms include falls, gait disturbances, tremor, drooling, and hypokinesia. Available data suggest symptoms resolve following discontinuation of valbenazine.

Reduce the dose or discontinue valbenazine in patients who develop clinically significant parkinson-like signs or symptoms.

Specific Populations

Pregnancy

Limited available data on valbenazine use in pregnant women insufficient to inform a drug-associated risk. No teratogenicity observed in animal studies at supratherapeutic dosages, but increased stillbirths and reduced postnatal pup survival observed when administered to pregnant rats during organogenesis and lactation at dosages less than the maximum recommended human dosage. Advise pregnant women of potential risk to the fetus.

Lactation

Valbenazine and its metabolites distribute into milk in rats at concentrations higher than those in maternal plasma. Not known whether drug and/or its metabolites distribute into human milk. Effects on breast-fed infants and on milk production also not known. Increased perinatal mortality in exposed fetuses and pups observed in animal studies. Manufacturer recommends women not breast-feed while receiving valbenazine and for 5 days after discontinuance of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients. Tardive dyskinesia rarely occurs in pediatric patients since prolonged antipsychotic therapy usually is necessary to cause the condition.

Geriatric Use

In clinical trials with valbenazine, 16% of patients were ≥65 years of age. No overall differences in safety or efficacy observed between geriatric and younger adults.

Hepatic Impairment

Systemic exposure of valbenazine and its active metabolite is substantially higher in patients with moderate to severe hepatic impairment (Child-Pugh score of 7–15); a reduced dosage of 40 mg once daily is recommended in such patients.

Renal Impairment

Valbenazine does not undergo primary renal clearance. Dosage adjustment not necessary in patients with mild, moderate, or severe renal impairment.

Poor CYP2D6 Metabolizers

Reduced dosage of 40 mg once daily recommended in patients known to be poor CYP2D6 metabolizers. Increased exposure of the active metabolite may increase the risk of exposure-related adverse effects.

Common Adverse Effects

Adverse effects occurring in ≥2% of patients receiving valbenazine in short-term tardive dyskinesia clinical trials and at a higher frequency than reported with placebo include somnolence (including fatigue and sedation), anticholinergic effects (including dry mouth, constipation, attention disturbance, blurred vision, and urinary retention), balance disorders (including falls, gait disturbances, and dizziness), headache, akathisia/restlessness, vomiting, nausea, and arthralgia.

Drug Interactions

Metabolized in part by CYP3A4/5; further biotransformation of the active metabolite mediated in part by CYP2D6.

Neither valbenazine nor its active metabolite inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5, or induce CYP isoenzymes 1A2, 2B6, or 3A4/5 at clinically relevant concentrations.

Neither valbenazine nor its active metabolite is likely to inhibit breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and OAT3, organic cation transporter (OCT) 2, or organic anion transport proteins (OATP) 1B1 and OATP1B3 at clinically relevant concentrations. Valbenazine inhibits intestinal P-glycoprotein (P-gp).

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Possible increased exposure of valbenazine and its active metabolite and increased risk of adverse effects. Reduce valbenazine dosage to 40 mg once daily during concurrent use.

Weak or moderate CYP3A4 inhibitors: Dosage reduction of valbenazine not necessary.

Strong CYP2D6 inhibitors: Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects; reduce valbenazine dosage to 40 mg once daily during concurrent use.

Strong CYP3A4 inducers: Possible decreased exposure of valbenazine and its active metabolite and reduced efficacy. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5: Pharmacokinetic interaction unlikely; dosage adjustment of the CYP substrate not necessary during concomitant use.

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Possible increased exposure of valbenazine and its active metabolite and increased risk of adverse effects

Ketoconazole: Increased exposure of valbenazine and its active metabolite approximately twofold

Reduce valbenazine dosage to 40 mg once daily

Carbamazepine

Carbamazepine (a strong CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite

Concomitant use not recommended

Clarithromycin

Possible increased exposure of valbenazine and its active metabolite and increased risk of adverse effects

Reduce valbenazine dosage to 40 mg once daily

Digoxin

Increased peak concentration and AUC of digoxin by approximately twofold and 1.5-fold, respectively, because of inhibition of intestinal P-gp

Monitor serum digoxin concentration and adjust digoxin dosage, if necessary

Fluoxetine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects

Reduce valbenazine dosage to 40 mg once daily

MAO inhibitors (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine)

Potentially increased risk of serotonin syndrome or other adverse reactions and reduced efficacy of valbenazine due to increased synaptic concentration of monoamine neurotransmitters

Avoid concomitant use

Midazolam

No clinically important effect on the pharmacokinetics of midazolam (a CYP3A4 substrate)

Dosage adjustment of valbenazine not necessary

Paroxetine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects

Reduce valbenazine dosage to 40 mg once daily

Phenytoin

Phenytoin (a strong CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite

Concomitant use not recommended

Quinidine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects

Reduce valbenazine dosage to 40 mg once daily

Rifampin

Decreased exposure of valbenazine and its active metabolite by approximately 70–80%; may reduce efficacy

Concomitant use not recommended

St. John's wort (Hypericum perforatum)

St. John's wort (a strong CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite

Concomitant use not recommended

Valbenazine Pharmacokinetics

Absorption

Bioavailability

Peak plasma valbenazine concentrations achieved within 30–60 minutes following oral administration; peak plasma concentrations of the active metabolite, (+)-α-dihydrotetrabenazine ([+]-α-HTBZ), achieved within 4–8 hours.

Valbenazine and (+)-α-HTBZ demonstrate approximately proportional increases in AUC and peak plasma concentrations after single oral doses of 40–300 mg.

Steady-state valbenazine concentrations achieved within 1 week.

Absolute bioavailability is approximately 49%.

Food

Administration with a high-fat meal decreases peak plasma concentration and AUC of valbenazine by approximately 47 and 13%, respectively; peak plasma concentration and AUC of active metabolite not affected.

Special Populations

Mild hepatic impairment: Peak plasma concentrations and AUC of valbenazine and its active metabolite are increased <1.5-fold.

Moderate or severe hepatic impairment: Peak plasma concentrations and AUC of valbenazine and its active metabolite are increased ≤2.5- and ≤3.4-fold, respectively.

Increased peak plasma concentration and AUC of valbenazine's active metabolite expected in poor CYP2D6 metabolizers.

Distribution

Extent

Valbenazine and its metabolites distribute into milk in rats at concentrations higher than those in maternal plasma; not known if drug and/or metabolites distribute into human milk.

Valbenazine can bind to melanin-containing structures of the eye (e.g., uveal tract) in animals; clinical relevance of this finding not known.

Plasma Protein Binding

Valbenazine: >99%.

Active metabolite: Approximately 64%.

Elimination

Metabolism

Extensively metabolized. Valbenazine undergoes ester hydrolysis to form the major active metabolite, (+)-α-HTBZ; also undergoes oxidative metabolism, mainly by CYP3A4/5, to form monooxidized valbenazine and other minor metabolites. The active metabolite (+)-α-HTBZ appears to be further metabolized in part by CYP2D6.

Elimination Route

Following administration of a single radiolabeled dose, approximately 60% recovered in urine and 30% in feces; <2% excreted unchanged as valbenazine or (+)-α-HTBZ in either urine or feces.

Half-life

Valbenazine: 15–22 hours.

Active metabolite: 15–22 hours.

Stability

Storage

Oral

Capsules

15–30°C.

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Valbenazine tosylate is available only through a specialty pharmacy. Patients and clinicians may contact the INBRACE Support Program at 844-647-3992 or visit [Web] for further information.

Valbenazine Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

40 mg (of valbenazine)

Ingrezza

Neurocrine

60 mg (of valbenazine)

Ingrezza

Neurocrine

80 mg (of valbenazine)

Ingrezza

Neurocrine

AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 25, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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