Valbenazine (Monograph)

Brand name: Ingrezza
Drug class: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors

Medically reviewed by Drugs.com on Apr 10, 2024. 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.

Chorea Associated with Huntington's Disease

Treatment of chorea associated with Huntington's disease.

Has been shown to improve chorea in patients with Huntington's disease in a 12-week study; additional study needed to determine long-term effectiveness and safety.

Valbenazine Dosage and Administration

General

Pretreatment Screening

• In patients with Huntington's disease, balance risk of depression and suicidal ideation and behavior with the clinical need for treatment of chorea when considering use of valbenazine.

• Evaluate baseline liver function.

Patient Monitoring

• Monitor for hypersensitivity reactions such as rash, urticaria, and angioedema (e.g., swelling of the face, lips, and mouth).

• Monitor QT interval if clinically indicated. For patients at increased risk of QT prolongation, assess the QT interval before increasing dosage.

• Monitor for signs or symptoms of parkinsonism.

Administration

Oral Administration

Administer orally once daily without regard to meals.

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 dosage of 40 or 60 mg once daily depending on response and tolerability.

Continued therapy appears to be necessary; tardive dyskinesia symptoms recurred following drug discontinuance in clinical studies.

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

Chorea Associated with Huntington's Disease

Oral

Initially, 40 mg once daily. Increase in 20 mg increments every 2 weeks to recommended dosage of 80 mg once daily. May consider dosage of 40 or 60 mg once daily depending on response and tolerability.

Continued therapy appears to be necessary; chorea symptoms associated with Huntington's disease recurred following drug discontinuance in clinical studies.

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.

Pharmacogenomics and Poor CYP2D6 Metabolizers

In patients known to be poor CYP2D6 metabolizers, recommended dosage is 40 mg once daily.

Patients Receiving Concomitant Therapy

Dosage adjustment recommended in patients receiving concomitant therapy with a strong CYP3A4 and/or CYP2D6 inhibitor.

If used concurrently with a strong CYP2D6 inhibitor, recommended dosage of valbenazine is 40 mg once daily.

If used concurrently with a strong CYP3A4 inhibitor, recommended dosage of valbenazine is 40 mg once daily.

Concomitant use of valbenazine and strong CYP3A4 inducers not recommended.

Related/similar drugs

Austedo, amantadine, pyridoxine, vitamin e, Ingrezza, tetrabenazine, Austedo XR

Cautions for Valbenazine

Contraindications

• History of hypersensitivity to valbenazine or any of its components.

Warnings/Precautions

Depression and Suicidal Ideation and Behavior in Patients with Huntington’s Disease

Increased risk for depression and suicidal ideation or behaviors with VMAT2 inhibitors, including valbenazine, in patients with Huntington’s disease. (See Boxed Warning.)

Depression or depressed mood and suicidal ideation and suicide attempts reported in clinical trials.

Consider risk of suicidal ideation and behaviors versus need for treatment with the drug.

Observe all patients for new or worsening depression and suicidal ideation or behaviors. Consider discontinuing treatment if any of these reactions occur and do not resolve.

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema involving the larynx, glottis, lips, and eyelids, reported.

Urticaria and rash also reported.

Discontinue if any of these reactions occur.

Somnolence and Sedation

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; dosage adjustments recommended in these patients.

Avoid use in patients with congenital long QT syndrome or 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.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, reported with drugs that reduce dopaminergic transmission such as VMAT2 inhibitors.

Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, andevidence of autonomic instability (e.g., irregular pulse or BP, tachycardia, diaphoresis, cardiacdysrhythmia); elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, andacute renal failure also may occur.

If NMS occurs, immediately discontinue valbenazine and provide intensive symptomatic treatment. Treat any concomitant serious medical problems.

Recurrence of NMS reported with resumption of drug therapy. If valbenazine treatment is needed after recovery from NMS, monitor patients for signs of recurrence.

Parkinsonism

Parkinsonism can occur, including severe cases requiring hospitalization.

Because rigidity can develop as part of the underlying disease process in Huntington’s disease, may bedifficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’sdisease.

Severe parkinsonism usually occurs within the first 2 weeks after starting or increasing dosage of valbenazine. Symptoms include falls, gait disturbances, tremor, drooling, and hypokinesia. Symptoms appear to resolve following discontinuation of therapy.

Reduce dosage or discontinue therapy in patients who develop clinically significant parkinson-like signs or symptoms.

Specific Populations

Pregnancy

Insufficient data in pregnant women 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 in patients with tardive dyskinesia, 16% of patients were ≥65 years of age. No overall differences in safety or efficacy observed between geriatric and younger adults in patients with tardive dyskinesia.

In a controlled study of valbenazine in patients with chorea associated with Huntington’s disease, an insufficient number of patients ≥65 years of age were included to determine whether geriatric patients respond differently from younger patients.

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.

Pharmacogenomics and Poor CYP2D6 Metabolizers

Reduced dosage of 40 mg once daily recommended in patients known to be poor CYP2D6 metabolizers (individuals with two non-functioning alleles). Increased exposure of the active metabolite may increase risk of exposure-related adverse effects.

Common Adverse Effects

Most common adverse reaction (≥5%) in patients with tardive dyskinesia: somnolence.

Most common adverse reactions (≥5%) in patients with chorea associated with Huntington's disease: somnolence/lethargy/sedation, urticaria, rash, insomnia.

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 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

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 active metabolite increased by <1.5-fold.

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

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

Distribution

Extent

Not known if valbenazine 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. Undergoes ester hydrolysis to form major active metabolite, (+)-α-HTBZ; also undergoes oxidative metabolism, mainly by CYP3A4/5, to form monooxidized valbenazine and other minor metabolites. The active metabolite 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

• A valine ester prodrug of (+)-α-dihydrotetrabenazine ([+]-α-HTBZ) and an active metabolite of tetrabenazine. Of the 4 tetrabenazine metabolite isomers, (+)-α-HTBZ has the highest binding affinity and selectivity for VMAT2, a transporter that regulates monoamine uptake from the cytoplasm to synaptic vesicles for storage and release.

• Precise mechanism of action in treatment of tardive dyskinesia and chorea in patients with Huntington's disease not fully elucidated, but appears to be related to reversible and selective inhibition of VMAT2 and decreased uptake of monoamines into synaptic vesicles in the CNS, resulting in depleted monoamine stores from nerve terminals.

• Inhibits human VMAT2 but exhibits no appreciable binding affinity for VMAT1 or for dopaminergic (including D₂), serotonergic (including 5-HT_2B), adrenergic, histaminergic, or muscarinic receptors.

Advice to Patients

• Advise patients to read the manufacturer's patient information.

• Inform patients, their caregivers, and families of the risks of depression, worsening depression, and suicidal ideation and behavior associated with valbenazine, and instruct them to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately.

• Inform patients about the signs and symptoms of hypersensitivity reactions, such as angioedema, including difficulty breathing and swelling of the face, lips, eyelids, tongue, or throat. Advise patients to discontinue valbenazine immediately if any of these reactions occur and report to the emergency room if symptoms of angioedema occur.

• Risk of somnolence and sedation. Advise patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination such as operating a motor vehicle or other dangerous machinery until the effects of the drug on the individual are known.

• Risk of QT-interval prolongation. Advise patients to inform clinicians immediately if abnormal heartbeat, palpitations, shortness of breath, feelings of dizziness or faintness, or loss of consciousness occurs.

• Inform patients about a potentially fatal adverse reaction, neuroleptic malignant syndrome (NMS), that has been reported in association with administration of VMAT2 inhibitors, including valbenazine. Advise patients to contact a healthcare provider or report to the emergency room if they experience signs or symptoms of NMS.

• Risk of parkinsonism. Advise patients to consult their clinician if they experience difficulty moving or loss of ability to move muscles voluntarily, tremor, gait disturbances, or drooling.

• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential risk to the fetus if used during pregnancy. Advise women to avoid breast-feeding while receiving valbenazine and for 5 days after discontinuance of the drug.

• Advise patient to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., liver or kidney disease, cardiovascular disease, arrhythmias).

• Inform patients of other important precautionary information.

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.

Reload page with references included

Frequently asked questions

• Which pharmacies can dispense Ingrezza?
• Does Ingrezza cause weight gain?
• How long does it take for Ingrezza to work?
• Can Ingrezza capsules be opened?
• How effective is Ingrezza?
• Austedo vs Ingrezza: How do they compare?

View more FAQ

Medical Disclaimer