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Valbenazine Tosylate

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
Brands: Ingrezza

Medically reviewed on November 20, 2017

Introduction

A monoamine-depleting agent; vesicular monoamine transporter 2 (VMAT2) inhibitor.1 6 7 8

Uses for Valbenazine Tosylate

Tardive Dyskinesia

Treatment of tardive dyskinesia.1 3 4 5

Tardive dyskinesia is a hyperkinetic movement disorder associated with prolonged use of antipsychotic agents or other antidopaminergic drugs (e.g., metoclopramide).28 100 101 102 104

Prior to the availability of valbenazine, there was no standard treatment for tardive dyskinesia.28 100 101 103 104 Management generally included discontinuance or reducing the dosage of the precipitating drug when possible, switching from a conventional or first-generation antipsychotic to an atypical or second-generation antipsychotic, or switching to clozapine therapy.28 100 101 103 104

Valbenazine Tosylate Dosage and Administration

General

Restricted Distribution

  • Available only through a specialty pharmacy.9

  • Contact the INBRACE Support Program at 844-647-3992 or visit [Web] for further information.9

Administration

Oral Administration

Administer orally once daily without regard to meals.1 (See Food under Pharmacokinetics.)

In the main clinical study, patients continued to receive the antipsychotic treatment regimen they had been stabilized on during valbenazine therapy.3

Dosage

Available as valbenazine tosylate; dosage expressed in terms of valbenazine.1

Adults

Tardive Dyskinesia
Oral

Initially, 40 mg once daily.1 After 1 week, increase to recommended dosage of 80 mg once daily.1 May consider continuing at a dosage of 40 mg once daily in some patients.1 5

Continued therapy appears to be necessary; tardive dyskinesia symptoms recur following drug discontinuance.4

Special Populations

Hepatic Impairment

Moderate or severe hepatic impairment (Child-Pugh score of 7–15): Recommended dosage is 40 mg once daily.1

Mild hepatic impairment: No specific dosage recommendations.1

Renal Impairment

Mild or moderate renal impairment (Clcr 30–90 mL/minute): Dosage adjustment not necessary.1

Severe renal impairment (Clcr <30 mL/minute): Use not recommended.1

Geriatric Patients

No dosage adjustment necessary.1

Poor CYP2D6 Metabolizer Phenotype

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

Dosage reduction may be required in patients who are poor CYP2D6 metabolizers based on tolerability.1 (See Poor CYP2D6 Metabolizers under Cautions.)

Cautions for Valbenazine Tosylate

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Somnolence

Somnolence, fatigue, or sedation can occur.1 May impair cognitive and/or physical abilities required to perform potentially hazardous tasks such as driving or operating machinery.1 (See Advice to Patients.)

Prolongation of QT Interval

QT-interval prolongation may occur, although degree of prolongation not clinically important at drug concentrations expected with recommended dosing.1 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 potent CYP2D6 or CYP3A4 inhibitor.1

In poor CYP2D6 metabolizers or patients concurrently receiving a potent CYP2D6 inhibitor, dosage reduction may be necessary.1 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration and also see Interactions.)

In patients concurrently receiving a potent CYP3A4 inhibitor, reduce valbenazine dosage to 40 mg once daily.1 (See Interactions.)

Avoid use in patients with congenital long QT syndrome or with cardiac arrhythmias associated with a prolonged QT interval.1

Assess QT interval prior to increasing valbenazine dosage in patients at increased risk of QT-interval prolongation.1

Specific Populations

Pregnancy

Limited available data on valbenazine use in pregnant women insufficient to inform a drug-associated risk.1 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.1 Advise pregnant women of potential risk to the fetus.1

Lactation

Valbenazine and its metabolites distribute into milk in rats at concentrations higher than those in maternal plasma.1 Not known whether drug and/or its metabolites distribute into human milk.1 Effects on nursing infants and on milk production also not known.1 Increased perinatal mortality in exposed fetuses and pups observed in animal studies.1 Manufacturer recommends women not breast-feed while receiving valbenazine and for 5 days after discontinuance of the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 Tardive dyskinesia rarely occurs in pediatric patients since prolonged antipsychotic therapy usually is necessary to cause the condition.5

Geriatric Use

In clinical trials with valbenazine, 16% of patients were ≥65 years of age.1 No overall differences in safety or efficacy observed between geriatric and younger adults.1 (See Geriatric Patients under Dosage and Administration.)

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); dosage reduction is recommended in such patients.1 10 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Valbenazine does not undergo primary renal clearance.1 Dosage adjustment not necessary in patients with mild to moderate renal impairment (Clcr 30–90 mL/minute).1 Use not recommended in patients with severe renal impairment (Clcr <30 mL/minute).1

Poor CYP2D6 Metabolizers

Dosage reduction may be required based on tolerability in patients known to be poor CYP2D6 metabolizers.1 Increased exposure of the active metabolite may increase the risk of exposure-related adverse effects.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Somnolence (including fatigue and sedation),1 3 anticholinergic effects (e.g., dry mouth, constipation, attention disturbance, blurred vision, urinary retention),1 3 balance disorders (including falls, gait disturbances, and dizziness),1 headache,1 akathisia/restlessness,1 3 vomiting,1 nausea,1 arthralgia.1

Interactions for Valbenazine Tosylate

Metabolized in part by CYP3A4/5; further biotransformation of the active metabolite mediated in part by CYP2D6.1

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.1

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.1 Valbenazine inhibits intestinal P-glycoprotein (P-gp).1 10

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased exposure of valbenazine and its active metabolite and increased risk of adverse effects.1 Reduce valbenazine dosage to 40 mg once daily during concurrent use.1 10

Weak or moderate CYP3A4 inhibitors: Dosage reduction of valbenazine not necessary.10

Potent CYP2D6 inhibitors: Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects; consider valbenazine dosage reduction based on tolerability during concurrent use.1

Potent CYP3A4 inducers: Possible decreased exposure of valbenazine and its active metabolite and reduced efficacy.1 10 Avoid concomitant use.1 10

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.1

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 effects1 10

Ketoconazole: Increased exposure of valbenazine and its active metabolite approximately twofold1 10

Reduce valbenazine dosage to 40 mg once daily1 10

Carbamazepine

Carbamazepine (a potent CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite1

Concomitant use not recommended1

Clarithromycin

Possible increased exposure of valbenazine and its active metabolite and increased risk of adverse effects1

Reduce valbenazine dosage to 40 mg once daily1

Digoxin

Increased peak concentration and AUC of digoxin by approximately twofold and 1.5-fold, respectively, because of inhibition of intestinal P-gp1

Monitor serum digoxin concentration and adjust digoxin dosage, if necessary1

Fluoxetine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects1

Consider valbenazine dosage reduction based on tolerability1

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 neurotransmitters1

Avoid concomitant use1

Midazolam

No clinically important effect on the pharmacokinetics of midazolam (a CYP3A4 substrate)1

Dosage adjustment of valbenazine not necessary1

Paroxetine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects1

Consider valbenazine dosage reduction based on tolerability1

Phenytoin

Phenytoin (a potent CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite1

Concomitant use not recommended1

Quinidine

Possible increased exposure of valbenazine's active metabolite and increased risk of adverse effects1

Consider valbenazine dosage reduction based on tolerability1

Rifampin

Decreased exposure of valbenazine and its active metabolite by approximately 70–80%; may reduce efficacy1 10

Concomitant use not recommended1 10

St. John's wort (Hypericum perforatum)

St. John's wort (a potent CYP3A4 inducer) potentially can decrease exposure and reduce efficacy of valbenazine and its active metabolite1

Concomitant use not recommended1

Valbenazine Tosylate 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.1 10

Valbenazine and (+)-α-HTBZ demonstrate approximately proportional increases in AUC and peak plasma concentrations after single oral doses of 40–300 mg.1

Steady-state valbenazine concentrations achieved within 1 week.1

Absolute bioavailability is approximately 49%.1 10

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.1

Special Populations

Mild hepatic impairment: Peak plasma concentrations and AUC of valbenazine and its active metabolite are increased <1.5-fold.1 10

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.1 10

Increased peak plasma concentration and AUC of valbenazine's active metabolite expected in poor CYP2D6 metabolizers.1

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.1

Valbenazine can bind to melanin-containing structures of the eye (e.g., uveal tract) in animals; clinical relevance of this finding not known.1

Plasma Protein Binding

Valbenazine: >99%.1

Active metabolite: Approximately 64%.1

Elimination

Metabolism

Extensively metabolized.1 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.1 The active metabolite (+)-α-HTBZ appears to be further metabolized in part by CYP2D6.1

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.1 10

Half-life

Valbenazine: 15–22 hours.1

Active metabolite: 15–22 hours.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Valbenazine is a valine ester prodrug of (+)-α-dihydrotetrabenazine ([+]-α-HTBZ), which also is one of the active metabolites of tetrabenazine.5 6 7 8 Of the 4 tetrabenazine metabolite isomers, (+)-α-HTBZ has the highest binding affinity and selectivity for VMAT2,6 a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicles for storage and release.1 6

  • Precise mechanism of action of valbenazine in treatment of tardive dyskinesia 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,1 6 7 resulting in depleted monoamine stores from nerve terminals.8

  • Inhibits human VMAT2 but exhibits no appreciable binding affinity for VMAT1 or for dopaminergic (including D2), serotonergic (including 5-HT2B), adrenergic, histaminergic, or muscarinic receptors.1 6

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • Risk of somnolence.1 2 Importance of advising patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination (e.g., operating a motor vehicle or other dangerous machinery) until the effects of the drug on the individual are known.1 2

  • Risk of QT-interval prolongation.1 2 Importance of informing clinicians immediately if abnormal heartbeat, palpitations, shortness of breath, feelings of dizziness or faintness, or loss of consciousness occurs.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Apprise patient of potential risk to the fetus if used during pregnancy.1 Importance of advising women to avoid breast-feeding while receiving valbenazine and for 5 days after discontinuance of the drug.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements (see Interactions), as well as any concomitant illnesses (e.g., liver or kidney disease, cardiovascular disease, arrhythmias).1 2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Distribution of valbenazine is restricted.9 (See Restricted Distribution under Dosage and Administration.)

Valbenazine Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

40 mg (of valbenazine)

Ingrezza

Neurocrine

AHFS DI Essentials. © Copyright 2018, Selected Revisions November 20, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Neurocrine Biosciences, Inc. Ingrezza (valbenazine) capsules prescribing information. San Diego, CA; 2017 Apr.

2. Neurocrine Biosciences, Inc. Ingrezza (valbenazine) capsules patient information. San Diego, CA; 2017 Apr.

3. Hauser RA, Factor SA, Marder SR et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017; 174:476-84. http://www.ncbi.nlm.nih.gov/pubmed/28320223?dopt=AbstractPlus

4. Factor S, Comella C, Correll C et al. Efficacy of valbenazine (NBI-98854) in subjects with tardive dyskinesia: results of a long-term study (KINECT 3 Extension) (S56.005). Neurology. 2017; 88 (Suppl S56.005).

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209241Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209241Orig1s000SumR.pdf

6. Grigoriadis DE, Smith E, Hoare SRJ et al. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. J Pharmacol Exp Ther. 2017; 361:454-61. http://www.ncbi.nlm.nih.gov/pubmed/28404690?dopt=AbstractPlus

7. Müller T. Valbenazine granted breakthrough drug status for treating tardive dyskinesia. Expert Opin Investig Drugs. 2015; 24:737-42. http://www.ncbi.nlm.nih.gov/pubmed/25809133?dopt=AbstractPlus

8. Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother. 2016; 17:2461-70. http://www.ncbi.nlm.nih.gov/pubmed/27819145?dopt=AbstractPlus

9. Neurocrine Biosciences, Inc. Starting on Ingrezza (valbenazine) capsules: what you need to know. 2017 Apr. From INBRACE support program website. https://www.inbracesupportprogram.com/

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209241Orig1s000: Clinical pharmacology and biopharmaceutics review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209241Oirg1s000ClinPharmR.pdf

28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(2 Suppl):1-56.

100. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y). 2013; 3

101. Rakesh G, Muzyk A, Szabo ST et al. Tardive dyskinesia: 21st century may bring new treatments to a forgotten disorder. Ann Clin Psychiatry. 2017; 29:108-19. http://www.ncbi.nlm.nih.gov/pubmed/28207919?dopt=AbstractPlus

102. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction. Can J Psychiatry. 2005; 50:541-7. http://www.ncbi.nlm.nih.gov/pubmed/16262110?dopt=AbstractPlus

103. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry. 2005; 50:703-14. http://www.ncbi.nlm.nih.gov/pubmed/16363464?dopt=AbstractPlus

104. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci. 2015; 69:321-34. http://www.ncbi.nlm.nih.gov/pubmed/25556809?dopt=AbstractPlus

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