valbenazine (Rx)

>10%

Somnolence (10.9%)

1-10%

Anticholinergic effects (5.4%)

Balance disorders/fall (4.1%)

Headache (3.4%)

Akathisia (2.7%)

Vomiting (2.6%)

Nausea (2.3%)

Arthralgia (2.3%)

Postmarketing Reports

Hypersensitivity

QT prolongation

Skin and subcutaneous tissue disorders: rash

Contraindications

History of hypersensitivity to drug or components; rash urticaria, and reactions consistent with angioedema (eg, swelling of face, lips, mouth) reported

Cautions

Can cause somnolence; warn patients not to perform activities requiring mental alertness (eg, driving or operating hazardous machinery) until they know how they will be affected

Increased exposure (Cmax and AUC) to active metabolite is anticipated in CYP2D6 poor metabolizers; increased exposure of active metabolite may increase risk of exposure-related adverse reactions; dose reduction recommended

Parkinsonism

• May cause parkinsonism in patients with tardive dyskinesia
• Also reported with other VMAT2 inhibitors
• Postmarketing safety reports have described parkinson-like symptoms that required hospitalization
• In most cases, severe parkinsonism occurred within first two weeks of initiating or increasing dose of drug
• 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 therapy
• Reduce dose or discontinue treatment in patients who develop clinically significant parkinson-like signs or symptoms

QT prolongation

• May prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing
• If coadministered with a strong CYP2D6 or CYP3A4 inhibitor, or patients who are CYP2D6 poor metabolizers, valbenazine concentrations may increase and cause clinically significant QT prolongation (see Dosage Modifications)
• Avoid 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

Drug interaction overview

• MAOIs

  • Avoid coadministration
  • Concomitant use may increase concentration of monoamine neurotransmitters in synapses, potentially leading to increased risk of adverse reactions (eg, serotonin syndrome) or attenuated treatment effect of valbenazine

• Strong CYP3A4 inhibitors

  • Reduce valbenazine dose (see Dosage Modifications)
  • Coadministration increases exposure (Cmax and AUC) to valbenazine and its active metabolite compared with the use of valbenazine alone

• Strong CYP2D6 inhibitors

  • Reduce valbenazine dose (see Dosage Modifications)
  • Coadministration increases exposure (Cmax and AUC) to valbenazine’s active metabolite compared with the use of valbenazine alone

• Strong CYP3A4 inducers

  • Concomitant use not recommended
  • Coadministration decreases systemic exposure of valbenazine and its active metabolite, thereby decreasing efficacy

• Digoxin

  • Coadministration increases digoxin levels owing to P-gp inhibition
  • Monitor digoxin levels if coadministered; dosage adjustment of digoxin may be necessary

Pregnancy

Data are limited on use in pregnant women

Based on animal studies, may cause fetal harm; advise pregnant women of the potential risk

Animal studies

• Administration 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 maximum recommended human dose (MRHD) of 80 mg/day based on mg/m² body surface area
• However, no malformations were observed when administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the MRHD

Lactation

Unknown if distributed in human breast milk

Valbenazine and its metabolites have been detected in rat milk at concentrations higher than in plasma following oral administration at doses 0.1-1.2 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 and for 5 days after the final dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

Absorption

Bioavailability: ~49%

Peak plasma time: 0.5-1 hr (parent); 4-8 hr (active metabolite)

Steady-state: 1 week

Distribution

Protein bound: >99% (parent); ~64% (active metabolite)

Vd: 92 L

Metabolism

Extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-alpha-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites

[+]-alpha-HTBZ appears to be further metabolized in part by CYP2D6

Elimination

Half-life: 15-22 hr (parent drug and active metabolite)

Total plasma clearance: 7.2 L/hr

Excretion: 60% urine; 30% feces; <2% excreted as unchanged valbenazine or [+]-alpha-HTBZ

Pharmacogenomics

CYP2D6 poor metabolizers

• Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers
• Increased exposure (Cmax and AUC) to the active metabolite is anticipated in CYP2D6 poor metabolizers, which may increase risk for exposure-related adverse effects

Oral Administration

May take with or without food

Storage

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)