Drug information of valbenazine

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

Valbenazine decreases the availability of monoamine neurotransmitters by preventing their storage in synaptic vesicles. This is believed to be the reason behind its therapeutic effect in tardive dyskinesia although the exact mechanism is unknown

: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  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
less than 2% excreted as unchanged valbenazine or [+]-alpha-HTBZ

40 mg PO qDay x1 week, then increase to the recommended dose of 80 mg PO qDay

:Dosage Modifications
Strong CYP3A4 inducers: Coadministration not recommended
Strong CYP3A4 inhibitors: If coadministered, reduce valbenazine dose to 40 mg/day
Strong CYP2D6 inhibitors or known CYP2D6 poor metabolizers: If coadministered, consider reducing dose

Hepatic Impairment: If moderate-to-severe (Child-Pugh 7-15): Not to exceed 40 mg/day

: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

: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
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, Coadministration increases exposure (Cmax and AUC) to valbenazine and its active metabolite compared with the use of valbenazine alone

:Strong CYP2D6 inhibitors
Consider reducing valbenazine dose based on tolerability, 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

:Adverse Effects
Somnolence, Anticholinergic effects, Balance disorders/fall, Headache, Akathisia, Vomiting, Nausea, Arthralgia, Hypersensitivity, QT prolongation, rash

:Drug Interactions
Contraindicated: deutetrabenazine, tetrabenazine
Serious,Use Alternative: abametapir, amobarbital, apalutamide, atazanavir, butalbital,  carbamazepine, chloramphenicol, cobicistat, dabrafenib, dacomitinib, dexamethasone, enzalutamide, eslicarbazepine acetate, fosphenytoin, givosiran, iobenguane I 131, isocarboxazid, ivosidenib, linezolid, lumacaftor/ivacaftor, methylene blue, mifepristone, mitotane, nevirapine, oxcarbazepine, pentobarbital, phenelzine, phenobarbital, phenytoin, primidone, rasagiline, ribociclib, rifabutin, rifampin, rifapentine, safinamide, secobarbital, selegiline, selegiline transdermal, St John's Wort, tranylcypromine, tucatinib, voxelotor
Monitor Closely: bupropion, chlorpromazine, cinacalcet, clarithromycin, cobicistat, cocaine, conivaptan, darunavir, dexmedetomidine, duvelisib, elagolix, elvitegravir/cobicistat/emtricitabine/tenofovir DF, encorafenib, fedratinib, fluoxetine, fosamprenavir, grapefruit, idelalisib, imatinib, indinavir, isoniazid, istradefylline, itraconazole, ketoconazole, lofexidine, lopinavir, lorcaserin, nefazodone, nelfinavir, nicardipine, paroxetine, posaconazole, quinidine, remimazolam, ritonavir, rolapitant, rucaparib, saquinavir, stiripentol, tazemetostat, tecovirimat, terbinafine, tipranavir, voriconazole

:Contraindications
Patients with a history of hypersensitivity to drug or components of the formulation

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