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Valbenazine

Pronunciation

(val BEN a zeen)

Index Terms

  • Ingrezza
  • Valbenazine Tosylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Ingrezza: 40 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Ingrezza: 80 mg [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c red #40]

Brand Names: U.S.

  • Ingrezza

Pharmacologic Category

  • Central Monoamine-Depleting Agent
  • Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor

Pharmacology

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 and its active metabolite have no appreciable binding affinity for VMAT1 or dopaminergic, serotonergic, adrenergic, histaminergic or muscarinic receptors.

Absorption

High-fat meals decrease Cmax by 47% and AUC by 13%.

Distribution

Vd: 92 L

Metabolism

Metabolism: Extensively metabolized by hydrolysis to form active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form monooxidized valbenazine and other minor metabolites. The active metabolite is further metabolized in part by CYP2D6.

Excretion

Urine (~60%, primarily as inactive metabolites); feces (~30%, primarily as inactive metabolites)

Time to Peak

Valbenazine: 0.5 to 1 hours; Active metabolite: 4 to 8 hours

Half-Life Elimination

15 to 22 hours (valbenazine and active metabolite)

Protein Binding

Valbenazine: >99%; Active metabolite: ~64%

Use: Labeled Indications

Tardive dyskinesia: Treatment of adults with tardive dyskinesia

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Tardive dyskinesia: Oral: Initial: 40 mg once daily; after 1 week, increase to 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients based on response and tolerability.

Dosage adjustment for concomitant CYP3A4 and CYP2D6 inhibitors/inducers:

Concomitant administration with a strong CYP3A4 inducer (eg, carbamazepine, phenytoin, rifampin, St John's wort): Use is not recommended.

Concomitant administration with a strong CYP3A4 inhibitor (eg, clarithromycin, itraconazole, ketoconazole): Maximum dose: 40 mg once daily

Concomitant administration with a strong CYP2D6 inhibitor (eg, fluoxetine, paroxetine, quinidine): Dosage adjustment is not provided in the manufacturer's labeling, however, a dose reduction may be necessary based on tolerability.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment (CrCl 30 to 90 mL/minute): No dosage adjustment necessary.

Severe impairment (CrCl <30 mL/minute): Use is not recommended.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling.

Moderate to severe impairment (Child-Pugh class B or C): 40 mg once daily

Administration

Administer with or without food.

Storage

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

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Valbenazine. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Valbenazine. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Valbenazine. Avoid combination

Digoxin: Valbenazine may increase the serum concentration of Digoxin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Monoamine Oxidase Inhibitors: Valbenazine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of Valbenazine. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Valbenazine. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%: Central nervous system: Drowsiness (≤11%), fatigue (≤11%), sedation (≤11%)

1% to 10%:

Central nervous system: Abnormal gait (≤4%), dizziness (≤4%), equilibrium disturbance (≤4%), falling (≤4%), akathisia (≤3%), restlessness (≤3%), anxiety (≥1% to <2%), drooling (≥1% to <2%), extrapyramidal reaction (≥1% to <2%), insomnia (≥1% to <2%)

Endocrine & metabolic: Increased serum glucose (≥1% to <2%), weight gain (≥1% to <2%)

Gastrointestinal: Vomiting (3%)

Neuromuscular & skeletal: Arthralgia (2%), dyskinesia (≥1% to <2%)

Respiratory: Respiratory tract infection (≥1% to <2%)

Frequency not defined:

Endocrine & metabolic: Increased serum prolactin (dose-related)

Hepatic: Increased serum alkaline phosphatase (dose-related), increased serum bilirubin (dose-related)

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Depression/suicidal ideation: VMAT inhibitors have been associated with depression and suicidal thoughts and behavior; although short-term studies with valbenazine have not detected this adverse effect, longer studies have not yet been published (O'Brien 2015).

• QT prolongation: May prolong the QT interval; use caution when used concomitantly with a strong CYP2D6 or CYP3A4 inhibitor or in a poor CYP2D6 metabolizer, dose reduction may be necessary. Avoid use in patients with congenital long QT syndrome or arrhythmias associated with prolonged QT interval. For patients at risk of prolonged QT interval, perform EKG before increasing the dosage.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with moderate or severe hepatic impairment; use reduced dose.

• Renal impairment: Use is not recommended in patients with severe renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2D6 poor metabolizers: CYP2D6 poor metabolizes may have increased levels of primary drug metabolites which may increase the risk of adverse effects; consider dose reduction based on tolerability.

Monitoring Parameters

Abnormal Involuntary Movement Scale (AIMS) or Dyskinesia Identification System Condensed User Scale (DISCUS); EKG (for patients at risk for QT prolongation)

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, loss of strength or energy, dry mouth, or constipation. Have patient report immediately to prescriber difficulty focusing, blurred vision, difficult urination, tachycardia, abnormal heartbeat, or passing out (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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