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]
Capsule Therapy Pack, Oral:
Ingrezza: 7 x valbenazine 40 mg and 21 x valbenazine 80 mg [28 day therapy pack] (28 ea) [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
Pharmacology
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. Valbenazine and its active metabolite have no appreciable binding affinity for VMAT1 or dopaminergic, serotonergic, adrenergic, histaminergic or muscarinic receptors.
Pharmacokinetics/Pharmacodynamics
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
Hypersensitivity to valbenazine or any component of the formulation
Dosage and Administration
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.
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
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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
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
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fosnetupitant: 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
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
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
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
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin
<1%, postmarketing and/or case reports: Hypersensitivity reaction, skin rash
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: Vesicular monoamine transport inhibitors have been associated with depression and suicidal thoughts and behavior. In a pooled analysis of two 6-week trials and a 42-week extension trial, 96.5% (N=113) of patients who reported no suicidal ideation at baseline continued to have no suicidal ideation at any time during the study; however, 4 patients (2 on placebo, 2 on valbenazine) reported a shift in their Columbia-Suicide Severity Rating Scale score to suicidal thoughts/ideation (McIntyre 2019).
- Parkinsonism: Cases of parkinson-like symptoms (eg, falls, gait disturbances, tremor, drooling, hypokinesia), some severe requiring hospitalization, have been reported. Onset of severe symptoms occurs most commonly within 2 weeks of the start of therapy or a dose increase; may resolve with 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; 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
Pregnancy Considerations
Adverse events were observed in some animal reproduction studies
Patient Education
What is this drug used for?
- It is used to treat tardive dyskinesia.
Frequently reported side effects of this drug
- Fatigue
- Loss of strength and energy
- Headache
- Restlessness
- Dry mouth
- Constipation
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Trouble focusing
- Blurred vision
- Trouble urinating
- Change in balance
- Trouble controlling body movements
- Twitching
- Trouble swallowing
- Trouble speaking
- Tremors
- Trouble moving
- Stiffness
- Drooling
- Slow heartbeat
- Shortness of breath
- Dizziness
- Fast heartbeat
- Abnormal heartbeat
- Passing out
- Signs of a significant reaction like 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. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
