Version May 2024
VMAT2 inhibitors, including valbenazine, can increase the risk of depression and suicidal thoughts and behavior in patients with Huntington disease. Anyone considering the use of valbenazine must balance the risks of depression and suicidal ideation and behavior with the clinical need for treatment of chorea. Closely monitor patients for the emergence of worsening of depression, suicidal ideation, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidal ideation and behavior and instruct them to report behaviors of concern promptly to the treating physician.
Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in patients with Huntington disease.
Chorea associated with Huntington disease : Oral: Initial: 40 mg once daily; increase dose in 20 mg increments every 2 weeks to a target dose of 80 mg once daily. Continuation of 40 to 60 mg once daily may be considered for some patients based on response and tolerability (Ref).
Tardive dyskinesia: Oral: Initial: 40 mg once daily; after 1 week, increase to 80 mg once daily. Continuation of 40 or 60 mg once daily may be considered for some patients based on response and tolerability (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to severe impairment: No dosage adjustment necessary.
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
Depression or suicidality, unresolving: Consider discontinuation of therapy.
Hypersensitivity reaction (eg, angioedema, rash, shortness of breath, urticaria): Discontinue therapy.
Neuroleptic malignant syndrome: Immediately discontinue valbenazine; monitor and manage symptoms and concomitant complications. If valbenazine therapy is reinitiated after recovery, monitor for signs of recurrence.
Parkinsonism: Reduce dose; discontinuation of therapy may be necessary.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%: Nervous system: Drowsiness (≤19%), fatigue (≤14%), lethargy (≤19%), sedated state (≤19%)
1% to 10%:
Dermatologic: Skin rash (8%), urticaria (9%)
Endocrine & metabolic: Increased serum glucose (≥1%), weight gain (≥1%)
Gastrointestinal: Diarrhea (5%), nausea (5%), vomiting (3%)
Nervous system: Abnormal gait (≤4%), akathisia (≤6%), anxiety (≥1%), balance impairment (≤4%), depressed mood (≤5%), depression (≤5%), dizziness (≤4%), drooling (≥1%), extrapyramidal reaction (≥1%), falling (≤4%), insomnia (6%; including middle insomnia), parkinsonism (3% to 5%), restlessness (≤3%)
Neuromuscular & skeletal: Arthralgia (2%), back pain (5%), dyskinesia (≥1%)
Respiratory: Respiratory tract infection (≥1%)
Frequency not defined:
Endocrine & metabolic: Hyperprolactinemia
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin
Nervous system: Suicidal ideation, suicidal tendencies
Postmarketing:
Hypersensitivity: Hypersensitivity reaction (including angioedema)
Nervous system: Neuroleptic malignant syndrome
Hypersensitivity (eg, rash, urticaria, symptoms consistent with angioedema [eg, swelling of the face, lips, and mouth]) to valbenazine or any component of the formulation.
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, including valbenazine, 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 with tardive dyskinesia 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). In patients with Huntington disease, depression or depressed mood was reported in 4.7% of patients receiving valbenazine (versus 1.6% placebo) in a randomized controlled trial; suicidal ideation (7.3%) and suicide attempts (2.4%) were also reported in an open-label extension trial.
• Hypersensitivity reactions: Hypersensitivity, including angioedema (which may be fatal) of the eyelids, glottis, larynx, and lips, have occurred after the first dose or subsequent doses of valbenazine. Rash, shortness of breath, and urticaria were also reported in patients with Huntington disease.
• Neuroleptic malignant syndrome: Vesicular monoamine transport inhibitors, including valbenazine, may be associated with neuroleptic malignant syndrome; signs/symptoms may include acute kidney failure, altered mental status, autonomic instability (eg, cardia dysrhythmia, diaphoresis, irregular pulse or BP, tachycardia), elevated creatine phosphokinase, fever, muscle rigidity, myoglobinuria, and rhabdomyolysis.
• Parkinsonism: Cases of parkinson-like symptoms (eg, falls, gait disturbances, tremor, drooling, hypokinesia), some severe requiring hospitalization, have been reported. Development of these symptoms in patients with Huntington disease may be difficult to differentiate from progression of the underlying disease; drug-induced parkinsonism may cause more functional disability than untreated chorea in Huntington disease. Onset of severe symptoms in patients receiving treatment for tardive dyskinesia occurs most commonly within 2 weeks of the start of therapy or a dose increase; may resolve with discontinuation of therapy.
• QT prolongation: QT prolongation may occur but may be clinically insignificant when valbenazine is administered within the recommended dosage range. Avoid use in patients with congenital QT prolongation or a history of cardiac arrhythmias associated with prolonged QT.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with moderate or severe hepatic impairment; dose reduction is recommended.
• Huntington disease: Underlying chorea may improve over time in some patients, thereby decreasing the need for therapy. Reevaluate patients' need for treatment by periodically assessing the effect on chorea and possible adverse effects (Hermann 2015).
Special populations:
• CYP2D6 poor metabolizers: CYP2D6 poor metabolizes may have increased levels of primary drug metabolites, which may increase the risk of adverse effects (eg, QT interval prolongation); dosage reduction is recommended.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as tosylate:
Ingrezza: 40 mg, 60 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Ingrezza: 80 mg [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Capsule Therapy Pack, Oral, as tosylate:
Ingrezza: Valbenazine 40 mg (7s) and valbenazine 80 mg (21s) [28 day therapy pack] (28 ea) [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
No
Capsule Therapy Pack (Ingrezza Oral)
40 & 80 mg (per each): $353.79
Capsules (Ingrezza Oral)
40 mg (per each): $300.56
60 mg (per each): $330.20
80 mg (per each): $330.20
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Oral: Administer with or without food.
Chorea associated with Huntington disease: Treatment of adults with chorea associated with Huntington disease.
Tardive dyskinesia: Treatment of adults with tardive dyskinesia.
Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP2D6 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Valbenazine. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Valbenazine. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Valbenazine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Valbenazine. 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. Risk D: Consider therapy modification
Deutetrabenazine: May enhance the adverse/toxic effect of Valbenazine. Risk X: Avoid combination
Digoxin: Valbenazine may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Levodopa-Foslevodopa: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors may diminish the therapeutic effect of Levodopa-Foslevodopa. Management: Consider alternatives to the coadministration of levodopa and vesicular monoamine transporter 2 (VMAT2) inhibitors. If combined, monitor for reduced levodopa efficacy. Risk D: Consider therapy modification
MetyroSINE: May enhance the adverse/toxic effect of Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors. Specifically, the risk for extrapyramidal symptoms and excessive sedation may be increased. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: Valbenazine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Valbenazine. Risk X: Avoid combination
Tetrabenazine: May enhance the adverse/toxic effect of Valbenazine. Risk X: Avoid combination
Adverse events were observed in some animal reproduction studies
It is not known if valbenazine is present in breast milk. Based on data from animal studies, the manufacturer does not recommend breastfeeding during therapy or until 5 days after the last dose.
EKG (for patients at risk for QT prolongation; prior to dose increase); signs/symptoms of suicidal ideation.
The mechanism of action of valbenazine in the treatment of tardive dyskinesia and chorea in patients with Huntington disease 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
Protein binding: Valbenazine: >99%; Active metabolite: ~64%
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.
Bioavailability: ~49%
Half-life elimination: 15 to 22 hours (valbenazine and active metabolite)
Time to peak: Valbenazine: 0.5 to 1 hours; Active metabolite: 4 to 8 hours
Excretion: Urine (~60%, primarily as inactive metabolites); feces (~30%, primarily as inactive metabolites)
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