By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first drug for the treatment of tardive dyskinesia in adults. Valbenazine is a vesicular monoamine transporter inhibitor type 2 (VMAT2). Two other VMAT2 inhibitors, tetrabenazine and deutetrabenazine, are approved for chorea associated with Huntington disease. Valbenazine is marketed as Ingrezza.
Valbenazine is indicated for the treatment of tardive dyskinesia in adults.1
The initial dose is 40 mg once daily for one week, followed by an increase to 80 mg (2 x 40 mg) once daily.1 It may be taken without regard to meals. For these with moderate to severe hepatic dysfunction, taking a strong CYP3A4 inhibitor, or those who are poor CYP2D6 metabolizers, the dose should be 40 mg. Valbenazine is available as 40 mg capsules.
Valbenazine is the only approved drug for tardive dyskinesia.
The most common adverse reaction (vs. placebo) is somnolence (11% vs. 4%).1 Clinically significant QT interval prolongation may occur in patients taking strong CYP2D6 or CYP3A4 inhibitors or who are poor CYP2D6 metabolizers.
Valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with prolonged QT interval. Concomitant use with a strong CYPA4 inducer is not recommended.
Tardive dyskinesia is believed to result from upregulation of postsynaptic dopamine receptors due to long-standing blockade by dopamine-blocking drugs.2,3 VMAT2 is a protein/transporter in the neurons that regulates the storage, packaging, and release of dopamine into the synapse. Inhibitors of VMAT2 decrease the amount of dopamine released. Valbenazine does not appear to exhibit appreciable affinity to dopaminergic, serotonergic, muscarinic, or histaminergic receptors.1
The efficacy of valbenazine was evaluated in a double-blind, placebo-controlled trial in 234 subjects with moderate to severe tardive dyskinesia.1,4 These subjects presented with schizophrenia, schizoaffective disorder, or mood disorder of three months or greater duration and dopamine receptor blocker-induced tardive dyskinesia. Subjects were randomized to valbenazine 40 mg, 80 mg, or placebo. The primary endpoint was change from baseline to week six on the sum of items 1-7 of the Abnormal Involuntary Movement Scale (AIMS dyskinesia score). Items 1-7 assess the severity of involuntary movements across body regions (scored 0-4).
Overall mean baseline AIMS dyskinesia score was about 10.0 ± 4.0. Mean changes at endpoint compared to placebo were -1.8 for 40 mg (effect size, 0.53) and -3.1 for 80 mg (effect size, 0.90). AIMS dyskinesia responses (≥ 50% reduction) were 23.8%, 40.0%, and 8.7%, respectively, for the 40 mg dose, 80 mg dose, and placebo. This translates to a number needed to treat of 4 for the 80 mg dose. Effect for the 80 mg was observed in week two. The psychiatric status of subjects remained stable at the two-week washout period after the six-week treatment.3 The drug appears to be well-tolerated, as only two subjects assigned to the 80 mg aim required a dose reduction and 3% of taking valbenazine discontinued treatment compare to 2% for placebo. Treatment effect appeared to be maintained for 42 weeks in an extension study. AIMS dyskinesia scores revert toward baseline after discontinuation of treatment.1 A 72-week rollover study is in progress.5
Tardive dyskinesia is a potentially disabling neurological disorder characterized by repetitive involuntary movements, including grimacing, sticking out the tongue, and lip smacking.6 Often, it is associated with use of antipsychotics, with an annual incidence of 8.5% for typical antipsychotics and 3.1% for atypical antipsychotics.2 Currently, treatment options for tardive syndromes are limited; the American Academy of Neurology lists amantadine and tetrabenazine as possibly effective for short-term use.7 Valbenazine is the first drug approved for tardive dyskinesia. It appears to be effective, with a favorable benefit-to-risk ratio. The cost was not available at the time of this review.
- Ingrezza Prescribing Information. Neurocrine Biosciences, Inc. April 2017.
- Davis MC, Miller BJ, Kalsi JK, et al. Efficient trial design - FDA approval of valbenazine for tardive dyskinesia. N Engl J Med 2017 May 10. doi: 10.1056/NEJMp1704898. [Epub ahead of print].
- Citrome L. Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2017 May 12. doi: 10.1111/ijcp.12964. [Epub ahead of print] Review.
- Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry 2017;174:476-484.
- ClinicalTrials.gov. Rollover study for continuing valbenazine (NBI-98854) administration for the treatment of tardive dyskinesia. Available at: . Accessed June 23, 2017.
- U.S. Food and Drug Administration. FDA approves first drug to treat tardive dyskinesia. Available at: . Accessed June 23, 2017.
- American Academy of Neurology. Treatment of Tardive Syndromes. Available at: . Accessed June 23, 2017.