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Valbenazine (Ingrezza®): The First FDA Approved Drug for Tardive Dyskinesia

By: Yan Yi Chan, PharmD Candidate c/o 2018

Tardive dyskinesia is a movement disorder characterized by involuntary and repetitive movements of the tongue, jaw, lips, face, trunk, upper and lower extremities, and respiratory system.1 This is usually associated with the use of dopamine receptor blockers such as antipsychotic medications in treating psychiatric disorders and antiemetic medications, such as metoclopramide, in treating symptomatic gastroesophageal reflux.1 Even though the risk of developing tardive dyskinesia is lower with the newer atypical antipsychotics as compared to the first generation antipsychotics, this condition can still develop in some patients with long term use.2  Unfortunately, tardive dyskinesia is often irreversible and can have significant effects on a patient’s functioning. It can cause speech impairment, difficulties in chewing and swallowing, and increase the risk of falls.3 Because of the public perception of these involuntary movements, patients with this condition may feel shameful, depressed, or socially isolated. Treating tardive dyskinesia can be challenging. Discontinuing or lowering doses of antipsychotics is sometimes not an option because it can exacerbate tardive dyskinesia symptoms or worsen a patient’s psychiatric condition. Symptoms of tardive dyskinesia often are still present even with the discontinuation or dose reduction of the offending drug. Increasing doses of antipsychotics may reduce or mask the involuntary movements initially, but can worsen tardive dyskinesia in the long run.4 However, hope has arrived for patients with tardive dyskinesia with the FDA approval of a new drug – valbenazine (Ingrezza®).

On April 11, 2017, the FDA approved of the first drug indicated for the treatment of tardive dyskinesia.5 Valbenazine is a reversible and selective vesicular monoamine transporter 2 (VMAT2) inhibitor. VMAT2 is a protein present in neurons that regulates the packaging of dopamine and other monoamines from the cytoplasm into vesicles for storage and release into the synapse. Valbenazine reduces the amount of dopamine that is released into the synapse by modulating dopamine transport into the vesicles. As a result, there is less stimulation of the postsynaptic dopamine receptors in the nigro-striatal pathway, thus reducing the degree and intensity of the involuntary movements.1

The phase 3 trial of valbenazine was a randomized, double blind, placebo controlled, parallel group, and fixed dose study that was 6 weeks in duration.6 It enrolled 234 patients age 18 to 85 who were medically stable and were diagnosed according to DSM-IV criteria with schizophrenia, schizoaffective disorder, or mood disorder for 3 months or more prior to screening. Of the 234 patients, 66% were diagnosed with schizophrenia or schizoaffective disorder while the remainder of the patients had a mood disorder. Patients also had to be diagnosed with moderate to severe tardive dyskinesia for 3 or more months prior to screening. Patients were allowed to continue the use of medications for their psychiatric and other medical conditions, but had to have been stable on their medications for at least 30 days prior and could not make changes in therapy during the length of the study. Patients were randomized to receive either placebo, valbenazine 40 mg once daily, or valbenazine 80 mg once daily. The primary efficacy was change in the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score for items 1-7 from baseline to week 6. An AIMS response was defined as achieving at least a 50% reduction from baseline in dyskinesia score. The patients were video recorded at each study visit at baseline and weeks 2, 4 and 6. They were reviewed by neurologists who specialize in movement disorders and were blind to treatment and study visit sequence. Patients were also evaluated for vital signs, physical examinations, ECG, laboratory tests, psychiatric or mood status, and suicidal ideation or behavior, in which there were no clinically relevant changes observed throughout the entire length of the study. Improvements in AIMS dyskinesia score was observed in both treatment groups within 2 weeks of initiating treatment. From baseline to week 6, the changes in AIMS dyskinesia score were -3.2 in the 80 mg group and -1.9 in the 40 mg group compared to -0.1 in the placebo group. At week 6, 40% of the 80 mg group and 23.8% of the 40 mg group had an AIMS response compared to 8.7% in the placebo group. The common side effects observed were somnolence, akathisia, and dry mouth.  The number needed to treat (NNT) in the 80 mg group was 4 while the number needed to harm (NNH) was 13; the NNT in the 40 mg group was 7 and NNH was -32. This suggests that the benefits of valbenazine may outweigh the risks.

The dosing of valbenazine is 40 mg once daily initially for 4 weeks, then increase to 80 mg once daily. Patients can also be continued on 40 mg daily if needed. Use of valbenazine with a strong CYP3A4 inducer or monoamine oxidase inhibitor is not recommended. If coadministered with a strong CYP3A4 inhibitor, reduce the dose of valbenazine to 40 mg once daily. Dose reduction should be considered if coadministered with a strong CYP2D6 inhibitor. Dose reduction is not necessary in the elderly or patients with renal impairment. However, use should be avoided in patients with severe renal impairment (creatinine clearance less than 30 mL/min). In patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15), the recommended dose is 40 mg once daily.7 In addition, valbenazine may cause QT prolongation but the degree of it is not clinically significant with the recommended dosing.1

Valbenazine improved tardive dyskinesia regardless of the antipsychotic drug patients were using, psychiatric diagnosis, and severity of tardive dyskinesia.1 It was well tolerated during the clinical trials and patients’ psychiatric status were stable while using valbenazine.6 This drug is very promising for patients with tardive dyskinesia, especially for those where switching or discontinuing the antipsychotic drug is not possible.



  1. 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;71(7). doi: 10.1111/ijcp.12964. Accessed 08/21/2017.
  2. Freudenreich O, Remington G. Valbenazine for Tardive Dyskinesia. Clin Schizophr Relat Psychoses. Summer;11(2):113-119. doi: 10.3371/CSRP.OFGR.071717. Accessed 08/21/2017.
  3. Davis MC, Miller BJ, Kalsi JK, Birkner T, Mathis MV. Efficient Trial Design – FDA Approval of Valbenazine for Tardive Dyskinesia. N Engl J Med. 2017;376(26):2503-2506. doi: 10.1056/NEJMp1704898. Accessed 08/21/2017.
  4. Seeberger LC, Hauser RA. Valbenazine for the treatment of tardive dyskinesia. Expert Opin Pharmacother. 2017;18(12):1279-1287. doi: 10.1080/14656566.2017.1353078. Accessed 08/21/2017.
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