Treatments for Tardive Dyskinesia: What Pharmacists Should Know

AUGUST 30, 2017
Tardive dyskinesia (TD) is an involuntary movement disorder caused by chronic use of dopamine receptor-blocking drugs, also known as neuroleptics. Individuals with TD typically experience involuntary and abnormal movements of different muscles and the tongue, lips, or jaw.1 It has been estimated that between 20-50% of all patients treated with chronic neuroleptic therapy will develop TD, with prevalence increasing with advanced age. Since there is no cure available for TD, prevention is critical.2 

In March 2017, the FDA approved Neurocrine Bioscience’s valbenazine (Ingrezza) for the treatment of adults with TD. With its approval, Ingrezza became the first FDA approved medication for this indication. In a press release issued today, officials with Teva announced that deutetrabenazine (Austedo) tablets have been approved by the US Food and Drug Administration (FDA) for the treatment of TD. 
 
This article will highlight several key therapeutics areas that every pharmacist should know.
 
History
Over recent years, prescribing of antipsychotics has been increasing at a steady rate. While the introduction of atypical antipsychotics has helped limit the risk of extrapyramidal symptoms, tardive dyskinesia remains a concern among treated patients. Because TD is irreversible, physicians often focus on prevention and decreasing antipsychotic doses when symptoms begin.
 
A number of different medications have been studied to treat TD symptoms, including benzodiazepines and supplements, such as Vitamin E and Ginkgo biloba, with inconclusive results.1 Tetrabenazine, used off-label, has been considered a first-line agent and the most effective medication to treat TD. Although tetrabenazine is generally well-tolerated, higher doses are often needed to control TD symptoms, leading to side effects such as depression, lethargy, akathisia, and parkinsonism. Additionally, its short half-life requires three times daily dosing.2

Clinical trials evaluating the use of valbenazine, a purified prodrug of an isomer of tetrabenazine, began as early as 2011.3 Its approval in March 2017 marked it as the first FDA-approved medication for treating TD in adults. More recently, the manufacturer announced on May 23, 2017 that Ingrezza did not meet its primary endpoint in a phase 2 study for the treatment of Tourette Syndrome although they will continue studying the medication for this indication.4 

According to the press release on Austedo, 2 fixed doses of deutetrabenazine for TD were studied for efficacy and safety in TD treatment, versus placebo.
 
 
Efficacy
The efficacy of Ingrezza was assessed in a randomized, double-blind, placebo-controlled trial of 225 patients with moderate to severe TD. All patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals were randomized to receive Ingrezza 40 mg, Ingrezza 80 mg, or placebo. The primary efficacy endpoint was the mean change from baseline to week 6 in the Abnormal Involuntary Movement Scale (AIMS) total score. At the end of week 6, those taking placebo were re-randomized to receive Ingrezza 40 mg or 80 mg for 42 weeks.
 
Study results showed that after 6 weeks, there was a statistically significant higher mean change from baseline in the AIMS score in patients who received Ingrezza 80 mg per day versus placebo (-3.2 vs -0.1). A numerical improvement was seen with the 40 mg dose although it did not reach significance (-1.9 vs -0.1). Subgroup analyses did not demonstrate any clear evidence of differential response. Among patients remaining in the study at the end of the 48 weeks, discontinuation of Ingrezza was shown to result in AIM score returning toward baseline.

Safety
The most common adverse reaction seen in patients receiving Ingrezza during clinical trials was somnolence. Warnings and precautions included with Ingrezza’s prescribing information include a possible impaired ability to drive or operate hazardous machinery due to somnolence and increased risk for QT prolongation.5
 
Combination use of Ingrezza with MAOIs and strong CYP3A4 inducers (e.g. rifampin, carbamazepine, phenytoin) is not recommended. The dose of Ingrezza should be reduced to 40 mg when used with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin). In poor CYP2D6 metabolizers, levels of valbenazine metabolites may increase which may lead to more adverse reactions. In this case, dose reduction should be considered based on tolerability to Ingrezza.

Austedo has a black box warning for an increased risk of depression and suicidality with patients with Huntington's disease. 

Product Cost
The annual cost for Ingrezza (two 30 count bottles of 40 mg capsules per month) is $151,920 per Lexi-Drugs.7 This price may decrease with the introduction of the 80 mg capsules later this year or early 2018.6
 
Generic tetrabenazine can run between $92,000 and $96,000 annually. Teva’s Austedo, is currently listed at $60,000 per year.8
 
Notably, cost to the patient will vary based on insurance coverage.
 
Conclusion
Ingrezza is the first FDA-approved treatment for adults with TD. Its efficacy and safety profile make it an attractive agent for treating any adult with TD. The introduction of Austedo to the market  will add additional competition to Ingrezza.

References
1. Tardive Dyskinesia. National Alliance on Mental Illness. Available at: https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Tardive-Dyskinesia. Accessed May 30, 2017.
2. Wain O, Jankovic J. An Update on Tardive Dyskinesia: From Phenomenology to Treatment. Tremor Other Hyperkinet Mov. 2013; 3: tre-03-161-4138-1.
3. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/results?term=NBI-98854&Search=Search. Accessed May 30, 2017.
4. Hefland C. Tourette was supposed to be Ingrezza's big driver, but a trial flop has forced a detour. FiercePharma. May 24, 2017. Available at: www.fiercepharma.com/marketing/neurocrine-s-bid-for-ingrezza-expansion-stalls-tourette-study-miss
5. Ingrezza [Prescribing Information]. Neurocrine Biosciences, Inc. San Diego, CA. April 2017.
6. Court E. Why Neurocrine is charging twice as much for its new drug as it said it would. May 3, 2017. MarketWatch. Available at: www.marketwatch.com/story/why-neurocrine-is-charging-twice-as-much-for-its-new-drug-as-it-said-it-would-2017-05-02
7. Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; May 30, 2017.
8. Hefland C. Hungry for brand sales, Teva undercuts generics with new, $60K Huntington's med Austedo. April 4, 2017. FiercePharma. Available at: http://www.fiercepharma.com/pharma/hungry-for-specialty-sales-teva-undercuts-generics-new-huntington-s-med-austedo

Timothy O'Shea, PharmD
Timothy O'Shea, PharmD
Timothy O'Shea, PharmD, is a Clinical Pharmacist working at a large health insurance plan on the east coast. Additionally he works per diem at a retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.
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