FDA Approves First Drug to Treat Tardive Dyskinesia
Talia Puzantian
Deputy editor, The Carlat Psychiatry Report
Dr. Puzantian has disclosed that she has no relevant relationships or financial interests in any commercial company pertaining to this educational activity.
On April 11, the U.S. Food and Drug Administration approved Ingrezza (valbenazine) for the treatment of tardive dyskinesia (TD), a disabling movement disorder that afflicts 10%–20% of people on chronic antipsychotic medication.
The approval was based on a clinical trial in which 234 patients with moderate to severe TD were randomly assigned to a higher or lower dose of valbenazine or placebo. After 6 weeks, patients on 80 mg, but not 40 mg, of valbenazine had a statistically significant greater improvement in Abnormal Involuntary Movement Scale (AIMS) score than those in the placebo arm (-3.2 for valbenazine 80 mg vs -1.9 for 40 mg and -0.1 for placebo). Patients on both doses of valbenazine also had higher AIMS response rates at 6 weeks (defined as a 50% reduction in the AIMS score) than those on placebo (80 mg, 40% response rate; 40 mg, 23.8%; placebo, 8.7%).
Because TD is a serious disorder and no other medication has been approved for its treatment, the FDA fast-tracked its approval, leading to sooner-than-normal market arrival.
How does the drug work? It’s classified as a VMAT2 inhibitor (vesicular monoamine transporter type 2 inhibitor). VMAT2 is a protein that regulates the packaging and release of dopamine from synaptic vesicles. Inhibiting it essentially decreases dopamine release. Since TD is probably caused by dopamine hypersensitivity, inhibiting dopamine release logically decreases these symptoms.
If you want to prescribe the new medication, start it at 40 mg/day and increase to 80 mg/day after a week. The most common side effects are sedation, somnolence, and akathisia. Additionally, valbenazine may increase the QT interval (mean of 11.7 msec in CYP2D6 poor metabolizers and 6.7 msec in healthy volunteers). This degree of prolongation may be clinically significant, albeit rarely, in those at risk (eg, poor metabolizers, congenital QT syndrome, or concomitant meds that increase QT). Longer-term studies will help determine whether there is an associated increase in risk for depression or suicidality as has been reported with other VMAT inhibitors.
For now, the major side effect may be sticker shock. Manufacturer Neurocrine Biosciences is asking $5,275 for a 30-day supply (that’s $63,300 per year). Another company, Teva, is seeking a TD indication for their own VMAT2 inhibitor deutetrabenazine (Austedo, now approved for Huntington’s). But don’t expect the price to come down with the added competition: the projected price for Austedo will be $70,000 per year.
While it’s great to finally have a drug for TD, the best policy is to prevent it in the first place by avoiding drugs most likely to cause it (first-generation high-potency drugs like haloperidol), and by monitoring for TD (using the AIMS scale: www.cqaimh.org/pdf/tool_aims.pdf).
General PsychiatryThe approval was based on a clinical trial in which 234 patients with moderate to severe TD were randomly assigned to a higher or lower dose of valbenazine or placebo. After 6 weeks, patients on 80 mg, but not 40 mg, of valbenazine had a statistically significant greater improvement in Abnormal Involuntary Movement Scale (AIMS) score than those in the placebo arm (-3.2 for valbenazine 80 mg vs -1.9 for 40 mg and -0.1 for placebo). Patients on both doses of valbenazine also had higher AIMS response rates at 6 weeks (defined as a 50% reduction in the AIMS score) than those on placebo (80 mg, 40% response rate; 40 mg, 23.8%; placebo, 8.7%).
Because TD is a serious disorder and no other medication has been approved for its treatment, the FDA fast-tracked its approval, leading to sooner-than-normal market arrival.
How does the drug work? It’s classified as a VMAT2 inhibitor (vesicular monoamine transporter type 2 inhibitor). VMAT2 is a protein that regulates the packaging and release of dopamine from synaptic vesicles. Inhibiting it essentially decreases dopamine release. Since TD is probably caused by dopamine hypersensitivity, inhibiting dopamine release logically decreases these symptoms.
If you want to prescribe the new medication, start it at 40 mg/day and increase to 80 mg/day after a week. The most common side effects are sedation, somnolence, and akathisia. Additionally, valbenazine may increase the QT interval (mean of 11.7 msec in CYP2D6 poor metabolizers and 6.7 msec in healthy volunteers). This degree of prolongation may be clinically significant, albeit rarely, in those at risk (eg, poor metabolizers, congenital QT syndrome, or concomitant meds that increase QT). Longer-term studies will help determine whether there is an associated increase in risk for depression or suicidality as has been reported with other VMAT inhibitors.
For now, the major side effect may be sticker shock. Manufacturer Neurocrine Biosciences is asking $5,275 for a 30-day supply (that’s $63,300 per year). Another company, Teva, is seeking a TD indication for their own VMAT2 inhibitor deutetrabenazine (Austedo, now approved for Huntington’s). But don’t expect the price to come down with the added competition: the projected price for Austedo will be $70,000 per year.
While it’s great to finally have a drug for TD, the best policy is to prevent it in the first place by avoiding drugs most likely to cause it (first-generation high-potency drugs like haloperidol), and by monitoring for TD (using the AIMS scale: www.cqaimh.org/pdf/tool_aims.pdf).
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