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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors

Last Update: April 2, 2019.

OVERVIEW

Introduction

The vesicular monoamine transporter type 2 (VMAT2) inhibitors are agents that cause a depletion of neuroactive peptides such as dopamine in nerve terminals and are used to treat chorea due to neurodegenerative diseases (such as Huntington chorea) or dyskinesias due to neuroleptic medications (tardive dyskinesia). As of 2019, three VMAT2 inhibitors have become available in the United States for management of dyskinesia syndromes, each with a somewhat different spectrum of approved indications: tetrabenazine (Xenazine and generics: 2008), deutetrabenazine (Austedo: 2017) and valbenazine (Ingressa: 2017). The VMAT2 inihibitors have not been associated with serum enzyme elevations during therapy or linked to instances of clinically apparent liver injury, but they have had limited general clinical use.

Tetrabenazine

Background

Tetrabenazine (tet" ra ben' a zeen) is an inhibitor of synaptic vesicular monoamine transporter 2 (VMAT2), the inhibition of which causes a depletion of neuroactive monoamines (serotonin, norepinephrine and particularly dopamine) in nerve terminals. The reduction in these active neurotransmitters results in a decrease in spontaneous jerk-like movements of the extremities, trunk, face and neck (chorea) that are typical of patients with degenerative neurologic conditions such as Huntington disease. Tetrabenazine, however, does not prevent the progression or alter the outcome of these diseases. Tetrabenazine was approved by the FDA in 2008 as an orphan disease agent for treatment of the chorea associated with Huntington disease. While it is used off-label to treat other abnormal movement disorders, tetrabenazine is not formally approved for those indications. Tetrabenazine is available as tablets of 12.5 and 25 mg generically and under the brand name Xenazine. The recommended initial dose is 12.5 mg once daily, with subsequent careful increase to a maximum of 50 mg given in three divided doses daily. Because of the variable metabolism of tetrabenazine (by CYP 2D6), the maintenance dose varies by individual, and inducers or inhibitors of CYP 2D6 should be avoided. Poor CYP 2D6 metabolizers may require even higher doses. Common side effects include fatigue, sedation, somnolence, insomnia, depression, restlessness (akathisia), agitation, and nausea. Rare potentially serious adverse events include severe depression, suicidality, symptomatic hypotension, prolongation of the QTc interval and neuroleptic malignant syndrome.

Hepatotoxicity

Tetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported by the sponsor. In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine. Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which tetrabenazine might cause liver injury is not known. Tetrabenazine undergoes hepatic metabolism largely by CYP 2D6 and is susceptible to drug-drug interactions with agents that induce or inhibit this enzyme.

Deutetrabenazine

Background

Deutetrabenazine (doo" tet ra ben' a zeen) is an inhibitor of synaptic vesicular monoamine transporter 2 (VMAT2), the inhibition of which causes a depletion of neuroactive monoamines (serotonin, norepinephrine and particularly dopamine) in nerve terminals. The reduction in these active neurotransmitters results in a decrease in spontaneous jerk-like movements of the extremities, trunk, face and neck (dyskinesia, chorea) that are typical of patients with degenerative neurologic conditions such as Huntington disease and the syndrome known as tardive dyskinesia. Tardive dyskinesia is a late ("tardive") and sometimes persistent complication of therapy with dopamine receptor anagonists including antipsychotic, antidepressant and antiemetic medications. The movements can involve any part of the body, but most characteristically cause facial tics and tongue rolling which can be particularly distressing and interfere with speech and eating. Deutetrabenazine was found to ameliorate the involuntary movements of tardive dyskinesia and Huntington disease but does not appear to prevent or retard their progression. Deutetrabenazine was approved by the FDA in 2017 for treatment of the movement disorders associated with tardive dyskinesia and Huntington disease. It is available as tablets of 6, 9 and 12 mg under the brand name Austedo. Deutetrabenazine is similar in chemical structure to tetrabenazine but has several molecules of deuterium instead of hydrogen, which creates a stronger bond with carbon and higher molecular weight. These features make it less suceptible to CYP 2D6 metabolism, improving its pharmacologic properties and allowing for twice daily dosing with more reliable drug exposure. The recommended initial dose is 6 mg once daily, with subsequent careful increase to a maximum of 48 mg (24 mg twice daily). Because of the hepatic metabolism of deutetrabenazine, the maintenance dose may be less in patients taking potent CYP 2D6 inhibitors. Common side effects resemble those of tetrabenazine and include fatigue, sedation, somnolence, insomnia, depression, restlessness (akathisia), agitation, and nausea. Rare potentially serious adverse events reported with tetrabenazine include severe depression, suicidality, symptomatic hypotension, prolongation of the QTc interval and neuroleptic malignant syndrome.

Hepatotoxicity

Deutetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited. In prelicensure pivotal registration trials in several hundred patients, deutetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to deutetrabenazine. Thus, clinically apparent liver injury with jaundice due to deutetrabenazine must be rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which deutetrabenazine might cause liver injury is not known. Deutetrabenazine undergoes hepatic metabolism largely by CYP 2D6 and is susceptible to drug-drug interactions with agents that are strong inhibitors of enzyme.

Valbenazine

Background

Valbenazine (val ben' a zeen) is an inhibitor of synaptic vesicular monoamine transporter 2 (VMAT2), the inhibition of which causes a depletion of neuroactive monoamines (serotonin, norepinephrine and particularly dopamine) in nerve terminals. The reduction in these active neurotransmitters results in a decrease in spontaneous jerk-like movements of the extremities, trunk, face and neck (chorea) that are typical of patients with degenerative neurologic conditions such as Huntington disease and the abnormal involuntary movements of the condition known as tardive dyskinesia. Tardive dyskinesia is a late ("tardive") and sometimes persistent complication of therapy with dopamine receptor anagonists including antipsychotic, antidepressant and antiemetic medications. The movements can involve any part of the body, but most characteristically cause facial tics and tongue rolling which can be particularly distressing and interfere with speech and eating. Valbenazine has been shown to decrease the frequency of involuntary movements in patients with tardive dyskinesia and was approved for this use in 2017. Unlike deutetrabenazine, valbenazine has not been approved for use in Huntington disease. Valbenazine is available as tablets of 40 mg under the brand name Ingrezza. The recommended initial dose is 40 mg once daily, with subsequent increase to a maximum of 80 mg daily. Valbenazine is a prodrug that is metabolized by CYP 3A4 in the liver to its active metabolite (alpha-dihydrotetrabenazine) which is subsequently metabolized by CYP 2D6. For these reasons, its use with strong inhibitors of CYP 3A4 or 2D6 should be avoided or the dose reduced accordingly. Common side effects are similar to those of tetrabenazine and include fatigue, sedation, somnolence, insomnia, depression, restlessness (akathisia), agitation, and nausea. Rare potentially serious adverse events include severe depression, suicidality, symptomatic hypotension, prolongation of the QTc interval and neuroleptic malignant syndrome.

Hepatotoxicity

In prelicensure studies, valbenazine was not been associated with rates of serum enzyme elevations greater than occurred with placebo therapy, and no instances of clinically apparent liver injury, jaundice or hepatitis was reported, although a case of "reactivation of viral hepatitis" was reported in a patient with preexisting hepatitis C virus infection. Valbenazine has had limited general clinical use, but there have been no published reports of clinically apparent liver injury with jaundice associated with its use. Thus, clinically apparent liver injury due to valbenazine must be rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which valbenazine might cause liver injury is not known. Valbenazine undergoes hepatic metabolism by CYP 3A4 followed by CYP 2D6 and is susceptible to drug-drug interactions with agents that induce or inhibit these enzymes.

Drug Class: Genetic Disorder Agents, Huntington Disease Agents (for Chorea)

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Deutetrabenazine – Austedo®

Tetrabenazine – Generic, Xenazine®

Valbenazine – Ingrezza®

DRUG CLASS

Genetic Disorder Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Deutetrabenazine 1392826-25-3 C19-H21-D6-N-O3 (USP)
C19-H27-N-O3 (FDA)
2D chemical structure of 1392826-25-3
Tetrabenazine 58-46-8 C19-H27-N-O3
Tetrabenazine Chemical Structure
Valbenazine 1025504-45-3 C24-H38-N2-O4
2D chemical structure of 1025504-45-3

ANNOTATED BIBLIOGRAPHY

References updated: 02 April 2019

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