AHFS Class:

• Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors 28:56

Generic Name(s):

• Deutetrabenazine

Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.1,5,8 The drug is a deuterium-substituted derivative of tetrabenazine.2,5,8

Deutetrabenazine is available as immediate- and extended-release formulations.1 The clinical studies detailed in this section were conducted with the immediate-release formulation.1 The efficacy of the extended-release formulation is based on a relative bioavailability study comparing extended-release tablets given once daily to immediate-release tablets twice daily.1

Huntington's Chorea

Deutetrabenazine is used in the treatment of chorea associated with Huntington's disease in adults.1,2 The drug has been designated an orphan drug by FDA for the treatment of Huntington's disease.3

Clinical Experience

Efficacy of deutetrabenazine in the management of chorea associated with Huntington's disease was established primarily in a randomized, double-blind, placebo-controlled, multicenter study in 90 ambulatory adults with manifest chorea associated with Huntington's disease.1,2 The treatment duration in the study was 12 weeks, and included an 8-week dosage titration period, followed by a 4-week maintenance period, and a 1-week washout period.1,2 Deutetrabenazine therapy was initiated at a dosage of 6 mg daily and then titrated in 6-mg increments every week until satisfactory control of chorea was achieved or intolerable adverse effects occurred, up to a maximum dosage of 48 mg daily.1,2 The mean deutetrabenazine dosage after titration was approximately 40 mg daily.1,2 The primary measure of efficacy was the Total Maximal Chorea (TMC) score, an item from the Unified Huntington's Disease Rating Scale that totals maximal chorea scores for 7 regions of the body.1,2 From baseline to the 4-week maintenance period, the TMC score (average of the scores obtained at weeks 9 and 12) was substantially reduced in deutetrabenazine-treated patients compared with those who received placebo (a reduction of approximately 4.4 units compared with a reduction of approximately 1.9 units, respectively).1,2 In addition, in both patient- and physician-rated global impression of change scales, a substantially greater percentage of patients receiving deutetrabenazine achieved treatment success (i.e., a rating of their symptoms as “much improved” or “very much improved”) compared with those who received placebo.1,2 Following discontinuance of therapy, TMC scores in both groups of patients returned to pretreatment baseline values following the 1-week washout period in this study.1

Although no direct, comparative studies between deutetrabenazine and tetrabenazine have been conducted to date, an analysis of the similarly designed, principal phase 3 efficacy studies of both drugs in patients with Huntington's disease suggested that deutetrabenazine is associated with a lower risk of moderate to severe adverse effects than tetrabenazine.9 The rate of dosage reduction or drug discontinuance due to adverse effects also was lower in the deutetrabenazine study than in the tetrabenazine study.9 In addition to an apparently lower risk of adverse effects with deutetrabenazine compared with tetrabenazine, immediate-release deutetrabenazine may be given twice daily compared with 3 times daily for most patients receiving tetrabenazine.5,9 These clinical differences appear to be related to the different pharmacokinetic profiles of deutetrabenazine and tetrabenazine.5,9

Tardive Dyskinesia

Deutetrabenazine is used for the treatment of tardive dyskinesia in adults.1,6,12

Clinical Experience

Efficacy of deutetrabenazine in the management of tardive dyskinesia was established in 2 randomized, double-blind, placebo-controlled, multicenter studies of 12 weeks' duration conducted in 335 ambulatory adults with tardive dyskinesia caused by dopamine receptor antagonists (the AIM-TD and ARM-TD studies).1,6,12 In both of these studies, deutetrabenazine-treated patients experienced greater improvement in tardive dyskinesia symptoms compared with those who received placebo.1,6,12 Patients in both studies had a diagnosis of tardive dyskinesia for at least 3 months prior to screening with a score of at least 6 on the Abnormal Involuntary Movement Scale (AIMS) and a history of antidopaminergic drug exposure for at least 3 months (or at least 1 month in patients ≥60 years of age).1,6,12 In both of these studies, 62% of patients had schizophrenia or schizoaffective disorder and 33% had a mood disorder; 64% of patients were concurrently receiving atypical antipsychotics, 12% were receiving first-generation or combination antipsychotic therapy, and 24% were not receiving any antipsychotic therapy.1 Patients with suicidal ideation or behavior within 6 months of screening and those with untreated or undertreated psychiatric conditions were excluded from the studies.6,12 The primary measure of efficacy for assessing tardive dyskinesia was the AIMS dyskinesia total score, a subset of items 1-7 of the 12-item AIMS that assesses the severity of involuntary movements across body regions;1 the primary efficacy endpoint in both studies was the change in AIMS total score from baseline to week 12.1,6,12 AIMS scores were verified by expert central reviewers blinded to treatment assignment, visit number, investigation site, and recording date via video recording.6,12

AIM-TD was a fixed-dose study; patients were randomized in a 1:1:1:1 ratio to receive fixed deutetrabenazine target dosages of 12, 24, or 36 mg daily or placebo.1,12 Deutetrabenazine was initiated at a dosage of 12 mg daily (administered as 6 mg twice daily) and then increased in 6-mg increments at weekly intervals over 4 weeks until the target dosage was reached; the target dosage was then maintained for 8 weeks followed by a 1-week washout period.1,12 From baseline to week 12, the mean AIMS dyskinesia total score significantly improved in patients receiving deutetrabenazine 24 or 36 mg daily but not in those receiving deutetrabenazine 12 mg daily or placebo;1,12 the improvement was evident by week 2 and maintained throughout the treatment period.12

ARM-TD was a flexible-dose study; deutetrabenazine was initiated at a dosage of 12 mg daily (administered as 6 mg twice daily) and then increased in 6-mg increments at weekly intervals over 6 weeks until satisfactory control of dyskinesia was achieved, intolerable adverse effects occurred, or a maximum dosage of 48 mg daily was reached; the individualized dosage was maintained for another 6 weeks followed by a 1-week washout period.1,6 From baseline to week 12, the mean AIMS dyskinesia total score significantly improved in patients receiving deutetrabenazine compared with patients receiving placebo.1,6 The average deutetrabenazine dosage after titration was 38.8 mg daily,6 and the dosage remained stable (38.3 mg) through week 12.1,6

Clinical Perspective

Tardive dyskinesia is a hyperkinetic movement disorder characterized by stereotypical, repetitive, involuntary movements in the oral-facial region (e.g., lip smacking or pursing, movement and/or protrusion of the tongue, chewing movements); symptoms can range from mild to severe and can be socially and functionally disabling in some patients.28,100,101,102,104 Involvement of the trunk, extremities, and respiratory system occurs less commonly and can affect balance, speech, and breathing.100,101,102,104 The syndrome can develop with prolonged use of antidopaminergic drugs, particularly conventional or first-generation antipsychotic agents and metoclopramide; symptoms of tardive dyskinesia typically persist for years or decades.28,100,101,102 The risk of developing tardive dyskinesia appears to be greater in geriatric patients and women (particularly postmenopausal women); other risk factors include the use of higher dosages and longer duration of antidopaminergic drug exposure, presence of antipsychotic-induced parkinsonian symptoms, concurrent affective disorder, presence of negative schizophrenia symptoms, alcohol and drug abuse, and certain concurrent medical conditions (such as diabetes mellitus).28,100,101,102

Management of tardive dyskinesia generally includes gradual discontinuance of the precipitating drug or reducing its dosage, if possible; switching from a conventional or first-generation antipsychotic agent to an atypical or second-generation antipsychotic agent; or switching to clozapine therapy.28,100,101,103,104 The American Psychiatric Association (APA) recommends treatment of moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy with a VMAT2 inhibitor such as deutetrabenazine, valbenazine, or tetrabenazine; such treatment may also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial function.62

General

Pretreatment Screening

• Evaluate baseline liver function; deutetrabenazine is contraindicated in patients with hepatic impairment.1

Patient Monitoring

• Monitor patients with Huntington's disease closely for clinical worsening or emergence of depression, suicidal thoughts or behavior (suicidality), or unusual changes in behavior.1
• Monitor patients with Huntington's disease for worsening cognition, functional capacity, mood, or rigidity and periodically re-evaluate continued need for deutetrabenazine.1
• Monitor for signs or symptoms of akathisia, parkinsonism, or neuroleptic malignant syndrome (NMS).1

Other General Considerations

• At least 14 days must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor and initiation of deutetrabenazine; in addition, at least 20 days must elapse between discontinuance of reserpine and initiation of deutetrabenazine.1

Administration

Deutetrabenazine immediate-release tablets should be administered orally with food.1 Extended-release deutetrabenazine tablets are administered orally with or without food.1 Both immediate- and extended-release tablets should be swallowed whole and not chewed, crushed, or broken.1

Total daily dosages of the immediate-release tablets less than 12 mg are administered once daily; total daily dosages of 12 mg or higher should be administered in 2 divided doses.1

Store deutetrabenazine immediate- and extended-release tablets at 25°C; excursions permitted between 15-30°C.1 Protect from light and moisture.1

Dosage

Dosage of deutetrabenazine should be individualized based on efficacy (i.e., reduction of chorea or tardive dyskinesia) and tolerability.1

Huntington's Chorea

In patients not currently receiving tetrabenazine (a related VMAT2 inhibitor), the recommended initial dosage of immediate-release deutetrabenazine for the management of chorea associated with Huntington's disease in adults is 12 mg daily administered in 2 divided doses (6 mg twice daily).1 The recommended initial dosage of extended-release deutetrabenazine is 12 mg once daily.1

Dosage of either formulation may be increased in 6-mg increments at weekly intervals up to the maximum recommended dosage of 48 mg daily.1

When switching between a twice daily immediate-release dosage regimen and a once daily extended-release dosage regimen, switch to the same total daily deutetrabenazine dosage.1

If deutetrabenazine therapy is interrupted for more than 1 week, both formulations should be retitrated when resumed.1 Following treatment interruptions of less than 1 week, treatment can be resumed at the previous maintenance dosage without titration.1

Treatment with immediate- or extended-release deutetrabenazine may be discontinued without tapering the dosage.1

Tardive Dyskinesia

In patients not currently receiving tetrabenazine (a related VMAT2 inhibitor), the recommended initial dosage of immediate-release deutetrabenazine for the treatment of tardive dyskinesia in adults is 12 mg daily administered in 2 divided doses (6 mg twice daily).1 The recommended initial dosage of extended-release deutetrabenazine is 12 mg once daily.1

Dosage of either formulation may be increased in 6-mg increments at weekly intervals up to the maximum recommended dosage of 48 mg daily.1

When switching between a twice daily immediate-release dosage regimen and a once daily extended-release dosage regimen, switch to the same total daily deutetrabenazine dosage.1

If deutetrabenazine therapy is interrupted for more than 1 week, both formulations should be retitrated when resumed.1 Following treatment interruptions of less than 1 week, treatment can be resumed at the previous maintenance dosage without titration.1

Treatment with immediate-or extended-release deutetrabenazine may be discontinued without tapering the dosage.1

Patients treated with deutetrabenazine in the principle efficacy studies continued to receive previous stable antipsychotic regimens, including typical or atypical antipsychotics.1

Transferring Patients from Tetrabenazine to Deutetrabenazine

When transferring patients from tetrabenazine to deutetrabenazine therapy, the manufacturer states that tetrabenazine should be discontinued and deutetrabenazine initiated the following day.1 The recommended initial dosage of immediate- or extended-release deutetrabenazine when switching from tetrabenazine is in the table below (see Table 1).1 After switching to deutetrabenazine therapy, dosage of the drug may be adjusted at weekly intervals.1

Special Populations

Hepatic Impairment

Deutetrabenazine is contraindicated in patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for deutetrabenazine in patients with renal impairment.1 The drug has not been evaluated in such patients.1

Geriatric Patients

The manufacturer states that dosage of deutetrabenazine should be selected with caution in geriatric patients, usually beginning with the lower end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in such patients.1

Hepatic Microsomal Enzyme Considerations

In patients who are known poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates, the maximum recommended total daily dosage of either formulation of deutetrabenazine is 36 mg.1

If deutetrabenazine is used concurrently with strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine), the maximum recommended total daily dosage of either formulation of deutetrabenazine is 36 mg.1

Contraindications

• Patients with Huntington's disease who are suicidal or have untreated or inadequately treated depression.1
• Hepatic impairment.1
• Concomitant therapy with reserpine.1 At least 20 days should elapse between discontinuance of reserpine and initiation of deutetrabenazine.1
• Concomitant therapy with a monoamine oxidase (MAO) inhibitor.1 At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of deutetrabenazine.1
• Concomitant therapy with tetrabenazine or valbenazine.1

Warnings/Precautions

Warnings

Depression and Suicidality in Patients with Huntington's Disease

A boxed warning about the risk of depression and suicidality is included in the prescribing information for deutetrabenazine.1 Patients with Huntington's disease are at an increased risk for depression and suicidal ideation or behavior (suicidality).1 Deutetrabenazine may increase this risk.1 In the principal efficacy study evaluating deutetrabenazine in Huntington's disease, depression and suicidal ideation were reported in 4 and 2% of deutetrabenazine-treated patients, respectively, compared with none of the patients receiving placebo.1 No suicide attempts or completed suicides were reported.1

Clinicians considering the use of deutetrabenazine in patients with Huntington's disease must balance the risks of depression and suicidality with the clinical need for treatment of chorea.1 Patients with Huntington's disease receiving deutetrabenazine should be closely monitored for the emergence or worsening of depression, suicidality, or unusual changes in behavior.1 In addition, patients and their caregivers and families should be informed of the risk of depression and suicidality and instructed to promptly report any behaviors of concern to the treating clinician.1 Patients with Huntington's disease who express suicidal ideation require immediate evaluation.1 If depression or suicidality does not resolve, discontinuance of deutetrabenazine should be considered.1

Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in patients with Huntington's disease.1 Deutetrabenazine is contraindicated in patients with Huntington's disease who are suicidal or have untreated or inadequately treated depression.1

Other Warnings and Precautions

Clinical Worsening and Adverse Effects in Patients with Huntington's Disease

Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time.1 Vesicular monoamine transporter 2 (VMAT2) inhibitors, including deutetrabenazine, may cause worsening in mood, cognition, rigidity, and functional capacity.1

Clinicians should periodically reevaluate the need for deutetrabenazine in individual patients by assessing its effect on chorea and possible adverse effects, including sedation or somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline.1 Distinguishing between drug-induced adverse effects and progression of the underlying disease may be difficult; decreasing the dosage of deutetrabenazine or discontinuing the drug may help the clinician to distinguish between these two possibilities.1 Underlying chorea also may improve over time in some patients, which may decrease the need for deutetrabenazine.1

Prolongation of QT Interval

Deutetrabenazine may prolong the QT interval, but the degree of QT-interval prolongation is not clinically significant when the drug is administered within the recommended dosage range.1 An exposure-response analysis on QT_c prolongation in extensive or intermediate and poor CYP2D6 metabolizers excluded a clinically relevant effect on the QT interval at exposures following single 24-mg and 48-mg doses of deutetrabenazine.1

The risk of torsades de pointes and/or sudden death in association with drugs that prolong the QT_c interval may be increased in certain circumstances, including patients with bradycardia, hypokalemia, or hypomagnesemia; patients receiving other drugs that prolong the QT_c interval; and those with congenital long QT syndrome.1 Therefore, the manufacturer states that deutetrabenazine should be avoided in patients with congenital long QT syndrome and in those with a history of cardiac arrhythmias.1

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported with drugs that reduce dopaminergic transmission.1 Although NMS has not been reported in patients receiving deutetrabenazine, the syndrome has been reported in patients receiving tetrabenazine (a closely related VMAT2 inhibitor).1,4 Clinicians should be aware of the manifestations of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular heart rate, labile blood pressure, tachycardia, diaphoresis, cardiac arrhythmias).1 Other signs may include increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, myoglobinuria, rhabdomyolysis, and acute renal failure.1 Management of NMS should include immediate discontinuance of deutetrabenazine, intensive symptomatic treatment and medical monitoring, and treatment of any serious concomitant medical conditions for which specific treatments are available.1 Recurrence of NMS has been reported; if deutetrabenazine is required following recovery from NMS, the patient should be monitored for signs of recurrence.1

Akathisia, Agitation, and Restlessness

Deutetrabenazine can increase the risk of akathisia, agitation, and restlessness in patients with Huntington's disease or tardive dyskinesia.1 In patients with Huntington's disease, akathisia, agitation, or restlessness was reported in 4% of deutetrabenazine-treated patients compared with 2% of patients receiving placebo.1 In patients with tardive dyskinesia, these adverse effects were reported in 2% of deutetrabenazine-treated patients compared with 1% of patients receiving placebo.1

Patients receiving deutetrabenazine should be monitored for the presence of akathisia as well as for signs and symptoms of restlessness and agitation since they may indicate developing akathisia.1 If a patient develops akathisia, the dosage of deutetrabenazine should be reduced; discontinuance of the drug may be necessary in some patients.1

Parkinsonism

Deutetrabenazine may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia.1 Parkinsonism has also been observed with other VMAT2 inhibitors.1 Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced adverse effect and possible disease progression.1 Drug-induced parkinsonism potentially can cause more functional disability than untreated chorea for some patients with Huntington's disease.1

Postmarketing cases of parkinsonism in patients treated with deutetrabenazine for tardive dyskinesia have been reported.1 Observed signs and symptoms include bradykinesia, gait disturbances, leading to falls in some cases, and the emergence or worsening of tremor.1 Symptoms occurred within the first 2 weeks after starting or increasing the dose of deutetrabenazine and resolved following discontinuation of therapy.1

If parkinsonism develops during deutetrabenazine therapy, the dosage should be reduced; discontinuance of the drug may be necessary in some patients.1

Sedation and Somnolence

Sedation is a common dose-limiting adverse effect of deutetrabenazine.1 In the principal efficacy study in patients with Huntington's disease, somnolence and fatigue were reported in 11 and 9% of patients receiving the drug, respectively.1 Deutetrabenazine may impair cognitive and/or motor skills required to perform tasks such as driving or operating complex machinery.1 These tasks should be avoided until the patient is on a maintenance dose of deutetrabenazine and knows how the drug affects them.1

Hyperprolactinemia

Although prolactin concentrations were not evaluated in the deutetrabenazine clinical development program, elevated prolactin concentrations have been observed with tetrabenazine, a closely related VMAT2 inhibitor.1,4 Peak plasma prolactin concentrations increased four- to fivefold following a single 25-mg tetrabenazine dose in healthy individuals.1,4 Although amenorrhea, galactorrhea, gynecomastia, and impotence have been associated with elevated prolactin concentrations, the clinical importance of such elevations for most patients is unknown.1

If deutetrabenazine therapy is considered for a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.1 In addition, chronic hyperprolactinemia (although not evaluated in the deutetrabenazine or tetrabenazine clinical development programs) has been associated with low estrogen concentrations and an increased risk of osteoporosis.1 If symptomatic hyperprolactinemia is suspected during deutetrabenazine therapy, appropriate laboratory testing should be performed and discontinuance of the drug should be considered.1

Binding to Melanin-containing Tissues

Deutetrabenazine and/or its metabolites bind to melanin-containing tissues, which may result in accumulation and possible toxicity with long-term use.1 The clinical importance of the drug's binding to these tissues is unknown; ophthalmologic monitoring in clinical studies was inadequate to exclude the possibility of injury after long-term drug exposure.1 Although the manufacturer does not make specific recommendations for periodic ophthalmologic monitoring during deutetrabenazine therapy, the manufacturer states that clinicians should be aware of possible long-term ophthalmologic effects in patients receiving the drug.1

Specific Populations

Pregnancy

The manufacturer states that there are no adequate data regarding the developmental risk associated with the use of deutetrabenazine in pregnant women.1 Reproduction studies revealed no clear adverse effect on embryofetal development when deutetrabenazine was administered orally during the period of organogenesis to rats at dosages up to 6 times the maximum recommended human dosage.1 However, when tetrabenazine (a closely related VMAT2 inhibitor) was administered to rats throughout pregnancy and lactation, increased stillbirths, reduced pup survival, and delayed pup maturation were observed.1,4

Lactation

It is not known whether deutetrabenazine or its metabolites are distributed into milk in humans.1 The effects of deutetrabenazine or its metabolites on breast-fed infants or on milk production also are unknown.1 The developmental and health benefits of breast-feeding to the infant should be considered along with the mother's clinical need for deutetrabenazine and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

The manufacturer states that the safety and efficacy of deutetrabenazine in pediatric patients have not been established for the treatment of chorea associated with Huntington's disease or for the treatment of tardive dyskinesia.1

Safety and efficacy of deutetrabenazine have not been established in pediatric patients for the treatment of Tourette syndrome†.1 Efficacy was not demonstrated in 2 randomized controlled trials in patients 6-16 years of age with Tourette syndrome†.1,14,15 One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256);1,14 the other study evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943).1,15 The studies included 274 patients who received at least one dose of deutetrabenazine or placebo.1 The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (TGTSS-TSS).1,14,15 Deutetrabenazine was not substantially different from placebo in reducing tics based on changes from baseline to week 8 on the YGTSS-TTS in either study.1,14,15 Adverse effects were mild to moderate and no new safety signals were identified.1,14,15

Geriatric Use

Clinical studies of deutetrabenazine did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Other clinical experience with deutetrabenazine has not identified differences in responses between geriatric and younger adult patients.1

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer recommends that dosage selection of deutetrabenazine in geriatric patients should be cautious, usually beginning with the lower end of the dosage range.1

Renal Impairment

The pharmacokinetics of deutetrabenazine have not been evaluated to date in patients with renal impairment.1

Hepatic Impairment

Pharmacokinetics of deutetrabenazine have not been evaluated in patients with hepatic impairment; however, in a clinical study of tetrabenazine (a closely related VMAT2 inhibitor) in patients with hepatic impairment, substantially increased exposure of tetrabenazine and its active metabolites was observed.1,4 The clinical importance of this increased exposure of tetrabenazine and its metabolites is unknown.1,4 Because of the potential for serious adverse reactions, the manufacturer states that deutetrabenazine is contraindicated in patients with hepatic impairment.1

Poor CYP2D6 Metabolizers

Increased exposure of deutetrabenazine's active metabolites (deuterated α-dihydrotetrabenazine [deuterated α-HTBZ] and deuterated β-dihydrotetrabenazine [deuterated β-HTBZ]) is expected in patients who are poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 substrates; in such patients the maximum recommended daily dosage of both formulations of deutetrabenazine is 36 mg.1

Common Adverse Effects

Adverse effects occurring in patients with Huntington's disease with an incidence >8% and more than placebo include: somnolence, diarrhea, dry mouth, and fatigue.1

Adverse effects occurring in patients with tardive dyskinesia with an incidence of 4% and more than placebo include: nasopharyngitis and insomnia.1

Drug interaction studies evaluating the effect of deutetrabenazine or its active metabolites (deuterated α-dihydrotetrabenazine [deuterated α-HTBZ] and deuterated β-dihydrotetrabenazine [deuterated β-HTBZ]) on cytochrome P-450 (CYP) isoenzymes or P-glycoprotein (P-gp) have not been conducted to date.1 In vitro studies indicate that other metabolites of deutetrabenazine (M1 and M4) are not expected to cause clinically important drug interactions.1

Tetrabenazine, a closely related VMAT2 inhibitor, and its active metabolites (α-HTBZ and β-HTBZ) do not substantially inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor do they substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro.1,4 Neither tetrabenazine nor its active metabolites are likely to be substrates or inhibitors of P-gp at clinically relevant concentrations.1,4

Deutetrabenazine's active metabolites (deuterated α-HTBZ and deuterated β-HTBZ) are substrates of CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of deutetrabenazine with strong inhibitors of CYP2D6 (e.g., bupropion, fluoxetine, paroxetine, quinidine) can result in decreased clearance and substantially increased exposure of deutetrabenazine's active metabolites, deuterated α-HTBZ and deuterated β-HTBZ.1 When the strong CYP2D6 inhibitor paroxetine (20 mg daily for 8 days) was administered concomitantly with deutetrabenazine (single 22.5-mg dose) in healthy individuals, peak plasma concentrations of deuterated α-HTBZ and deuterated β-HTBZ increased 1.2- and 2.2-fold, and AUC increased 1.9- and 6.5-fold, respectively; total combined AUC of deuterated α-HTBZ and deuterated β-HTBZ increased approximately threefold.1

Dosage reduction of deutetrabenazine may be required when the drug is used concomitantly with strong CYP2D6 inhibitors.1 During concurrent use with strong CYP2D6 inhibitors, the maximum recommended daily dosage of deutetrabenazine is 36 mg.1 The effect of moderate or weak CYP2D6 inhibitors (e.g., amiodarone, duloxetine, sertraline, terbinafine) on the pharmacokinetics of deutetrabenazine and its metabolites has not been evaluated.1

Alcohol and Other CNS Depressants

Additive CNS depressant effects (e.g., worsening of sedation and somnolence) may occur when deutetrabenazine is used concomitantly with alcohol or other CNS depressants.1

Antipsychotic Agents and Other Dopamine Antagonists

The manufacturer states that the risk of certain adverse effects associated with deutetrabenazine (e.g., parkinsonism, akathisia, neuroleptic malignant syndrome [NMS]) may be increased with concomitant use of deutetrabenazine and dopamine antagonists, including antipsychotic agents.1

Monoamine Oxidase Inhibitors

Because of the potential for antagonistic effects and increased toxicity, concomitant use of deutetrabenazine with a monoamine oxidase (MAO) inhibitor is contraindicated.1 At least 14 days should elapse between discontinuance of MAO inhibitor therapy and initiation of deutetrabenazine.1

Reserpine

Concomitant use of deutetrabenazine and reserpine (an irreversible VMAT2 inhibitor with a long duration of effect) may result in deutetrabenazine overdosage and major serotonin and norepinephrine depletion in the CNS.1 Concomitant use of deutetrabenazine with reserpine is therefore contraindicated.1 Clinicians should wait for signs of chorea or dyskinesia to reemerge after discontinuing reserpine before initiating deutetrabenazine therapy.1 At least 20 days should elapse after reserpine discontinuance prior to initiating deutetrabenazine therapy.1

Tetrabenazine and Valbenazine

Concomitant use of deutetrabenazine and the related VMAT2 inhibitors tetrabenazine and valbenazine is contraindicated.1,13 In patients switching from tetrabenazine therapy, deutetrabenazine may be initiated the following day after discontinuance of tetrabenazine.1

Description

Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.1,5,8 The drug is a deuterium-substituted analog of tetrabenazine; deuterium, a nontoxic, naturally occurring isotope of hydrogen with a higher relative mass, forms a stronger bond with carbon molecules that hinders metabolism by cytochrome P-450 isoenzymes.2,5,8 Deuterium substitution results in deutetrabenazine active metabolites that have a longer elimination half-life, higher AUC, and lower peak plasma concentrations than those achieved with an equivalent dose of tetrabenazine.5,8

Patients with Huntington's disease appear to exhibit oversensitivity to dopamine stimulation, resulting in choreic movements.11 Although the exact mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington's disease has not been fully elucidated, the drug, like tetrabenazine, selectively and reversibly inhibits VMAT2-mediated uptake of monoamine neurotransmitters (e.g., dopamine, norepinephrine, serotonin, histamine) into presynaptic vesicles in the CNS; monoamines not transported into synaptic vesicles are degraded by monoamine oxidase (MAO), resulting in depleted monoamine stores in nerve terminals.1,4,5,8,59 Like tetrabenazine, deutetrabenazine and its active metabolites preferentially affect dopaminergic neurotransmission in the CNS over adrenergic, serotonergic, and histaminergic neurotransmission at clinically relevant plasma concentrations.5,8,11

Following oral administration, deutetrabenazine is rapidly and extensively metabolized, mainly by carbonyl reductase, to the active metabolites deuterated α-dihydrotetrabenazine (deuterated α-HTBZ) and deuterated β-dihydrotetrabenazine (deuterated β-HTBZ); plasma concentrations of the parent drug are generally undetectable.1,5 Peak plasma concentrations of deuterated α-HTBZ and deuterated β-HTBZ occur within 3-4 hours following oral administration of the drug; sustained concentration plateaus for several hours are achieved with the extended-release formulation.1 Administration with food increases peak plasma concentrations of deuterated α-HTBZ and deuterated β-HTBZ by approximately 50% with the immediate-release formulation, but has no effect on the AUC.1 The drug distributes rapidly into the CNS, with highest and lowest concentrations occurring in the striatum and cortex, respectively.1 Deuterated α-HTBZ and deuterated β-HTBZ are metabolized primarily by CYP2D6 with minor contributions by CYP isoenzymes 1A2 and 3A4/5 to form several minor metabolites.1 Approximately 75-86 and 8-11% of a deutetrabenazine dose is eliminated in urine and feces, respectively, with <10% eliminated as unchanged deuterated α-HTBZ and deuterated β-HTBZ.1 The half-life of deuterated α-HTBZ and deuterated β-HTBZ combined is approximately 9-10 hours.1

Advice to Patients

• Advise patients and their caregivers to read the manufacturer's patient information (medication guide).1
• Inform patients that immediate-release deutetrabenazine should be taken with food and that immediate- and extended-release tablets should be swallowed whole and not chewed, crushed, or broken.1
• Risk of depression, worsening of depression, and suicidality in patients with Huntington's disease.1 Advise patients and caregivers to immediately notify clinicians of emergence of suicidality, emergence or worsening of depression, or unusual changes in behavior in such patients.1
• Risk of corrected QT (QT_c)-interval prolongation.1 Stress importance of patients immediately notifying clinicians if they feel faint, lose consciousness, or experience heart palpitations.1 Stress importance of patients advising clinicians that they are taking deutetrabenazine before any new drug is taken.1
• Risk of parkinson-like symptoms.1 Advise patients to inform clinicians if they experience slight shaking, body stiffness, trouble moving, trouble keeping their balance, or falls.1
• Risk of sedation and somnolence.1 Advise patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination such as operating a motor vehicle or other dangerous machinery until they are receiving a maintenance dosage of deutetrabenazine and the effects of the drug on the individual are known.1
• Inform patients that concomitant use of alcohol or other CNS depressants may worsen the sedative effects of deutetrabenazine.1
• Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., depression or other psychiatric disorders, liver disease, arrhythmias).1
• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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