Deutetrabenazine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Austedo: 6 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Austedo: 9 mg [contains fd&c blue #2 aluminum lake]

Austedo: 12 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #6 aluminum lake]

Pharmacology

Mechanism of Action

The precise mechanism by which deutetrabenazine exerts its effects is unknown. Its major metabolites (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) act as reversible inhibitors of the human vesicular monoamine transporter type 2 (VMAT-2) and thereby decrease the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and deplete the monoamine stores.

Pharmacokinetics/Pharmacodynamics

Absorption

80%

Distribution

alpha-HTBZ: ~500 L; beta-HTBZ: 730 L

Metabolism

Extensive hepatic metabolism via carbonyl reductase to alpha-dihydrotetrabenazine (HTBZ) and beta-HTBZ (active major metabolites), which are subsequently metabolized via CYP2D6 (minor contributions of CYP1A2 and CYP3A4/5) to form several minor metabolites.

Excretion

Urine (75% to 86%; <10% as active major metabolites); feces (8% to 11%)

Time to Peak

Plasma: 3 to 4 hours

Half-Life Elimination

9 to 10 hours

Protein Binding

alpha-HTBZ: 60% to 68%; beta-HTBZ: 59% to 63%

Use in Specific Populations

Special Populations Note

Poor CYP2D6 metabolizers: It is likely that the exposure to alpha-HTBZ and beta-HTBZ would be increased ~3-fold.

Use: Labeled Indications

Chorea associated with Huntington disease: Treatment of chorea associated with Huntington disease.

Tardive dyskinesia: Treatment of tardive dyskinesia in adults.

Contraindications

Hepatic impairment; patients with Huntington disease who are suicidal or have untreated or inadequately treated depression; coadministration with tetrabenazine or valbenazine; coadministration with or within 14 days of discontinuing monoamine oxidase inhibitors (MAOIs); coadministration with or within 20 days of discontinuing reserpine.

Dosage and Administration

Dosing: Adult

Note: Dose should be individualized.

Chorea associated with Huntington disease: Oral: Initial: 6 mg once daily; may increase dose weekly based on response and tolerability in increments of 6 mg/day; administer in two divided doses if total daily dose ≥12 mg; maximum recommended dose: 48 mg/day.

Tardive dyskinesia: Oral: Initial: 6 mg twice daily; may increase dose weekly based on response and tolerability in increments of 6 mg/day. Administer in two divided doses if total daily dose ≥12 mg; maximum recommended dose: 48 mg/day.

Conversion from tetrabenazine: Discontinue tetrabenazine and initiate deutetrabenazine the following day, using the following conversion. May adjust dose weekly based on response and tolerability.

Tetrabenazine 12.5 mg/day = deutetrabenazine 6 mg once daily

Tetrabenazine 25 mg/day = deutetrabenazine 6 mg twice daily

Tetrabenazine 37.5 mg/day = deutetrabenazine 9 mg twice daily

Tetrabenazine 50 mg/day = deutetrabenazine 12 mg twice daily

Tetrabenazine 62.5 mg/day = deutetrabenazine 15 mg twice daily

Tetrabenazine 75 mg/day = deutetrabenazine 18 mg twice daily

Tetrabenazine 87.5 mg/day = deutetrabenazine 21 mg twice daily

Tetrabenazine 100 mg/day = deutetrabenazine 24 mg twice daily

Concomitant strong CYP2D6 inhibitors (eg, quinidine, paroxetine, fluoxetine, bupropion) and poor CYP2D6 metabolizers: Oral: Maximum: 18 mg/dose or 36 mg/day.

Reinitiation of therapy: If dosing is interrupted for >7 days, retitrate when resuming.

Dosing: Geriatric

Refer to adult dosing; use with caution.

Dosing: Adjustment for Toxicity

For toxicity/adverse reaction, including agitation, akathisia, anxiety, cognitive decline, depression, restlessness, parkinsonism, sedation (intolerable), somnolence, suicidality: Decrease or discontinue deutetrabenazine.

Administration

Oral: Administer with food. Swallow tablets whole and do not chew, crush, or break.

Dietary Considerations

Administer with food.

Storage

Store at 25ºC (77ºF); excursions permitted between 15°C and 30ºC (59°F and 86ºF). Protect from light and moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Antipsychotic Agents: Deutetrabenazine may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Deutetrabenazine. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metoclopramide: Deutetrabenazine may enhance the adverse/toxic effect of Metoclopramide. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Deutetrabenazine. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Reserpine: May enhance the adverse/toxic effect of Deutetrabenazine. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrabenazine: Deutetrabenazine may enhance the adverse/toxic effect of Tetrabenazine. Avoid combination

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Valbenazine: Deutetrabenazine may enhance the adverse/toxic effect of Valbenazine. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%: Central nervous system: Drowsiness (11%)

1% to 10%:

Central nervous system: Fatigue (9%), insomnia (4% to 7%), anxiety (4%), depression (≤4%), agitation (≤4%), akathisia (≤4%), restlessness (≤4%), suicidal ideation (2%)

Gastrointestinal: Diarrhea (9%), xerostomia (9%), constipation (4%)

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Bruise (4%)

Respiratory: Nasopharyngitis (4%)

Frequency not defined:

Central nervous system: Sedation

Warnings/Precautions

Concerns related to adverse effects:

• Akathisia: Use has been associated with akathisia; monitor for signs and symptoms of restlessness and agitation. Dosage reduction or discontinuation may be necessary.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Depression/suicidal ideation: [US Boxed Warning]: Use can increase risk for depression and suicidal thoughts and behavior in patients with Huntington disease; closely monitor for emergence or worsening of depression, suicidality, or unusual behavior changes. Use caution in patients with a history of depression or prior suicide attempts or ideation. Use is contraindicated in patients with Huntington disease who are suicidal or have untreated or inadequately treated depression. Consider discontinuing use if depression/suicidal ideation does not resolve.
• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.
• Neuroleptic malignant syndrome: Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability. Discontinue with confirmed NMS; may recur with reintroduction of treatment; monitor carefully.
• Ophthalmic effects: Binds to melanin-containing tissues in animal studies; may result in accumulation and toxicity with extended use and long-term ophthalmic effects. Clinical relevance and monitoring recommendations are unknown.
• Parkinsonism: Parkinsonism, including bradykinesia and gait disturbances (leading to falls or the emergence/worsening of tremor in some cases), has been reported in patients with Huntington disease. Most cases occurred within 2 weeks of initiation or dose escalation and resolved following discontinuation. Development of these symptoms may be difficult to differentiate from progression of the underlying disease; dose reduction or discontinuation of therapy may be necessary.
• QTc prolongation: QTc prolongation may occur in patients who are CYP2D6 poor metabolizers or are coadministered a strong CYP2D6 inhibitor. Avoid use in patients with congenital QT prolongation or a history of cardiac arrhythmias. For patients requiring a deutetrabenazine dose above 24 mg/day and taking concomitant drugs known to cause QT prolongation, assess the QT interval before and after increasing the deutetrabenazine dose or before and after increasing the dose of the drug known to cause QT prolongation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2D6 poor metabolizers: CYP2D6 poor metabolizers have increased levels of primary drug metabolites; maximum dosage should not exceed 36 mg/day in poor metabolizers.
• Huntington disease: May worsen mood, cognition, rigidity, and functional capacity in patients with Huntington disease, which can be difficult to differentiate from progression of the underlying disease. Underlying chorea may improve over time in some patients, thereby decreasing the need for therapy. Reevaluate patients' need for treatment by periodically assessing the effect on chorea and possible adverse effects. Dose reduction or discontinuation of therapy may be necessary.

Monitoring Parameters

Electrolytes; EKG (QT interval before and after dose is increased to >24 mg/day in patients with increased risk for QTc prolongation); signs/symptoms of depression or suicidal ideation; signs and/or symptoms of NMS, restlessness and agitation.

Pregnancy

Pregnancy Considerations

Adverse events were not observed in available animal reproduction studies. Although not evaluated in preclinical studies, deutetrabenazine may increase serum prolactin concentrations which may lead to amenorrhea or impotence.

Patient Education

What is this drug used for?

• It is used to treat disabling involuntary movements in Huntington's chorea.
• It is used to treat tardive dyskinesia.

Frequently reported side effects of this drug

• Fatigue
• Loss of strength and energy
• Diarrhea
• Dry mouth
• Trouble sleeping
• Nose irritation
• Throat irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Abnormal movements
• Change in balance
• Tremors
• Stiff muscles
• Restlessness
• Confusion
• Agitation
• Vision changes
• Fast heartbeat
• Abnormal heartbeat
• Dizziness
• Passing out
• Nipple discharge
• Enlarged breasts
• Sexual dysfunction
• Menstrual changes
• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.