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Deutetrabenazine (Austedo) - Uses, Dose, MOA, Side effects

Tetrabenazine has an isomer called deutetrabenazine (Austedo). It inhibits vesicular monoamine transporter 2 specifically (VMAT-2). It is used to treat people with tardive dyskinesia and chorea linked to Huntington's disease.

Deutetrabenazine (Austedo) Uses:

Chorea associated with Huntington disease:
- Used for treating chorea associated with Huntington's disease.
Tardive dyskinesia:
- Used for treating tardive dyskinesia in adults.

Deutetrabenazine (Austedo) Dose in Adults

Note: Dose should be adjusted for every individual.

Deutetrabenazine (Austedo) Dose in the treatment of Chorea associated with Huntington disease:

Oral: Start with 6 mg once daily, and then raise the dose by 6 mg every week, up to a maximum of 48 mg per day, depending on response and tolerability.
The dose should be given in two divided doses if total daily dose ≥12 mg;

Deutetrabenazine (Austedo) Dose in the treatment of Tardive dyskinesia:

Oral: Start with 6 mg once day; the amount may be increased weekly in increments of 6 mg every 24 hours, depending on response and tolerability;
The dose should be given in two divided doses if total daily dose ≥12 mg;
The maximum recommended dose: 48 mg per 24 hours.

Conversion from tetrabenazine:

Discontinue tetrabenazine and start Deutetrabenazine the following day by using the following conversion.
The dose may be adjusted weekly depending upon response and tolerability.
- Tetrabenazine 12.5 mg per 24 hours = deutetrabenazine 6 mg once a day
- Tetrabenazine 25 mg per 24 hours= deutetrabenazine 6 mg twice a day
- Tetrabenazine 37.5 mg per 24 hours = deutetrabenazine 9 mg twice a day
- Tetrabenazine 50 mg per 24 hours = deutetrabenazine 12 mg twice a day
- Tetrabenazine 62.5 mg per 24 hours = deutetrabenazine 15 mg twice a day
- Tetrabenazine 75 mg per 24 hours = deutetrabenazine 18 mg twice a day
- Tetrabenazine 87.5 mg per 24 hours= deutetrabenazine 21 mg twice a day
- Tetrabenazine 100 mg per 24 hours = deutetrabenazine 24 mg twice a day
Concomitant strong CYP2D6 inhibitors (eg, quinidine, paroxetine, fluoxetine, bupropion) and poor CYP2D6 metabolizers:
- Oral: Maximum: 18 mg per dose or 36 mg per 24 hours.
The reinitiation of therapy:
- If dosing is interrupted for more than a week, must re-initiate it when restarting.

Use in Children:

Not indicated.

Pregnancy Risk Category: N

Studies on animal reproduction have not shown any adverse effects.
Although not observed in preclinical studies, serum prolactin levels may rise with deutetrabenazine, which can cause amenorrhea or galactorrhea.

Use while breastfeeding

It is not known if it is present in breast milk.
According to the manufacturer, breastfeeding should be continued during therapy if there is a risk to infant exposure.
Also, consider the benefits to the mother of continuing breastfeeding.

Dose in Kidney Disease:

No dosage adjustments on labeling

Dose in Liver disease:

Contraindicated in liver disease.

Side Effects of Deutetrabenazine (Austedo):

Central nervous system:
- Drowsiness
- Fatigue
- Insomnia
- Anxiety
- Depression
- Agitation
- Akathisia
- Restlessness
- Suicidal ideation

Gastrointestinal:
- Diarrhea
- Xerostomia
- Constipation
Genitourinary:
- Urinary tract infection
Hematologic & oncologic:
- Bruise
Respiratory:
- Nasopharyngitis

Frequency of side effects not defined:

Central nervous system:
- Sedation

Contraindications to Deutetrabenazine (Austedo):

Hepatic impairment
Huntington disease patients with suicidal tendencies or poorly treated depression
Concurrent administration of tetrabenazine and valbenazine
Concurrent administration within 2 weeks after discontinuing monoamine-oxidase inhibitors.
Concurrent use within 20 days after stopping reserpine.

Warnings and precautions

Akathisia
- Akathisia can occur; patients should be closely monitored for signs and symptoms such as restlessness or agitation.
- You may need to reduce or stop taking the medication.
Depression in the CNS:
- CNS depression can cause impairments in mental or physical abilities. Patients should be careful when operating machinery or driving.
Suicidal ideation and Depression: [US Boxed Warn]
- Patients with Huntington's disease may be more likely to experience depression and consider or act suicidally. Patients need to be watched carefully.
- Patients with a history or attempted suicide or other mental disorders should be cautious.
- Patients with Huntington disease, who are suicidal or have not been treated for depression, should not use this medication.
- If depression/suicidal thoughts persist, discontinue use.
Hyperprolactinemia
- Hyperprolactinemia may occur in some patients with carcinoma of breast or other prolactin dependent tumors.
Neuroleptic malignant Syndrome (NMS).
- NMS may occur; patients should be closely monitored for changes in mental status, fever, rigidity of the muscles, and/or signs of autonomic instability.
- It is best to stop using confirmed NMS.
- NMS can recur if treatment is stopped. Close monitoring should be performed.
Ophthalmic effects
- It has been shown to be a binding agent in animal studies.
- However, prolonged use can lead to toxicity and accumulation as well as long-term ophthalmic effects.
Parkinsonism
- Huntington's patients may experience parkinsonism symptoms, i.e. bradykinesia hypertonia rigidity.
- This can make it difficult to distinguish the progress of the underlying condition.
- It is possible to reduce or stop therapy.
Extension of QTc:
- Patients with weak CYP2D6 metabolism or when the medication is given along with a potent CYP2D6 inhibitor may experience QTc prolongation.
- This drug should not be used by anyone who have congenital QT prolongation or a history of cardiac arrhythmias.
- Patients who require a deutetrabenazine dosage above 24 mg/24 hours and are taking concomitantly drugs known to prolong QT should have their QT interval assessed prior to and after increasing deutetrabenazine or increasing the dosage of the drug known for QT prolongation.

Deutetrabenazine: Drug Interaction

Note: Drug Interaction Categories:

Risk Factor C: Monitor When Using Combination
Risk Factor D: Consider Treatment Modification
Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Ajmaline	High risk of Inhibitors causing an increase in serum CYP2D6 Substrates concentrations
Alcohol (Ethyl).	Alcohol (Ethyl), which has a CNS depressant effect, may be enhanced by CNS-depressants.
Alizapride	CNS Depressants can have a stronger depressant effect on the CNS.
Antipsychotic Agents	Deutetrabenazine may increase the toxic/adverse effects of Antipsychotic Agents. This includes parkinsonism, akathisia and neuroleptic malignant Syndrome.
Brexanolone	CNS depressants may increase the CNS depressant effects of Brexanolone.
Brimonidine	The CNS can be more significantly depressed by CNS Depressants.
Bromopride	Deutetrabenazine may increase the toxic/adverse effects of Antipsychotic Agents. This includes parkinsonism, akathisia and neuroleptic malignant Syndrome.
Cannabidiol	The CNS can be more significantly depressed by CNS Depressants.
Cannabis	The CNS can be more significantly depressed by CNS Depressants.
Chlorphenesin Carbamate	CNS Depressants can have a greater adverse/toxic impact.
CloBAZam	The serum concentrations of CYP2D6 Substrates could be higher (High risk when taking Inhibitors).
CNS Depressants	CNS Depressants can have a stronger depressant effect on the CNS
Cobicistat	High risk of Inhibitors causing an increase in serum CYP2D6 Substrates concentrations
Moderate CYP2D6 inhibitors	High risk of Inhibitors causing a decrease in metabolism of CYP2D6 substrates
Darunavir	High risk of Inhibitors may cause an increase in serum concentrations of CYP2D6 Substrates.
Dimethindene (Topical).	CNS Depressants can have a stronger depressant effect on the CNS.
Doxylamine	CNS Depressants can have a stronger CNS depressant effect. Management: Diclegis (doxylamine/pyridoxine), which is intended for pregnancy, has been specifically stated that it is not recommended to use with other CNS depressionants.
Dronabinol	The CNS can be more significantly depressed by CNS Depressants.
Esketamine	The CNS can be more significantly depressed by CNS Depressants.
Haloperidol	The QTc-prolonging effects of haloperidol may be amplified by QT-prolonging substances (Indeterminate risk - Caution).
Hydroxyzine	Could be to blame for CNS depressants' increased CNS depressive effects.
Imatinib	High risk of Inhibitors may cause an increase in serum concentrations of CYP2D6 Substrates.
Kava Kava	CNS Depressants can have a greater adverse/toxic impact.
Lofexidine	CNS Depressants can have a stronger depressant effect on the CNS. Management: The drug interactions monographs for each drug listed in this monograph provide more information about the drugs.
Lumefantrine	High risk of Inhibitors may cause an increase in serum concentrations of CYP2D6 Substrates.
Magnesium Sulfate	The CNS can be more significantly depressed by CNS Depressants.
Metoclopramide	Greater negative/toxic side effects are possible with methoclopramide. Parkinsonism, neuroleptic malignant syndrome, and akathisia may become more likely.
MetyroSINE	CNS depressants may increase the sedative effects of MetyroSINE.
Minocycline	CNS Depressants can have a stronger depressant effect on the CNS.
Mirtazapine	CNS depressants may increase the CNS depressant effects of Mirtazapine.
Nabilone	CNS Depressants can have a stronger depressant effect on the CNS.
Panobinostat	High risk of Inhibitors may cause an increase in serum concentrations of CYP2D6 Substrates.
Peginterferon Alfa-2b	It is possible to decrease the serum concentration of CYP2D6 substrates (High Risk with Inhibitors). Prginterferon Alfa-2b may increase the serum concentration of CYP2D6 substrates (High Risk with Inhibitors).
Perhexiline	Perhexiline's serum concentration may increase due to CYP2D6 Substrates (High risk with inhibitors). Perhexiline can cause an increase of CYP2D6 Substrates in the serum (High risk with inhibitors).
Piribedil	CNS depressants may increase the CNS depressant effects of Piribedil.
Pramipexole	CNS depressants may increase Pramipexole's sedative effects.
Agents that prolong QT (Highest risk)	The effects of QTc-prolonging medications can be amplified by QT-prolonging agents (Highest risk) (Highest risk). Management: It's critical to watch for QTc interval prolongation or ventricular arrhythmias when both drugs are used at the same time. Patients may be more at risk if their risk factors for QTc prolongation are more severe.
QuiNINE	High risk of Inhibitors causing an increase in serum CYP2D6 Substrates concentrations
ROPINIRole	CNS depressants may increase the sedative effects of ROPINIRole.
Rotigotine	CNS depressants may increase the sedative effects of Rotigotine.
Rufinamide	CNS Depressants can have a more harmful/toxic effect. Particularly, dizziness and sleepiness may be increased.
Selective Serotonin Reuptake inhibitors	Selective Serotonin Reuptake inhibitors may have a greater toxic/adverse effect. Particularly, psychomotor impairment could be increased.
Tetrahydrocannabinol	CNS The CNS can be more significantly depressed by depressants.
Tetrahydrocannabinol, and Cannabidiol	CNS The CNS can be more significantly depressed by depressants.
Trimeprazine	CNS The CNS can be more significantly depressed by depressants.
Risk Factor D (Consider therapy modifications)
Abiraterone Acetate	There is a chance that the serum level of CYP2D6 Substrates (High Risk with Inhibitors) will increase. Avoid using abiraterone in combination with CYP2D6 substrates that have a limited therapeutic index. For any symptoms of hazardous consequences, concurrent use should be strictly watched.
Asunaprevir	It is possible for the serum concentration of CYP2D6 Substrates (High Risk with Inhibitors), to be elevated.
Blonanserin	CNS Depressants may increase the CNS depressant effects of Blonanserin.
Buprenorphine	The CNS Depressants may increase the CNS depressant effects of buprenorphine. Management: Patients at high risk for buprenorphine self-injection/overuse should consider reducing their doses. Adults should receive 5 mg/hr of buprenorphine patches (Butrans) when combined with other CNS depression drugs.
Chlormethiazole	CNS Depressants may increase the CNS depressant effect. Monitoring: For excessive CNS depression, it is important to monitor closely. If you must use a combination of chlormethiazole and other medications, it is best to reduce the dose.
Strong CYP2D6 inhibitors	Deutetrabenazine serum concentrations can be raised. Management: The maximum recommended daily dose of deutetrabenazine is 36 mg. The highest single dose shouldn't go over 18, and using a potent CYP2D6 inhibitor concurrently shouldn't go over 18mg.
Dacomitinib	There is a chance that the serum level of CYP2D6 Substrates (High Risk with Inhibitors) will increase. Management: Steer clear of utilising dacomitinib and CYP2D6 substrates simultaneously.
Droperidol	CNS Depressants may increase the CNS depressant effect. Management: Droperidol and other CNS agents (eg opioids, barbiturates), should be reduced with concomitant usage. Separate drug interaction monographs provide details on exceptions to the monograph.
Flunitrazepam	CNS Depressants may increase the CNS depressant effects of Flunitrazepam.
HYDROcodone	CNS Depressants may increase the CNS depressant effects of HYDROcodone. Management: Avoid concomitant use hydrocodone, benzodiazepines, or any other CNS depressants whenever possible. If other treatment options are not available, do not combine these drugs. Combining drugs should limit the dosage and duration.
Methotrimeprazine	Methotrimeprazine's CNS depressant effects may be amplified by taking CNS Depressants. Management: Reduce the adult dose of CNS-depressant agents by half and start concomitant methotrimeprazine treatment. After determining the clinically effective dose, you should adjust your CNS depressant dosage.
Opioid Agonists	CNS Depressants may increase the CNS depressant effects of Opioid Agonists. Management: Avoid the use of opioid agonists, benzodiazepines, or any other CNS depressants together whenever possible. Combinations of these drugs should be avoided if other treatment options are not available. If you use these drugs together, limit the duration and dosages.
OxyCODONE	CNS Depressants may increase OxyCODONE's CNS depressant effects. Management: Avoid the use of oxycodone, benzodiazepines, or any other CNS depressants together. Combinations of these drugs should be avoided if other treatment options are not available. If you use these drugs together, limit the duration and dosages.
Perampanel	CNS Depressants may increase the CNS depressant effect. Management: Patients taking perampanel along with any other drugs that have CNS depressant properties should avoid complex and high-risk behaviors (especially driving, which requires coordination and alertness).
Sodium Oxybate	CNS Depressants may increase the CNS depressant effect. Management: There are alternatives to combination therapy. When combined use is necessary, it is important to reduce the doses of any one or more drugs. Use of sodium oxybate in combination with alcohol or other sedative-hypnotics is not recommended.
Suvorexant	CNS Depressants may increase the CNS depressant effect. Management: This may require a reduction of suvorexant or any other CNS depressant. Suvorexant should not be used in combination with alcohol or other drugs to treat insomnia.
Tapentadol	CNS Depressants may increase the CNS depressant effect. Management: Avoid concomitant use with benzodiazepines, tapentadol or any other CNS depressants whenever possible. Combinations of these agents should be avoided if other treatment options are not available. If you use these drugs together, limit the duration and dosages.
Zolpidem	CNS Depressants may intensify the effects of CNS Depressants. Management: Men receiving other CNS depressants may choose to lower their daily dose of sublingual Zolpidem, trade name Intermezzo, to 1.75mg. For women, this dose reduction is not advised. Avoid drinking alcohol and CNS depressants before bed.
Risk Factor X (Avoid Combination)
Azelastine - Nasal	CNS Depressants may increase the CNS depressant effect.
Bromperidol	CNS Depressants may increase the CNS depressant effect.
Monoamine Oxidase inhibitors	CNS Depressants may increase the CNS depressant effect.
Orphenadrine	CNS Depressants may increase the CNS depressant effect.
Oxomemazine	CNS Depressants may increase the CNS depressant effect.
Paraldehyde	CNS Depressants may increase the CNS depressant effect.
Reserpine	CNS Depressants may increase the CNS depressant effect.
Tetrabenazine	CNS Depressants may increase the CNS depressant effect.
Thalidomide	CNS Depressants may increase the CNS depressant effect.
Valbenazine	CNS Depressants may increase the CNS depressant effect.

Monitoring parameters:

Serum electrolytes
ECG (Monitor QT interval before and after the dose is increased to >24 mg per 24 hours in patients with increased risk for QTc prolongation)
Signs & symptoms of depression or suicidal ideation
Signs and/or symptoms of the neuroleptic malignant syndrome, restlessness, and agitation.

How to administer Deutetrabenazine (Austedo)?

Oral: Give with a meal. The tablet should be swallowed as a whole. Do not chew, crush, or break.

Mechanism of action of Deutetrabenazine (Austedo):

It is unknown exactly how deutetrabenazine works.
The two major metabolites of deutetrabenazine are alpha-dihydrotetrabenazine (HTBZ) and beta-HTBZ.
They are believed to cause the reversible inhibition (VMAT-2 in humans) of the human vesicular monoaminetransporter type 2 (HTBZ).
This decreases the uptake of monoamines into synaptic vessels and depletes monoamine stores.

Absorption:

80% is absorbed

Distribution:

~500 L for alpha-HTBZ & 730 L for beta-HTBZ

Protein binding:

60% to 68% protein binding for alpha-HTBZ & 59% to 63% protein binding for beta-HTB

Metabolism:

Undergoes an extensive metabolism in liver 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

Half-life elimination: