Deutetrabenazine

Introduction Overview

Generic Name

deutetrabenazine

Brand Name

Austedo, Austedo XR

Dosage Form

Oral tablets and extended-release oral tablets

Drug Class

VMAT2 inhibitors (vesicular monoamine transporter 2 inhibitor)

Pharmacokinetics

Absorption:
Deutetrabenazine is rapidly absorbed after oral administration. The immediate-release Austedo tablets are taken twice daily with food to optimize absorption, whereas Austedo XR extended-release tablets are administered once daily and can be taken with or without food. The extended-release formulation provides gradual systemic availability, reducing peak plasma fluctuations. The bioavailability of deutetrabenazine is influenced by food intake, with administration alongside food recommended for immediate-release tablets to enhance absorption and minimize gastrointestinal side effects. Peak plasma concentrations for immediate-release tablets occur approximately 3 hours post-dose, while the extended-release formulation achieves peak plasma concentrations over an extended timeframe, reflecting its sustained-release properties.

Distribution:
Deutetrabenazine and its active metabolites (notably alpha- and beta-dihydrotetrabenazine isotopes) exhibit moderate plasma protein binding, primarily to albumin. The volume of distribution indicates moderate tissue penetration, with the capacity to cross the blood-brain barrier to reach CNS neuronal targets. As a VMAT2 inhibitor, effective CNS distribution is critical for clinical efficacy in managing chorea and tardive dyskinesia. Deutetrabenazine undergoes substantial first-pass metabolism which shapes its distribution profile. The active metabolites have CNS penetrance sufficient to inhibit VMAT2 proteins on synaptic vesicles within dopaminergic neurons.

Metabolism:
Deutetrabenazine is extensively metabolized predominantly by hepatic enzymes, chiefly CYP2D6, to active deuterated dihydrotetrabenazine metabolites responsible for therapeutic effects. The deuteration reduces metabolic clearance compared to tetrabenazine, leading to increased half-life and more stable plasma concentrations. This metabolic pathway is critical as CYP2D6 polymorphisms significantly influence drug exposure and require dose adjustments in poor CYP2D6 metabolizers or when co-administered with CYP2D6 inhibitors. Metabolism involves O-demethylation and carbonyl reduction steps forming active alpha- and beta-dihydrotetrabenazine derivatives with VMAT2 inhibitory activity.

Elimination:
The elimination half-life of deutetrabenazine active metabolites ranges approximately 9 to 10 hours for immediate-release and extended-release formulations, supporting twice-daily and once-daily dosing regimens respectively. Excretion primarily occurs through renal (urinary) routes as metabolites, with minor fecal elimination. Dose adjustments are recommended in hepatic impairment due to metabolism dependence, while no significant data indicate the need for adjustment in renal impairment. Steady-state is generally reached within one week. The drug and metabolites are eliminated efficiently, and plasma levels correlate with observed clinical effects on chorea suppression and tardive dyskinesia symptom improvement.

Dosage Forms

Available Dosage Forms:
- Austedo immediate-release tablets: 6 mg, 9 mg, and 12 mg
- Austedo XR extended-release tablets: 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg

Dosages for Adults and Adolescents:
- Austedo (immediate release): Initial dose typically 6 mg twice daily (total 12 mg/day). Dose can be increased weekly by increments of 6 mg/day based on symptom control and tolerability, with a maximum dose of 48 mg/day divided into two doses.
- Austedo XR (extended release): Initial dose 12 mg once daily. Dose titrated weekly by increments of 6 mg/day up to 48 mg/day based on clinical response and adverse effects.
- When switching between formulations, the total daily dose remains the same, adjusting administration frequency.

Specific Patient Populations:
- CYP2D6 Poor Metabolizers: Dose modification recommended; adjust dosing to reduce risk of elevated exposure.
- Hepatic Impairment: Caution advised; dosing modification may be necessary due to metabolism by liver enzymes.
- Pediatric Use: Safety and efficacy not established in pediatric population; usage typically limited to adults.
- Geriatric Use: Monitor for increased sensitivity; adverse effects such as sedation more pronounced.

Administration Guidelines:
- Austedo tablets should be taken twice daily with food; do not chew, crush, or break tablets.
- Austedo XR tablets are taken once daily, with or without food; swallow whole without crushing or chewing as the tablet shell is non-absorbable.
- Tablets may appear in stool due to non-absorbed shell; this is normal and does not affect efficacy.

Mechanism Of Action

Deutetrabenazine primarily exerts its therapeutic effect through selective irreversible inhibition of the vesicular monoamine transporter 2 (VMAT2) protein. VMAT2 is responsible for the uptake of monoamine neurotransmitters such as dopamine, serotonin, norepinephrine, and histamine into synaptic vesicles within presynaptic neurons. By blocking VMAT2, deutetrabenazine effectively reduces the vesicular storage and subsequent synaptic release of dopamine and other monoamines, particularly within neuronal pathways of the basal ganglia involved in the coordination of movement.

The reduction in synaptic dopamine availability mitigates the hyperkinetic movements characteristic of Huntington's chorea and tardive dyskinesia by dampening abnormal dopaminergic signaling that drives involuntary muscle contractions. The drug's action modulates aberrant neurotransmission rather than directly treating the neurodegenerative process underlying Huntington’s disease or the basal ganglia dysfunction that causes tardive movements.

Compared to its predecessor tetrabenazine, deutetrabenazine utilizes strategic deuterium substitution which slows metabolism, prolonging plasma half-life of active metabolites and providing a more stable pharmacokinetic profile. This results in fewer peak-trough fluctuations, potentially reducing side effects and enhancing tolerability. Moreover, this enhanced stability enables flexible dosing regimens including once-daily administration with Austedo XR formulation.

Clinical trials such as First-HD, AIM-TD, and ARM-TD have demonstrated deutetrabenazine’s efficacy in significant reductions in chorea severity and tardive dyskinesia symptoms, correlating with its potent VMAT2 inhibition and consequent normalization of neurotransmitter dynamics within motor control pathways. This mechanism is shared among other VMAT2 inhibitors (e.g., tetrabenazine, valbenazine), but deutetrabenazine offers advantageous pharmacokinetics and safety profiles arising from deuterium modification.

Pharmacological Actions

Selective inhibition of vesicular monoamine transporter 2 (VMAT2), reducing dopamine storage and release.
Reduction of abnormal involuntary movements by modulating dopaminergic neurotransmission.
Decrease in synaptic levels of monoamines such as dopamine, serotonin, norepinephrine, and histamine.
Improvement of motor control in hyperkinetic disorders without direct neuroprotective effects.
Longer half-life and improved metabolic stability compared to tetrabenazine due to deuterium substitution.
Reduced peak-to-trough plasma fluctuations, leading to improved tolerability and adherence.
Differential pharmacokinetics allowing once-daily dosing with extended-release formulation.
Dampening of overactive basal ganglia signaling pathways involved in chorea and tardive dyskinesia.
Minimal off-target receptor activity, focusing action on vesicular monoamine storage.
Potential modulation of serotonin and norepinephrine contributing to side effect profile.
Absence of direct impact on the progression of underlying neurodegenerative diseases.
Lower propensity for drug-induced parkinsonism relative to earlier VMAT2 inhibitors.
Compatibility with various concomitant medications through manageable drug interaction profile.
Allows dose titration tailored to symptom severity and patient tolerance.

Therapeutic Or Clinical Uses

Treatment of chorea associated with Huntington's disease to reduce involuntary movements.
Management of tardive dyskinesia symptoms to alleviate repetitive, uncontrolled muscle movements.
Improvement of quality of life in patients with hyperkinetic movement disorders.
Reduction of the severity of abnormal movements in neurological conditions linked to dopamine dysregulation.
Alternative to tetrabenazine with improved dosing convenience and tolerability.
Therapeutic option for patients requiring long-term management of chorea and tardive dyskinesia.
Used to control symptoms resulting from prolonged antipsychotic therapy causing tardive dyskinesia.
Adjunctive therapy in Huntington’s disease addressing motor symptom burden.
Pharmacological intervention targeting symptomatic relief without disease modification.
Dose flexibility with immediate and extended-release formulations allowing individualized treatment.
Beneficial in patients with contraindications or intolerance to other VMAT2 inhibitors.
FDA-approved option for chorea in Huntington’s disease and tardive dyskinesia in adults.
Potential to reduce caregiver burden by improving patient motor function.
Utilized in clinical practice for patients with significant impairment from involuntary movements.
Supportive treatment to improve motor control and prevent complications related to involuntary movements.

Side Or Adverse Effects

Drowsiness and somnolence occurring in approximately 11% of patients with Huntington’s disease.
Fatigue and tiredness reported in about 9% of treated individuals.
Dry mouth affecting roughly 9% of patients taking the drug.
Urinary tract infections with an incidence near 7% among Huntington’s disease patients.
Anxiety symptoms experienced by approximately 4% of users.
Sleep disturbances including insomnia reported in 7% of patients for Huntington’s and 4% in tardive dyskinesia trials.
Gastrointestinal effects such as diarrhea (9%) and constipation (4%).
Confusion manifested in 4% of clinical trial participants.
Nasopharyngitis reported in 4% of tardive dyskinesia patients.
Depression and mood disorders including dysthymic disorder appearing in up to 2% of patients.
Agitation, restlessness, and akathisia observed in about 2% of users.
Serious allergic reactions including hives, swelling, and breathing difficulties are rare but require immediate attention.
Suicidal ideation and changes in mood necessitating close monitoring, especially in Huntington’s disease patients.
Potential for cardiac adverse events such as palpitations and QT prolongation under specific conditions.
Other extrapyramidal symptoms including tremors, muscle rigidity, and balance problems reported in serious cases.
Symptoms resembling Parkinsonism like resting tremor and bradykinesia may occur during therapy.
Potential for neuroleptic malignant syndrome-like reactions characterized by rigidity, fever, and autonomic instability.

Precautions

Avoid use in patients with untreated or uncontrolled depression or suicidal thoughts.
Monitor for mood changes, anxiety, and emergence of suicidal ideation during therapy.
Caution in patients with liver impairment due to metabolism by hepatic enzymes.
Dose adjustments recommended for poor CYP2D6 metabolizers or when co-administered with CYP2D6 inhibitors.
Regular monitoring of cardiac function advised, especially in patients with known cardiac risk factors.
Avoid abrupt discontinuation; if treatment is interrupted for over one week, re-titration is necessary.
Use caution in elderly patients due to increased risk of sedation and falls.
Monitor for development of Parkinsonian symptoms during treatment.
Avoid concomitant use with MAO inhibitors and reserpine-containing drugs due to severe interactions.
Advise patients to avoid alcohol and CNS depressants to reduce risk of excessive sedation.
Consider electrolyte monitoring for patients with risk factors for QT prolongation.
Inform patients that tablet shells may pass in stool and this is not indicative of medication loss.
Pregnancy and breastfeeding considerations require weighing risks and benefits due to limited data.
Educate patients to avoid driving or hazardous activities until effects on alertness are known.
Review concurrent medications thoroughly to avoid harmful drug interactions.
Monitor for worsening of underlying Huntington’s disease symptoms during treatment.

Warnings

Risk of QT interval prolongation; avoid in patients with congenital long QT syndrome or history of cardiac arrhythmias associated with prolonged QT.
Increased risk factors for torsade de pointes include bradycardia, hypokalemia, hypomagnesemia, and concomitant QT-prolonging drugs.
Potential for depression exacerbation and suicidal ideation; any sudden mood or behavioral changes require immediate medical evaluation.
Contraindicated in patients with a recent history of MAO inhibitor or reserpine use due to the risk of hypertensive crises or serotonin syndrome.
Patients with Huntington’s disease and untreated depression or suicidal ideation should not use deutetrabenazine.
Serious side effects such as neuroleptic malignant syndrome-like reactions including muscle rigidity and fever may occur.
Possibility of severe sedation leading to falls, especially in elderly or those with comorbidities.
Use under close surveillance in patients prone to psychiatric illness or suicide risk.
Not to be used in combination with tetrabenazine or valbenazine to avoid additive toxicities.
Immediate medical attention required for symptoms of allergic reactions such as angioedema or anaphylaxis.
May cause Parkinsonism-like symptoms necessitating differential diagnosis from disease progression.
Withdrawal symptoms or exacerbation of symptoms can occur if medication is abruptly stopped.
Risk-benefit balance must be assessed in pregnancy and lactation due to unknown risks.
Dose-dependent risk of side effects; adherence to titration schedules essential to minimize adverse events.
Long-term safety profile under continuous evaluation; patients should be monitored regularly.

Contraindication

Known hypersensitivity to deutetrabenazine or any component of the formulation.
Untreated or uncontrolled depression or active suicidal ideation.
Recent treatment with reserpine within 20 days prior to deutetrabenazine initiation.
Use of monoamine oxidase inhibitors (MAOIs) within 14 days before starting deutetrabenazine.
Concurrent use with tetrabenazine or valbenazine to prevent additive toxicities.
Patients with hepatic impairment without proper dose adjustment and monitoring.
Known congenital long QT syndrome or history of significant cardiac arrhythmias.
Severe psychiatric disorders where worsening mood or psychosis would pose a high risk.
Breastfeeding women due to unknown drug excretion in human milk and potential adverse effects.
Patients with hypersensitivity to dyes or inactive ingredients present in tablet formulations.
Patients who cannot swallow tablets whole due to the inability to administer properly.
Any patient with previous serious adverse reactions to VMAT2 inhibitors.
Individuals with electrolyte imbalances not corrected prior to therapy.
Situations where close medical supervision and frequent monitoring are not feasible.
Pregnant women unless benefits clearly outweigh potential risks and under careful monitoring.

Drug Interactions

Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) can increase deutetrabenazine plasma levels requiring dose reduction.
Concurrent use with monoamine oxidase inhibitors (MAOIs) is contraindicated due to risk of serotonin syndrome and hypertensive crisis.
Additive sedative effects with opioid analgesics, benzodiazepines, muscle relaxants, and other CNS depressants.
Drugs prolonging QT interval may potentiate risk of cardiac arrhythmias when combined with deutetrabenazine.
Concomitant use with reserpine or tetrabenazine can cause excessive dopamine depletion and increased adverse effects.
Medications that alter electrolyte balance (e.g., diuretics) may exacerbate QT prolongation risk.
Possible interaction with antipsychotics increasing risk of movement disorders or sedation.
Co-administration with inhibitors or inducers of CYP enzymes other than CYP2D6 may alter metabolism and efficacy.
Alcohol may enhance CNS depressant effects and increase risk of sedation and hypotension.
Some antidepressants may interact via serotonergic pathways influencing neuropsychiatric side effects.
Combination with certain antiarrhythmics needs caution due to overlapping cardiac risks.
Herbal products like St. John's Wort may induce hepatic enzymes reducing deutetrabenazine efficacy.
Warfarin and other anticoagulants should be monitored as indirect interactions could affect bleeding risk.
CYP2D6 poor metabolizers may experience higher exposure and potential toxicity if interacting drugs inhibit CYP2D6.
Drug interactions necessitate thorough medication reconciliation before starting deutetrabenazine.

Preparations Of The Drug

Austedo immediate-release tablets formulated in strengths of 6 mg, 9 mg, and 12 mg available for twice-daily dosing.
Austedo XR extended-release tablets manufactured in 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg strengths.
Tablets include inactive ingredients such as ammonium hydroxide, black iron oxide, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, and polyethylene glycol.
Immediate-release tablets contain colorants including FD&C red #40 lake and FD&C yellow #6 lake depending on dosage strength.
Extended-release formulations incorporate cellulose acetate, hydroxypropyl cellulose, hypromellose, shellac, talc, titanium dioxide, and various FD&C colorants.
Non-absorbable tablet shells in XR formulations designed to maintain controlled release profile; visible excretion in stool.
Manufactured by Teva Neuroscience, Inc., adhering to FDA guidelines for quality and consistency.
Available in bottles or blister packaging designed to protect from moisture and light, with desiccant canisters included.
Stable at room temperature between 20°C to 25°C (68°F to 77°F); packaging instructions emphasize keeping bottles tightly closed.
Packaged with detailed patient medication guides outlining dosing, warnings, and storage instructions.
Complemented by copay cards and savings programs to improve patient access and affordability.
Commercial distribution includes both immediate and extended-release tablets to accommodate varied clinical needs.
Produced with a focus on minimizing impurities and ensuring consistent batch potency.
Includes comprehensive labeling with prescribing information and safety data to guide healthcare providers.
Formulation optimized for CNS penetration and favorable pharmacokinetic properties through deuterium substitution.