What to do if Austedo XR (deutetrabenazine) 48 mg is not effective?

When Austedo XR 48 mg Is Not Effective

If Austedo XR 48 mg is not providing adequate symptom control, you should first verify that the patient is taking the medication correctly (once daily, swallowed whole without crushing), confirm adequate treatment duration (at least 4-8 weeks at maximum dose), and then consider dose titration beyond 48 mg if tolerated, as the maximum approved daily dose is 48 mg for tardive dyskinesia and chorea associated with Huntington's disease. 1

Verify Treatment Adequacy First

Before concluding treatment failure, confirm these critical factors:

• Medication administration: Ensure the patient is taking Austedo XR once daily and swallowing tablets whole without crushing, chewing, or splitting, as the extended-release formulation depends on intact osmotic delivery system 1
• Treatment duration: Allow at least 4-8 weeks at the target dose before determining efficacy, as clinical response may be gradual 2, 3
• Dose optimization: Confirm the patient has been titrated to 48 mg daily, which is the maximum approved dose for both tardive dyskinesia and Huntington's disease-associated chorea 1
• Drug interactions: Check for strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, bupropion) which can increase exposure to active metabolites approximately 3-fold and may require dose reduction 1

Assess for Factors Limiting Response

Several patient-specific factors may reduce treatment efficacy:

• CYP2D6 poor metabolizers: These patients have approximately 3-fold higher exposure to active metabolites and should not exceed 36 mg daily, meaning they may already be at maximum tolerated dose 1
• Concomitant medications: Dopamine receptor antagonists or other medications affecting monoamine systems may interfere with deutetrabenazine's mechanism of action 2
• Underlying disease severity: Patients with more severe baseline symptoms (higher Yale Global Tic Severity Scale scores or Unified Huntington's Disease Rating Scale scores) may have limited response to any VMAT2 inhibitor 2, 4

Management Options When 48 mg Is Insufficient

Option 1: Switch to Standard Austedo (Immediate-Release)

• Consider switching from Austedo XR (once-daily extended-release) to standard Austedo (immediate-release, twice-daily dosing) at equivalent total daily dose 1
• The immediate-release formulation may provide different pharmacokinetic profiles with potentially better symptom control throughout the day, though this has not been directly studied 5, 6
• Maximum dose remains 48 mg daily regardless of formulation 1

Option 2: Add Adjunctive Behavioral or Physical Interventions

• For tardive dyskinesia: No specific adjunctive pharmacologic treatments are established, but physical therapy and occupational therapy may help manage functional impairment 2
• For Huntington's disease chorea: Combine with comprehensive multidisciplinary care including physical therapy, speech therapy, and nutritional support 3

Option 3: Consider Alternative VMAT2 Inhibitor

• Valbenazine is an alternative VMAT2 inhibitor approved for tardive dyskinesia with a different pharmacokinetic profile and once-daily dosing up to 80 mg 2
• Tetrabenazine (the non-deuterated predecessor) can be used up to 100 mg daily in divided doses, though it has shorter half-life and requires three-times-daily dosing with potentially more adverse effects 3, 5, 6
• Direct head-to-head comparisons suggest similar efficacy between deutetrabenazine and tetrabenazine, but deutetrabenazine has superior tolerability profile 3

Option 4: Reassess Diagnosis and Treatment Goals

• For tardive dyskinesia: Confirm the diagnosis is truly tardive dyskinesia and not another movement disorder; consider reducing or discontinuing the causative antipsychotic if clinically feasible 2
• For Huntington's disease chorea: Reassess whether chorea is the primary source of disability or if other HD symptoms (cognitive decline, psychiatric symptoms, dystonia) are more problematic and require different treatment approaches 3
• Set realistic treatment expectations: Complete elimination of involuntary movements is rarely achieved; meaningful improvement is typically defined as 20-30% reduction in movement disorder rating scales 2, 3

Monitor for Adverse Effects That May Limit Dose Escalation

Even if 48 mg is theoretically not the maximum tolerated dose for an individual patient, these adverse effects may prevent further optimization:

• Somnolence and sedation: Most common adverse effect, occurring in up to 11% of patients at therapeutic doses 2, 4
• Parkinsonism and akathisia: VMAT2 inhibitors can cause drug-induced parkinsonism; if present, dose reduction rather than escalation is indicated 1, 3
• Depression and suicidality: Black box warning for depression and suicidal thoughts/behavior requires careful monitoring, particularly in Huntington's disease patients who have baseline increased suicide risk 1
• QTc prolongation: Although not clinically significant at approved doses, monitor ECG if combining with other QT-prolonging medications 1

Common Pitfalls to Avoid

• Do not crush or split Austedo XR tablets: This destroys the extended-release mechanism and can lead to immediate release of the entire dose with potential toxicity 1
• Do not abruptly discontinue: Taper gradually to avoid potential withdrawal dyskinesia or rebound worsening of symptoms 1
• Do not exceed 36 mg daily in CYP2D6 poor metabolizers: These patients have significantly higher exposure to active metabolites and are at increased risk for adverse effects 1
• Do not use in patients with hepatic impairment: Deutetrabenazine is contraindicated in any degree of hepatic impairment due to large increases in exposure seen with the related compound tetrabenazine 1