Can a patient intolerant of valbenazine (deutetrabenazine) be given austedo (deutetrabenazine)?

Can a Patient Intolerant of Valbenazine Be Given Austedo (Deutetrabenazine)?

No, Austedo (deutetrabenazine) is contraindicated in patients currently taking valbenazine, and extreme caution is warranted in patients with valbenazine intolerance due to the shared mechanism of action and similar adverse effect profiles. 1

Contraindication and Mechanism

• The FDA label for Austedo explicitly states that AUSTEDO is contraindicated in patients currently taking valbenazine. 1
• Both valbenazine and deutetrabenazine are VMAT2 (vesicular monoamine transporter 2) inhibitors that work through the same pharmacologic mechanism to treat tardive dyskinesia and chorea. 2
• The contraindication exists because concurrent use could lead to excessive VMAT2 inhibition, resulting in major depletion of serotonin and norepinephrine in the central nervous system. 1

Critical Pharmacologic Differences

While both drugs inhibit VMAT2, there are important distinctions in their metabolite profiles:

• Valbenazine produces a single active metabolite ([+]-α-HTBZ) that is a potent VMAT2 inhibitor with negligible off-target receptor activity and a half-life of approximately 22.2 hours. 2
• Deutetrabenazine produces four deuterated HTBZ metabolites, with the most abundant ([-]-α-deuHTBZ, representing 66% of circulating metabolites) being a relatively weak VMAT2 inhibitor but having appreciable affinity for dopamine (D2S, D3) and serotonin (5-HT1A, 5-HT2B, 5-HT7) receptors. 2
• The most potent VMAT2-inhibiting metabolite of deutetrabenazine ([+]-β-deuHTBZ) represents only 29% of total circulating metabolites and has a shorter half-life (7.7 hours) compared to valbenazine's metabolite. 2

Assessing the Nature of Valbenazine Intolerance

The decision to attempt deutetrabenazine depends entirely on the specific adverse effects that caused valbenazine intolerance:

If Intolerance Was Due to VMAT2-Related Effects:

• Sedation, somnolence, or fatigue: These are class effects of VMAT2 inhibitors and would likely recur with deutetrabenazine. 1, 3
• Parkinsonism or akathisia: Both drugs can cause these dopamine-depleting effects; deutetrabenazine may actually pose higher risk given its off-target dopamine receptor affinity. 1, 2
• Depression or suicidal ideation: This is a serious concern with all VMAT2 inhibitors due to monoamine depletion and would not be avoided by switching. 1

If Intolerance Was Due to Off-Target Effects:

• Deutetrabenazine's predominant metabolite has significant off-target activity at dopamine and serotonin receptors, potentially causing different or additional adverse effects compared to valbenazine. 2
• This makes deutetrabenazine potentially more problematic rather than safer in patients with certain intolerances.

Practical Clinical Algorithm

If considering deutetrabenazine after valbenazine intolerance:

1. Wait at least 24 hours after discontinuing valbenazine before initiating deutetrabenazine (the FDA label specifies this timing for tetrabenazine, and the same principle applies). 1

2. Document the specific adverse effects that caused valbenazine intolerance to determine if they are likely class effects or drug-specific.

3. If the intolerance involved depression, suicidality, sedation, parkinsonism, or akathisia, do not attempt deutetrabenazine as these are mechanism-based effects. 1, 2

4. Start at the lowest possible dose (6 mg twice daily with food) and titrate slowly if a trial is deemed appropriate, with weekly monitoring for recurrence of intolerance symptoms. 1

5. Monitor closely for depression, suicidality, sedation, parkinsonism, akathisia, and restlessness during the first 4-8 weeks. 1, 3

Common Pitfalls to Avoid

• Do not assume deutetrabenazine will be better tolerated simply because it is a different drug - the shared VMAT2 mechanism means most adverse effects will be similar. 2
• Do not overlook the increased off-target receptor binding of deutetrabenazine's metabolites, which may cause additional dopaminergic and serotonergic side effects not seen with valbenazine. 2
• Do not use deutetrabenazine in patients taking MAOIs or within 14 days of MAOI discontinuation, as this is an absolute contraindication. 1
• Do not exceed 36 mg/day total dose in patients taking strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, bupropion), as exposure to active metabolites increases approximately 3-fold. 1

Alternative Considerations

Given the high likelihood of cross-intolerance between these VMAT2 inhibitors, consider alternative management strategies:

• Re-evaluate the underlying psychiatric medication regimen if tardive dyskinesia is the indication, as dose reduction or switching antipsychotics may be appropriate. 4
• Consider non-pharmacologic interventions or watchful waiting if symptoms are mild and not functionally impairing.
• Recognize that there are no other FDA-approved alternatives for tardive dyskinesia beyond these two VMAT2 inhibitors, making the risk-benefit assessment critical. 5