If a patient had a reaction to Ingrezza (valbenazine), can we switch to Austedo (deutetrabenazine)?

Switching from Ingrezza to Austedo After a Reaction

No, you should not routinely switch from Ingrezza (valbenazine) to Austedo (deutetrabenazine) after a reaction, as both are VMAT2 inhibitors with overlapping mechanisms and potential for cross-reactivity. The nature and severity of the reaction should guide your decision, with most adverse effects being class-related rather than drug-specific.

Understanding the Reaction Type

Determine whether the reaction was a true hypersensitivity reaction versus a pharmacologic side effect:

• Class-related pharmacologic effects (somnolence, akathisia, parkinsonism, depression) are likely to recur with any VMAT2 inhibitor, making a switch futile 1, 2
• True hypersensitivity reactions (rash, angioedema, anaphylaxis) to excipients or the drug molecule itself may allow for switching, though caution is warranted 3
• The FDA label for Austedo explicitly warns against use in patients taking valbenazine, indicating concern about overlapping effects 1

Key Pharmacologic Differences That May Influence Decision

While both drugs inhibit VMAT2, their metabolite profiles differ substantially:

• Valbenazine produces a single active metabolite ([+]-α-HTBZ) that potently inhibits VMAT2 with negligible off-target receptor binding and a long half-life of 22.2 hours 4
• Deutetrabenazine produces four deuterated metabolites, with the most abundant ([-]-α-deuHTBZ, representing 66% of circulating metabolites) being a weak VMAT2 inhibitor but having appreciable affinity for dopamine (D2S, D3) and serotonin (5-HT1A, 5-HT2B, 5-HT7) receptors 4
• The most potent VMAT2-inhibiting deutetrabenazine metabolite ([+]-β-deuHTBZ) represents only 29% of circulating metabolites with a shorter half-life of 7.7 hours 4

When Switching May Be Considered

A switch might be reasonable only in specific circumstances:

• Excipient-related reactions: If the reaction was clearly related to a specific inactive ingredient in Ingrezza's formulation rather than the active drug 3
• Dosing flexibility needs: Deutetrabenazine allows twice-daily dosing which may provide better symptom control throughout the day, though this is not a reaction-related consideration 1, 5
• Psychiatric side effects: Given deutetrabenazine's off-target serotonergic and dopaminergic activity, it may theoretically cause different psychiatric side effects than valbenazine, though both carry black box warnings for depression and suicidality in Huntington's disease patients 1, 4

Critical Contraindications to Switching

Do not attempt a switch if:

• The patient experienced depression, suicidal ideation, or neuroleptic malignant syndrome, as these are class effects that will recur 1, 2
• The reaction involved QT prolongation or cardiac arrhythmias, as both drugs carry this risk 1
• Somnolence or sedation was the primary issue, as this is common to all VMAT2 inhibitors (reported in both agents) 2, 5

Alternative Management Strategies

Instead of switching between VMAT2 inhibitors, consider:

• Dose reduction: Both drugs show dose-dependent efficacy, and lower doses may be tolerated while maintaining some benefit 5, 6
• Symptomatic management: Treat specific side effects (e.g., akathisia with beta-blockers, somnolence with dose timing adjustments) while continuing the effective VMAT2 inhibitor 2
• Alternative TD treatments: Consider other evidence-based options including amantadine, clonazepam, Ginkgo biloba, or botulinum toxin for localized dyskinesia 2
• Discontinuation and observation: If the underlying antipsychotic can be stopped or switched to a lower-risk agent, TD may improve without specific treatment 2

Monitoring Requirements If Switch Attempted

If you proceed with a switch despite the concerns:

• Wait at least 5 half-lives of valbenazine (approximately 5 days given its 22-hour half-life) before initiating deutetrabenazine to minimize overlapping exposure 4
• Start deutetrabenazine at the lowest dose (6 mg twice daily) and titrate slowly while monitoring for recurrence of the original reaction 1
• Document the specific reaction that occurred with Ingrezza and monitor closely for similar or cross-reactive symptoms 3
• Be prepared to discontinue immediately if the reaction recurs, as this would confirm a class effect 2

Common Pitfall to Avoid

The most critical error is assuming that switching between VMAT2 inhibitors will solve a problem that is inherent to the drug class. Most adverse effects of these medications—including sedation, parkinsonism, akathisia, depression, and QT prolongation—are mechanism-based and will occur with any VMAT2 inhibitor 1, 2, 5. Only true hypersensitivity reactions to specific drug components might benefit from a switch, and even then, cross-reactivity remains possible given the structural similarities between these compounds 4.