What is the appropriate dosing and safety considerations for initiating Austedo (dextromethorphan/bupropion) in an adult with tardive dyskinesia who has no contraindicating drug interactions or severe hepatic impairment?

Austedo Dosing and Safety for Tardive Dyskinesia

For an adult with tardive dyskinesia without contraindicating drug interactions or severe hepatic impairment, initiate Austedo (deutetrabenazine) at 6 mg twice daily with food, titrating weekly by 6 mg per day increments based on symptom reduction and tolerability, up to a maximum of 48 mg per day. 1

Initial Dosing Protocol

• Start with 6 mg twice daily (12 mg total per day) administered with food 1
• Swallow tablets whole—do not chew, crush, or break 1
• The extended-release formulation (Austedo XR) can be dosed once daily at 12 mg if preferred, also with or without food 1

Titration Schedule

• Increase dose weekly by 6 mg per day based on reduction of tardive dyskinesia movements and patient tolerability 1
• Continue titration until optimal symptom control is achieved or side effects limit further increases 1
• Maximum recommended daily dose is 48 mg per day (24 mg twice daily for standard formulation) 1
• The therapeutic dose range typically falls between 12-48 mg per day, with individual optimization required 2

Critical Safety Monitoring

Depression and Suicidality Screening

• Austedo carries a boxed warning for depression and suicidality in Huntington's disease patients, though this applies to all users 1
• Screen for active suicidal ideation, untreated depression, or inadequately treated depression before initiating—these are absolute contraindications 1
• Monitor continuously for emergence or worsening of depression, suicidal thoughts, or unusual behavioral changes 1
• Exercise heightened caution in patients with history of depression or prior suicide attempts 1

Cardiac Considerations

• Avoid use in patients with congenital long QT syndrome or arrhythmias associated with QT prolongation 1
• While concentration-QTc modeling demonstrates deutetrabenazine does not cause clinically relevant QT prolongation at maximum recommended doses, baseline ECG assessment is prudent in high-risk patients 3

Neurological Adverse Effects

• Monitor for akathisia, agitation, restlessness, and parkinsonism—reduce dose or discontinue if these occur 1
• Watch for neuroleptic malignant syndrome (NMS), though rare—discontinue immediately if suspected 1
• Sedation and somnolence are common (occurred in >8% of patients), which may impair driving or operating machinery 1

Drug Interaction Management

• Contraindicated with MAOIs, reserpine, tetrabenazine, or valbenazine 1
• Allow at least 20 days after stopping reserpine before initiating Austedo (reserpine depletes monoamine stores) 1
• With strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine): maximum dose is 36 mg per day 1
• In CYP2D6 poor metabolizers: maximum dose is also 36 mg per day due to increased exposure to active metabolites 1
• Alcohol and other sedating drugs may have additive sedation effects 1

Common Adverse Effects

• Most frequent reactions (≥4% and greater than placebo): nasopharyngitis and insomnia 1, 2
• Other common effects include somnolence, diarrhea, dry mouth, and fatigue 1
• Number needed to harm for insomnia is 34, while discontinuation due to adverse events occurred in only 3.6% versus 3.1% for placebo (not statistically significant) 2

Efficacy Expectations

• Number needed to treat is 5-7 for clinically meaningful improvement in tardive dyskinesia 2
• In pivotal trials, 46% of patients showed "much improved" or "very much improved" status versus 26% on placebo 2
• 34% achieved ≥50% reduction in AIMS severity scores versus 12% on placebo 2
• The likelihood to be helped versus harmed is 27:1, indicating a highly favorable benefit-risk profile 2

Special Populations

• Absolutely contraindicated in hepatic impairment of any severity 1
• Pregnancy: May cause fetal harm based on animal data—discuss risks versus benefits 1
• No dose adjustment needed for renal impairment unless concurrent hepatic dysfunction 1

Clinical Pitfalls to Avoid

• Do not confuse Austedo (deutetrabenazine) with Auvelity (dextromethorphan/bupropion)—the latter is for depression, not tardive dyskinesia 4
• Do not use anticholinergics like benztropine or trihexyphenidyl to manage any extrapyramidal symptoms that emerge, as these can worsen tardive dyskinesia 5
• Do not abruptly discontinue after prolonged use—taper if discontinuation is needed 1
• Ensure the patient understands this is deutetrabenazine, not tetrabenazine—deutetrabenazine has more stable pharmacokinetics and better tolerability due to deuteration 6