What is the recommended starting dose of FANAPT (iloperidone) for an adult patient with bipolar disorder?

FANAPT (Iloperidone) is Not FDA-Approved for Bipolar Disorder

FANAPT (iloperidone) is FDA-approved only for schizophrenia in adults, not for bipolar disorder. However, a recent 2024 randomized controlled trial demonstrated efficacy for bipolar mania, and if used off-label for this indication, the starting dose would be 1 mg twice daily, titrated over 4-7 days to a target of 12-24 mg/day 1, 2, 3.

FDA-Approved First-Line Options for Bipolar Disorder

The American Academy of Child and Adolescent Psychiatry recommends lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone) as first-line treatments for acute mania/mixed episodes in bipolar disorder 4. Iloperidone is notably absent from these guideline recommendations.

Off-Label Use: Evidence from Recent Research

Efficacy Data for Bipolar Mania

A 2024 phase 3 randomized controlled trial (n=414) demonstrated that iloperidone significantly reduced YMRS total scores versus placebo at week 4 (difference: -4.0 points; P=0.000008), establishing efficacy for bipolar mania 3.

Dosing Protocol for Bipolar Mania (Based on 2024 Trial)

• Starting dose: 1 mg twice daily 1, 2
• Titration schedule: Increase over 4-7 days to reach target dose 1, 2
• Target dose: 12 mg twice daily (24 mg/day total) 1, 2, 3
• Maximum dose: 12 mg twice daily 2
• Titration is mandatory to minimize orthostatic hypotension and dizziness 1, 2

The 2024 bipolar mania trial used doses up to 24 mg/day given twice daily, consistent with schizophrenia dosing 3.

Clinical Considerations for Off-Label Use

Advantages of Iloperidone

• Minimal extrapyramidal symptoms and akathisia throughout the recommended dose range 2, 3
• Modest weight gain and no medically important changes in lipid/glucose levels 2
• Little prolactin elevation 2
• Low incidence of akathisia (3.7%) and extrapyramidal symptoms (2.5%) 5

Disadvantages and Safety Concerns

• Requires slow 4-7 day titration, delaying therapeutic effect 1, 2
• Twice-daily dosing may reduce adherence 1
• Can prolong QTc interval on ECG 2
• Most common adverse events: tachycardia, dizziness (5.1%-23.2%), dry mouth (5.2%-10.4%), somnolence (4%-13%), and nasal congestion 1, 3
• Dizziness is dose-related and necessitates slow titration 1

Recommended Clinical Algorithm

For acute bipolar mania, prioritize FDA-approved first-line agents (lithium, valproate, aripiprazole, olanzapine, risperidone, quetiapine) over iloperidone 4.

Consider iloperidone only when:

• Patient has failed or cannot tolerate first-line agents 4
• Patient is particularly sensitive to akathisia or extrapyramidal symptoms 2
• Patient cannot tolerate sedation and weight gain from other antipsychotics 2

If prescribing iloperidone off-label for bipolar mania:

1. Obtain baseline ECG to assess QTc interval 2
2. Start 1 mg twice daily 1, 2
3. Titrate over 4-7 days to 12 mg twice daily 1, 2
4. Monitor orthostatic vital signs during titration 1, 2
5. Assess for dizziness, tachycardia, and somnolence 3
6. Expect therapeutic response by week 4 3

Critical Pitfalls to Avoid

• Never skip the titration phase—this dramatically increases orthostatic hypotension and dizziness risk 1, 2
• Do not use iloperidone as first-line therapy when guideline-recommended agents are available and appropriate 4
• Avoid in patients with baseline QTc prolongation or those taking other QTc-prolonging medications 2
• Do not assume once-daily dosing is adequate—iloperidone requires twice-daily administration 1