FDA Approves Iloperidone for Bipolar Disorder

The US Food and Drug Administration (FDA) has approved iloperidone tablets (Fanapt) for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Iloperidone is a mixed dopamine D2/serotonin 5-HT2A receptor antagonist and belongs to the class of atypical antipsychotics. It was first approved by the FDA in 2009 for the acute treatment of schizophrenia in adults. 

The latest approval was based on results of a phase 3 randomized, double-blind, placebo-controlled trial showing that patients with bipolar mania treated with iloperidone had significantly better outcomes vs those who received placebo, with symptom improvement as early as 14 days after the initial dose.

“Manic or mixed episodes associated with bipolar I disorder are highly complex conditions, which require a host of trusted options to meet individual patient needs. With over 100,000 patient years of experience, Fanapt is a familiar therapeutic agent that offers flexible dosing with a well-known safety profile. This FDA approval gives patients and service providers a new treatment option for managing bipolar I disorder,” Mihael H. Polymeropoulos, MD, president, CEO, and chair of the board of the drug manufacturer Vanda Pharmaceuticals, said in a press release.

As previously reported by Medscape Medical News, the phase 3 trial of iloperidone for bipolar I disorder included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n=206) or placebo (n=208) for 28 days. 

Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the Young Mania Rating Scale of -4.0 (P=.000008). The treatment group also reported significant decreases on the on the Clinical Global Impressions-Severity scale (mean, -0.4; P=.0005) and Clinical Global Impression of Change scale (mean, -0.5; P=.0002).

Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28.

The incidence of akathisia and extrapyramidal symptoms was low in the treatment group, and the medication was well tolerated. The most common adverse events were tachycardia, dizziness, dry mouth, increased alanine aminotransferase level, nasal congestion, weight gain, and somnolence.

Investigators leading the clinical trial noted that iloperidone and its primary metabolite, P88, possess high binding affinity for serotonin 5-HT2A and dopamine D2 and D3 receptors. Inhibiting these receptors is thought to contribute to the antimanic effects of iloperidone and other atypical antipsychotics, whether the bipolar mania is psychotic or nonpsychotic, they added.

The drug comes with a boxed warning that older adults with dementia-related psychosis treated with antipsychotic drugs are at an increased risk for death. Iloperidone is not approved for use in patients with dementia-related psychosis. 

Vanda Pharmaceuticals’ press release did not include information about specific dosage but referred to safety information on its Fanapt website, which stipulates iloperidone should be taken as directed starting at a low dose and slowly increasing the strength. This may delay the control of symptoms in the first 1- 2 weeks of treatment, the company noted. Dosage should also be titrated to avoid orthostatic hypotension.

Contraindications include known hypersensitivity to the drug or to any components in the formulation. Anaphylaxis, angioedema, and other hypersensitivity reactions have been reported.

Kelli Whitlock Burton is an assistant managing editor for Medscape who covers neurology and psychiatry.

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