FDA Panel Recommends Approval of Inhaled Antipsychotic

A US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) has recommended approval of inhaled loxapine (Adasuve, Alexza Pharmaceuticals), as the first inhaled antipsychotic for agitation associated with schizophrenia and bipolar disorder (BD).

The handheld, single-dose inhaler enables rapid drug delivery with greater comfort and convenience for patients who typically must be physically restrained and treated by injection.

In October 2010, the FDA declined approval of the rapid-acting drug because of concerns regarding pulmonary toxicity, particularly in patients with asthma or chronic obstructive pulmonary disorder.

If approved, inhaled loxapine will be administered once every 24 hours, in accordance with a proposed Risk Evaluation and Mitigation Strategy (REMS) that includes screening patients for respiratory risks and monitoring them for 1 hour after treatment.

However, it may be difficult for health-care providers to identify respiratory distress in psychiatric patients who are "uncooperative and severely disorganized," Francis Becker, MD, a medical officer in the FDA's division of psychiatry products, told the advisory panel.

Inhaled loxapine is a thermally generated aerosol formulation that represents a new formulation of the antipsychotic that has been orally available in the United States since 1975.

Its approval would engender competition with injectable forms of olanzapine (Zyprexa, Eli Lilly & Co), aripiprazole (Abilify, Bristol-Myers Squibb, Co), and ziprasidone HCl (Geodon, Pfizer, Inc), which are part of a newer class of medicines known as atypical antipsychotics.

The product is also being considered for approval by the European Medicines Agency (EMA).

Beneficial Effects

A company-funded study published in January in the British Journal of Psychiatry demonstrated the potential benefits of inhaled loxapine in that effects were noticeable within 10 minutes and more effective than placebo for cutting agitation levels within 2 hours.

However, pulmonary safety data from 3 double-blind, placebo-controlled studies (n = 1,653) revealed respiratory concerns.

The studies evaluated the use of two 10-mg doses of inhaled loxapine given 8 to 10 hours apart in 30 healthy patients with normal pulmonary function, 52 with mild to persistent asthma, and 53 with chronic obstructive pulmonary disease (COPD).

Although adverse events were generally mild to moderate in severity (dysgeusia, 13%; sedation, 10.5%), the rate of "notable" respiratory signs and symptoms were significantly higher among patients with asthma who received inhaled loxapine rather than placebo (69% vs 12%).

"Notable signs" were defined as a ≥20% decrease from baseline in forced expiratory volume in the first second (FEV1), an airway adverse event, or use of rescue bronchodilator medication.

Overall, about 54% of patients who had asthma and were treated with inhaled loxapine experienced adverse airway events (vs placebo, 11.5%), including bronchospasm (27%), chest discomfort (23%), wheezing (15%), and dyspnea (11.5%).

Similarly, 58% of COPD patients given inhaled loxapine experienced respiratory symptoms, compared with 22% of COPD patients who were given placebo, corresponding with an increased rate of airway adverse events (19% vs 11%), which included dyspnea (11.5%), cough (11.5%), and wheezing (8%). None of these events occurred in more than 1 COPD patient given placebo.

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REFERENCE :MEDSCAPE