WASHINGTON -- An FDA advisory panel punted on the question of approval for an inhaled version of the antipsychotic drug loxapine (Adasuve) to treat agitation in bipolar and schizophrenic patients, despite the risk for respiratory side effects.
The actual vote -- 9-8 with one member abstaining -- was so close that it is not considered an endorsement. The inhaled drug was developed as an alternative to injection for quickly sedating bipolar and schizophrenic patients who present to emergency rooms highly agitated.
The FDA does not have to follow the advice of its advisory committees, and, in this case, there is scant advice to follow.
The device delivers a vaporized form of the antipsychotic medication loxapine to the lungs, which is rapidly absorbed in the bloodstream. Loxapine, an antipsychotic with dopamine-D2-blocking activity, has been available in the U.S. since 1975.
Inhaled loxapine works much faster than a pill, doesn't come with the pain of an injection (or the risk of healthcare workers accidentally sticking themselves with a needle) and is a good additional option for sedating agitated patients quickly, according to Alexza, the company that makes the drug.
"Agitation," while not a disease itself, is common in bipolar and schizophrenic patients and accounts for an estimated 1.7 million psychiatric emergencies every year, according to Alexza. Agitation in schizophrenic and bipolar patients can include panic, hostility, difficulty controlling impulses, and the potential for violence.
While the inhaled vaporized form of loxapine works more quickly than a pill and may be a more welcome option for patients than an injection, inhaling the drug can pose pulmonary side effects, including brochospasms, which are a particularly serious risk for patients with preexisting respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD).
Patients with schizophrenia and mania are much more likely to be smokers than the general population, which means they are at a higher risk for lung disease.
The FDA rejected Alexza's inhaled loxapine in 2010, saying that although the company had proved the drug's efficacy, it had not shown that inhaled loxapine was safe to use, given that it was known to increase the risk of pulmonary adverse events such as bronchospasm.
The company has since submitted a Risk Evaluation and Mitigation Strategy (REMS) that aimed to address some of the FDA's concerns. However, in an FDA review released last week, the agency said that plan fell short and proposed a tougher REMS that would require any hospital using the Adasuve device to have access to advanced airway managment capabilities, and for relevant staff to be trained in using inhaled loxapine.
The panel reviewed the company's two phase III, placebo-controlled clinical efficacy studies that investigated one to three doses of inhaled loxapine (5 mg or 10 mg) in agitated patients with schizophrenia or bipolar disorder. The studies found the inhaled loxapine was efficacious, based on a medical scale used to measure severity of schizophrenia symptoms.
The panel voted 17-1 that inhaled loxapine has been shown to be effective.
It wasn't as sure about the safety of the inhaled version of the drug.
Pulmonary safety was tested via three double-blind, placebo-controlled studies that looked at two 10-mg doses of loxapine in 30 healthy subjects with normal pulmonary function; in 52 patients with mild to persistent asthma; and in 53 subjects with chronic obstructive pulmonary disease.
The most common adverse events were dysgeusia, sedation, fatigue, and throat irritation.
About 54% of patients who had asthma and were treated with loxapine experienced airway adverse events versus 12% of placebo-treated subjects. The most common airway adverse events in subjects with asthma were bronchospasm (27%), chest discomfort (23%), wheezing (15%), and dyspnea (12%).
About 12% of placebo patients had "notable" respiratory signs or symptoms.
In a trial involving patients with COPD, 58% of loxapine-treated subjects had respiratory symptoms versus 22% of placebo-treated patients. Airway adverse events were reported for 19% of loxapine-treated patients compared with 11% of placebo-treated patients.
While the company proposed that the drug be used up to three times in each patient over a 24-hour period, the panelists were more comfortable with allowing for just one dose, and voted 11-5, with one panelist abstaining, that a single dose of loxapine inhalation powder is safe to treat agitation in patients with schizophrenia or bipolar mania when used in conjunction with the FDA's proposed REMS.
Some panelists expressed concern that agitated psychotic patients presenting to the emergency room may not be able to give an accurate assessment history of respiratory disease or even understand how to use the device.
In addition, because loxapine is a sedative, there was some concern that the patients would be too sedated to communicate with healthcare staff if they experience respiratory symptoms after inhaling the drug.