Old Drug in New Package Promises to Calm the Agitated

Adasuve helps people with bipolar disease or schizophrenia recover from an intense state of agitation

Thomas Morrow, MD

Adasuve, an orally inhaled version of loxapine, may fill a void in the management of patients with schizophrenia or bipolar disorder.

Agitation is a ubiquitous human experience. Defined as an inner distress, it is associated with a number of feelings described as nervousness, restlessness, anguish, or panic or as a sensation of being out of control or overwhelmed. Most people have developed mechanisms to control these feelings and prevent them from degenerating to a dysfunctional state unless there is some catastrophic event, such as a death or a massive natural disaster.

But some people with bipolar disease or schizophrenia deteriorate into a dysfunctional state. These feelings result in a manifestation of hostility, difficulty controlling impulses, uncooperative behavior, and even violence. The time of escalation to agitation can be minutes to days, and it can happen randomly.

Current treatment can take hours to days to calm and stabilize the patient. During my ER service, it was not uncommon for a severely agitated patient to require three to four Marine-size orderlies to restrain him to administer an injection, typically of an antipsychotic. Often there was injury in these dramatic confrontations to aid a patient.

Inpatient psychiatric units and emergency rooms still routinely face this behavior. In fact, a survey of psychiatric emergency service facilities reported an average of eight patient-to-staff assaults per year; most resulted in injury to a staffer sufficient to cause work-time loss. In another survey, done by the Emergency Nurses Association, more than 50% of nurses reported having been verbally or physically abused at work within the previous week.

For serious escalation of agitation, effective intervention is paramount. The Consensus Guidelines for Treatment of Behavioral Emergencies, published in 2001, identified a number of requirements for effective antiagitation therapy. The ideal drug would have rapid onset, provide control of aggressive behavior, be reliable, and preserve the physician-patient relationship. Until recently, no drug met all of these criteria.

Current standard-of-care drug classes are antipsychotics in occasional combination with benzodiazepines. These drugs are available in pills and liquids, orally disintegrating tablets, and intramuscular formulations. Intramuscular forms are the most rapid, but even these have an onset of between 15 and 120 minutes for patients with schizophrenia and 30 to 90 minutes in patients with bipolar disorder. In addition, patients often resist, with the result that they need to be manually immobilized, risking a needle stick or other injury to the health care provider. The use of force to immobilize the patient can lead to mental trauma that compromises the patient-physician relationship.

New treatment for agitation

A unique technology has recently resulted in the reformulation of an old and trusted drug to allow for a rapid, readily available, and acceptable method of meeting the criteria of the consensus guidelines. Relying on the huge drug-absorptive surface area of the lungs that allows therapeutic peak serum levels in about two minutes, loxapine, introduced in 1975, is now approved for use in the proprietary Staccato delivery system developed by Alexza. Named Adasuve and marketed by Teva, this orally inhaled product consists of controlled, rapid heating of a thin film of loxapine to form a thermally generated, highly pure drug vapor. Inhaled, this vapor condenses into aerosol particles of a size that allows distribution deeply into the lung. It has gained approval “for the acute treatment of agitation associated with schizophrenia or bipolar disorder in adults.”

Adasuve places an old drug, loxapine, in a device that rapidly turns it into a vapor that penetrates deeply into the lungs.

Source: Alexza.com

The device reminds one of an electronic cigarette, though functionally it is not similar. It consists of a tube-shaped article with a sealed inner assembly of stainless steel with a battery-operated heat-generating unit coated with loxapine.

A breath sensor activates the heat package, causing the drug to be vaporized and allowing it to be delivered in about 200 milliseconds after activation by the breath.

After the drug leaves the device, a 99.6% pure drug aerosol rapidly cools to a safe temperature in the airflow and condenses to form the small particles that are distributed to the lung mucosa and then absorbed. There is no reliance on breath-hand coordination as with a metered-dose inhaler, nor on forceful inhalation, as with a dry powder inhaler. It also requires no priming, cleaning or maintenance, as it is a one-time-use device.

Adasuve was investigated in 11 studies including eight phase 1 studies, one phase 2 study and two phase 3 studies, providing sufficient safety and efficacy data to lead to FDA approval. The primary efficacy endpoint was the change in Positive and Negative Symptom Scale, Excited Component score as compared with placebo. This scale asks the investigator to rate, from 1 to 7, five symptoms associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement. The secondary endpoint was the Clinical Global Impression Scales, another measure of agitation and improvement over time. A given study participant received up to three doses and was observed for 24 hours, consistent with the intended short-term use of Adasuve.

Measurable effect

The Staccato aerosolized drug delivery technology provides intravenous-like kinetics. After administration, loxapine binds to and blocks several dopamine and serotonin receptors, providing rapid relief of agitation. On sedation scales, the effect can be measured in as little as two minutes. The effectiveness of Adasuve was evident in virtually all patients within 10 minutes, with the peak effect at about one half hour. In addition, efficacy was evident for all assessment times in the 24 hours after the first dose. Adasuve produced significant improvement of agitation in both scoring endpoints.

Roughly half of patients in all clinical studies required just a single dose of Adasuve.

Safety was studied in 524 patients who received the active drug, and it was compared with 263 people who received the placebo. Three patients using Adasuve required discontinuations, one experienced bronchospasm, and two experienced anxiety. No serious adverse events were thought to be due to the study drug. Most were mild and self-limited, with dysgeusia, an odd taste in the mouth, the most common, followed by throat irritation.

Other adverse events were expected: sedation, somnolence, and fatigue. The drug carries a warning that it can cause bronchospasm and has the potential to lead to respiratory distress and respiratory arrest.

This has led to a Risk Evaluation and Management Strategy. The drug should be administered only in a health care facility prepared to handle airway emergencies.

Adasuve provides a welcome development for those health care professionals caring for patients with schizophrenia or bipolar disorder — and yet another example of how yesterday’s medicine can often be improved to provide Tomorrow’s Medicine for people in need.