Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author has disclosed no potential conflicts of interest, financial or otherwise.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Acute agitation in patients with schizophrenia or bipolar disorder is an important clinical management problem. Emergency use of medication(s) is often required to treat the underlying disorder and to ensure the safety of patients and staff. First-generation (typical) antipsychotic (FGA) drugs (e.g., haloperidol, Haldol®) and benzodiazepine drugs (e.g., lorazepam, Ativan®)—both of which are available in liquid and intramuscular (IM) formulations—had long been used most commonly. However, the use of FGA drugs has been gradually supplanted by the availability of liquid concentrates, orally disintegrating tablets (ODT), and/or IM formulations of several second-generation (atypical) antipsychotic drugs (e.g., risperidone, Risperdal®; olanzapine, Zyprexa®; ziprasidone, Geodon®; aripiprazole, Abilify®). Liquid and ODT formulations are bioequivalent to tablet formulations, but IM formulations are more rapidly absorbed and have an earlier peak serum concentration compared with oral formulations. Therefore, medications given intramuscularly have the advantage of a faster onset of action. Currently in development is a novel inhalable formulation of the FGA drug loxapine. The investigational use of inhaled loxapine for the treatment of agitation in patients with schizophrenia and bipolar disorder will be described in this article.
Loxapine succinate (Loxitane®) is an antipsychotic drug that was first approved in 1975 by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia. Although loxapine is considered a typical antipsychotic drug because it blocks dopamine type 2 (D2) receptors, there is some evidence that it binds to other nondopamine neurotransmitter receptors, not unlike the pharmacological profile of some atypical antipsychotic drugs (Glazer, 1999). Loxapine hydrochloride is an FDA-approved IM formulation that has been shown to be effective for treating acute agitation in older studies (Dubin & Weiss, 1986).
Because the lungs have a very large surface area and good epithelial permeability with the vascular system, small molecules deposited in the lungs are very rapidly absorbed into the systemic circulation, providing the fastest uptake of any route of delivery other than intravenous (Patton & Byron, 2007). Also, drug-metabolizing enzymes are in much lower concentrations in the lungs compared with the gastrointestinal tract and liver, such that inhaled molecules are less likely to be degraded than orally administered drugs. For these reasons, inhaling medication is a potentially viable and clinically useful drug delivery method.
The Staccato® system (Alexza Pharmaceuticals, Mountain View, CA) is a device designed to provide rapid drug delivery via inhalation of thermally generated aerosols (Rabinowitz et al., 2006). The flow of inspired air through the device is detected instantaneously by a breath sensor, which causes a rapid activation of a sealed drug-coated heat source. This heating results in complete drug vaporization in less than 1 second. The vaporized drug rapidly cools and condenses into aerosol particles before leaving the device via inspired air. The aerosolized drug particles generated by the device are of a particular diameter that is optimal for deep lung delivery (rather than in the airways), resulting in rapid systemic drug absorption. Staccato loxapine (Adasuve™) is an investigational device system using a loxapine-coated heat source to administer loxapine by inhalation.
Pharmacokinetic studies of Staccato loxapine in healthy volunteers confirm that the absorption of inhaled loxapine is very rapid (Spyker, Munzar, & Cassella, 2010). The median time to peak serum loxapine concentration is 2 minutes, compared with a much more delayed time to peak concentration of 1 to 2 hours after oral or IM loxapine administration. In addition, the peak serum concentration of inhaled loxapine 10 mg is higher than the peak serum concentrations obtained with oral loxapine 25 mg to 50 mg or IM loxapine 50 mg. Hence, the rate and extent of loxapine absorption via inhalation is greater than that following oral or IM administration.
Clinical Studies of Staccato Loxapine
Three multicenter, randomized, double-blind, placebo-controlled efficacy and safety studies of Staccato loxapine have been conducted: two studies in patients with acute agitation associated with schizophrenia or schizoaffective disorder (Allen et al., 2011; Lesem et al., 2011), and one study in patients with acute agitation associated with bipolar disorder (Citrome, 2011). Each study compared inhaled loxapine 5 mg or 10 mg to inhaled placebo. Participants could receive up to three doses during the 24-hour study period. After initial randomization, Dose 1 was administered. If necessary, participants could receive a second dose no sooner than 2 hours after Dose 1 and a third dose no sooner than 4 hours after Dose 2. The main outcome measure was the excited component subscale on the Positive and Negative Syndrome Scale (PANSS-EC). An additional outcome measure was the Clinical Global Impressions-Improvement Scale (CGI-I). Participants were evaluated 10, 20, 30, 45, 60, and 90 minutes and 2, 4, and 24 hours after Dose 1. The primary efficacy endpoint was the change in PANSS-EC score at 2 hours. Secondary efficacy endpoints were the change in PANSS-EC scores at each time point (10 minutes through 24 hours) and the CGI-I assessment at 2 hours.
In the study by Allen et al. (2011), 129 agitated participants with schizophrenia or schizoaffective disorder were enrolled. On the primary efficacy endpoint (PANSS-EC at 2 hours), loxapine 10 mg was significantly better than placebo, and loxapine 5 mg approached significance. The CGI-I scores for loxapine 5 mg and 10 mg were each significantly superior to placebo at 2 hours. Loxapine 10 mg was significantly better than placebo by 20 minutes and throughout the 24-hour study period. In general, the results for 5 mg were intermediate between those for 10 mg and placebo.
Lesem et al. (2011) enrolled 344 agitated participants with schizophrenia. On the primary efficacy endpoint (PANSS-EC at 2 hours), loxapine 5 mg and 10 mg were each significantly better than placebo. The CGI-I scores for loxapine 5 mg and 10 mg were also significantly superior to placebo at 2 hours. Both loxapine doses were significantly better than placebo by 10 minutes and throughout the 24-hour study period.
The study enrolling agitated participants with bipolar disorder (314 enrolled participants) has not yet been published, but the results have been described by Citrome (2011). On the primary efficacy endpoint (PANSS-EC at 2 hours) and on the CGI-I, loxapine 5 mg and 10 mg were each significantly better than placebo. Both loxapine doses were significantly better than placebo by 10 minutes and throughout the 24-hour study period.
Safety and Tolerability of Staccato Loxapine
In the placebo-controlled pharmacokinetic study of Staccato loxapine in healthy volunteers, participants were randomized to receive 0.625, 1.25, 2.5, 5, or 10 mg of loxapine. The most common adverse events were dizziness, somnolence, and dysgeusia (bad taste). There was a small but statistically significant dose-related drop in blood pressure. No other cardiac or laboratory changes were noted. There were no changes in pulmonary function tests.
In the three clinical trials, the proportion of participants who had at least one adverse event was similar for 10 mg, 5 mg, and placebo. Most adverse events were mild to moderate in severity. The most common adverse events were dizziness, sedation/somnolence, and dysgeusia. Because loxapine is a dopamine receptor-blocking drug, potential adverse events include acute dystonia, which can occur even after a single drug dose. Several participants in the trials developed dystonia, but this is easily treated with anticholinergic drugs (e.g., benztropine, Cogentin®; trihexyphenidyl, Artane®). Other potential adverse motor effects, such as extrapyramidal (parkinsonian) symptoms, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome, would be considered very unlikely to occur with only one to three doses of loxapine. No vital sign or laboratory abnormalities were reported in any of the three clinical trials.
In addition to the pharmacokinetic study and three clinical trials, three pulmonary safety studies have been conducted (one with healthy participants, one with participants with chronic obstructive lung disease, and one with participants with asthma). Although complete details are not available, the FDA has expressed concern about the pulmonary safety of inhaled loxapine (Citrome, 2011). Decreases in forced expiratory volume (a standard measure of pulmonary function) were observed with Staccato loxapine and Staccato placebo, but no serious or severe respiratory adverse events were reported in these trials.
Staccato loxapine represents a novel method for administering an “older” antipsychotic drug for use in an important clinical situation. Various anti-psychotic drug formulations are available for treating agitation associated with schizophrenia or bipolar disorder, but inhaled loxapine has a more rapid onset of effect. For many patients, this may also be a more acceptable way of taking medication than by injection. The FDA’s Psychopharmacologic Drugs Advisory Committee is scheduled to review the safety and efficacy of Staccato loxapine on December 12, 2011 (FDA, 2011a). In advance of this meeting, a background report was prepared and is available online (FDA, 2011b). Nurses working in emergency or hospital settings should become familiar with this product. All nurses should be aware of the evolving concept of administering psychotropic medication through inhalation, since Staccato loxapine is also being investigated for the treatment of migraine headache (Citrome, 2011).
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- U.S. Food and Drug Administration. (2011a). December 12, 2011: Psychopharmacologic Drugs Advisory Committee meeting announcement. Retrieved from http://www.fda.gov/AdvisoryCommittees/Calendar/ucm277069.htm
- U.S. Food and Drug Administration. (2011b). Memorandum: December 12, 2011 Meeting of the Psychopharmacologic Drugs Advisory Committee. Retrieved from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM282897.pdf