Inhaled loxapine for agitation
Reformulation allows for direct administration to the lungs, resulting in rapid absorption into systemic circulation
Tolerability and safety
Combined safety results from phase III trials10,11 as well as information about a phase I ECG QT interval study were presented in a poster.15 Among 524 patients receiving loxapine vs 263 receiving placebo, there were no significant differences in the likelihood of experiencing any adverse event, a nervous system adverse event, sedation, sedation or somnolence, or sedation, somnolence or dizziness, when stratified by lorazepam rescue.16 Adverse events that were more frequently encountered with both doses of loxapine (ie, 5 and 10 mg) than placebo are listed in Table 3,15 along with the number needed to harm (NNH). The most commonly encountered adverse event was dysgeusia. The NNH of 10 for dysgeusia for loxapine, 10 mg, vs placebo means that for every 10 patients receiving inhaled loxapine, 10 mg, instead of inhaled placebo, you would encounter 1 additional case of dysgeusia. This contrasts with the NNT for response of 4 and 3 for agitation associated with schizophrenia and BD, respectively. Therefore, one would encounter response more often than dysgeusia when comparing loxapine with placebo.
No important changes in the ECG QT interval after inhaled loxapine, 10 mg, were observed in a phase I study with healthy volunteers.15 Difference from placebo in change from baseline for QTc was
Additional details regarding overall safety and tolerability can be found in a previously published review.17
Table 3
Inhaled loxapine: Incidence of adverse events
| Adverse event | Placebo (n=220) | Loxapine | |||
|---|---|---|---|---|---|
| 5 mg (n=220) | 10 mg (n=218) | ||||
| Rate | Rate | NNH vs placebo | Rate | NNH vs placebo | |
| Dysgeusia | 4% | 13% | 12 | 14% | 10 |
| Sedation or somnolence | 8% | 11% | 34 | 10% | 50 |
| Oral hypoesthesia | 0% | 200 | 2% | 50 | |
| NNH: number needed to harm Source: Reference 15 | |||||
Pulmonary safety
Because this product is inhaled, additional information on pulmonary safety was gathered.18,19 Among 1,095 patients without active airways disease, 1 (0.09%) required treatment for post-treatment airway-related symptoms (bronchospasm). In the agitated patient population, the rate of airway adverse events was 0.4% of loxapine exposures among 524 patients, in which 6.7% had a history of asthma or chronic obstructive pulmonary disease (COPD). Others were likely to have some respiratory impairment because of a history of cigarette smoking, but they did not have active respiratory symptoms that required treatment because such patients were excluded from the trials.12 Phase I spirometry-based studies also were completed in healthy nonsmoking volunteers, in patients with asthma, and in patients with COPD. No clinically relevant effects were observed in healthy volunteers, but in patients with asthma or COPD a reduction in forced expiratory volume was observed. In patients with asthma, rates of bronchospasm as an adverse event were 26.9% for loxapine vs 3.8% for placebo, for a NNH of 5.12 Bronchospasm was not reported for patients with COPD receiving loxapine but was observed in 1 patient who received placebo. All airway adverse events in patients with asthma or COPD were mild or moderate. All respiratory signs or symptoms requiring treatment in the phase I asthma and COPD studies were managed with an inhaled bronchodilator.
Product labeling notes in a warning that inhaled loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest.2 Therefore, inhaled loxapine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the “ADASUVE REMS.” Enrolled health care facilities are required to have immediate, on-site access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Inhaled loxapine is contraindicated in patients with a current diagnosis or history of asthma, COPD, or other lung diseases associated with bronchospasm; acute respiratory signs or symptoms such as wheezing; current use of medications to treat airway diseases such as asthma or COPD; history of bronchospasm following inhaled loxapine treatment; or known hypersensitivity to loxapine and amoxapine.
Only a single dose within a 24-hour period is recommended. Before administration, patients should be screened for a history of pulmonary disease and examined (including chest auscultation) for respiratory abnormalities (eg, wheezing). After administration, patients require monitoring for signs and symptoms of bronchospasm at least every 15 minutes for ≥1 hour.
Related Resource
- Dinh K, Myers DJ, Glazer M, et al. In vitro aerosol characterization of Staccato(®) Loxapine. Int J Pharm. 2011; 403(1-2):101-108.
Drug Brand Names
- Haloperidol • Haldol
- Lorazepam • Ativan
- Loxapine • Loxitane
- Loxapine inhalation powder • Adasuve
