ygen and intravenous fluids.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: psycholeptics, antipsychotics; ATC code: N05AH01
The efficacy of loxapine is proposed to be mediated through high affinity antagonism of dopamine D2 receptors and serotonin 5-HT2A receptors. Loxapine binds with noradrenergic, histaminergic, and cholinergic receptors, and its interaction with these systems may influence the spectrum of its pharmacological effects.
Changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species, associated with calming effects and suppression of aggressive behaviour.
Clinical efficacy
In the two Phase 3 studies patients were enrolled who had acute agitation of at least moderate level (14 or higher on Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) scale (poor impulse control, tension, hostility, uncooperativeness, and excitement). Inclusion in Study 004-301 required a diagnosis of schizophrenia. Inclusion in Study 004-302 required a diagnosis of bipolar disorder (current episode manic or mixed). Patients had significant and long-standing psychiatric disease (Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)), based on years since diagnosis and previous hospitalizations. Patients were randomised to placebo, ADASUVE 4.5 mg and ADASUVE 9.1 mg.
The mean age of randomized patients was 43.1 years in Study 004-301 and 40.8 years in Study 004-302: young adults (18-25 years old) were scarcely (7.3%) represented in either trial. Women in the schizophrenia trial were scarcely represented (26.5%), and about half of the patients were male (49.7%) in Study 004-302. About 35% of the patients with schizophrenia were taking concomitant antipsychotics at the time of dosing while approximately 13% of the patients with bipolar disorder were taking these drugs. A majority of the patients in both Phase 3 studies were smokers with about 82% of the patients with schizophrenia and 74% of the patients with bipolar disorder currently smoking.
After the first dose, a second dose was administered at least 2 hours later if the agitation had not subsided sufficiently. A third dose was administered if needed after at least 4 hours after dose 2. Rescue medication (intramuscular lorazepam) was given if medically required. Primary endpoint was absolute change in PEC score from baseline to 2 hours following Dose 1 for both doses of ADASUVE compared with placebo. Among the other endpoints were PEC and Clinical Global Impression – Improvement (CGI-I) responders at 2 hours after dose 1, and total number of patients per group who received 1, 2, or 3 doses of study medication with and without rescue medication. Responders were considered patients with a ≥40% decrease from baseline in the total PEC score or patients with CGI-I score of 1 (very much improved) or 2 (much improved).
Decreased agitation was evident 10 minutes after Dose 1, the first assessment time, and at all subsequent assessments during the 24 hour eva luation period, for both 4.5 mg and 9.1 mg doses in both schizophrenia and bipolar disorder patients.
Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.
For the main results, see the table below.Main results of the pivotal efficacy studies: comparisons between ADASUVE 4.5 mg, 9.1 mg, and placebo
Study
P
