Adasuve (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: No adequate studies have been conducted.

Mutagenesis: Loxapine did not cause mutation or chromosomal aberration when tested in vitro and in vivo. Loxapine was negative in the Ames gene mutation assay, the human peripheral blood lymphocyte chromosomal aberration assay, and in the in vivo mouse bone marrow micronucleus assay up to 40 mg/kg (20-fold the MRHD on mg/m2 basis).

Loxapine metabolite 8-OH-loxapine was not mutagenic in the in vitro Ames reverse mutation assay and was not clastogenic in the in vitro human peripheral blood lymphocyte chromosomal aberration assay.

Impairment of Fertility: Loxapine had no effects on fertility or early embryonic development in male rats or in male and female rabbits following oral administration. Mating was decreased in female rats because these animals were in persistent diestrus, an expected pharmacologic effect for this class of compounds. This occurred at doses approximately 0.2- and 1-fold the MRHD of 10 mg/day on a mg/m2 basis.

13.2 Animal Toxicology and/or Pharmacology

In the rat, minimal and reversible squamous metaplasia of the larynx was observed after daily inhalation exposure of loxapine for 14 days at 1.7 to 13 mg/kg/day (approximately 2- to 13-fold the MRHD of 10 mg/day on a mg/m2 basis, respectively). This finding was considered a nonspecific particle impaction effect. Mammary hyperplasia in males and females and ovarian follicular cysts and mucification of vaginal epithelium in female rats were observed at all doses, with partial or complete recovery at the end of 14 days of treatment. In the dog, no effects on the respiratory tract or reproductive tissues were observed after inhalation exposure to loxapine for 28 days at doses up to 1.8 mg/kg/day (approximately 6-fold the MRHD of 10 mg/day on a mg/m2 basis).

14 CLINICAL STUDIES

The efficacy of ADASUVE 10 mg in the acute treatment of agitation associated with schizophrenia or bipolar I disorder was established in two short-term (24-hour), randomized, double-blind, placebo-controlled, fixed-dose trials. Study 1 included 344 patients who met DSM-IV criteria for schizophrenia. Study 2 included 314 patients who met DSM-IV criteria for bipolar I disorder, manic or mixed episodes with or without psychotic features.

Patients were judged by the clinical investigators to be clinically agitated, with a level of agitation that met or exceeded a specific severity threshold as measured by the Positive and Negative Syndrome Scale-Excited Component (PEC). The PEC is an investigator-rated instrument consisting of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1 = absent, 4 = moderate, 7 = extreme). Thus, the total PEC score can range from 5 to 35. For enrollment in the studies, patients had to have a PEC score of ≥ 14, with at least one individual item score ≥ 4.

Patients whose agitation was related to acute alcohol or drug intoxication were excluded. Patients with clinically significant acute or chronic pulmonary disease (e.g., asthma, COPD, chronic bronchitis, and emphysema) were excluded from the trials [See Contraindications (4)].

The primary efficacy endpoint in both trials was the mean change from baseline in the PEC score, assessed 2 hours following dosing. The key secondary endpoint was the mean Clinical Global Impression Improvement (CGI-I) Scale score at two hours. The CGI-I is an investigator-rated global assessment of symptom improvement, scored on a scale of 1 to 7: 1 = very much improved; 4 = no change from baseline; 7 = very much worse.

In both studies, mean baseline PEC scores were similar in all treatment groups, averaging 17.3 to 17.7 (Table 4), with individual patient scores ranging from 14 to 31, indicating predominantly moderate levels of agitation. The mean baseline Clinical Global Impression Severity Scale (CGI-S) score in both studies was 4 (moderately ill). In Study 2, 69% of patients had a current manic episode, and 31% had a mixed/manic episode.

In Studies 1 and 2, treatment with ADASUVE was statistically significantly superior to placebo on the mean change in PEC score at 2 hours (Table 4). In both studies, the effect of ADASUVE was apparent at 10 minutes following dosing (Figures 9 and 10).

Table 4. Change from Baseline in the PEC Score at 2 Hours Post-Dose in the Schizophrenia (Study 1) and Bipolar I Disorder (Study 2) Trials
a Least squares mean for the difference defined as the change from baselineb Least squares mean for the difference defined as the change from baseline at hour 2 in the drug group minus that in the placebo group.
Placebo ADASUVE
Study 1 (Schizophrenia)
N 115 112
PEC score
Mean baseline 17.4 17.6
Change at 2 hoursa -5.8 -8.7
Difference from placebo (95% CI)b -2.9 (-4.2, -1.6)
p-value < 0.0001
Study 2 (Bipolar Disorder )
N 105 105
PEC score
Mean baseline 17.7 17.3
Change at 2 hoursa -4.7 -9.2
Difference from placebo (95% CI)b -4.5 (-5.8, -3.1)
p-value < 0.0001

Examination of population subsets (age, race, and gender) on the primary endpoint did not reveal any differential responsiveness on the basis of these subgroupings.

Figures 9 and 10 show the decreases in PEC score at each time point assessed in the trials. In both trials, the decrease in agitation with ADASUVE was apparent at each time point tested (10, 20, 30, 45, 60, 90, and 120 minutes post-dose).

Figure 9. Mean Change from Baseline in PEC Score through 2 Hours after a Single Dose in Agitated Patients with Schizophrenia (Study 1)


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(click image for full-size original)

Figure 10. Mean Change from Baseline in PEC Score through 2 Hours after a Single Dose in Agitated Patients with Bipolar Disorder (Study 2)


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(click image for full-size original)

The results of the secondary endpoint, CGI-I scores, are shown in Table 5.

Table 5. CGI-I Score at 2 Hours Post-Dose in the Schizophrenia and Bipolar I Disorder Trials
a Least squares mean
Placebo ADASUVE
Study 1 (Schizophrenia)
N 115 112
CGI-I score at 2 hoursa 2.8 2.1
Difference from placebo (95% CI) -0.8 (-1.1, -0.4)
p-value <0.0001
Study 2 (Bipolar Disorder)
N 105 105
CGI-I score at 2 hoursa 3.0 1.9
Difference from placebo (95% CI) a -1.1 (-1. 4, -0.8)
p-value <0.0001

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