atients
004-301
Schizophrenia
004-302
Bipolar Disorder
Treatment
N
PBO
115
4.5 mg
116
9.1 mg
112
PBO
105
4.5 mg
104
9.1 mg
105
PEC Change
Baseline
17.4
17.8
17.6
17.7
17.4
17.3
Change at 2 hr post dose
-5.5
-8.1+
-8.6*
-4.9
-8.1*
-9.0*
SD
4.9
5.2
4.4
4.8
4.9
4.7
PEC Responders
30 min post dose
27.8%
46.6%
57.1%
23.8%
59.6%
61.9%
2 hr post dose
38.3%
62.9%
69.6%
27.6%
62.5%
73.3%
CGI-I Responder
% CGI-I Responders
35.7%
57.4%
67.0%
27.6%
66.3%
74.3%
# Doses Needed
One
46.1%
54.4%
60.9%
26.7%
41.3%
61.5%
Two
29.6%
30.7%
26.4%
41.0%
44.2%
26.0%
Three
8.7%
8.8%
7.3%
11.4%
5.8%
3.8%
Rescue
15.6%
6.1%
5.4%
21.0%
8.6%
8.6%
*= p<0.0001 += p<0.01
PEC Responders = ≥ 40% change from PEC Baseline;
CGI-I Responders = Score of 1 (Very Much Improved) or 2 (Much Improved)
PBO = placebo SD=Standard Deviation
In a supportive Phase 2 single dose study enrolling a total of 129 patients with schizophrenia and schizoaffective disorder the decrease in PEC change after 2 hours was -5.0 for placebo, -6.7 for ADASUVE 4.5 mg, and -8.6 (p<0.001) for ADASUVE 9.1 mg. Rescue medication was administered in respectively 32.6%, 11.1 % and 14.6 % of patients.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with ADASUVE in the subset of the paediatric population from birth to less than 12 years of age for the treatment of schizophrenia and in the subset from birth to less than 10 years of age for the treatment of bipolar disorder (see section 4.2 for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with ADASUVE in the subset of the paediatric population from 12 to less than 18 years of age for the treatment of schizophrenia and in the subset from 10 years to less than 18 years of age in bipolar disorder (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Administration of ADASUVE resulted in rapid absorption of loxapine with a median time of maximum plasma concentration (Tmax) by 2 minutes. Loxapine exposure in the first 2 hours after administration (AUC0-2h, a measure of early exposure that is relevant to the onset of therapeutic effect) was 25.6 ng*h/mL for the 4.5 mg dose and 66.7 ng*h/mL for the 9.1 mg dose in healthy subjects.
The pharmacokinetic parameters of loxapine were determined in subjects on chronic, stable antipsychotic regimens following repeat administration of ADASUVE every 4 hours for a total of 3 doses (either 4.5 mg or 9.1 mg). Mean peak plasma concentrations were similar after the first and third dose of ADASUVE, indicating minimal accumulation during the 4-hour dosing interval.
Distribution
Loxapine is removed rapidly from the plasma and distributed in tissues. Animal studies following oral administration suggest an initial preferential distribution in the lungs, brain, spleen, heart and kidney. Loxapine is 96.6% bound to human plasma proteins.
Biotransformation
Loxapine is metabolised extensively in the liver, with multiple metabolites formed. The main metabolic pathways include hydroxylation to form 8-OH-loxapine and 7-OH-loxapine, N-oxidation to form loxapine N- |
