Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Ferrer Internacional, S.A., Gran Vía Carlos III, 94, 08028- Barcelona, España
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.
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 evaluation 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 Patients | 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.
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).
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.
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.
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-oxide, and de-methylation to form amoxapine. For ADASUVE, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine >> loxapine N oxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine similar to the parent compound. 8-OH-loxapine is not pharmacologically active at the D2 receptor while the minor metabolite, 7-OH-loxapine, has high binding affinity to D2 receptors.
Loxapine is a substrate for several CYP450 isozymes; in vitro studies demonstrated that 7-OHloxapine is formed mainly by CYPs 3A4 and 2D6, 8-OH-loxapine is formed mainly by CYP1A2, amoxapine is formed mainly by CYP3A4, 2C19, and 2C8, and loxapine N-oxide is formed by FMOs.
The potential for loxapine and its metabolites (amoxapine, 7-OH-loxapine, 8-OH-loxapine, and loxapine-N-oxide) to inhibit CYP450 – mediated drug metabolism has been examined in vitro for CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. No significant inhibition was observed. In vitro studies indicate that loxapine and 8-OH-loxapine are not inducers of CYP1A2, 2B6 or 3A4 enzymes at clinically relevant concentrations. In addition, in vitro studies indicate that loxapine and 8-OH-loxapine are not inhibitors of UGT1A1, 1A3, 1A4, 2B7 and 2B15.
Loxapine excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the faeces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8 hours.
The mean plasma loxapine concentrations following administration of ADASUVE were linear over the clinical dose range. AUC0-2h, AUCinf, and Cmax increased in a dose-dependent manner.
A population pharmacokinetic analysis that compared exposures in smokers versus non-smokers indicated that smoking, which induces CYP1A2, had a minimal effect on the exposure to ADASUVE. No dosage adjustment is recommended based on smoking status.
In female smokers exposure (AUCinf) to ADASUVE and its active metabolite 7-OH-loxapine is lower than in female non-smokers (84% vs 109% 7-OH-loxapine/Loxapine Ratio), which is probably due to an increase in loxapine clearance in smokers.
There were no important differences in the exposure or disposition of loxapine following administration of ADASUVE due to age, gender, race, weight, or body mass index (BMI).
Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, and genotoxicity, except for changes to reproductive tissues related to the extended pharmacology of loxapine. Similar changes, e.g., gynecomastia, are known in humans, but only after long-term administration of medicines causing hyperprolactinaemia.
Female rats did not mate due to persistent diestrus after oral treatment with loxapine. Embryo/fetal developmental and perinatal studies have shown indications of developmental delay (reduced weights, delayed ossification, hydronephrosis, hydrourether, and/or distended renal pelvis with reduced or absent papillae) as well as increased numbers of perinatal and neonatal deaths in offspring of rats treated from mid-pregnancy with oral doses below the maximum recommended human dose for ADASUVE on a mg/m² basis (see section 4.6).
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