Adasuve

Name: Adasuve

Clinical pharmacology

Mechanism Of Action

The mechanism of action of loxapine in the treatment of agitation associated with schizophrenia is unknown. However, its efficacy could be mediated through a combination of antagonism of central dopamine D2 and serotonin 5-HT2A receptors. The mechanism of action of loxapine in the treatment of agitation associated with bipolar I disorder is unknown.

Pharmacodynamics

Loxapine acts as an antagonist at central serotonin and dopamine receptors, with high affinity for serotonin 5-HT2A and dopamine D1, D2, D3, and D4 receptors (Ki values of 2 nM, 18 nM, 10 nM, 21 nM, 9 nM, respectively). Some of the adverse effects of loxapine may be related to the antagonism of histamine H1 (somnolence), muscarinic M1 (anticholinergic), and adrenergic a2 (orthostatic hypotension) receptors (Ki values of 15 nM, 117 nM and 250 nM, respectively).

Thorough QTc Study

ADASUVE did not prolong the QTc interval. The effect of ADASUVE on QTc prolongation was evaluated in a randomized, double-blinded, positive- (moxifloxacin 400 mg) and placebo-controlled parallel study in healthy subjects. A total of 48 healthy subjects were administered ADASUVE 10 mg. In this study with a demonstrated ability to detect small effects, the upper bound of the 90% confidence interval (CI) for the largest placeboadjusted, baseline-corrected QTc based on individual correction method was below 10 milliseconds, the threshold for regulatory concern.

Pharmacokinetics

Absorption

The single-dose pharmacokinetic parameters of loxapine following administration of single doses of ADASUVE 10 mg in healthy adult subjects are presented in Table 3 and Figure 8.

Administration of ADASUVE resulted in rapid absorption of loxapine, with a median time of maximum plasma concentration (Tmax) of 2 minutes. Loxapine exposure in the first 2 hours after administration (AUC0-2h) was 66.7 ng•h/mL for the 10 mg dose. As a consequence of the very rapid absorption of loxapine after oral inhalation, there is substantial variability in the early plasma concentrations of loxapine. 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.

Table 3: Pharmacokinetics in Healthy Adult Subjects Administered a Single Dose of ADASUVE 10 mg

Parameter Healthy Subjects
ADASUVE 10 mg
(N=114)
AUC0-2h (ng•h/mL), mean ± SD 66.7 ± 18.2
AUCinf (ng•h/mL), mean ± SD 188 ± 47
Cmax (ng/mL), mean ± SD 9 21 +1 7 5 2
Tmax (minutes), median (25%, 75%) 1.13 (1, 2)
Half-life(h), mean ± SD 7.61 ± 1.87

Figure 8: Mean Plasma Concentrations of Loxapine following Single-Dose Administration ADASUVE 10 mg in Healthy Subjects

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.

Metabolism

Loxapine is metabolized extensively in the liver following oral administration, with multiple metabolites formed. The main metabolic pathways include: 1) hydroxylation to form 8-OH-loxapine by CYP1A2 and 7-OH-loxapine by CYP3A4 and CYP2D6, 2) N-oxidation to form loxapine N-oxide by flavanoid monoamine oxidases (FMOs), and 3) de-methylation to form amoxapine. Because there are multiple metabolic pathways, the risk of metabolic interactions caused by an effect on an individual isoform is minimal. For ADASUVE, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine > > loxapine N-oxide, 7-OH-loxapine > amoxapine. Plasma levels of 8-OH-loxapine are similar to those of the parent compound.

Excretion

Excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8 hours.

Transporter Interaction

In vitro studies indicated that loxapine was not a substrate for p-glycoprotein (P-gp): however, loxapine inhibited P-gp.

Special Populations

Pharmacokinetics in Smokers: Loxapine exposures in nonsmokers and smokers are similar, with geometric mean ratios of 92%, 85%, and 99% for AUC0-2h, AUCinf, and Cmax respectively. No dosage adjustment is recommended based on smoking status.

Demographic Effects: There were no clinically significant differences in loxapine pharmacokinetics following administration of ADASUVE in subgroups based on age, weight, body mass index, gender, or race.

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).

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].

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

  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
a Least squares mean for the difference defined as the change from baseline
b 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.

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)

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

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

  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
a Least squares mean

Use in specific populations

In general, no dose adjustment for Adasuve is required on the basis of a patient’s age, gender, race, smoking status, hepatic function, or renal function.

8.1 Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies of Adasuve use in pregnant women. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Loxapine, the active ingredient in Adasuve, has demonstrated increased embryofetal toxicity and death in rat fetuses and offspring exposed to doses approximately 0.5-fold the maximum recommended human dose (MRHD) on a mg/m2 basis. Adasuve should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Human Data

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders in these neonates. These complications have varied in severity; in some cases symptoms have been self-limited, but in other cases neonates have required intensive care unit support and prolonged hospitalization.

Animal Data

In rats, embryofetal toxicity (increased fetal resorptions, reduced weights, and hydronephrosis with hydroureter) was observed following oral administration of loxapine during the period of organogenesis at a dose of 1 mg/kg/day. This dose is equivalent to the MRHD of 10 mg/day on a mg/m2 basis. In addition, fetal toxicity (increased prenatal death, decreased postnatal survival, reduced fetal weights, delayed ossification, and/or distended renal pelvis with reduced or absent papillae) was observed following oral administration of loxapine from mid-pregnancy through weaning at doses of 0.6 mg/kg and higher. This dose is approximately half the MRHD of 10 mg/day on a mg/m2 basis.

No teratogenicity was observed following oral administration of loxapine during the period of organogenesis in the rat, rabbit, or dog at doses up to 12, 60, and 10 mg/kg, respectively. These doses are approximately 12-, 120-, and 32-fold the MRHD of 10 mg/day on a mg/m2 basis, respectively.

8.3 Nursing Mothers 

It is not known whether Adasuve is present in human milk. Loxapine and its metabolites are present in the milk of lactating dogs. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Adasuve, a decision should be made whether to discontinue nursing or discontinue Adasuve, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Adasuve in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Boxed Warning and Warnings and Precautions (5.3)]. Adasuve is not approved for the treatment of dementia-related psychosis.  Placebo-controlled studies of Adasuve in patients with agitation associated with schizophrenia or bipolar disorder did not include patients over 65 years of age.

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).

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