Adasuve for the Rapid Treatment of Agitation in Schizophrenia

JoAnn Filipov, Mercer University College of Pharmacy

Limited options of antipsychotic drug administration exist in the current standard of care for the acute treatment of agitation. [1] According to the Expert Consensus Guidelines for Treatment of Behavioral Emergencies, speed of onset is key in choosing medication administration route. [2] Since intravenous administration of antipsychotics necessitates established intravenous access, oral and intramuscular administrations are more prominently used. However, oral and intramuscular formulations have a more gradual onset of action, unlike intravenous pharmacokinetics, thus allowing for symptoms to escalate before they begin to resolve. [3] It is reported that patients with an episode of acute agitation often resist intramuscular administration, further escalating the risk of intensifying symptoms. Therefore, there is a need for anti-agitation medications with rapid onset of action and acceptable safety profile that are easy to administer. [4]

Loxapine, an antipsychotic indicated for the treatment of schizophrenia. [5] Loxapine is available as a capsule and intramuscular injection formulations, that have demonstrated efficacy in the treatment of agitation. [6] Due to the unmet need, a new formulation of loxapine, AdasuveÒ, was developed that can be inhaled via Staccato inhalation system. The system is shown to distribute loxapine with intravenous-like pharmacokinetics. [7] Below article summarized the efficacy and safety of Adasuve®. [8]

 

Rapid acute treatment of agitation in individuals with schizophrenia: multicenter, randomized, placebo-controlled study of inhale loxapine
Design Multicenter, randomized, double-blind, placebo-controlled, parallel-group; N=344

 

Objective To evaluate the efficacy and safety of inhaled loxapine in treating agitation in individuals with schizophrenia and to confirm to the tolerability of up to three doses administered in a 24-hour period

 

Study Groups Inhaled loxapine 5 mg (n=116), inhaled loxapine 10 mg (n=113), and inhaled placebo (n=115)
Methods Inclusion criteria:

– agitated patients with schizophrenia (according to DSM-IV criteria) in inpatient settings (newly admitted or had been hospitalized) or in psychiatric emergency department that could allow extended patient stays in a secluded observation room for the study period

– agitation total score of greater than or equal to 14 (out of 35) and had a score of greater than or equal to four (out of seven) on at least one out of the five items on the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC)

– males & females (not pregnant or lactating)

– 18-65 years of age

– medically stable

 

Exclusion criteria:

– agitation primary due to intoxication

– positive urine drug screen for psychostimulants or alcohol dependence within the previous two months

– serious risk of suicide

– use of benzodiazepines/ other hypnotics/ oral or short-acting intramuscular antipsychotics drugs in the four hours prior to study treatment

– use of injectable depot antipsychotics within a one-dose interval prior to study treatment

– use on an investigational drug in the 30 days prior to screening

– clinical significant acute or chronic pulmonary disease

– medically unstable

Thirty minutes prior to study treatment, the baseline agitation was recorded using the PANSS-EC scale, Clinical Global Impression-Severity scale (CGI-S; a pre-treatment agitation assessment), the Agitation-Calmness Evaluation Scale (ACES), and vital signs measurements were also gathered. Participants were randomized via block randomization in a 1:1:1 ratio into study groups. Once randomized, dose one was administered, then patients were monitored for 24 hours. Additional doses (two additional doses maximum) were administered only if necessary, during the period. This was defined as: if agitation did not subside sufficiently after dose one or it recurred. Dose two was given if more than two hours had passed from dose one, and the third dose was given if more than four hours had lapsed after the second dose. Rescue medication, intramuscular lorazepam, was not permitted unless medically necessary, until after the two-hour assessments were recorded, dose two was administered, and minimum 20 minutes had lapsed after the last dose of the study drug.

In the 24-hour evaluation period, two scales were used:

1) PANSS-EC scale, which measured five symptoms associate with agitation (poor impulse control, tension, hostility, uncooperativeness, and excitement) rated from one (absent) to seven (extreme) with the summation to total the participant’s score

2) CGI-I scale, which assessed the participant’s change from baseline agitation rated from one (very much improved) to seven (very much worse)

Patients were evaluated with the PANSS-EC scale at 10, 20, 30, and 45-minute intervals and one, one and a half, two, four, and 24-hours after dose one. Two hours after dose one, they were evaluated with the CGI-I scale. Sedation was assessed by ACES at two hours after dose one to rate the participants on an agitated-calm-sleeping continuum.

For the statistical analysis, power calculations were based on the previous phase II trial. For the primary efficacy outcome, 100 participants per study group (300 participants in total) would provide a 99% statistical power for the 10 mg/placebo pair-wise comparison, 79% statistical power for the 5 mg/placebo pair-wise comparison, and overall, a = 0.05 for the two active/placebo comparisons, which was the standard for all statistical comparisons. Analysis of covariance (ANCOVA) was used for the primary analysis adjusted for baseline PANSS-EC score, treatment, and center, with a global F-test and pair-wise Dunnett’s t-tests for the two follow-up loxapine/placebo pair-wise comparisons.

Duration February 2008 – June 2008
Primary Outcome Measure A change from baseline in the PANNS-EC score two hours after dose one of inhaled loxapine compared with the change from baseline after inhaled placebo
Baseline Characteristics Table 1: Baseline characteristics and disease severity (safety population)

Inhaled placebo (n=115) Inhaled loxapine 5 mg (n=116) Inhaled loxapine 10 mg (n=113)
Age, years
Mean (s.d) 43.9 (9.45) 43.2 (10.24) 42.2 (9.82)
Median 45.0 44.5 44.0
Minimum, maximum 23.0, 63.0 18.0, 65.0 21.0, 62.0
Gender, n (%)
Female 35 (30.4) 29 (25.0) 27 (23.9)
Male 80 (69.6) 87 (75.0) 86 (76.1)
Ethnicity, n (%)
White 32 (27.8) 48 (41.4) 36 (31.9)
Black 70 (60.9) 61 (52.6) 67 (59.3)
Hispanic 9 (7.8) 6 (5.2) 8 (7.1)
Asian 4 (3.5) 1 (0.9) 1 (0.9)
Other 0 0 1 (0.9)
Smoking history, n (%)
Never smoked 15 (13.0) 13 (11.2) 8 (7.1)
Current smoker 90 (78.3) 94 (81.0) 97 (85.8)
Ex-smoker 10 (8.7) 9 (7.8) 8 (7.1)
Time since diagnosis, years
Mean (s.d.) 18.8 (10.34) 16.5 (10.80) 18.2 (10.03)
Minimum, maximum <1, 40 <1, 41 1, 49
Duration of current agitation episode, days
Mean (s.d) 6.9 (9.21) 6.1 (7.50) 7.6 (11.5)
Minimum, maximum <1, 72 <1, 45 <1, 90
Number of previous hospitalizations
Mean (s.d) 9.6 (8.96) 9.2 (12.22) 9.7 (11.26)
Minimum, maximum 0, 50 0,99 0, 90

 

Results Table 2: Baseline mean scores of intention-to-treat population

Inhaled placebo (n=115) Inhaled loxapine 5 mg (n=116) Inhaled loxapine 10 mg (n=112)
 

Mean PANSS-EC score

 

17.4

 

17.8

 

17.6

 

Mean CGI-I score

 

3.9

 

4.0

 

4.1

Table 3: Change from baseline in the PANSS-EC score at two hours post-dose in intention-to-treat population

Inhaled placebo (n=115) Inhaled loxapine 5 mg (n=116) Inhaled loxapine 10 mg (n=112)
 

PANSS-EC score at 2 hours

 

2.8

 

2.3

 

2.1

 

p-value

 

 

0.0015

 

<0.0001

Table 4: CGI-I score at least two hours post-dose in intention-to-treat population

Inhaled placebo (n=115) Inhaled loxapine 5 mg (n=116) Inhaled loxapine 10 mg (n=112)
 

CGI-I Score at 2 hours

 

2.8

 

2.3

 

2.1

 

p-value

 

 

0.0015

 

<0.0001

 

Adverse Events Table 5: Treatment-emergency adverse events in 2% of participants in any treatment group (safety population)

Inhaled placebo (n=115) Inhaled loxapine 5 mg (n=116) Inhaled loxapine 10 mg (n=113)
Participants with an adverse event, n (%) 44 (38.3) 40 (34.5) 43 (38.1)
Adverse events, n (%)
Dysgeusia 3 (2.6) 10 (8.6) 12 (10.6)
Dizziness 11 (9.6) 6 (5.2) 12 (10.6)
Sedation 11 (9.6) 15 (12.9) 12 (10.6)
Hypoaesthenia, oral 0 (0.0) 1 (0.9) 4 (3.5)
Headache 16 (13.9) 3 (2.6) 3 (2.7)
Somnolence 3 (2.6) 3 (2.6) 3 (2.7)
Nausea 6 (5.2) 1 (0.9) 2 (1.8)
Vomiting 3 (2.6) 1 (0.9) 1 (0.9)
Agitation 4 (3.5) 1(0.9) 0 (0.0)
Study Author Conclusions Inhaled loxapine is a rapid, well-tolerated, and safe acute treatment for agitation in people with schizophrenia that may have the potential to be more successful than the previous standard of care options for the management of acute agitation.

 

The trial design aimed to prevent bias introduction to strengthen the study’s internal validity and utilized PANSS-EC and CGI-I scales, validated tools to evaluate schizophrenia symptoms, to produce reliable assessment outcomes. This study did not evaluate the efficacy, safety, and tolerability of inhaled loxapine in an outpatient setting, creating a possible study limitation because many schizophrenia patients are managed in the outpatient setting. Additionally, the trial endpoints were not evaluated in patients with clinically significant pulmonary diseases due to risk of bronchospasm and respiratory distress/arrest. Excluding these patients represents another study limitation and possible risk for individual self-administering inhaled loxapine.

Due to these concerns, the Food and Drug Administration (FDA) created a black boxed warning for bronchospasms when approving inhaled loxapine and can only be administered under in a Risk Evaluation and Mitigation Strategy (REMS) program enrolled healthcare facility. Approved healthcare facilities are required to have a short-acting bronchodilator available for immediate bronchospasm treatment, trained respiratory personnel, and set access to emergency response services. [9] Despite study limitations, inhaled loxapine represents a viable option for acute agitation management in schizophrenia patients because of its rapid onset and ease of administration when utilized in controlled, in-patient settings.

References

[1] Yildiz A, Sachs GS, Turgay A. Pharmacological management of agitation in emergency settings. Emerg Med J. 2003; 20: 339–46.

[2] Allen MH, Currier GW, Hughes DH, Reyes-Harde M, Docherty JP. The expert consensus guideline series:  treatment of behavioral emergencies. Postgrad Med. 2001; May (special number): 1–88.

[3] Breier A, Meehan K, Birkett M, David S, et al. A double- blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002; 59: 441–8.

[4] Battaglia J. The treatment of acute agitation in schizophrenia. CNS Spectr. 2007; 12 (suppl 11): 4–5.

[5] Chakrabarti A, Bagnall A, Chue P, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev. 2007; 4: CD001943.

[6] Gaussares C, Gerard H, Bosc M. Interest in injectable Loxapine for severe agitation. Inf Psychiatr. 1989; 69: 656–60.

[7] Spyker DA, Munzar P, Cassella JV. Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol. 2010; 50: 169–79.

[8] Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation inindividuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011 Jan;198(1):51-8.

[9] Adasuve [package insert]. Souderton, PA: Galen US; August 2017.

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