Out Of The Pipeline

Inhaled loxapine for agitation

Current Psychiatry. 2013 February;12(2):31-36

References

1. Alexza Pharmaceuticals U.S. FDA Approves Alexza’s ADASUVE (loxapine) inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. http://nocache-phx.corporate-ir.net/phoenix.zhtml?c=196151
&p=RssLanding&cat=news&id=1769476. Published December 21, 2012. Accessed January 2, 2013.

2. ADASUVE [package insert]. Mountain View, CA: Alexza Pharmaceuticals; 2012.

3. Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry. 1999;60(suppl 10):20-30.

4. Citrome L. Comparison of intramuscular ziprasidone olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68(12):1876-1885.

5. Noymer P, Myers D, Glazer M, et al. The staccato system: inhaler design characteristics for rapid treatment of CNS disorders. Respiratory Drug Delivery. 2010;1(1):11-20.

6. Spyker DA, Munzar P, Cassella JV. Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol. 2010;50(2):169-179.

7. Dinh KV, Myers DJ, Noymer PD, et al. In vitro aerosol deposition in the oropharyngeal region for Staccato Loxapine. J Aerosol Med Pulm Drug Deliv. 2010;23(4):253-260.

8. Brunton LL, Lazo JS, Parker KL. eds. Goodman & Gilman’s: the pharmacological basis of therapeutics. 11th ed. New York, NY: McGraw-Hill; 2005:472.

9. Allen MH, Feifel DA, Lesem MD, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo controlled trial. J Clin Psychiatry. 2011;72(10):1313-1321.

10. Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198(1):51-58.

11. Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14(1):31-40.

12. Citrome L. Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Int J Clin Pract. 2012;66(3):318-325.

13. Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419.

14. Cassella J, Spyker D, Kwentus J, et al. Rapid improvement in the five-item Positive and Negative Syndrome-Excited Component (PANSS-EC) scale for agitation with inhaled loxapine. Poster presented at: 50th meeting of New Research Approaches for Mental Health Interventions; June 14-17, 2010; Boca Raton, FL.

15. Fishman R, Gottwald M, Cassella J. Inhaled loxapine (AZ-004) rapidly and effectively reduces agitation in patients with schizophrenia and bipolar disorder. Poster presented at: 13th annual meeting of the College of Psychiatric and Neurologic Pharmacists; April 18-21 2010; San Antonio, TX.

16. Fishman R, Spyker D, Cassella J. The safety of concomitant use of lorazepam rescue in treating agitation with inhaled loxapine (AZ-004). Poster presented at: 50th meeting of New Research Approaches for Mental Health Interventions; June 14-17, 2010; Boca Raton, FL.

17. Citrome L. Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder. Int J Clin Pract. 2011;65(3):330-340.

18. Alexza Pharmaceuticals. Adasuve (loxapine) inhalation powder NDA 022549. Psychopharmacologic drug advisory committee briefing document. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psychopharma
cologicDrugsAdvisoryCommittee/UCM282900.pdf. Published December 12, 2011. Accessed January 2, 2013.

19. Food and Drug Administration Briefing document for NDA 022549. Psychopharmacologic Drug Advisory Committee Briefing Document. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Psychopharma
cologicDrugsAdvisoryCommittee/UCM282897.pdf. Accessed January 2, 2013.

¹² The lower the NNT, the stronger the effect size.¹³ See the Box for an explanation of NNT. NNTs in the range of 3 to 5 are comparable to other agents used to treat agitation.⁴

When examining each individual item on the PANSS-EC in each of the phase III trials, every item improved with treatment, starting 10 to 20 minutes after dosing.¹⁴ Each item improved an average of 1 to 2 units from baseline over the first 2 hours post-dose. Moreover, inhaled loxapine appears to reduce agitation equally well in patients with higher or lower levels of agitation at baseline.

Clinical Point

Inhaled loxapine appears to reduce agitation equally well in patients with higher or lower levels of agitation at baseline

Another clinically relevant outcome is whether or not a patient required an additional dose or rescue medication within 24 hours. In the phase III schizophrenia trial,¹⁰ 60.9% of patients randomized to loxapine, 10 mg, did not require an additional dose or rescue medication, compared with 54.4% and 46.1% for loxapine, 5 mg, and placebo, respectively. This yielded an NNT of 7 when comparing loxapine, 10 mg, with placebo.¹² In the BD study,¹⁰ 61.5%, 41.3%, and 26.7% did not require an additional dose or rescue medication within 24 hours for loxapine, 10 mg, 5 mg, and placebo, respectively. In this study, the NNT for loxapine, 10 mg, vs placebo was 3.¹²

In general, there appears to be a dose response for efficacy with inhaled loxapine, and therefore the FDA approved the 10-mg dose.²

Table 2

Summary of double-blind RCTs for inhaled loxapine vs inhaled placebo

Study	Diagnosis	Loxapine		Placebo	Outcomes	Loxapine vs placebo NNT for response at 2 hours^a
Study	Diagnosis	5 mg	10 mg	Placebo	Outcomes	5 mg	10 mg
Allen et al, 2011⁹ (Phase II)	Agitation associated with schizophrenia	n=45	n=41	n=43	On the PANSS-EC score at 2 hours, loxapine, 10 mg, but not 5 mg, was superior to placebo. Loxapine, 10 mg, separated from placebo at 20 minutes, and control was sustained. On the CGI-I at 2 hours, both doses of loxapine were superior to placebo. Using the BARS, loxapine, 10 mg, was superior to placebo starting at 30 minutes and this effect was sustained. Dysgeusia was observed in 4% and 17% for loxapine, 5 mg and 10 mg, respectively, and 9% for placebo	4	3
Lesem et al, 2011¹⁰ (Phase III)	Agitation associated with schizophrenia	n=116	n=113	n=115	On the PANSS-EC score and CGI-I at 2 hours, both doses of loxapine were superior to placebo. Loxapine separated from placebo at 10 minutes. Sustained control was observed over 24 hours. Dysgeusia was observed in 9% and 11% for loxapine 5 mg and 10 mg, respectively, and 3% for placebo	5	4
Kwentus et al, 2012¹¹ (Phase III)	Agitation associated with bipolar I disorder (manic or mixed episode)	n=104	n=105	n=105	On the PANSS-EC score and CGI-I at 2 hours, both doses of loxapine were superior to placebo. Loxapine separated from placebo at 10 minutes. Sustained control was observed over 24 hours. Dysgeusia was observed in 17% for either loxapine 5 mg or 10 mg, respectively, and 6% for placebo	3	3
^aas measured by a CGI-I score of 1 or 2 BARS: Behavioral Activity Rating Scale; CGI-I: Clinical Global Impression Improvement Scale; NNT: number needed to treat; PANSS-EC: Positive and Negative Syndrome Scale Excited Component; RCTs: randomized controlled trials

Box

What is number needed to treat?

Clinical trials produce a mountain of data that can be difficult to interpret and apply to clinical practice. When reading about studies you may wonder:

How large is the effect being measured?
Is it clinically important?
Are we dealing with a result that may be statistically significant but irrelevant for day-to-day patient care?

Number needed to treat (NNT) and number needed to harm (NNH)—2 tools of evidence-based medicine—can help answer these questions. NNT helps us gauge effect size—or clinical significance. It is different from knowing if a clinical trial result is statistically significant. NNT allows us to place a number on how often we can expect to encounter a difference between 2 interventions. If we see a therapeutic difference once every 100 patients (an NNT of 100), the difference between 2 treatments is not of great concern under most circumstances. But if a difference in outcome is seen once in every 5 patients being treated with 1 intervention vs another (an NNT of 5), the result likely will influence day-to-day practice.

How to calculate NNT (or NNH)

What is the NNT for an outcome for drug A vs drug B?

f_A= frequency of outcome for drug A

f_B= frequency of outcome for drug B

NNT = 1/[ f_A - f_B]

By convention, we round up the NNT to the next higher whole number.

For example, let’s say drugs A and B are used to treat depression, and they result in 6-week response rates of 55% and 75%, respectively. The NNT to encounter a difference between drug B and drug A in terms of responders at 6 weeks can be calculated as follows:

Difference in response rates = 0.75 - 0.55 = 0.20
NNT = 1 / 0.20 = 5.

Source: Adapted from Citrome L. Dissecting clinical trials with ‘number needed to treat.’ Current Psychiatry. 2007;6(3): 66-71 and Citrome L. Can you interpret confidence intervals? It’s not that difficult. Current Psychiatry. 2007;6(8):77-82