Loxapine

Articles · Lactation Safety Information · New Medicines ·

59270007

Articles

Lactation Safety Information

Inhalation

Inhalation
Quetiapine, Haloperidol
No published evidence of safety
Low levels anticipated in milk due to high protein binding
Withhold breast feeding for 12 hours after a dose to reduce risk of infant sedation
Monitor infant for drowsiness, poor feeding, irritability, and behavioural effects
9th November 2018

New Medicines

Adasuve · Bipolar disorder; acute agitation and disturbed behaviour

Information

Adasuve
New molecular entity
Galen
Galen

Development and Regulatory status

Launched
Launched
Launched
01. PIII study for acute agitation in patients with bipolar I disorder (1)
02. Oct 08: US regulatory filing expected early 2010 (2).
03. Dec 09: Filedin the US for the rapid treatment of agitation in pts with schizophrenia or bipolar disorder. Application contains efficacy & safety data from >1600 pts and 13 clinical studies (4)
04. Feb 10: FDA is expected to make a decision on approval by October 11, 2010 [6].
05. 8th Oct 10: FDA has issued a complete response letter. The agency has concerns: relating to data from the 3 PI pulmonary safety studies which identified dose-related post-dose decreases in FEV1 in healthy subjects and in subjects with COPD and asthma; about the suitability of the stability studies undertaken; and about issues relating to the pre-approval manufacturing inspection [8].
06. Dec 10: EU filing expected mid-2011 [9].
07. Jan 11: Plan to re-submit filing in US in July 2011 [9]
08. Aug 11: Company has resubmitted in the US following the Complete Response Letter in Oct 2010. The submission contains new data from the human factors study, stability data from new production batches manufactured late last year, updated manufacturing and controls sections addressing findings from the Company´s Pre-Approval Inspection, and updated draft labeling and a comprehensive REMS proposal [1].
09. Aug 11: US FDA have accepted the New Drug Application (NDA) for Adasuve (loxapine) as a complete, class II response to the FDA´s action letter, with an indicated Prescription Drug User Fee Act (PDUFA) goal date of 04 February 2012. [11]
10. Oct 11: Filed in the EU [12].
11. Nov 11: Loxapine will be discussed at the FDA’s Psychopharmacologic Drugs Advisory Committee on Dec 12, 2011 [13].
12. Dec 11: Outside advisers to the FDA recommended that the agency approve a single daily dose of loxapine for schizophrenia and bipolar mania. The 9-8 vote was contingent on the company using a risk mitigation plan proposed by the FDA. [14]
13. May 12: FDA issues a complete response letter because of manufacturing deficiencies related to the inhaler device used to administer Adasuve [15].
14. Jul 12: Refiled in the US. Decision on approval expected by 21 Dec 12 [16].
15. Dec 12: Recommended for approval in the EU for the rapid control of mild-to- moderate agitation in adult patients with schizophrenia or bipolar disorder [18].
16. Dec 12: Approved in US for acute treatment of agitation of pts with bipolar I disorder [19]
17. Feb 13: Approved in the EU. Adasuve 4.5 mg and 9.1 mg inhalation powder loxapine, pre-dispensed, is authorized for the rapid control of mild-to-moderate agitation in adult patients with schizophrenia or bipolar disorder. Marketing authorization requires that patients receive regular treatment immediately after control of acute agitation symptoms, and that Adasuve is administered only in a hospital setting under the supervision of a healthcare professional. Short-acting beta-agonist bronchodilator treatment should be available for treatment of possible severe respiratory side-effects (bronchospasm). The EU marketing partner, Grupo Ferrer, is preparing for launch. First EU launches will be in Germany and Austria in Q3 2013, with a planned launch into the rest of the EU countries in 2014 [20].
18. Aug 13: Launched in Germany by Grupo Ferrer Internacional [21].
19. Mar 14: Launched in the US [22]
20. Jan 17: Inhaled loxapine is launched in the US, Argentina, Austria, Colombia, Czech Republic, Denmark, Finland, France, Germany, Guatemala, Hungary, Latvia, Lithuania, Norway, Poland, Romania, Slovakia, Spain and Sweden, and is approved in the EU, Iceland, Liechtenstein, Chile, Costa Rica, Ecuador, El Salvador, Honduras and Paraguay for the treatment of acute agitation associated with schizophrenia or bipolar disorders, in adults [25].
21. Sept 17: Galen has acquired the US commercial rights of loxapine from Alexza [26].
22. Oct 17: Launched in UK by Galen. Price per single-dose inhaler = £58.30 [27].

Category

Dopamine D2 receptor antagonist
Patients with schizophrenia and bipolar disorder experience an average of 11 to 12 episodes of acute agitation each year. Agitation episodes are currently treated about 55% of the time with oral antipsychotics and about 45% of the time with IM injections
Bipolar disorder; acute agitation and disturbed behaviour
Inhalation

Further information

Yes
May 2013

Trial or other data

01. PIII RCT - 300 pts with bipolar I admitted with acute agitation - loxapine 5mg and 10mg with up to 3 doses in a 24-hr period depending on clinical status. Main outcome = change from baseline in the PANSS (Positive and Negative Symptom Scale) Excited Component (also known as PEC) score, measured at 2 hours after the first dose. (1)
02. Oct 08: Enrollment in PIII trial complete. Results expected late 2008 (2).
03. Dec 08: A P3 multicentre, randomised, double-blind, placebo-controlled trial enrolled 314 acutely agitated patients with bipolar I disorder at 17 U.S. centers. Both doses (5mg and 10mg) of Staccato loxapine met the study primary endpoint, showing a significant improvement in the reduction of acute agitation compared with placebo, according to the company (3)
04. The Staccato system is a hand-held, single-dose inhaler that delivers a drug aerosol to the deep lung that results in IV-like pharmacokinetics and rapid systemic effects. The core of the hand-held Staccato system is a heat package with a stainless steel substrate, onto which a thin film of drug is coated. When the patient draws a single normal breath through the Staccato device, the substrate surface instantly heats to create an aerosol of optimally-sized, excipient-free particles of drug that are drawn into the patient´s lungs. The entire Staccato system actuation and drug delivery occur in less than one second [5].
05. Feb 10: Alexza has established a collaboration with Biovail to develop and commercialize AZ-004 (Staccato loxapine) in the US and Canada. The collaboration provides for the development and commercialization of AZ-004 for multiple indications, including the proposed initial indication of treating agitation in schizophrenia and bipolar patients, as well as potential future clinical development in additional psychiatric and neurological indications. Biovail will lead the commercialization activities for AZ-004. Alexza will continue to manage the ongoing AZ-004 NDA review and approval process in connection with the initial indication [5].
06. May 10: Additional efficacy results from two PIII trials of loxapine in treating agitation in patients with schizophrenia or bipolar disorder were presented at the American Psychiatric Association 2010 meeting. 344 patients with schizophrenia and 314 patients with bipolar I disorder were randomized to receive either 5 or 10mg loxapine or placebo in an in-patient treatment facility. Up to three doses of loxapine could be given during the 24-hour study period. The primary efficacy assessment was change from baseline at 2 hours post-dose using the total Positive and Negative Syndrome Scale - Excited Component (PEC) score. The PEC score comprises 5 elements (hostility, uncooperativeness, excitement, poor impulse control and tension, each score 1-7). Each PEC item improved with loxapine treatment, with differences vs placebo starting at 10 minutes after dosing. On average, each item improved 1 to 2 units over the first 2 hours for both patient groups [7].
07. Results of the PIII study in 314 patients with agitation associated with bipolar disease publisehed in: Bipolar Disorders Volume 14, Issue 1, pages 31–40, February 2012 (http://onlinelibrary.wiley.com/doi/10.1111/j.1399-5618.2011.00975.x/full)
08. Aug 12: Alexza has received its EU Certificate of GMP Compliance of a Manufacturer, valid to May 15, 2015 [23].Aug 12: Alexza has received its EU Certificate of GMP Compliance of a Manufacturer, valid to May 15, 2015 [17].
09. May 13: NICE is unable to recommend the use in the NHS of loxapine inhalation for treating acute agitation and disturbed behaviours associated with schizophrenia and bipolar disorder because no evidence submission was received from the manufacturer of the technology [23].

Evidence based evaluations

Adasuve · Schizophrenia; acute agitation and disturbed behaviour

Information

Adasuve
New molecular entity
Galen
Galen

Development and Regulatory status

Launched
Launched
Launched
October 2017
01. PIII study for acute agitation in patients with schizophrenia (1)
02. Dec 09: New Drug Application filed with FDA for loxapine for the rapid treatment of agitation in pts with schizophrenia or bipolar disorder. NDA contains efficacy & safety data from >1600 pts and 13 clinical studies (3)
03. Feb 10: FDA is expected to make a decision on approval by October 11, 2010 [5].
04. 8th Oct 10: FDA has issued a complete response letter. The agency has concerns: relating to data from the 3 PI pulmonary safety studies which identified dose-related post-dose decreases in FEV1 in healthy subjects and in subjects with COPD and asthma; about the suitability of the stability studies undertaken; and about issues relating to the pre-approval manufacturing inspection [7].
05. Dec 10: Filing in EU expected mid-2011 [8].
06. Jan 11: Plan to re-submit filing in US in July 2011 [9]
07. Aug 11: Company has resubmitted in the US following the Complete Response Letter in Oct 2010. The submission contains new data from the human factors study, stability data from new production batches manufactured late last year, updated manufacturing and controls sections addressing findings from the Company´s Pre-Approval Inspection, and updated draft labeling and a comprehensive REMS proposal [11]
08. Aug 11: US FDA have accepted the New Drug Application (NDA) for Adasuve (loxapine) as a complete, class II response to the FDA´s action letter, with an indicated Prescription Drug User Fee Act (PDUFA) goal date of 04 February 2012. [12]
09. Oct 11: Planning to file the ADASUVE in the EU in 2H 2011 [13].
10. Oct 11: Filed in EU [14].
11. Oct 11: European Medicines Agency (EMA) Marketing Authorisation Application (MAA) filed for rapid control of agitation in adult patients with schizophrenia. [15]
12. Nov 11: Nov 11: Loxapine will be discussed at the FDA’s Psychopharmacologic Drugs Advisory Committee on Dec 12, 2011 [16].
13. Nov 11: FDA approval decision date: Feb. 4, 2012 [17]
14. Dec 11: US FDA is concerned that inhaled loxapine may put some patients at risk for respiratory failure: it can cause bronchial spasms that may be fatal in people with conditions such as asthma. Outside advisers to the FDA plan to meet Dec. 12th to evaluate the findings. [18]
15. Dec 11: Outside advisers to the FDA recommended that the agency approve a single daily dose of loxapine for schizophrenia and bipolar mania. The 9-8 vote was contingent on the company using a risk mitigation plan proposed by the FDA. [19]
16. Jan 12: FDA decision date now May 4; review extended as the risk evaluation and mitigation strategy programme has been designated a major amendment [20].
17. May 12: FDA issues a complete response letter because of manufacturing deficiencies related to the inhaler device used to administer Adasuve [21].
18. Jul 12: Refiled in the US. Decision on approval expected by 21 Dec 12 [22].
19. Dec 12: Recommended for approval in the EU for the rapid control of mild-to- moderate agitation in adult patients with schizophrenia or bipolar disorder [24].
20. Dec 12: Approved in US for acute treatment of agitation in pts with schizophrenia [25]
21. Feb 13: Approved in the EU. Adasuve 4.5 mg and 9.1 mg inhalation powder loxapine, pre-dispensed, is authorized for the rapid control of mild-to-moderate agitation in adult patients with schizophrenia or bipolar disorder. Marketing authorization requires that patients receive regular treatment immediately after control of acute agitation symptoms, and that Adasuve is administered only in a hospital setting under the supervision of a healthcare professional. Short-acting beta-agonist bronchodilator treatment should be available for treatment of possible severe respiratory side-effects (bronchospasm). The EU marketing partner, Grupo Ferrer, is preparing for launch. First EU launches will be in Germany and Austria in Q3 2013, with a planned launch into the rest of the EU countries in 2014 [26].
22. Aug 13: Launched in Germay by Grupo Ferrer Internacional [27].
23. Mar 14: Launched in the US [28,30].
24. Jan 17: Inhaled loxapine is launched in the US, Argentina, Austria, Colombia, Czech Republic, Denmark, Finland, France, Germany, Guatemala, Hungary, Latvia, Lithuania, Norway, Poland, Romania, Slovakia, Spain and Sweden, and is approved in the EU, Iceland, Liechtenstein, Chile, Costa Rica, Ecuador, El Salvador, Honduras and Paraguay for the treatment of acute agitation associated with schizophrenia or bipolar disorders, in adults [31].
25. Sep 17: Galen has acquired the US commercial rights of loxapine from Alexza [32].
26. Oct 17: Launched in UK by Galen. Price per single-dose inhaler = £58.30 [33].

Category

Dopamine D2 receptor antagonist
Patients with schizophrenia and bipolar disorder experience an average of 11 to 12 episodes of acute agitation each year. Agitation episodes are currently treated about 55% of the time with oral antipsychotics and about 45% of the time with IM injections
Schizophrenia; acute agitation and disturbed behaviour
Inhalation

Further information

Yes
May 2013

Trial or other data

01. PIII study in 300 pts with acute agitation in schizophrenia. The study will examine AZ 004 at two dose levels, 5 and 10 mg with up to 3 doses in a 24-hour period, depending on the patient’s clinical status. The main outcome for the trial is the change from baseline in the PANSS (Positive and Negative Symptom Scale) Excited Component (also known as PEC) score, measured at 2 hours after the first dose. (1)
02. PIII trial results - 344 pts. Both doses of loxapine (5 mg and 10 mg) met the primary endpoint, (PANSS (Positive and Negative Symptom Scale) Excited Component score) which was a statistically noteworthy reduction in agitation from baseline to the 2-hour post-dose time point vs. placebo. (2)
03. The Staccato system is a hand-held, single-dose inhaler that delivers a drug aerosol to the deep lung that results in IV-like pharmacokinetics and rapid systemic effects. The core of the hand-held Staccato system is a heat package with a stainless steel substrate, onto which a thin film of drug is coated. When the patient draws a single normal breath through the Staccato device, the substrate surface instantly heats to create an aerosol of optimally-sized, excipient-free particles of drug that are drawn into the patient´s lungs. The entire Staccato system actuation and drug delivery occur in less than one second [4].
04. Feb 10: Alexza has established a collaboration with Biovail to develop and commercialize AZ-004 (Staccato loxapine) in the US and Canada. The collaboration provides for the development and commercialization of AZ-004 for multiple indications, including the proposed initial indication of treating agitation in schizophrenia and bipolar patients, as well as potential future clinical development in additional psychiatric and neurological indications. Biovail will lead the commercialization activities for AZ-004. Alexza will continue to manage the ongoing AZ-004 NDA review and approval process in connection with the initial indication [4].
05. May 10: Additional efficacy results from two PIII trials of loxapine in treating agitation in patients with schizophrenia or bipolar disorder were presented at the American Psychiatric Association 2010 meeting. 344 patients with schizophrenia and 314 patients with bipolar I disorder were randomized to receive either 5 or 10mg loxapine or placebo in an in-patient treatment facility. Up to three doses of loxapine could be given during the 24-hour study period. The primary efficacy assessment was change from baseline at 2 hours post-dose using the total Positive and Negative Syndrome Scale - Excited Component (PEC) score. The PEC score comprises 5 elements (hostility, uncooperativeness, excitement, poor impulse control and tension, each score 1-7). Each PEC item improved with loxapine treatment, with differences vs placebo starting at 10 minutes after dosing. On average, each item improved 1 to 2 units over the first 2 hours for both patient groups [6].
06. Jan 11: PIII study results (n=344 pts with schizophrenia experiencing agitation). Pts received 1-3 doses of loxapine 5mg or 10mg or placebo. Change from baseline to 2 hours after first dose of study med in the PANSS Excited Component (PEC) score was from 17.6 to 9.0 (-8.6) (10mg, p<0.0001), from 17.8 to 9.8 (-8.0) (5mg, p=0.0004) and from 17.4 to 11.8 (-5.6) (placebo). CGI Improvement scale score 2 hours after first dose was 2.1 (10mg, p<0.0001), 2.3 (5mg, p=0.0015) and 2.8 (placebo). Both doses of loxapine provided statistically significant reduction in agitation vs. placebo. A statistically significant reduction in PEC score was evident 10mins after dose one with both 5mg and 10mg doses. [10]
07. Oct 11: Alexza and Grupo Ferrer International have entered into a commercial partnership for Adasuve (Staccato loxapine) and will be partners in the registration, distribution and promotion of ADASUVE in Europe, Latin America, Russia and the Commonwealth of Independent States countries [13].
08. Aug 12: Alexza has received its EU Certificate of GMP Compliance of a Manufacturer, valid to May 15, 2015 [23].
09. May 13: NICE is unable to recommend the use in the NHS of loxapine inhalation for treating acute agitation and disturbed behaviours associated with schizophrenia and bipolar disorder because no evidence submission was received from the manufacturer of the technology [29].

Evidence based evaluations