Loxapine Inhalation Powder (Adasuve)

Abstract

Loxapine inhalation powder (Adasuve): an innovative formulation of an antipsychotic treatment for agitation

INTRODUCTION

Schizophrenia is a disabling chronic mental illness that is ranked by the World Health Organization among the top 10 illnesses that contribute to the global burden of disease.¹ Approximately 1% of people living in the United States have this illness.² Lifetime prevalence of schizophrenia can range from 0.3% to 0.7% without variation based on race, ethnicity, culture, or geographic location. Social and occupational functioning are significantly reduced with the disease, which makes attaining and maintaining employment difficult and can interfere with continuing education, since psychotic features usually emerge between the late teens and mid-30s.³ Clinical manifestations of schizophrenia can present in a range of ways, such as positive and/or negative symptoms, cognitive impairment, dysphoric mood, anxiety, abnormalities in sensory processing, and lack of insight. Lack of insight increases the risk of non-adherence, relapse, and aggression.³

Aggressive behavior in general may be more common in bipolar disorder than in other psychiatric disorders.^4,5 Studies have found physical aggression was higher in patients with bipolar disorder (75%) compared with other psychiatric disorders.⁶ Lifetime prevalence of bipolar I disorder is similar to that of schizophrenia at 1%, with a mean age at onset of approximately 18 years.⁷ Mania, the classic symptom of bipolar I, is classified as having an abnormally, persistently elevated, expansive, and/or irritable mood with increased levels of energy/activity for most of the day, almost every day for a week or longer. Often described as “feeling on top of the world,” patients do not perceive that they are ill or in need of treatment. While some individuals become more sexually provocative or have excessive optimism and feelings of grandiosity, others may become hostile and physically threatening. These actions can quickly escalate and lead to physical assault and even emergency room visits.³

This state of motor restlessness and mental tension puts emergency room patients and staff at an increased risk for injury. Agitation may necessitate the use of physical restraints, seclusion, or psycho-tropics to calm the patient. Anti psychotic medications are the treatments of choice, as they have been shown in several clinical trials^8,14 to address the symptoms and behaviors associated with schizophrenia and agitation. Sedating benzodiazepines are often prescribed to patients with a history of aggression in an effort to reduce episodes; however, aggression often requires emergency treatment with “as needed” medications, typically in an oral or injectable formulation. Speed of onset is the most important factor in choosing a route of administration, according to the Expert Consensus Guidelines for Treatment of Behavioral Emergencies.⁸ While oral drugs are generally slower to act than intramuscular injections, some intramuscular formulations have a delayed onset, taking up to 60 minutes to act.⁹ Thus the need for a fast-acting, effective, and well-tolerated mechanism is evident.

Loxapine inhalation powder (Adasuve, Teva), approved by the FDA on December 21, 2012, utilizes an antipsychotic with more than three decades of experience in a novel delivery system for the treatment of agitation associated with schizophrenia or bipolar mania.

PHARMACOLOGY AND MECHANISM OF ACTION

Loxapine is regarded as a dibenzoxazepine compound found in a subclass of tricyclic antipsychotic agents, chemically distinct from many antipsychotics available in the thioxanthene, butyrophenone, and phenothiazine classes. Chemically, 2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f ] [1,4] oxazepine has a molecular formula of C₁₈H₁₈ClN₃O and a melting point of 109 to 110 degrees Celsius.¹⁰

Adasuve utilizes a Staccato delivery system developed by Alexza. This single-use device and drug film combination allows rapid systemic delivery of loxapine via inhalation through thermally generated aerosolization of the excipient-free product. Aerosolization is achieved by pulling a tab on the opposed end of the mouthpiece to initiate the heating process. Heating of the film inside the unit is rapid and even to prevent denaturing of the drug; this allows vaporization of the product, which condenses into aerosol particles. Illumination of a green light indicates that the product is ready to be inhaled. The aerosolized product is dispersed into the airstream created by the patient inhaling through the mouthpiece. After inhalation, the green light shuts off, indicating a dose has been delivered successfully. A 10-mg dose of Adasuve delivers 9.1 mg of loxapine, according to in vitro tests. Each unit is packaged inside a sealed foil pouch.¹¹

Loxapine exerts its antipsychotic effect by acting as an antagonist at central serotonin and dopamine receptors. Loxapine has high affinity for D₁, D₂, D₃, and D₄ receptors and 5-HT_2A receptors. Treatment of agitation is not fully understood, but loxapine possesses moderate anticholinergic activity (via muscarinic M1 antagonism), strong α₁- and α₂-adrenergic receptor antagonism, and moderate histaminergic antagonism (via histamine [H₁] receptors). Antagonism of α₁-adrenergic as well H₁ receptors is thought to be responsible for the sedation caused by loxapine administration.¹¹

PHARMACOKINETICS

Absorption

Administration of Adasuve results in rapid absorption with a T_max of two minutes, reaching a mean maximum plasma concentration (C_max) of 257 ng/mL plus or minus 219 ng/mL. Exposure in the first two hours after administration of a 10-mg dose was 66.7 ng•h/mL.¹¹

Distribution

After inhalation, animal studies show an initial preferential distribution in the lungs, brain, spleen, heart, and kidneys. Loxapine is removed rapidly from the plasma and distributed throughout the body; 96.6% is protein-bound.¹¹

Metabolism

Loxapine is hepatically metabolized following oral administration through multiple metabolic pathways. Hydroxylation, N-oxidation, and de-methylation form 8-OH-loxapine (CYP1A2) and 7-OH-loxapine (CYP3A4 and CYP2D6), loxapine N-oxide by flavanoid monoamine oxidases (FMOs), and amoxapine, respectively. Due to extensive metabolism through various pathways, metabolic interactions should be minimal. It should be noted, however, that loxapine inhibits p-glycoprotein, although it is not a substrate for that transporter.¹¹

Excretion

Conjugated metabolites are renally eliminated and unconjugated via feces. The drug’s half-life ranges from six to eight hours.¹¹

INDICATIONS AND DOSAGE

Adasuve is indicated for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. To alleviate the risk of bronchospasm, Adasuve may be administered only to patients in a health care facility enrolled in the Adasuve Risk Evaulation and Mitigation Strategy (REMS) program. One 10-mg unit may be used once in a 24-hour period. After inhalation the patient must be monitored, including a physical exam with chest auscultation, for signs and symptoms of bronchospasm or other respiratory distress every 15 minutes for a minimum of one hour. Sites enrolled in the Adasuve REMS program must have immediate on-site access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation).¹¹

Adasuve is contraindicated in patients with a history or current diagnosis of asthma, chronic obstructive pulmonary disease, emphysema, or other pulmonary disease associated with bronchospasm. Also, patients with acute respiratory signs or symptoms (wheezing, acute bronchospasms, and/or dyspnea) or currently receiving medications for airway diseases are contraindicated, as are patients with a known hypersensitivity to loxapine or amoxapine.¹¹

The efficacy data for clinical trials of Adasuve are summarized in Table 1, while data from trials of the drug’s pulmonary safety are summarized in Table 2.

Table 1.

Summary of Clinical Trials of Inhaled Loxapine

	Allen et al.13	Lesem et al.14	Kwentus et al.9
Location, dates	18 U.S. clinical or hospital sites, September 2006–January 2007	24 U.S. clinical or hospital sites, September 2006–January 2007	17 U.S. clinical or hospital sites, July 2008–November 2008
Study subjects	129 patients ages 18–65; DSM-IV criteria for schizophrenia, schizoaffective disorder, schizophreniform, and visible agitation	344 patients ages 18–65; DSM-IV diagnosis of schizophrenia and clinically agitated	314 patients ages 18–65; DSM-IV diagnosis of bipolar I (manic or mixed manic) confirmed with MINI and clinically agitated
Primary objective	Assess efficacy and safety of inhaled loxapine	Assess efficacy of 1 to 3 doses of inhaled loxapine
Study design	Single-dose, randomized, double-blind, placebo-controlled, parallel-group study comparing 5 mg and 10 mg of inhaled loxapine with inhaled placebo	Repeat-dose, randomized, double-blind, placebo-controlled, parallel-group study comparing 5 mg and 10 mg of inhaled loxapine with inhaled placebo
Primary efficacy endpoints	Absolute change in PANSS-EC score from baseline to 2 hours following dose 1 of inhaled loxapine
Primary endpoint results	Statically significant for 10 mg vs. placebo (P = 0.0002)	Statically significant decrease for 10 mg and 5 mg inhaled loxapine vs. placebo (P < 0.0001 in both studies)
Secondary efficacy endpoints	Change in PANSS-EC from baseline at any time over 24 hours Change in CGI-I at 2 hours after dose 1 Frequency of CGI-I responses achieving a score of 1 (very much improved) and/or 2 (much improved) at 2 hours after dose 1 Change from baseline in BARS score at any time over 24 hours after dose 1	Change in PANSS-EC from baseline at any time over 24 hours Change in CGI-I at 2 hours after dose 1 Frequency of CGI-I responses achieving a score of 1 (very much improved) and/or 2 (much improved) at 2 hours after dose 1
Secondary efficacy endpoint results	Significant for 10 mg vs. placebo at 20 minutes (P < 0.05) Significant for both 5 mg (P = 0.0067) and 10 mg (P = 0.0003) vs. placebo Significant decrease for both 5 mg (P = 0.0067) and 10 mg (P = 0.0003) Significant at 2 hours for 10 mg inhaled loxapine (P < 0.0001)	Significant for both strengths vs. placebo at 10 minutes (P = 0.0003 for 5 mg, P < 0.0001 for 10 mg) Significant difference in CGI-I scores at 2 hours for 5 mg (2.3) and 10 mg (2.1) vs. placebo (2.8) (P = 0.0015 for 5 mg; P < 0.0001 for 10 mg) Significantly greater for 5 mg (57%) and 10 mg (67%) vs. placebo (36%) (P = 0.0015 for 5 mg, P < 0.0001 for 10 mg)	Significant for both strengths vs. placebo at 10 minutes (P = 0.0001 for 5 mg, P < 0.0001 for 10 mg) Significant decrease for 5 mg (P < 0.0001) and 10 mg (P < 0.0001) vs. placebo Significant for 5 mg (66%) and 10 mg (75%) (P = 0.0001 for 5 mg, P < 0.0001 for 10 mg)
Adverse events	Most frequently reported for 5 mg and 10 mg, respectively: dysgeusia (4%, 17%); somnolence (4%, 10%); dizziness (11%, 5%)	For 5 mg and 10 mg, respectively: sedation (12.9%, 10.6%); dysgeusia (8.6%, 10.6%); dizziness (5.2%, 10.6%); hypoaesthenia (0.9%, 3.5%); headache (2.6%, 2.7%); somnolence (2.6%, 2.7%); nausea (0.9%, 1.8%). Serious: wheezing/bronchospasms (n = 3), neck dystonia/oculogyration (n = 1), severe sedation (n = 1); coughing (n = 1)	For 5 mg and 10 mg, respectively: sedation (6.7%, 5.7%); dysgeusia (17.3%, 17.1%); dizziness (5.8%, 4.8%); fatigue (3.8%, 2.9%); headache (3.8%, 1.9%); stomach discomfort (2.9%, 1%); throat irritation (0%, 3.8%). Moderate akathisia (n = 1); hypotension (n = 1); hypertension (n = 1); anxiety (n = 2). No coughing, wheezing, or bronchospasm reported*

BARS = Behavioral Activity Rating Scale; CGI–I = Clinical Global Impression–Improvement Scale; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4^th edition; MINI = Mini International Neuropsychiatric Interview; PANSS–EC = Positive and Negative Syndrome Scale–Excited Component

^*This finding is likely due to the addition of an exclusion criterion preventing patients with an acute or chronic pulmonary condition from participating.

Table 2.

Summary of Trials of Inhaled Loxapine’s Pulmonary Safety¹⁵

Primary outcome measure: Change in FEV₁ from baseline in 16 post-treatment tests

	004–104	004–105	004–108
Study subjects	30 healthy nonsmokers ages 18–65	52 subjects with mild-to-moderate persistent asthma	53 subjects with COPD
Study design	Randomized, double-blind, placebo-controlled, two-way crossover study	Randomized, double-blind, placebo-controlled, parallel-group study
Procedure summary	Participants received either inhaled placebo or 10 mg of inhaled loxapine in 2 doses within 24 hours with doses separated by 8 hours.	Participants received either inhaled placebo or 10 mg of inhaled loxapine in 2 doses within 24 hours with doses separated by 10 hours.
Results	After 8 hours, 26.9% of participants in both the inhaled loxapine and placebo groups had a ≥ 10% reduction in FEV1. FEV1 reductions of ≥ 15% were experienced by 19.2% of those using inhaled loxapine compared with 3.8% using placebo. One patient had an FEV1 reduction of ≥ 20% compared with none using placebo.	Of patients receiving inhaled loxapine, 69% (n = 18) experienced severe AEs* compared with 12% (n = 3) receiving inhaled placebo. The most commonly reported AEs with loxapine: bronchospasm (27%); chest discomfort (23%); wheezing (15%); and dyspnea (11.5%).	Of patients receiving inhaled loxapine, 58% (n = 15) experienced notable respiratory symptoms compared with 22% (n = 6) receiving inhaled placebo. The most commonly reported AEs with loxapine: dyspnea (11.5%); cough (11.5%); and wheezing (7.7%). There were no reports of bronchospasm.

AE = adverse event; COPD = chronic obstructive pulmonary disease; FEV₁ = forced expiratory volume in one second

^*Severe AE was defined as a ≥ 20% reduction in FEV1 from baseline at first measurement, or use of rescue medication (bronchodilator).

ADVERSE EFFECTS

In three short-term (24-hour), randomized, double-blind, placebo-controlled clinical trials, 259 patients received Adasuve 10 mg. Based on pooled data from these trials, the most common adverse reactions were dysgeusia (14%), sedation (12%), and throat irritation (3%). Bronchospasms occurred in 0.8% of patients with no airway disease, 54% of patients with asthma (12% with placebo), and 19% of patients with COPD (11% with placebo). There were possible dose-related bronchospasms in patients with asthma (27% after one dose, 41% after a second dose). Other adverse effects include extrapyramidal symptoms (neck dystonia, 0.4%, and akathisia, 0.4%, versus 0% on placebo), tachycardia, hypotension, hypertension, orthostatic hypotension, lightheadedness, and syncope.¹¹ This medication is in pregnancy category C in all three trimesters.

DRUG INTERACTIONS

The concomitant use of central nervous system depressants such as loxapine with other agents, including sedatives, opioids, and antidepressants, may increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Anticholinergic drugs, or those with anticholinergic properties, that are used with Adasuve may exacerbate glaucoma and urinary retention. ¹¹ Given the drug’s multiple pathways for metabolism, the risk for pharmacokinetic drug interactions is believed to be minimal. Further research is needed to study specific agents in combination with loxapine.

COST

The average wholesale price for a 10-mg package of Adasuve was $174 in August 2014.¹²

CONCLUSION

Adasuve consists of a novel inhalation delivery system combined with a well-studied and established antipsychotic agent. Although the system is relatively simple to self-administer, Adasuve requires cooperation from the patient. In some emergencies, this may not be an option when a patient is actively refusing medications. Clinical trials have established effectiveness for this route of delivery; however, clinicians should be mindful of the risks associated with it. If an institution meets the requirement for REMS authorization, Adasuve may be a less invasive or even patient-preferred option (as opposed to intramuscular routes) when emergency treatment of agitation is necessary.