Limitations of Use:

As part of the ADASUVE REMS Program to mitigate the risk of bronchospasm, ADASUVE must be administered only in a certified healthcare setting [see Warnings and Precautions (5.2)] .

2.1 Dosing Information

ADASUVE must be administered only by a healthcare professional. ADASUVE is administered by oral inhalation only. The recommended dose for acute agitation is 10 mg administered by oral inhalation, using a single-use inhaler. Administer only a single dose within a 24-hour period [see Warnings and Precautions (5.1)] .

2.2 Required Examination Prior to Dosing

Prior to administering ADASUVE, screen all patients for a history of asthma, COPD, or other pulmonary disease, and assess patients (including chest auscultation) for respiratory signs (e.g. wheezing) [see Warnings and Precautions (5.1)] .

2.3 Important Administration Instructions

Read all of these instructions prior to administering ADASUVE.

Step 1. Open the Pouch

When ready to use, tear open the foil pouch and remove the inhaler from the package (see Figure 1).

Figure 1. Tearing the pouch

When the ADASUVE inhaler is removed from the pouch, the indicator light is off (see Figure 2).

Figure 2. ADASUVE Inhaler with Indicator Light

Step 2. Pull Tab

Firmly pull the plastic tab from the rear of the inhaler (see Figure 3). Check that the green light turns on. This indicates that the inhaler is ready for use. Use the inhaler within 15 minutes after removing the tab to prevent automatic deactivation of the inhaler. The green light will turn off, indicating that the inhaler is not usable. Discard the inhaler after one use.

Figure 3.

Step 3. Explain Procedures to the Patient

Explain the administration procedures to the patient prior to use, and advise the patient that it is important to follow the instructions. Inform the patient that the inhaler may produce a flash of light and a clicking sound, and it may become warm during use. These are normal.

Step 4. Instruct the Patient to Exhale

Instruct the patient to hold the inhaler away from the mouth and breathe out fully to empty the lungs (see Figure 4).

Figure 4. Exhale

Step 5. Instruct the Patient to Inhale

Instruct the patient to put the mouthpiece of the inhaler between the lips, close the lips, and inhale through the mouthpiece with a steady deep breath (see Figure 5). Check that the green light turns off indicating that the dose has been delivered.

Figure 5. Inhale

Step 6. Instruct the Patient to Hold Breath

Instruct the patient to remove the mouthpiece from the mouth and hold the breath for as long as possible, up to 10 seconds (see Figure 6).

Figure 6. Hold Breath

Important: If the green light remains on after the patient inhales, the dose of ADASUVE has NOT been delivered. Instruct the patient to repeat Step 4, Step 5, and Step 6 up to 2 additional times. If the green light still does not turn off, discard the inhaler and use a new one.

2.4 Monitoring to Assess Safety

Monitor the patient for signs and symptoms of bronchospasm after ADASUVE administration for at least one hour [see Warnings and Precautions (5.1)] .

5.1 Bronchospasm

ADASUVE can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest [see Adverse Reactions (6.1)] . Administer ADASUVE only in a certified healthcare setting that has immediate access on site to supplies and healthcare professionals competent in the management of acute bronchospasm and access to emergency assistance for symptoms that require immediate medical attention. Certified healthcare settings must have a short-acting bronchodilator (e.g. albuterol) available for the immediate treatment of bronchospasm; this short-acting bronchodilator can be delivered by inhaler (with spacer) or nebulizer [see Boxed Warning and Warnings and Precautions (5.2)] .

Prior to administering ADASUVE, screen patients regarding a current diagnosis or history of asthma, COPD, and other lung disease associated with bronchospasm, acute respiratory symptoms or signs, current use of medications to treat airways disease, such as asthma or COPD; and assess patients (including chest auscultation) for respiratory abnormalities (e.g., wheezing) [See Dosage and Administration (2.2) and Contraindications (4)] . Monitor patients for symptoms and signs of bronchospasm for a minimum of one hour following treatment with ADASUVE [see Dosage and Administration (2.4)] . ADASUVE can cause sedation, which can mask the symptoms of bronchospasm.

Because clinical trials in patients with asthma or COPD demonstrated that the degree of bronchospasm, as indicated by changes in forced expiratory volume in 1 second (FEV1), was greater following a second dose of ADASUVE, limit ADASUVE use to a single dose within a 24-hour period.

Advise all patients of the risk of bronchospasm. Advise them to inform the healthcare professional if they develop any breathing problems such as wheezing, shortness of breath, chest tightness, or cough following treatment with ADASUVE.

5.2 ADASUVE REMS to Mitigate Bronchospasm

Because of the risk of bronchospasm, ADASUVE is available only through a restricted program under a REMS called the ADASUVE REMS [see Boxed Warning and Warnings and Precautions (5.1)] .

Required components of the ADASUVE REMS are:

• Healthcare settings that dispense and administer ADASUVE must be certified and comply with the REMS requirements. Certified healthcare settings must be able to provide immediate access on site to supplies and healthcare professionals competent in the management of acute bronchospasm and access to emergency assistance for symptoms that require immediate medical attention. Settings must have a short-acting bronchodilator (e.g. albuterol) available for the immediate treatment of bronchospasm; this short-acting bronchodilator can be delivered by inhaler (with spacer) or nebulizer.
• Wholesalers and distributors that distribute ADASUVE must distribute only to certified healthcare settings.

Further information is available at www.adasuverems.com or 1-855-755-0492.

5.3 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the cases of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies can be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ADASUVE is not approved for the treatment of elderly patients with dementia-related psychosis [see Boxed Warning] .

5.4 Neuroleptic Malignant Syndrome

Antipsychotic drugs can cause a potentially fatal symptom complex termed Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Associated features can include elevated serum creatine phosphokinase (CPK) concentration, rhabdomyolysis, elevated serum and urine myoglobin concentration, and renal failure. NMS did not occur in the ADASUVE clinical program.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, or drug fever).

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs that may contribute to the underlying disorder, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.5 Hypotension and Syncope

ADASUVE can cause hypotension, orthostatic hypotension, and syncope. Use ADASUVE with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, or treatment with antihypertensive medications or other drugs that affect blood pressure or reduce heart rate).

In the presence of severe hypotension requiring vasopressor therapy, the preferred drugs may be norepinephrine or phenylephrine. Epinephrine should not be used, because beta stimulation may worsen hypotension in the setting of ADASUVE-induced partial alpha blockade.

In short-term (24-hour) placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar I disorder, hypotension occurred in 0.4% and 0.8% in the ADASUVE 10 mg and placebo groups, respectively. There were no cases of orthostatic hypotension, postural symptoms, presyncope or syncope. A systolic blood pressure ≤ 90 mm Hg with a decrease of ≥ 20 mm Hg occurred in 1.5% and 0.8% of the ADASUVE 10 mg and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm Hg with a decrease of ≥15 mm Hg occurred in 0.8% and 0.4% of the ADASUVE 10 mg and placebo groups, respectively.

In 5 Phase 1 studies in normal volunteers, the incidence of hypotension was 3% and 0% in ADASUVE 10 mg and the placebo groups, respectively. The incidence of syncope or presyncope in normal volunteers was 2.3% and 0% in the ADASUVE and placebo groups, respectively. In normal volunteers, a systolic blood pressure ≤ 90 mm Hg with a decrease of ≥ 20 mm Hg occurred in 5.3% and 1.1% in the ADASUVE and placebo groups, respectively. A diastolic blood pressure ≤ 50 mm Hg with a decrease of ≥ 15 mm Hg occurred in 7.5% and 3.3% in the ADASUVE and placebo groups, respectively.

5.6 Falls

ADASUVE may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.7 Seizures

ADASUVE lowers the seizure threshold. Seizures have occurred in patients treated with oral loxapine. Seizures can occur in epileptic patients even during antiepileptic drug maintenance therapy. In short term (24 hour), placebo-controlled trials of ADASUVE, there were no reports of seizures.

5.8 Potential for Cognitive and Motor Impairment

ADASUVE can impair judgment, thinking, and motor skills. In short-term, placebo-controlled trials, sedation and/or somnolence were reported in 12% and 10% in the ADASUVE and placebo groups, respectively. No patients discontinued treatment because of sedation or somnolence.

The potential for cognitive and motor impairment is increased when ADASUVE is administered concurrently with other CNS depressants [see Drug Interactions (7.1)] . Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ADASUVE does not affect them adversely.

5.9 Cerebrovascular Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with atypical antipsychotics in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (stroke and transient ischemic attacks), including fatalities, compared to placebo-treated patients. ADASUVE is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.3)] .

5.10 Anticholinergic Reactions Including Exacerbation of Glaucoma and Urinary Retention

ADASUVE has anticholinergic activity, and it has the potential to cause anticholinergic adverse reactions including exacerbation of glaucoma or urinary retention. The concomitant use of other anticholinergic drugs (e.g., antiparkinson drugs) with ADASUVE could have additive effects.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following findings are based on pooled data from three short-term (24-hour), randomized, double-blind, placebo-controlled clinical trials (Studies 1, 2, and 3) of ADASUVE 10 mg in the treatment of patients with acute agitation associated with schizophrenia or bipolar I disorder. In the 3 trials, 259 patients received ADASUVE 10 mg, and 263 received placebo [see Clinical Studies (14)] .

7.1 CNS Depressants

ADASUVE is a central nervous system (CNS) depressant. The concurrent use of ADASUVE with other CNS depressants (e.g., alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, general anesthetics, phenothiazines, sedative/hypnotics, muscle relaxants, and/or illicit CNS depressants) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with ADASUVE.

7.2 Anticholinergic Drugs

ADASUVE has anticholinergic activity. The concomitant use of ADASUVE and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma and urinary retention.

8.1 Pregnancy

8.2 Lactation

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.

Signs and Symptoms of Overdosage

As would be expected from the pharmacologic actions of loxapine, the clinical findings may include CNS depression, unconsciousness, profound hypotension, respiratory depression, extrapyramidal symptoms, and seizure.

Management of Overdosage

For the most up to date information on the management of ADASUVE overdosage, contact a certified poison control center (1-800-222-1222 or www.poison.org). Provide supportive care including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Active Ingredient: Loxapine (base). Loxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines. Chemically, it is 2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine.

ADASUVE is a single-use, drug-device combination product that provides rapid systemic delivery by inhalation of a thermally-generated aerosol of loxapine. Oral inhalation through the product initiates the controlled rapid heating of a thin film of excipient-free loxapine to form a thermally-generated drug vapor. The vapor condenses into aerosol particles that are dispersed into the airstream created by the patient inhaling through the mouthpiece.

Each product is packaged inside a sealed foil pouch. The product is a white to off-white plastic unit, with a mouthpiece on one end and a pull-tab protruding from the other end.

Removal of a pull-tab from the product renders it ready for use, as indicated by illumination of a green light. After inhalation through the mouthpiece, successful dosing is signaled by the green light turning off.

Under standardized in vitro test conditions, ADASUVE, 10 mg delivers 9.1 mg of loxapine out of the mouthpiece.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Loxapine acts as a monoaminergic antagonist with binding affinities (K i values) for central serotonin 5-HT 2A, dopamine D 1, D 2, D 3, and D 4, and histamine H 1 receptors of 2, 18, 10, 21, 9, and 15 nM, respectively. Loxapine also acts as an antagonist at muscarinic M1 and adrenergic α 2 receptors with binding affinities of 117 and 250 nM, respectively.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 times the MRHD based on a mg/m 2 body surface area, 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 (~6 times the MRHD based on a mg/m 2 body surface area).

16.1 How Supplied

ADASUVE ® (loxapine) inhalation powder is supplied as: ADASUVE 10 mg (NDC 51097-001-01) is a single-use, disposable inhaler containing 10 mg of loxapine, provided in a sealed foil pouch. ADASUVE, 10 mg is supplied in a carton of 5 units per carton (NDC 51097-001-02).

16.2 Restricted Access

ADASUVE is only available through a restricted program called the ADASUVE REMS Program [see Warnings and Precautions (5.2)] .

16.3 Storage and Handling

Store ADASUVE at room temperature, 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Keep ADASUVE in pouch until time of use.

ADASUVE contains a lithium battery. Dispose of ADASUVE in accordance with all federal, state and local laws.

Bronchospasm

Advise patients and caregivers that there is a risk of bronchospasm. Advise patients to inform their healthcare professional if they develop any breathing problems such as wheezing, shortness of breath, chest tightness, or cough following treatment with ADASUVE [see Boxed Warning and Warnings and Precautions (5.1)] .

Interference with Cognitive and Motor Performance

Caution patients and caregivers about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that ADASUVE has not affected them adversely [see Warnings and Precautions (5.8)] .

Caution patients and caregivers about the potential for sedation, especially when used concurrently with other CNS depressants (e.g., alcohol, opioid analgesics, benzodiazepines, tricyclic antidepressants, general anesthetics, phenothiazines, sedative/hypnotics, muscle relaxants, and/or illicit CNS depressants).

Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.4)] .

Hypotension and Syncope

Advise patients and caregivers of the risk of hypotension or orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) [see Warnings and Precautions (5.5)] .

Anticholinergic Reactions

Counsel patients and caregivers about the potential risks of anticholinergic reactions, such as exacerbation of glaucoma and urinary retention [see Warnings and Precautions (5.10)] .

Pregnancy

Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ADASUVE. Advise patients that ADASUVE may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADASUVE during pregnancy [see Use in Specific Populations (8.1)] .