Loxapine Inhalation Powder

ADASUVE, a typical antipsychotic, is an inhalation powder of loxapine supplied in a single-use, disposable inhaler containing 10 mg of loxapine base. ADASUVE is a drugdevice combination product.

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.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Hypersensitivity (serious skin reactions) [see CONTRAINDICATIONS]
• Bronchospasm [see WARNINGS AND PRECAUTIONS]
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
• Hypotension and syncope [see WARNINGS AND PRECAUTIONS]
• Seizure [see WARNINGS AND PRECAUTIONS]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
• Cerebrovascular Reactions, Including Stroke, in Elderly Patients with Dementia- Related Psychosis [see WARNINGS AND PRECAUTIONS]
• Anticholinergic Reactions Including Exacerbation of Glaucoma and Urinary Retention [see WARNINGS AND PRECAUTIONS]

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].

In the 3 trials in acute agitation, the most common adverse reactions were dysgeusia, sedation, and throat irritation. These reactions occurred at a rate of at least 2% of the ADASUVE group and at a rate greater than in the placebo group. (Refer to Table 1).

Table 1: Adverse Reactions in 3 Pooled Short-Term, Placebo-Controlled Trials (Studies 1, 2, and 3) in Patients with Schizophrenia or Bipolar Disorder

Agitated patients with Schizophrenia or Bipolar Disorder: In the 3 short-term (24-hour), placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar disorder (Studies 1, 2, and 3), bronchospasm (which includes reports of wheezing, shortness of breath and cough) occurred more frequently in the ADASUVE group, compared to the placebo group: 0% (0/263) in the placebo group and 0.8% (2/259) in the ADASUVE 10 mg group. One patient with schizophrenia, without a history of pulmonary disease, had significant bronchospasm requiring rescue treatment with a bronchodilator and oxygen.

Clinical pulmonary safety trials demonstrated that ADASUVE can cause bronchospasm as measured by FEV1, and as indicated by respiratory signs and symptoms in the trials. In addition, the trials demonstrated that patients with asthma or other pulmonary diseases, such as COPD are at increased risk of bronchospasm. The effect of ADASUVE on pulmonary function was evaluated in 3 randomized, double-blind, placebo-controlled clinical pulmonary safety trials in healthy volunteers, patients with asthma, and patients with COPD. Pulmonary function was assessed by serial FEV1 tests, and respiratory signs and symptoms were assessed. In the asthma and COPD trials, patients with respiratory symptoms or FEV1 decrease of ≥ 20% were administered rescue treatment with albuterol (metered dose inhaler or nebulizer) as required. These patients were not eligible for a second dose; however, they had continued FEV1 monitoring in the trial.

Healthy Volunteers: In the healthy volunteer crossover trial, 30 subjects received 2 doses of either ADASUVE or placebo 8 hours apart, and 2 doses of the alternate treatment at least 4 days later. The results for maximum decrease in FEV1 are presented in Table 2. No subjects in this trial developed airway related adverse reactions (cough, wheezing, chest tightness, or dyspnea).

Asthma Patients: In the asthma trial, 52 patients with mild-moderate persistent asthma (with FEV1 ≥ 60% of predicted) were randomized to treatment with 2 doses of ADASUVE 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 67% of these patients had a baseline FEV1 ≥ 80% of predicted. The remaining patients had an FEV1 60-80% of predicted. Nine patients (17%) were former smokers. As shown in Table 2 and Figure 7, there was a marked decrease in FEV1 immediately following the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 303 mL and 9.1%, respectively). Furthermore, the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 537 mL and 14.7 %, respectively). Respiratory-related adverse reactions (bronchospasm, chest discomfort, cough, dyspnea, throat tightness, and wheezing) occurred in 54% of ADASUVE-treated patients and 12% of placebo-treated patients. There were no serious adverse events. Nine of 26 (35%) patients in the ADASUVE group, compared to one of 26 (4%) in the placebo group, did not receive a second dose of study medication, because they had a ≥ 20% decrease in FEV1 or they developed respiratory symptoms after the first dose. Rescue medication (albuterol via metered dose inhaler or nebulizer) was administered to 54% of patients in the ADASUVE group [7 patients (27%) after the first dose and 7 of the remaining 17 patients (41%) after the second dose] and 12% in the placebo group (1 patient after the first dose and 2 patients after the second dose).

COPD Patients: In the COPD trial, 53 patients with mild to severe COPD (with FEV1 ≥ 40% of predicted) were randomized to treatment with 2 doses of ADASUVE 10 mg or placebo. The second dose was to be administered 10 hours after the first dose. Approximately 57% of these patients had moderate COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II]; 32% had severe disease (GOLD Stage III); and 11% had mild disease (GOLD Stage I). As illustrated in Table 2 there was a decrease in FEV1 soon after the first dose (maximum mean decreases in FEV1 and % predicted FEV1 were 96 mL and 3.5%, respectively), and the effect on FEV1 was greater following the second dose (maximum mean decreases in FEV1 and % predicted FEV1 were 125 mL and 4.5%, respectively). Respiratory adverse reactions occurred more frequently in the ADASUVE group (19%) than in the placebo group (11%). There were no serious adverse events. Seven of 25 (28%) patients in the ADASUVE group and 1of 27 (4%) in the placebo group did not receive a second dose of study medication because of a ≥ 20% decrease in FEV1 or the development of respiratory symptoms after the first dose. Rescue medication (albuterol via MDI or nebulizer) was administered to 23% of patients in the ADASUVE group: 8% of patients after the first dose and 21% of patients after the second dose, and to 15% of patients in the placebo group.

Table 2: Maximum Decrease in FEV1 from Baseline in the Healthy Volunteer, Asthma, and COPD Trials

FEV1 categories are cumulative; i.e. a subject with a maximum decrease of 21% is included in all 3 categories. Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug.

Figure 7: LS Mean Change from Baseline in FEV1 in Patients with Asthma

Patients with a ≥ 20% decrease in FEV1 did not receive a second dose of study drug and are not included in the curves beyond hour 10.

Extrapyramidal Symptoms (EPS): Extrapyramidal reactions have occurred during the administration of oral loxapine. In most patients, these reactions involved parkinsonian symptoms such as tremor, rigidity, and masked facies. Akathisia (motor restlessness) has also occurred.

In the 3 short-term (24-hour), placebo-controlled trials of ADASUVE in 259 patients with agitation associated with schizophrenia or bipolar disorder, extrapyramidal reactions occurred. One patient (0.4%) treated with ADASUVE developed neck dystonia and oculogyration. The incidence of akathisia was 0% and 0.4% in the placebo and ADASUVE groups, respectively.

Dystonia (Antipsychotic Class Effect): Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during treatment with ADASUVE. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, difficulty swallowing or breathing, and/or protrusion of the tongue.

Acute dystonia tends to be dose-related, but can occur at low doses, and occurs more frequently with first generation antipsychotic drugs such as ADASUVE. The risk is greater in males and younger age groups.

Cardiovascular Reactions: Tachycardia, hypotension, hypertension, orthostatic hypotension, lightheadedness, and syncope have been reported with oral administration of loxapine.

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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Trouble controlling body movements, twitching, change in balance, trouble swallowing or speaking.
• Shakiness, trouble moving around, or stiffness.
• Very bad dizziness or passing out.
• A fast heartbeat.
• Very bad headache.
• Feeling confused.
• Change in eyesight, eye pain, or very bad eye irritation.
• Seizures.
• Trouble passing urine.
• Slurred speech.
• Feeling very tired or weak.
• Any unexplained bruising or bleeding.
• Enlarged breasts.
• Nipple discharge.
• Change in sex ability.
• For women, no period.
• Restlessness.
• A very bad and sometimes deadly health problem called neuroleptic malignant syndrome (NMS) may happen. Call your doctor right away if you have any fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, heartbeat that does not feel normal, or are sweating a lot.
• Some people who take this medicine may get a very bad muscle problem called tardive dyskinesia. This muscle problem may not go away even if loxapine inhalation powder is stopped. Sometimes, signs may lessen or go away over time after this medicine is stopped. The risk of tardive dyskinesia may be greater in people with diabetes and in older adults, especially older women. The risk is also greater the longer you take loxapine inhalation powder or with higher doses. Muscle problems may also occur after short-term use with low doses. Call your doctor right away if you have trouble controlling body movements or if you have muscle problems with your tongue, face, mouth, or jaw like tongue sticking out, puffing cheeks, mouth puckering, or chewing.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Trouble sleeping.
• Dry mouth.
• Hard stools (constipation).
• Change in taste.
• Throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

LOXAPINE (LOX a peen) inhaler is used to treat certain symptoms of schizophrenia and bipolar disorder. Bipolar disorder is also known as manic-depression.

This drug also comes in other forms, including Oral capsule

This drug can cause serious side effects. See which side effects you should report to your doctor right away.

Know how to use your medication, and learn what might happen if you miss a dose.

Talk to your healthcare provider if you have any of these conditions.

Know what to watch for and get tips for reducing your risks while taking this drug.

• alcohol
• antihistamines for allergy, cough and cold
• atropine
• certain medicines for bladder problems like oxybutynin, tolterodine
• certain medicines for blood pressure, heart disease, irregular heart beat
• certain medicines for depression, anxiety, or psychotic disturbances
• certain medicines for Parkinson's disease like benztropine, trihexyphenidyl
• certain medicines for sleep
• certain medicines for stomach problems like dicyclomine, hyoscyamine
• certain medicines for travel sickness like scopolamine
• ipratropium
• medicines that relax muscles
• medicines used for anesthesia
• narcotic medicines (opiates) for pain