Adasuve Drug Information

is indicated for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults . ADASUVE is an atypical antipsychotic indicated for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Limitations of Use: ADASUVE must be administered only in a certified healthcare setting. 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 .

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 .

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) .

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.

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Monitoring to Assess Safety

Monitor the patient for signs and symptoms of bronchospasm after ADASUVE administration for at least one hour .

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 . Commonly Observed Adverse Reactions : 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 Adverse Reaction Placebo (n = 263) ADASUVE (n = 259) Dysgeusia 5% 14% Sedation 10% 12% Throat Irritation 0% 3% Airway Adverse Reactions in the 3 Trials in Acute Agitation 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. Bronchospasm and Airway Adverse Reactions in Pulmonary Safety Trials 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 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 ; 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 1 of 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 Healthy Volunteer Asthma COPD Maximum % FEV ↓ Placebo n (%) ADASUVE 10 mg n (%) Placebo n (%) ADASUVE 10 mg n (%) Placebo n (%) ADASUVE 10 mg n (%) After any Dose N=26 N=26 N=26 N=26 N=27 N=25 ≥10 7 7 3 22 18 20 ≥15 1 5 1 16 9 14 ≥20 0 1 1 11 3 10 After Dose 1 N=26 N=26 N=26 N=26 N=27 N=25 ≥10 4 5 2 16 8 16 ≥15 1 2 1 8 4 10 ≥20 0 0 1 6 2 9 After Dose 2 N=26 N=25 N=25 N=17 N=26 N=19 ≥10 5 6 3 12 15 12 ≥15 0 5 1 9 6 10 ≥20 0 1 1 5 1 5 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. Figure 7 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.

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.

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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including ADASUVE, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ). The available data from published case reports and pharmacovigilance cases with loxapine, the active ingredient in ADASUVE, in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder, and with exposure to antipsychotics, including ADASUVE, during pregnancy (see Clinical Considerations ). In animal reproduction studies, increased embryofetal toxicity and death in rat fetuses and offspring were observed when pregnant rats were orally administered loxapine, during the period of organogenesis, at doses approximately less than or equal to the maximum recommended human dose (MRHD) based on mg/m 2 body surface area (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ADASUVE, during the third trimester of pregnancy.

These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data Animal Data Pregnant rats were administered oral doses of 1, 4, and 12 mg/kg/day loxapine (~1, 4, and 12 times the MRHD of 10 mg/day based on mg/m 2 body surface area, respectively) during the period of organogenesis. Embryofetal toxicity (increased fetal resorptions, reduced weights, and hydronephrosis with hydroureter) was observed at doses equal to the MRHD and higher based on mg/m 2 body surface area. Pregnant rabbits were administered oral doses of 20 and 60 mg/kg/day loxapine (~40 and 120 times the MRHD based on mg/m 2 body surface area) during the period of organogenesis.

Loxapine did not cause adverse developmental effects in rabbits at doses up to 120 times the MRHD based on mg/m 2 body surface area. Pregnant rats were administered oral doses of 0.21, 0.62, and 1.86 mg/kg/day loxapine (~0.2, 0.6, and 1.8 times the MRHD based on mg/m 2 body surface area) during the period of organogenesis and through lactation. Fetal toxicity (increased prenatal death, decreased postnatal survival, reduced fetal weights, delayed ossification, and/or distended renal pelvis with reduced or absent papillae) was observed at doses of 0.6 times the MRHD and higher based on mg/m 2 body surface area.

Pediatric Use The safety and effectiveness of ADASUVE in pediatric patients have not been established.

is contraindicated in patients with the following: Current diagnosis or history of asthma, COPD, or other lung disease associated with bronchospasm Acute respiratory symptoms or signs (e.g., wheezing) Current use of medications to treat airways disease, such as asthma or COPD History of bronchospasm following ADASUVE treatment Known hypersensitivity to loxapine or amoxapine. Serious skin reactions have occurred with oral loxapine and amoxapine. Current diagnosis or history of asthma, chronic obstructive pulmonary disease (COPD), or other lung disease associated with bronchospasm Acute respiratory signs/symptoms (e.g., wheezing) Current use of medications to treat airways disease, such as asthma or COPD History of bronchospasm following ADASUVE treatment Known hypersensitivity to loxapine or amoxapine

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.