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warnings and cautions
5 WARNINGS AND PRECAUTIONS Neuroleptic Malignant Syndrome: May develop in patients treated with antipsychotic drugs. Discontinue treatment ( 5.4 ) Hypotension and Syncope: Use with caution in patients with known cardiovascular or cerebrovascular disease ( 5.5 ) Seizure: Use with caution in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.7 ) Potential for Cognitive and Motor Impairment: Use caution when driving or operating machinery ( 5.8 ) Cerebrovascular Adverse Reactions: Increased incidence of stroke and transient ischemic attack in elderly patients with dementia-related psychosis treated with antipsychotic drugs ( 5.9 ) 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 an enrolled healthcare facility that has immediate access on site to supplies and personnel trained to manage acute bronchospasm and ready access to emergency response services. Facilities must have a short-acting bronchodilator (e.g. albuterol), including a nebulizer and inhalation solution, for the immediate treatment of bronchospasm [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 examine 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 (i.e., vital signs and chest auscultation) at least every 15 minutes 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 facilities that dispense and administer ADASUVE must be enrolled and comply with the REMS requirements. Certified healthcare facilities must be able to provide immediate access on site to supplies and personnel trained to manage acute bronchospasm and ready access to emergency response services. Facilities must have a short-acting bronchodilator (e.g. albuterol), including a nebulizer and inhalation solution, for the immediate treatment of bronchospasm. • Wholesalers and distributors that distribute ADASUVE must distribute only to enrolled healthcare facilities. 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 Seizure s 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 A nticholinergic 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.