warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypotension, Orthostatic Hypotension, and Bradycardia: Avoid use of IGALMI in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. Ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation. ( 5.1 ) QT Interval Prolongation: IGALMI prolongs the QT interval; avoid use in patients with risk factors for prolonged QT interval. ( 5.2 ) Somnolence: Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery for at least eight hours after taking IGALMI. ( 5.3 ) 5.1 Hypotension, Orthostatic Hypotension, and Bradycardia IGALMI causes dose-dependent hypotension, orthostatic hypotension, and bradycardia . In clinical studies, 18%, 16%, and 9% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced orthostatic hypotension (defined as SBP decrease ≥ 20 mmHg or DBP decrease ≥ 10 mmHg after 1, 3, or 5 minutes of standing) at 2 hours post-dose. In those studies, 7%, 6%, and 1% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced HR ≤ 50 beats per minute within 2 hours of dosing [see Adverse Reactions (6.1) ]. In clinical studies with IGALMI, patients were excluded if they had treatment with alpha-1 noradrenergic blockers, benzodiazepines, other hypnotics or antipsychotic drugs four hours prior to study drug administration; had a history of syncope or syncopal attacks; SBP < 110 mmHg; DBP < 70 mmHg; HR < 55 beats per minute; or had evidence of hypovolemia or orthostatic hypotension. Reports of hypotension and bradycardia, including some resulting in fatalities, have been associated with the use of another dexmedetomidine product given intravenously (IGALMI is for sublingual or buccal use and is not approved for intravenous use). Clinically significant episodes of bradycardia and sinus arrest have been reported after administration of this other dexmedetomidine product to young, healthy adult volunteers with high vagal tone and when this product was given by rapid intravenous or bolus administration. Because IGALMI decreases sympathetic nervous system activity, hypotension and/or bradycardia may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in geriatric patients [see Dosage and Administration (2.2) and Use in Specific Populations (8.5) ]. Avoid use of IGALMI in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. After IGALMI administration, patients should be adequately hydrated and should sit or lie down until vital signs are within normal range. If a patient is unable to remain seated or lying down, precautions should be taken to reduce the risk of falls. Ensure that a patient is alert and not experiencing orthostatic hypotension or symptomatic hypotension prior to allowing them to resume ambulation [see Dosage and Administration (2.1) ]. 5.2 QT Interval Prolongation IGALMI prolongs the QT interval. Avoid use of IGALMI in patients at risk of torsades de pointes or sudden death including those with known QT prolongation, a history of other arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, and in patients receiving other drugs known to prolong the QT interval [see Drug Interactions (7.1) and Clinical Pharmacology (12.2) ]. 5.3 Somnolence IGALMI can cause somnolence. In placebo-controlled clinical studies in adults with agitation associated with schizophrenia or bipolar I or II disorder, somnolence (including fatigue and sluggishness) was reported in 23% and 22% of patients treated with IGALMI 180 mcg and 120 mcg, respectively, compared to 6% of placebo-treated patients. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, for at least eight hours after taking IGALMI [see Adverse Reactions (6.1) ] . 5.4 Risk of Withdrawal Reactions Symptoms of withdrawal have been observed after treatment with another dexmedetomidine product administered as a continuous IV infusion in the ICU for another indication. In this study, 12 (5%) adult patients who received intravenous dexmedetomidine up to 7 days (regardless of dose) experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing dexmedetomidine and 7 (3%) adult patients who received intravenous dexmedetomidine experienced at least 1 event related with withdrawal 24 to 48 hours after discontinuing dexmedetomidine. The most common withdrawal reactions were nausea, vomiting, and agitation. In these subjects, tachycardia and hypertension requiring intervention occurred at a frequency of <5% in the 48 hours following intravenous dexmedetomidine discontinuation. Withdrawal symptoms have been reported in pediatric patients who received another dexmedetomidine product intravenously for another indication. IGALMI is not approved for pediatric use. Withdrawal symptoms reported in published literature include cardiovascular symptoms, such as hypertension, tachycardia, arrhythmias, and in severe cases, hypertensive crisis; neurological symptoms, such as agitation, anxiety, tremors, seizures, and altered mental status; and autonomic symptoms such as diaphoresis, nausea, vomiting, hyperthermia, and mydriasis. In a randomized, double-blind, placebo-controlled, multiple ascending dose study assessing IGALMI at doses up to 120 mcg per day administered over 7 days in healthy volunteers, elevated heart rate and systolic blood pressure and vomiting occurred at a higher frequency upon abrupt discontinuation of 120-mcg doses of IGALMI as compared to placebo. There may be a risk of physical dependence and a withdrawal syndrome if IGALMI is used in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3) ] . 5.5 Tolerance and Tachyphylaxis Use of another dexmedetomidine product administered intravenously beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions. The effectiveness of IGALMI beyond 24 hours after the first dose has not been established. There may be a risk of tolerance and tachyphylaxis if IGALMI is administered at higher doses or for a longer duration than were evaluated, or in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3) ] .