5 WARNINGS AND PRECAUTIONS
5.1 Drug Administration
PRECEDEX should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of PRECEDEX, patients should be continuously monitored while receiving PRECEDEX.
5.2 Hypotension, Bradycardia, and Sinus Arrest
Clinically significant episodes of bradycardia and sinus arrest have been reported with PRECEDEX administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
Reports of hypotension and bradycardia have been associated with PRECEDEX infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of PRECEDEX, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because PRECEDEX has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of PRECEDEX-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
Caution should be exercised when administering PRECEDEX to patients with advanced heart block and/or severe ventricular dysfunction. Because PRECEDEX decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
In clinical trials where other vasodilators or negative chronotropic agents were co-administered with PRECEDEX an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with PRECEDEX.
5.3 Transient Hypertension
Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of PRECEDEX. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.
Some patients receiving PRECEDEX have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
Intensive Care Unit Sedation
With administration up to 7 days, regardless of dose, 12 (5%) PRECEDEX adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) PRECEDEX adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation [see Adverse Reactions (6.1)].
In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%.
In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of PRECEDEX (<6 hours).
In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short‑term infusions of PRECEDEX (<2 hours) [see Adverse Reactions (6.1)].
5.6 Tolerance and Tachyphylaxis
Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see Adverse Reactions (6.1)].
5.7 Hyperthermia or Pyrexia
PRECEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue PRECEDEX if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.
5.8 Hepatic Impairment
Since PRECEDEX clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2, 2.3)].