Dexmedetomidine Hydrochloride 100 ug/mL Injection, Solution

5 WARNINGS AND PRECAUTIONS Monitoring: Continuously monitor patients while receiving dexmedetomidine. (5.1) Bradycardia and Sinus Arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. (5.2) Hypotension and Bradycardia: May necessitate medical intervention.

May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. (5.2) Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects.

(5.2) Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. (5.3) Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy.

(5.4) Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. (5.6)

5.1Drug Administration Dexmedetomidine hydrochloride injection 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 dexmedetomidine, patients should be continuously monitored while receiving dexmedetomidine.

5.2Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine 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 dexmedetomidine infusion. Some of these cases have resulted in fatalities.

If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine 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 dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering dexmedetomidine to patients with advanced heart block and/or severe ventricular dysfunction.

Because dexmedetomidine 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 dexmedetomidine an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine.

5.3Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

5.4Arousability Some patients receiving dexmedetomidine 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.

5.5Withdrawal Intensive Care Unit Sedation With administration up to 7 days, regardless of dose, 12 (5%…

6 ADVERSE REACTIONS The most common adverse reactions (incidence greater than 2%) are hypotension, bradycardia, and dry mouth. ( 6.1 ) Adverse reactions associated with infusions greater than 24 hours in duration include ARDS, respiratory failure, and agitation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AuroMedics Pharma LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Use of dexmedetomidine has been associated with the following serious adverse reactions: Hypotension, bradycardia and sinus arrest [ see Warnings and Precautions (5.2) ] Transient hypertension [ see Warnings and Precautions (5.3) ] Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.

Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine for sedation in the Intensive Care Unit setting in which 1007 adult patients received dexmedetomidine. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian.

Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [ see Warnings and Precautions (5.2) ]. Table 2: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation Population <24 hours* *26 subjects in the all dexmedetomidine group and 10 subjects in the randomized dexmedetomidine group had exposure for greater than 24 hours.

Adverse Event All Dexmedetomidine (N = 1007) (%) Randomized Dexmedetomidine (N = 798) (%) Placebo (N = 400) (%) Propofol (N = 188) (%) Hypotension 25% 24% 12% 13% Hypertension 12% 13% 19% 4% Nausea 9% 9% 9% 11% Bradycardia 5% 5% 3% 0 Atrial Fibrillation 4% 5% 3% 7% Pyrexia 4% 4% 4% 4% Dry Mouth 4% 3% 1% 1% Vomiting 3% 3% 5% 3% Hypovolemia 3% 3% 2% 5% Atelectasis 3% 3% 3% 6% Pleural Effusion 2% 2% 1% 6% Agitation 2% 2% 3% 1% Tachycardia 2% 2% 4% 1% Anemia 2% 2% 2% 2% Hyperthermia 2% 2% 3% 0 Chills 2% 2% 3% 2% Hyperglycemia 2% 2% 2% 3% Hypoxia 2% 2% 2% 3% Post-procedural Hemorrhage 2% 2% 3% 4% Pulmonary Edema 1% 1% 1% 3% Hypocalcemia 1% 1% 0 2% Acidosis 1% 1% 1% 2% Urine Output Decreased 1% 1% 0 2% Sinus Tachycardia 1% 1% 1% 2% Ventricular Tachycardia <1% 1% 1% 5% Wheezing <1% 1% 0 2% Edema Peripheral <1% 0 1% 2% Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine for less than 24 hours.

The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3). Table 3: Treatment-Emergent Adverse Events Occurring in >1% of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies Adverse Event Randomized Dexmedetomidine (N = 387) Placebo (N = 379) Hypotension 28% 13% Hypertension 16% 18% Nausea 11% 9% Bradycardia 7% 3% Fever 5% 4% Vomiting 4% 6% Atrial Fibrillation 4% 3% Hypoxia 4% 4% Tachycardia 3% 5% Hemorrhage 3% 4% Anemia 3% 2% Dry Mouth 3% 1% Rigors 2% 3% Agitation 2% 3% Hyperpyrexia 2% 3% Pain 2% 2% Hyperglycemia 2% 2% Acidosis 2% 2% Pleural Effusion 2% 1% Oliguria 2% <1% Thirst 2% <1% In a controlled…

7 DRUG INTERACTIONS Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine or the concomitant medication may be required. (7.1)

7.1Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam have been demonstrated.

However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine, a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic or opioid may be required.

7.2Neuromuscular Blockers In one study of 10 healthy adult volunteers, administration of dexmedetomidine for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.