Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a alpha 2 -adrenergic receptor agonist indicated for: Sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Administer dexmedetomidine hydrochloride in 0.9% sodium chloride injection by continuous infusion not to exceed 24 hours. (1.1) Sedation of non-intubated adult patients prior to and/or during surgical and other procedures.
(1.2)
1.1Intensive Care Unit Sedation
Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered by continuous infusion not to exceed 24 hours. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been continuously infused in mechanically ventilated adult patients prior to extubation, during extubation, and post-extubation.
It is not necessary to discontinue dexmedetomidine hydrochloride in 0.9% sodium chloride injection prior to extubation.
1.2Procedural Sedation
Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures. Pediatric use information is approved for Hospira, Inc.’s PRECEDEX TM (dexmedetomidine hydrochloride in sodium chloride injection). However, due to Hospira, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
Contraindications
None. None ( 4 )
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.
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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) Tolerance and Tachyphylaxis: 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 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%) dexmedetomidine adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine 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 less than 5%.
Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of dexmedetomidine (less than 6 hours). In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short-term infusions of dexmedetomidine (<2 hours). Pediatric use information is approved for Hospira, Inc.’s PRECEDEXT M (dexmedetomidine hydrochloride in sodium chloride injection).
However, due to Hospira, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
5.6Tolerance 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) ].
5.7Hyperthermia or Pyrexia
Dexmedetomidine may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.
5.8Hepatic Impairment
Since dexmedetomidine 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) ].
Interactions
Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine or the concomitant medication may be required. (7.1)
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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores.
Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (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. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15).
No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25).
Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21).
In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
Adverse reactions
The most common adverse reactions (incidence greater than 2%) in adults are hypotension, bradycardia, and dry mouth. (6.1) Adverse reactions in adults, associated with infusions greater than 24 hours in duration include ARDS, respiratory failure, and agitation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia and sinus arrest [see Warnings and Precautions ( 5.2 )] Transient hypertension [see Warnings and Precautions ( 5.3 )]
6.1Clinical Trials 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 the clinical trials of another drug and may not reflect the rates observed in practice. Most common treatment-emergent adverse reactions, occurring in greater than 2% of adult 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 1,007 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) 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 greater than 2% are provided in Table 3 . The most frequent adverse reactions were hypotension, bradycardia and dry mouth [ see Warnings and Precautions (5.2) ]. Table 3: Adverse Reactions with an Incidence Greater than 2%—Adult Intensive Care Unit Sedation Population Less than 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 = 1,007) (%) 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 Less than 1% 1% 1% 5% Wheezing Less than 1% 1% 0 2% Edema Peripheral Less than 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 4 ). Table 4: Treatment-Emergent Adverse Events Occurring in Greater than 1% of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion Less than 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% Less than 1% Thirst 2% Less than 1% In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients.
Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated adult patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 5 . The number (%) of adult subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine group is provided in Table 6 .
Table 5: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study * Includes any type of hypertension † Hypotension was defined in absolute terms as Systolic blood pressure of less than 80 mmHg or Diastolic blood pressure of less than 50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value ‡ Bradycardia was defined in absolute terms as less than 40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value § Hypertension was defined in absolute terms as Systolic blood pressure greater than 180 mmHg or Diastolic blood pressure of greater than 100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value ¶ Tachycardia was defined in absolute terms as greater than 120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value Adverse Event Dexmedetomidine (N = 244) (%) Midazolam (N = 122) (%) Hypotension† 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia‡ 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension§ 28% 42% Tachycardia¶ 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension§ 12% 15% Hypertension§ 11% 15% Hypertension Requiring Intervention* 19% 30% Hypokalemia 9% 13% Pyrexia 7% 2% Agitation 7% 6% Hyperglycemia 7% 2% Constipation 6% 6% Hypoglycemia 5% 6% Respiratory Failure 5% 3% Renal Failure Acute 2% 1% Acute Respiratory Distress Syndrome 2% 1% Generalized Edema 2% 6% Hypomagnesemia 1% 7% The following adverse events occurred between 2 and 5% for dexmedetomidine and midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).
Table 6: Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Group Dexmedetomidine (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration (N = 95) (%) Greater than 0.7 to ≤1.1 (N = 78) (%) Greater than 1.1 (N = 71) (%) Constipation 6% 5% 14% Agitation 5% 8% 14% Anxiety 5% 5% 9% Edema Peripheral 3% 5% 7% Atrial Fibrillation 2% 4% 9% Respiratory Failure 2% 6% 10% Acute Respiratory Distress Syndrome 1% 3% 9% Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [ see Clinical Studies (14.2) ] in which 318 adult patients received dexmedetomidine.
The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian. Treatment-emergent adverse reactions occurring in adults at an incidence of greater than 2% are provided in Table 7 . The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [ see Warnings and Precautions (5.2) ].
Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine and comparator groups in bo
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