Dexmedetomidine Hcl Drug Information
Generic name: DEXMEDETOMIDINE HCL
Uses of Dexmedetomidine Hcl
Procedural Sedation Dexmedetomidine hydrochloride injection is indicated for sedation of non-intubated patients
prior to and/or during surgical and other procedures.
Dosage & Administration of Dexmedetomidine Hcl
Side Effects of Dexmedetomidine Hcl
Clinical 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 hydrochloride has been associated with the following serious adverse reactions: Hypotension, bradycardia and sinus arrest Transient hypertension Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in procedural sedation studies include hypotension, bradycardia and dry mouth. Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation in which 318 adult patients received dexmedetomidine hydrochloride.
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 at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth . 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 hydrochloride and comparator groups in both studies.
Table 2. Adverse Reactions With an Incidence >2%— Procedural Sedation Population Adverse Event Dexmedetomidine hydrochloride N = 318 (%) Placebo N = 113 (%) Hypotension 1 54% 30% Respiratory depression 2 37% 32% Bradycardia 3 14% 4% Hypertension 4 13% 24% Tachycardia 5 5% 17% Nausea 3% 2% Dry mouth 3% 1% Hypoxia 6 2% 3% Bradypnea 2% 4% 1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or < 30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg 2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline 3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or < 30% lower than pre-study drug infusion value. 4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or > 30% higher than pre-study drug infusion value or diastolic blood pressure of >100 mmHg. 5 Tachycardia was defined in absolute and relative terms as >120 beats per minute or > 30% greater than pre-study drug infusion value. 6 Hypoxia was defined in absolute and relative terms as SpO 2 <90% or 10% decrease from baseline.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of dexmedetomidine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine hydrochloride during post approval use of the drug.
Table 3: Adverse Reactions Experienced During Post-approval Use of Dexmedetomidine hydrochloride System Organ Class Preferred Term Blood and Lymphatic System Disorders Anemia Cardiac Disorders Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders Photopsia, visual impairment Gastrointestinal Disorders Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders Hepatic function abnormal, hyperbilirubinemia Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia Nervous System Disorders Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder Psychiatric Disorders Agitation, confusional state, delirium, hallucination, illusion Renal and Urinary Disorders Oliguria, polyuria Respiratory, Thoracic and Mediastinal Disorders Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis Skin and Subcutaneous Tissue Disorders Hyperhidrosis Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension
Warnings & Cautions for Dexmedetomidine Hcl
Drug
Administration Dexmedetomidine hydrochloride should be administered only by persons skilled in the management of patients in the operating room setting. Due to the known pharmacological effects of dexmedetomidine hydrochloride, patients should be continuously monitored while receiving dexmedetomidine hydrochloride.
Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus
arrest have been reported with dexmedetomidine hydrochloride 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 hydrochloride infusion. Some of these cases have resulted in fatalities.
If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine hydrochloride 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 hydrochloride-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering dexmedetomidine hydrochloride to patients with advanced heart block and/or severe ventricular dysfunction.
Because dexmedetomidine hydrochloride 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 hydrochloride an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride.
Transient Hypertension Transient hypertension has been observed primarily during the loading dose
in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.
Arousability Some patients receiving dexmedetomidine hydrochloride 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.
Withdrawal Procedural Sedation
In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of dexmedetomidine hydrochloride (<6 hours).
Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated
with tolerance and tachyphylaxis and a dose-related increase in adverse reactions .
Hepatic Impairment
Since dexmedetomidine hydrochloride clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function.
Drug Interactions with Dexmedetomidine Hcl
Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of dexmedetomidine hydrochloride 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 hydrochloride and isoflurane, propofol, alfentanil and midazolam have been demonstrated.
However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine hydrochloride, a reduction in dosage of dexmedetomidine hydrochloride or the concomitant anesthetic, sedative, hypnotic or opioid may be required.
Neuromuscular Blockers
In one study of 10 healthy adult volunteers, administration of dexmedetomidine hydrochloride for 45 minutes at a plasma concentration of 1 ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.
Pregnancy Safety for Dexmedetomidine Hcl
- Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of dexmedetomidine hydrochloride use in pregnant women. In an in vitro human placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. Thus, fetal exposure should be expected in humans, and dexmedetomidine hydrochloride should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Teratogenic effects were not observed in rats following subcutaneous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose approximately equal to the maximum recommended human intravenous dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcg/kg (representing approximately half the human exposure at the maximum recommended dose based on plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-implantation losses and reduced live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison). In another reproductive toxicity study when dexmedetomidine was administered subcutaneously to pregnant rats at 8 and 32 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed. Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development was observed in second generation offspring.
Pediatric Use of Dexmedetomidine Hcl
Pediatric Use Safety and efficacy have not been established for Procedural Sedation in pediatric patients. The use of dexmedetomidine for procedural sedation in pediatric patients has not been evaluated.
Overdosage Information for Dexmedetomidine Hcl
The tolerability of dexmedetomidine hydrochloride was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block.
No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute. One patient who received a loading bolus dose of undiluted dexmedetomidine hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.
Clinical Studies of Dexmedetomidine Hcl
Procedural Sedation
The safety and efficacy of dexmedetomidine hydrochloride for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine hydrochloride in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine hydrochloride in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
In Study 1, the sedative properties of dexmedetomidine hydrochloride were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (Table 5). Table 5 Observer’s Assessment of Alertness/Sedation Assessment Categories Responsiveness Speech Facial Expression Eyes Composite Score Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking Few recognizable words -- -- 2 Does not respond to mild prodding or shaking -- -- -- 1 (deep sleep) Patients were randomized to receive a loading infusion of either dexmedetomidine hydrochloride 1 mcg/kg, dexmedetomidine hydrochloride 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer’s Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer’s Assessment of Alertness/Sedation Scale < 4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine hydrochloride and comparator groups.
Efficacy results showed that dexmedetomidine hydrochloride was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures. (see Table 7) In Study 2, the sedative properties of dexmedetomidine hydrochloride were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score > 2 (see Table 6). Table 6: Ramsay Level of Sedation Scale Clinical Score Level of Sedation Achieved 6 Asleep, no response 5 Asleep, sluggish response to light glabellar tap or loud auditory stimulus 4 Asleep, but with brisk response to light glabellar tap or loud auditory stimulus 3 Patient responds to commands 2 Patient cooperative, oriented, and tranquil 1 Patient anxious, agitated, or restless Patients were randomized to receive a loading infusion of dexmedetomidine hydrochloride 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale > 2. Demographic characteristics were similar between the dexmedetomidine hydrochloride and comparator groups.
For efficacy results see Table 7. Table 7. Key Efficacy Results of Procedural Sedation Studies Study Loading Infusion Treatment Arm Number of Patients Enrolled a % Not Requiring Midazolam Rescue Confidence b Interval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required Confidence b Intervals of the Mean Rescue Dose Study 1 Dexmedetomidine 0.5 mcg/kg 134 40 37 1.4 -2.7 (-3.4, -2) Dexmedetomidine 1 mcg/kg 129 54 51 0.9 -3.1 (-3.8, -2.5) placebo 63 3 − 4.1 − Study 2 Dexmedetomidine 1 mcg/kg 55 53 39 1.1 -1.8 (-2.7, -0.9) placebo 50 14 − 2.9 − a Based on ITT population defined as all randomized and treated patients. b Normal approximation to the binomial with continuity correction.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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