Dexmedetomidine Drug Information
Generic name: DEXMEDETOMIDINE
Uses of Dexmedetomidine
Intensive Care Unit Sedation Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection should be administered by continuous infusion not to exceed 24 hours.
Procedural Sedation Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures.
Dosage & Administration of Dexmedetomidine
Administration Instructions • Individualize and titrate dosing to desired clinical response. • Administer by continuous intravenous infusion using a controlled infusion device. • Administration duration should not exceed 24 hours. • Dexmedetomidine Injection must be diluted prior to administration. • Dexmedetomidine in 5% Dextrose Injection 200 mcg/50 mL and 400mcg/100mL single-dose bags do not require further dilution prior to administration. • Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection should be administered only by health care providers skilled in the management of patients in the intensive care or operating room setting. • Continuously monitor blood pressure, heart rate and oxygen levels during the use of Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection and as clinically appropriate after discontinuation. • Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose 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 Injection and Dexmedetomidine in 5% Dextrose Injection prior to extubation. • Use administration components made with synthetic or coated natural rubber gaskets. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection has the potential for absorption into some types of natural rubber.
- Recommended Dosage Table 1: Recommended Dosage in Adult Patients INDICATION DOSAGE AND ADMINISTRATION Initiation of Intensive Care Unit Sedation For adult patients: a loading infusion of one mcg/kg over 10 minutes.
- For patients over 65 years of age: Consider a dose reduction.
- For adult patients with impaired hepatic function: Consider a dose reduction. Maintenance of Intensive Care Unit Sedation For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/ hour.
- For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes.
- Maintenance of Procedural Sedation For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/ hour.
Dosage Adjustment Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered. Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients.
Preparation of Solution
Strict aseptic technique must always be maintained during handling of Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if product is discolored or if precipitate matter is present.
Preparation of solutions is the same, whether for the loading dose or maintenance infusion. Discard unused portion. No further dilution of these preparations is necessary.
Administration with Other Fluids Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is compatible with and may be co-administered with: • 0.9% Sodium Chloride Injection • 5% Dextrose Injection in water • 20% Mannitol Injection • Lactated Ringer’s Injection • 100 mg/mL Magnesium Sulfate Injection • 0.3% potassium chloride solution
Compatibility with Natural Rubber
Compatibility studies have demonstrated the potential for absorption of dexmedetomidine to some types of natural rubber. Although dexmedetomidine is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
| INDICATION | DOSAGE AND ADMINISTRATION |
|---|---|
| Initiation of Intensive Care Unit Sedation | For adult patients: a loading infusion of one mcg/kg over 10 minutes. For adult patients being converted from alternate sedative therapy: a loading dose may not be required. For patients over 65 years of age: Consider a dose reduction [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: Consider a dose reduction [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. |
| Maintenance of Intensive Care Unit Sedation | For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/ hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: Consider a dose reduction [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: Consider a dose reduction [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] |
| Initiation of Procedural Sedation | For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes. For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: Consider a dose reduction [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. |
| Maintenance of Procedural Sedation | For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/ hour. Adjust the rate of the maintenance infusion to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: Consider a dose reduction [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: Consider a dose reduction [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. |
Side Effects of Dexmedetomidine
Clinical 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.
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. Table 2: Adverse Reactions with an Incidence >2%— Adult Intensive Care Unit Sedation Population <24 hours 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 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 4.
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 5. Table 5. 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 Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation in which 318 adult patients received dexmedetomidine.
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 both studies. Table 6: Adverse Reactions that Occurred with an Incidence of Greater than 2% and Greater in the Placebo Group in Clinical Trials of Dexmedetomidine for Adult Procedural 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.
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 during post approval use of the drug. Table 7: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine
| 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% |
| 26 subjects in the all dexmedetomidine group and 10 subjects in the randomized dexmedetomidine group had exposure for greater than 24 hours. | ||||
| 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% |
| Adverse Event | Dexmedetomidine (N = 244) | Midazolam (N = 122) |
|---|---|---|
| Hypotension 1 | 56% | 56% |
| Hypotension Requiring Intervention | 28% | 27% |
| Bradycardia 2 | 42% | 19% |
| Bradycardia Requiring Intervention | 5% | 1% |
| Systolic Hypertension 3 | 28% | 42% |
| Tachycardia 4 | 25% | 44% |
| Tachycardia Requiring Intervention | 10% | 10% |
| Diastolic Hypertension 3 | 12% | 15% |
| Hypertension 3 | 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% |
| Includes any type of hypertension. 1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. | ||
| Dexmedetomidine mcg/kg/hr | |||
| Adverse Event | ≤0.7* (N = 95) | >0.7 to ≤1.1* (N = 78) | >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% |
| *Average maintenance dose over the entire study drug administration | |||
| Adverse Event | Dexmedetomidine (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. Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see Clinical Studies (14.2)]. 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 SpO2 <90% or 10% decrease from baseline. | ||
| 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, diabetes insipidus (Cases of diabetes insipidus, with associated polyuria, dilute urine, and hypernatremia have been reported.) |
| 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, pruritus, rash, urticaria |
| Surgical and Medical Procedures | Light anesthesia |
| Vascular Disorders | Blood pressure fluctuation, hemorrhage, hypertension, hypotension |
Warnings & Cautions for Dexmedetomidine
Drug 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.
Hypotension, 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.
Transient 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.
Arousability
Some patients receiving dexmedetomidine have been observed to be arousable and alert when stimulated. The most common events were nausea, vomiting, and agitation. In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%.
Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of dexmedetomidine (<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).
Diabetes Insipidus Cases of diabetes insipidus (DI) have been reported with use of dexmedetomidine in the setting of sedation. Signs of DI in this setting include polyuria (output > 125 mL/hr), diluted urine (osmolality < 300 mOsm/kg), and hypernatremia (serum sodium > 145 mmol/L). If unrecognized, this condition can lead to hemodynamic instability including unstable blood pressure and increased risk of other cardiovascular sequelae.
In reported cases, signs of DI have spontaneously resolved following discontinuation of dexmedetomidine, with resolution often occurring after 24 hours. Monitor urine output and laboratory data for signs of DI during and after dexmedetomidine administration. If DI is suspected, adjust fluid management, provide supportive care, and consider discontinuing dexmedetomidine.
If such care is insufficient, or in a setting where dexmedetomidine is used for an extended treatment period, consider expert consultation to assist with patient management.
Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions.
Hyperthermia 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.
Hepatic Impairment
Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function.
Drug Interactions with Dexmedetomidine
Anesthetics, 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.
Neuromuscular 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 Safety for Dexmedetomidine
Pregnancy 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 2-4% and 15-20%, 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 ) during the period of organogenesis (Gestation Day 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 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. In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
Pediatric Use of Dexmedetomidine
Pediatric Use Safety and efficacy of dexmedetomidine have not been established for Procedural or ICU Sedation in pediatric patients.
Overdosage Information for Dexmedetomidine
The tolerability of dexmedetomidine 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. Five adult patients received an overdose of dexmedetomidine in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr.
Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.
Clinical Studies of Dexmedetomidine
Intensive Care Unit Sedation
Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between dexmedetomidine and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours.
The Ramsay Level of Sedation Scale is displayed in Table 9. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” midazolam as needed to augment the study drug infusion.
In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to dexmedetomidine (see Table 10).
A second prospective primary analysis assessed the sedative effects of dexmedetomidine by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 10). Table 10: Midazolam Use as Rescue Medication During Intubation (ITT) A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine and placebo groups.
On average, dexmedetomidine-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine (see Table 11). In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration.
Dexmedetomidine was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of dexmedetomidine for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events.
Procedural Sedation Adult Patients
The safety and efficacy of dexmedetomidine for sedation of non-intubated adult 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 in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
In Study 1, the sedative properties of dexmedetomidine were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 12). 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). Adult 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 and comparator groups. Efficacy results showed that dexmedetomidine 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 13).
In Study 2, the sedative properties of dexmedetomidine were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 9). Adult patients were randomized to receive a loading infusion of dexmedetomidine 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.
Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. For efficacy results see Table 13. Table 13: Key Efficacy Results of Adult Procedural Sedation Studies – 2.9 – a Based on ITT population defined as all randomized and treated patients. b Normal approximation to the binomial with continuity correction
| 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 |
| Placebo (N = 175) | Dexmedetomidine (N = 178) | p-value | |
|---|---|---|---|
| Mean Total Dose (mg) of Midazolam | 19 mg | 5 mg | 0.0011 |
| Standard deviation | 53 mg | 19 mg | |
| Categorized Midazolam Use | |||
| 0 mg | 43 (25%) | 108 (61%) | <0.001 |
| 0–4 mg | 34 (19%) | 36 (20%) | |
| >4 mg | 98 (56%) | 34 (19%) | |
| ITT (intent-to-treat) population includes all randomized patients. ANOVA model with treatment center. Chi-square. | |||
| Placebo (N = 198) | Dexmedetomidine (N = 203) | p-value | |
|---|---|---|---|
| Mean Total Dose (mg) of Propofol | 513 mg | 72 mg | <0.0001 |
| Standard deviation | 782 mg | 249 mg | |
| Categorized Propofol Use | |||
| 0 mg | 47 (24%) | 122 (60%) | <0.001 |
| 0–50 mg | 30 (15%) | 43 (21%) | |
| >50 mg | 121 (61%) | 38 (19%) | |
| ANOVA model with treatment center. Chi-square. | |||
| 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) |
| 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 (27, 48) | 1.4 (1.7) | -2.7 (-3.4, -2.0) |
| Dexmedetomidine 1 mcg/kg | 129 | 54 | 51 (40, 62) | 0.9 (1.5) | -3.1 (-3.8, -2.5) | |
| Placebo | 63 | 3 | – | 4.1 (3.0) | – | |
| Study 2 | Dexmedetomidine 1 mcg/kg | 55 | 53 | 39 (20, 57) | 1.1 (1.5) | -1.8 (-2.7, -0.9) |
| Placebo | 50 | 14 | – | 2.9 (3.0) | – |
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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