dexmedetomidine hydrochloride
Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Precedex
Intensive Care Unit Sedation
Precedex® is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Precedex should be administered by continuous infusion not to exceed 24 hours.
Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation.
Procedural Sedation
Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.
Precedex Dosage and Administration
Dosing Guidelines
Precedex dosing should be individualized and titrated to desired clinical response.
Precedex is not indicated for infusions lasting longer than 24 hours.
Precedex should be administered using a controlled infusion device.
Dosage Information
| 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 being converted from alternate sedative therapy: a loading dose may not be required [see Dosage and Administration: Maintenance of Intensive Care Unit Sedation (2.2)]. For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)]. For patients with impaired hepatic-function: a dose reduction should be considered [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/hr. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)]. For patients with impaired hepatic function: a dose reduction should be considered [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 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 patients with impaired hepatic function: a dose reduction should be considered [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/hr and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hr. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake fiberoptic intubation patients: a maintenance infusion of 0.7 mcg/kg/hr is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)]. For patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. |
Dosage Adjustment
Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug Interactions (7.1)].
Dosage reductions may need to be considered for patients with hepatic impairment, and geriatric patients [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Preparation of Solution
Precedex must be diluted in 0.9% sodium chloride solution to achieve required concentration (4 mcg/mL) prior to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion.
Strict aseptic technique must always be maintained during handling of Precedex.
To prepare the infusion, withdraw 2 mL of Precedex and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Administration with Other Fluids
Precedex infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.
Precedex has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.
Precedex has been shown to be compatible when administered with the following intravenous fluids:
- 0.9% sodium chloride in water
- 5% dextrose in water
- 20% mannitol
- Lactated Ringer's solution
- 100 mg/mL magnesium sulfate solution
- 0.3% potassium chloride solution
Compatibility with Natural Rubber
Compatibility studies have demonstrated the potential for absorption of Precedex to some types of natural rubber. Although Precedex is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
Dosage Forms and Strengths
200 mcg/2 mL (100 mcg/mL) in a glass vial
Contraindications
None
Warnings and Precautions
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.
Hypotension, Bradycardia, and Sinus Arrest
Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration in young, healthy 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. 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.
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.
Arousability
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.
Withdrawal
Intensive Care Unit Sedation
With administration up to 7 days, regardless of dose, 12 (5%) Precedex subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation.
Tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated.
Procedural Sedation
Withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<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 [see Adverse Reactions (6.1)].
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)].
Adverse Reactions
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 Precedex 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 Precedex for sedation in the Intensive Care Unit setting in which 1007 patients received Precedex. 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)].
| Adverse Event | All Precedex (N = 1007) (%) | Randomized Precedex (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 Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24 hours. | |||||
Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex for sedation in the surgical intensive care unit setting in which 387 patients received Precedex 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).
| 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 clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex group is provided in Table 5.
| Adverse Event | Dexmedetomidine (n=244) | Midazolam (n=122) |
|---|---|---|
Hypotension1 | 56% | 56% |
Hypotension requiring intervention | 28% | 27% |
Bradycardia2 | 42% | 19% |
Bradycardia requiring intervention | 5% | 1% |
Systolic Hypertension3 | 28% | 42% |
Tachycardia4 | 25% | 44% |
Tachycardia requiring intervention | 10% | 10% |
Diastolic Hypertension3 | 12% | 15% |
Hypertension3 | 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. | ||
The following adverse events occurred between 2 and 5% for Precedex 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%).
| Precedex 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% | ||
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