Precedex

Dexmedetomidine hydrochloride.

Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution.
Precedex (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3-dimethylphenyl)ethyl]- monohydrochloride, (S). Dexmedetomidine hydrochloride has a molecular weight of 236.7 and the empirical formula is C₁₃H₁₆N₂ HCl.
Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89.
Precedex injection is supplied as a clear, colorless, isotonic solution with a pH between 4.5 to 7.0. The solution is preservative free and contains no additives or chemical stabilizers.

Pharmacology: Mechanism of Action: Precedex is a relatively selective alpha₂-adrenergic agonist with sedative properties. Alpha₂ selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha₁ and alpha₂ activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration.
Pharmacodynamics: In a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2 - 0.7 mcg/kg/hr).
Clinical Studies: The safety and efficacy of Precedex has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 adult patients.
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 Precedex 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 Precedex 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 1. (See Table 1.)

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In the first study, 175 adult patients were randomized to receive placebo and 178 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. 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 Precedex (see Table 2).
A second prospective primary analysis assessed the sedative effects of Precedex by comparing the percentage of patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of patients in the Precedex group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 2).

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A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Precedex patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.
In a second study, 198 adult patients were randomized to receive placebo and 203 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated.
Patients randomized to placebo received significantly more propofol than patients randomized to Precedex (see Table 3).
A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 3).

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A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.
In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Precedex 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 Precedex for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Clinical Studies Experience under Adverse Reactions].
Procedural Sedation: The safety and efficacy of Precedex 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 Precedex in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Precedex in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
In Study 1, the sedative properties of Precedex 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 4).

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Patients were randomized to receive a loading infusion of either Precedex 1 mcg/kg, Precedex 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 Precedex and comparator groups. Efficacy results showed that Precedex 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 5).
In Study 2, the sedative properties of Precedex 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 (Table 1). Patients were randomized to receive a loading infusion of Precedex 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 Precedex and comparator groups. For efficacy results see Table 5. (See Table 5.)

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Pharmacokinetics: Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t_½) of approximately 6 minutes; a terminal elimination half-life (t_½) of approximately 2 hours; and steady-state volume of distribution (V_ss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.
Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. Table 6 shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. (See Table 6.)

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The loading doses for each of the previous indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.
Dexmedetomidine pharmacokinetic parameters after Precedex maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after Precedex maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t_½ were 39.4 L/hr, 152 L, and 2.67 hours, respectively.
Distribution: The steady-state volume of distribution (V_ss) of dexmedetomidine is approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.
The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex.
Elimination: Metabolism: Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxydexmedetomidine; and N methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.
Excretion: The terminal elimination half-life (t_½) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3 hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N methyl O glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.
Specific Populations: Gender: There was no observed difference in Precedex pharmacokinetics due to gender.
Geriatrics: The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18 - 40 years), middle age (41 - 65 years), and elderly (>65 years) subjects.
Hepatic Impairment: In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Precedex were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively.
Although Precedex is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage Information under Dosage & Administration and Hepatic Impairment under Precautions].
Renal Impairment: Precedex pharmacokinetics (C_max, T_max, AUC, t_½, CL, and V_SS) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.
Drug Interactions: In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with Precedex.
Mutagenesis: Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.
Impairment of Fertility: Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis) administered from 10 weeks prior to mating in males and 3 weeks prior to mating and during mating in females.
Animal Pharmacology and/or Toxicology: There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of Precedex at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.

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.

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: (See Table 7.)

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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 Anesthetics, Sedatives, Hypnotics, Opioids under Interactions].
Dosage reductions may need to be considered for patients with renal or hepatic impairment, and geriatric patients [see Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics under Actions].
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. Do not use if product is discolored or if precipitate matter is present.
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 and 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.

The tolerability of Precedex 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 Precedex 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 Precedex (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

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 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 Precedex infusion. Some of these cases have resulted in fatalities. 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 adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex 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.
In adult subjects, 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: In adult subjects, 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 Clinical Studies Experience under Adverse Reactions].
Hyperthermia or Pyrexia: Precedex may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue Precedex if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.
Drug Abuse and Dependence: Controlled Substance: Precedex (dexmedetomidine hydrochloride) is not a controlled substance.
Dependence: The dependence potential of Precedex has not been studied in humans. However, since studies in rodents and primates have demonstrated that Precedex exhibits pharmacologic actions similar to those of clonidine, it is possible that Precedex may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Withdrawal as previously mentioned].
Hepatic Impairment: Since Precedex clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage Information and Dosage Adjustment under Dosage & Administration, and Pharmacology: Pharmacokinetics under Actions].
Incompatibilities: Precedex infusion should not be co-administered through the same intravenous catheter with blood, serum, 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.
Use in Children: Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated.
Use in Elderly: Intensive Care Unit Sedation: A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of Precedex [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage Information under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions].
Procedural Sedation: A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in Precedex-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.

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 as follows).
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 [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.
Lactation: Risk Summary: Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data). There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Precedex and any potential adverse effects on the breastfed infant from Precedex or from the underlying condition.
Data: In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2-0.7 mcg/kg/hour.
Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia and sinus arrest [see Hypotension, Bradycardia, and Sinus Arrest under Precautions].
Transient hypertension [see Transient Hypertension under Precautions].
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 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 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 adult 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 8. The most frequent adverse reactions were hypotension, bradycardia and dry mouth. [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]. (See Table 8.)

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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 adult 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 9).

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In a controlled clinical trial, Precedex 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 patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 10. 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 11. (See Table 10.)

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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%). (See Table 11.)

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Procedural Sedation: Adverse reaction information is derived from the two trials for procedural sedation [see Pharmacology: Pharmacodynamics: Clinical Studies: Procedural Sedation under Actions] in which 318 adult patients received PRECEDEX. 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 12. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]. Prespecified criteria for the vital signs to be reported as adverse reactions are footnoted as follows on the table. The decrease in respiratory rate and hypoxia was similar between PRECEDEX and comparator groups in both studies. (See Table 12.)

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Postmarketing Experience: The following adverse reactions have been identified during post approval use of Precedex. 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 Precedex during post approval use of the drug. (See Table 13.)

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Anesthetics, Sedatives, Hypnotics, Opioids: Co-administration of Precedex 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 Precedex and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with Precedex, a reduction in dosage of Precedex or the concomitant anesthetic, sedative, hypnotic or opioid may be required.
Neuromuscular Blockers: In one study of 10 healthy adult volunteers, administration of Precedex 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.

Handling: Discard unused portion.

Store below 30°C. To reduce microbiological hazard, use as soon as possible after dilution. If storage is necessary, store at 2 to 8°C for not more than 24 hours.

Precedex is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of Precedex and as clinically appropriate after discontinuation.
When Precedex is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.
Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of Precedex such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness.
Advise breastfeeding mothers who were exposed to Precedex to monitor breastfed neonates for irritability [see Lactation under Use in Pregnancy & Lactation].

Hypnotics & Sedatives

N05CM18 - dexmedetomidine ; Belongs to the class of other hypnotics and sedatives.

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