Precedex

Dexmedetomidine HCl.

Each mL of dexmedetomidine contains dexmedetomidine HCl 8 mcg (equivalent to dexmedetomidine base 100 mcg) and sodium chloride in water 9 mg. The solution is preservative-free and contains no additives and chemical stabilizers.
Dexmedetomidine HCl is a sterile, nonpyrogenic solution suitable for IV infusion following dilution. It is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride, has a molecular weight of 236.7 and an empirical formula of C₁₃H₁₆N₂·HCl.
Dexmedetomidine HCl is a white or almost white powder, freely soluble in water and its pKa is 7.1. Dexmedetomidine is supplied as a clear, colorless, isotonic solution with a pH of 4.5-7.

Pharmacology: Pharmacodynamics: Dexmedetomidine is a potent and highly selective α₂-adrenoreceptor agonist with a broad range of pharmacologic properties. It provides sedation and analgesia without respiratory depression during which patients are arousable and cooperative. Additional sympatholytic properties include less anxiety, hemodynamic stability, blunting of stress hormone response and reduction of intraocular pressure.
The sedative actions of dexmedetomidine are believed to be mediated primarily by post-synaptic α₂-adrenoreceptors, which in turn act on inhibitory pertussis-toxin-sensitive G protein, thereby increasing conductance through potassium channels. The site of sedative effects of dexmedetomidine has been attributed to the locus ceruleus. The analgesic actions are believed to be mediated by a similar mechanism of action at the brain and spinal cord level.
Alpha₂ selectivity is demonstrated following low and medium doses given slowly. Alpha₂ and α₁-activity is seen following rapid administration or very high doses. Dexmedetomidine has no affinity for β-adrenergic, muscarinic, dopaminergic or serotonin receptors.
In clinical trials evaluating patients requiring intensive care, patients receiving dexmedetomidine reached desired levels of sedation, were less anxious and had a significant reduction in the need for analgesia. However, patients could be easily aroused, were cooperative and orientated, resulting in increased ease of patient management. In phase I studies in healthy volunteers, dexmedetomidine did not cause respiratory depression and demonstrated attenuation of the heart rate and blood pressure responses to stress. These effects were confirmed in phase III studies in intensive care patients.
Two phase III ICU sedation studies were conducted comparing the effects of dexmedetomidine HCl with placebo including propofol or midazolam as rescue medications for sedation. Results from these studies support the unique profile of dexmedetomidine HCl.
Sedation: Dexmedetomidine HCl-treated patients reached clinically indicated levels of sedation, as measured by Ramsay sedation scores, and were easily arousable and cooperative. Dexmedetomidine HCl-treated patients also required statistically significant less rescue sedative medication than placebo-treated patients. (See Figure 1.)


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In addition, at least 60% of dexmedetomidine HCl-treated patients required no midazolam or propofol to achieve clinically required levels of sedation, compared to approximately 60% of placebo-treated patients who required midazolam >4 mg or propofol >50 mg. (See Table 1.)


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Analgesia: Dexmedetomidine HCl-treated patients required statistically significantly less treatment with an analgesic (morphine) than placebo-treated patients in the intensive care setting. (See Figure 2.)


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Less Anxiety: Dexmedetomidine HCl-treated patients exhibited statistically less anxiety than placebo-treated patients. The mean percentage of the Ramsay assessments that equaled one (anxious, agitated or restless patient) for the dexmedetomidine HCl group (4%) was statistically significantly (p<0.0001) less than for the placebo group (7%).
Hemodynamic Stability: Dexmedetomidine HCl-treated patients exhibited lower blood pressure and heart rate values, attenuating stress-related increases in blood pressure and heart rate seen in placebo-treated patients. (See Figures 3-5.)


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Additional Studies: Reduction of Intraocular Pressure: Dexmedetomidine produced bilateral, dose-related decreases in intraocular pressure in rabbits when used topically unilaterally.
Clinical Trials: ICU Sedation: Dexmedetomidine HCl has been evaluated in 3 double-blind, placebo-controlled clinical trials in the surgical ICU involving 766 randomized patients. Of these, 387 received dexmedetomidine HCl. In these trials, dexmedetomidine was titrated to a desired level of sedation using a loading dose of 1 mcg/kg over 10 mins, followed by a maintenance infusion of 0.2-0.7 mcg/kg/hr. Doses as low as 0.05 mcg/kg/hr have been used with infusions up to 24 hrs. Results from these studies demonstrated a statistically significant reduction in the sedative medication and analgesia (morphine), as compared to the placebo group. At least 60% of dexmedetomidine HCl-treated patients required no midazolam or propofol to achieve clinically required levels of sedation, compared to approximately 60% of placebo-treated patients who required midazolam >4 mg or propofol >50 mg. Results also indicated significantly less anxiety, no respiratory depression and significantly increased ease of patient management, as compared to the placebo group.
Perioperative Studies: Dexmedetomidine HCl has been evaluated in 7 clinical trials involving a total of 1199 patients, with 761 receiving dexmedetomidine HCl. A loading dose followed by a maintenance infusion was administered to achieve target concentrations of 0.15, 0.3 or 0.6 ng/mL using continuous infusions of 15 min prior to anethesia induction and continued until determination of MAC response, the end of surgery, 1, 2, 6 or 12 hrs postoperatively. Dexmedetomidine HCl was well-tolerated during pre-, intra- and postoperative administration.
Pharmacokinetics: Following Precedex administration, dexmedetomidine HCl exhibits the following pharmacokinetic characteristics: Rapid distribution phase with a distribution half-life (t _½a) of about 6 min: terminal elimation half-life (t_½) approximately 2 hrs; steady-state volume of distribution (V_ss) approximately 118 L. Clearance has an estimated value of about 39 L/hr. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine HCl is eliminated almost exclusively by metabolism with 95% of a radiolabeled dose being excreted in the urine and 4% in the feces. The major excreted metabolites are glucuronides.
Dexmedetomidine HCl protein binding was assessed in the plasma of normal healthy male and female human subjects: The average binding was 94% and constant across the different concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine HCl that was bound to plasma proteins was statistically significantly decreased in subjects with hepatic impairment compared to healhty subjects.
The possibility of binding displacement of dexmedetomidine HCl by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, showing negligible change in the plasma protein binding of dexmedetomidine HCl.
The possibility of binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine HCl was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine HCl. Dexmedetomidine HCl is unlikely to cause clinically significant changes in the plasma protein binding of these medications.
Hepatic Impairment: In subjects with varying degrees of hepatic impairment (Child-Pugh class A, B or C), clearance values were lower than in healthy subjects. The mean clearance values for subjects 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 dexmedetomidine HCl is dosed to effect, it may be necessary to consider dose reduction depending on the degree of hepatic impairment.
Renal Impairment: Dexmedetomidine HCl pharmacokinetics (C_max, T_max, AUC, t, CL and V_ss) were not different in subjects with severe renal impairment (CrCl <30 mL/min) compared to healthy subjects.
Gender: No difference in dexmedetomidine HCl pharmacokinetics due to gender was observed.
Geriatrics: The pharmacokinetic profile of dexmedetomidine HCl was not altered by age.
Pediatrics: The pharmacokinetic profile of dexmedetomidine HCl has not been studied in children.

Precedex is an α₂-sedative with analgesic properties for use in an intensive care setting.

Adult: Precedex should be individualized and titrated to the desired clinical effect. It is recommended to initiate Precedex with a loading dose of 1 mcg/kg over 10 mins, followed by a maintenance infusion in the range of 0.2-0.7 mcg/kg/hr. Maintenance infusion rate can be adjusted in order to achieve the desired clinical effect. Dosages as low as 0.05 mcg/kg/hr have been used in clinical studies. In clinical trials, infusions up to 24 hrs have been studied.
Precedex has been administered to patients requiring mechanical ventilation as well as to patients breathing spontaneously after extubation. There is no respiratory depression associated with Precedex administration.
Impaired Hepatic Function: Dosage reductions may need to be considered for patients with hepatic impairment, as dexmedetomidine hydrochloride is metabolized primarily in the liver.
Impaired Renal Function: No dosage adjustment is necessary.
Elderly: No dosage adjustment is necessary in elderly patients.
Children: Safety and efficacy of Precedex have not been studied in children.
Administration: A controlled infusion device should be used to administer Precedex.
Strict aseptic technique must always be maintained during handling of Precedex infusion. Preparation of infusion solutions is the same, whether for the loading or maintainance dose. To prepare the infusion, withdraw 2 mL of Precedex concentration for solution for infusion and add to 48 mL of sodium chloride 0.9% to total 50 mL. Shake gently to mix well. A controlled infusion device should be used to administer Precedex. After dilution, Precedex is intended for immediate use and should be discarded after 24 hrs.
Parenteral products should be inspected visually for particulate matter and discoloration prior to administration.
Ampoules are intended for single-patient use only.

The tolerability of dexmedetomidine HCl was noted in 1 study in which healthy subjects achieved plasma concentrations from 1.8-13 times the upper boundary of the therapeutic range. The most notable effects observed in 2 subjects who achieved the highest plasma concentrations were 1st-degree AV block and 2nd-degree heart block. No hemodynamic compromise was noted with the AV block and the heart block resolved spontaneously within 1 min.
Of 5 patients reported with overdose of dexmedetomidine hydrochloride in the phase II/III ICU sedation studies, 2 had no symptoms reported; 2 had bradycardia with or without hypotension; and 1 who received 20 times the upper limit of the therapeutic range had a cardiac arrest from which he was successfully resuscitated.
Because dexmedetomidine HCl has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. In clinical trials, atropine and glycopyrrolate were effective in the treatment of Precedex-induced bradycardia.

Known hypersensitivity to dexmedetomidine.

Precedex should be administered only by persons skilled in the management of patients in the intensive care setting. Due to the known pharmacological effects, patients should be continuously monitored.
Bolus injections of Precedex should not be used in order to minimize undesirable pharmacological side effects. Clinical events of bradycardia and sinus arrest have been associated with Precedex administration in some young, healthy volunteers with high vagal tone or with different routes of administration including rapid IV or bolus administration of Precedex.

Reports of bradycardia and hypotension have been associated with Precedex. If medical intervention is required, treatment may include increasing the rate of fluid administration, elevation of lower extremities or use of pressor agents. The IV administration of anticholinergics (eg, atropine) should be considered to modify vagal tone.
In addition, transient hypertension has been observed primarily during the loading dose, associated with initial peripheral vasoconstrictive effects of Precedex. If intervention is necessary, reduction of the loading infusion rate may be desirable.
Precedex should not be co-administered through the same IV catheter with blood or plasma because physical compatibility has not been established.
Based on the knowledge that dexmedetomidine hydrochloride is primarily metabolized in the liver, dose reduction should be considered in hepatically impaired patients.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Animal carcinogenicity studies have not been performed with dexmedetomidine.
Dexmedetomidine HCl was not mutagenic in vitro, with or without metabolic activation, in either the bacterial reverse mutation assay (E. coli and Salmonella) or the mammalian cell forward mutation assay (mouse lymphoma).
There was no evidence of clastogenicity in the in vitro cytogenetics assay (human lymphocytes), with and without metabolic activation.
There was no evidence of clastogenicity in the in vivo mouse micronucleus test at doses as high as 250 mcg/kg (≥15 times the maximum recommended total daily human dose). There was evidence of clastogenic activity in the in vivo mouse micronucleus assay at a dose of 5000 mcg/kg, but this dose produced profound and sustained hypothermia that could have led to these results.
Dexmedetomidine did not affect reproductive capacity or fertility in male or female rats after daily SC administration as high as 54 mcg/kg/day for 70+ or 14+ days, respectively, approximately 3 times the maximum recommended human dose of 17.8 mcg/kg/day.
Dexmedetomidine did not affect reproductive capacity of fertility in the F1 generation of female rats receiving as much as 32 mcg/kg/day SC (gestation day 16 through postpartum day 25), approximately 2 times the maximum recommended human dose of 17.8 mcg/kg/day.
Use in pregnancy: Teratogenic effects were not observed following administration of dexmedetomidine at SC doses as high as 200 mcg/kg/day (gestation days 5-16) in rats or IV doses as high as 96 mcg/kg/day (gestation days 6-18) in rabbits. These doses are approximately 11 and 5 times the maximum recommended human dose of 17.8 mcg/kg/day, respectively.
Dexmedetomidine reduced fetal and pup body weights (18 and 54 mcg/kg/day SC, segment I; 200 mcg/kg/day, segment II), numbers of live pups/litter (18 and 54 mcg/kg/day, segment I), and increased post-implantation losses (200 mcg/kg/day, segment II) in rats. These findings are consistent with those of clonidine, another α₂-adrenoreceptor agonist. Dexmedetomidine has no effect on fetal body weight at doses as high as 96 mcg/kg/day IV in rabbits (segment II).
Radiolabeled dexmedetomidine administered SC to female rats gestation day 18 crosses the placental barrier to fetal tissue.
There are no adequate and well-controlled studies in pregnant women. Precedex should be used during prenancy only if the potential benefits justify the potential risk to the fetus.
Labor and Delivery: The safety of Precedex in labor and delivery has not been studied and is, therefore, not recommended for obstetrics, including cesarean section deliveries.
Use in lactation: It is not known whether dexmedetomidine hydrchloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Precedex infusion is administered to a nursing woman. Radiolabeled dexmedetomidine administered SC to lactating female rats was distributed to, but did not accumulate in milk.
Use in children: Safety and efficacy of Precedex in children <18 years have not been studied.
Use in the elderly: The safety and efficacy of Precedex were not altered by age.

Adverse event information is derived from all phase II/III clinical trials using continuous infusion of Precedex and from the subset of controlled infusion phase II/III trials for ICU sedation.
Phase II/III Continuous Infusion Trials: Adverse events include data from clinical trials of ICU sedation and perioperative administration in which 1337 patients received dexmedetomidine hydrochloride. Overall, the most frequently observed treatment-emergent adverse events considered by the investigator to have some relationship to study drug administration included hypotension, hypertension, bradycardia, nausea, dry mouth and hypoxia. (See Tables 2 and 3.)


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Phase ll/lll Continuous Infusion ICU Sedation Trials: Adverse events include data from clinical trials of ICU sedation in which 576 patients received dexmedetomidine HCl. Overall, the most frequently observed treatment-emergent adverse events considered by the investigator to have some relationship to study drug administration included hypotension, hypertension, bradycardia, dry mouth, nausea and somnolence. (See Tables 4 and 5.)


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Drud Abuse and Dependence: None known.

General: In vitro studies indicate that clinically relevant cytochrome P-450-mediated drug interactions are unlikely.
Anesthetics/Sedatives/Hypnotics/Opioids: Co-administration of Precedex is likely to lead to an enhancement of effects with anesthetics, sedatives, hypnotics, and opioids. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam were demonstrated. However, due to pharmacodynamic effects, when co-administered with Precedex, a dosage reduction with these agents may be required.
Neuromuscular Blockers: No clinically significant increases in the magnitude of neuromuscular blokade and no pharmacokinetic interactions were observed with Precedex and rocuronium administration.
Compatibility: Precedex been shown to be compatible when administered with the following IV fluids and drugs: Lactated Ringer's, dextrose 5% in water, 0.9% sodium chloride in water, 20% mannitol, thiopental sodium, etomiate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, glycopyrrolate bromide, phenylephrine HCl, atropine sulphate, midazolam, morphine sulphate, fentanyl citrate, and a plasma substitute.
Compatibility studies have shown potential for adsorption of dexmedetomidine HCl to some types of natural rubber. Although dexmedetomidine HCl is dosed to effect, it is advisable to use components with synthetic or coated natural rubber gaskets.
Incompatibilities: Compatibility of dexmedetomidine hydrochloride with co-administration of blood, serum or plasma has not been established. Precedex must not be mixed with other medicinal products or diluents except those mentioned previously.

Store at controlled room temperature, 15-30°C (59-86°F).
Shelf-Life: 24 hrs after dilution.

Hypnotics & Sedatives

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

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