Precedex PI 58-6023 - Dexmedetomidine

1 Precedex Dexmedetomidine Hydrochloride Injection1 This information intended for residents only. Abbott Laboratories 2001 Reference 58-6388-R4-Rev. Feb., 2001 DESCRIPTIONP recedex ( Dexmedetomidine hydrochloride injection) is a sterile, nonpyrogenic solution suitable forintravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-enantiomer ofmedetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]- 1H-imidazolemonohydrochloride. Dexmedetomidine has a molecular weight of and the empirical formula isC13H16N2 HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and hasa pKa of Its partition coefficient in-octanol.

2 Water at pH is Precedex is supplied as a clear,colorless, isotonic solution with a pH of to Each 1 mL of Precedex contains 118 mcg ofdexmedetomidine HCl (equivalent to 100 mcg Dexmedetomidine base) and 9 mg of sodium chloride in solution is preservative-free and contains no additives or chemical PHARMACOLOGYG eneral: Dexmedetomidine is a relatively selective alpha2-adrenoceptor agonist with sedative properties. Alpha2selectivity is observed in animals following slow Intravenous (IV) infusion of low and medium doses (10-300 mcg/kg).

3 Both alpha1and alpha2activity is observed following slow IV infusion of high doses ( 1000 mcg/kg) or with rapid IV a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normallimits and there was no evidence of respiratory depression when Precedex was administered by IV infusionat doses within the recommended dose range ( mcg/kg/hr).Pharmacokinetics:Following intravenous administration, Dexmedetomidine exhibits the following pharmacokineticparameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; aterminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) ofapproximately 118 liters.

4 Clearance is estimated to be approximately 39 L/h. The mean body weightassociated with this clearance estimate was 72 exhibits linear kinetics in the dosage range of to g/kg/hr when administered byIV infusion for up to 24 hours. Table 1 shows the main pharmacokinetic parameters when Precedex wasinfused (after appropriate loading doses) at maintenance infusion rates of g/kg/hr (targetconcentration of ng/mL) for 12 and 24 hours, g/kg/hr (target concentration of ng/mL) for 24 hours, and g/kg/hr (target concentration of ng/mL) for 24 HCINHHNCH3CH3 Precedex Dexmedetomidine Hydrochloride Injection2 This information intended for residents only.

5 Abbott Laboratories 2001 Reference 58-6388-R4-Rev. Feb., 2001* Presented as harmonic mean and pseudo standard deviation.# Avg Css = Average steady-state concentration of Dexmedetomidine . ( 9 hour samples for 12 hourinfusion and 18 hour samples for 24 hour infusions).DistributionThe steady-state volume of distribution (Vss) of Dexmedetomidine is approximately 118 protein binding was assessed in the plasma of normal healthy male and femalevolunteers. The average protein binding was 94% and was constant across the different concentrationstested.

6 Protein binding was similar in males and females. The fraction of Dexmedetomidine that was boundto plasma proteins was statistically significantly decreased in subjects with hepatic impairment comparedto healthy 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 ofdexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Dexmedetomidine was exploredinvitro and none of these compounds appeared to be significantly displaced by undergoes almost complete biotransformation with very little unchangeddexmedetomidine excreted in urine and feces.

7 Biotransformation involves both direct glucuronidation aswell as cytochrome P450 mediated metabolism. The major metabolic pathways of Dexmedetomidine are:direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6) ofdexmedetomidine to generate 3-hydroxy Dexmedetomidine , the glucuronide of 3-hydroxydexmedetomidine, and 3-carboxy Dexmedetomidine ; and N-methylation of Dexmedetomidine to generate 3-hydroxy N-methyl Dexmedetomidine , 3-carboxy N-methyl Dexmedetomidine , and N-methyl terminal elimination half-life (t1/2) of Dexmedetomidine is approximately 2 hours and clearance isestimated to be approximately 39 L/h.

8 A mass balance study demonstrated that after nine days an averageof 95% of the radioactivity, following IV administration of radiolabeled Dexmedetomidine , was recovered inthe urine and 4% in the feces. No unchanged Dexmedetomidine was detected in the urine. Approximately85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionationof the radioactivity excreted in urine demonstrated that products of N-glucoronidation accounted forapproximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug toTable SD Pharmacokinetic ParametersParameterLoading Infusion (min)/Total infusion duration (hrs)10 min/12 hrs10 min/24 hrs10 min/24 hrs35 min/24 hrsDexmedetomidine Target Concentration (ng/mL)and Dose (mcg/kg/hr) *, , , Css #, 3-hydroxy Dexmedetomidine , the glucuronide of 3-hydroxy Dexmedetomidine , and 3-carboxylic aciddexmedetomidine together represented approximately 14% of the dose in urine.

9 N-methylation ofdexmedetomidine 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. TheN-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately28% of the urinary metabolites have not been :There was no observed difference in Dexmedetomidine pharmacokinetics due to :The pharmacokinetic profile of Dexmedetomidine was not altered by age. There were no differences in thepharmacokinetics of Dexmedetomidine in young (18 40 years), middle age (41 65 years), and elderly (>65 years) :The pharmacokinetic profile of Dexmedetomidine has not been studied in pediatric Impairment: Dexmedetomidine pharmacokinetics (Cmax, Tmax,AUC, t1/2,CL, and VSS) were not significantly different insubjects with severe renal impairment (creatinine clearance.)

10 <30 mL/min) compared to healthy , the pharmacokinetics of the metabolites of Dexmedetomidine have not been evaluated in patientswith impaired renal function. Since the majority of metabolites are excreted in the urine, it is possible thatthe metabolites may accumulate upon long-term infusions in patients with impaired renal function. (SeePRECAUTIONS, DOSAGE AND ADMINISTRATION).Hepatic Impairment:In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values fordexmedetomidine 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 healthysubjects, respectively.