DEXISUN Concentrated solution for infusion Ref.[50700] Active ingredients: Dexmedetomidine

Following administration, dexmedetomidine exhibits the following pharmacokinetic characteristics: rapid distribution phase with a distribution half-life (t_1/2α) of about 6 minutes; terminal elimination half-life (t_1/2) of approximately two hours; steady state volume of distribution (V_ss) of approximately 118 litres. Clearance has an estimated value of about 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.

Dexmedetomidine 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 that was bound to plasma proteins was statistically significantly decreased in subjects with hepatic impairment compared with healthy subjects.

Dexmedetomidine is unlikely to cause clinically significant changes in the plasma protein binding of fentanyl, ketorolac, theophylline, digoxin, lidocaine, phenytoin, warfarin, ibuprofen and propranolol.

Dexmedetomidine is eliminated almost exclusively by metabolism with 95% of a radiolabelled dose being excreted in the urine and 4% in the faeces. Approximately 34% of the excreted metabolites are products of N-glucuronidation.

Hepatic Impairment

In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values were reported to be lower than in healthy subjects. The mean clearance values for subjects with mild, moderate, and severe hepatic impairment were reported to be 74%, 64% and 53% respectively, of those reported in the normal healthy subjects. Mean clearances for free drug were reported to be 59%, 51%, and 32% respectively, of those reported in the normal healthy subjects. Although dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction depending on the degree of hepatic impairment (see section 4.2).

Renal Impairment

Dexmedetomidine pharmacokinetics (C_max, T_max, AUC, t_½, CL and V_ss) were not reported to be different in subjects with severe renal impairment (Cr CI: <30 ml/min) compared with healthy subjects.

Gender

No difference in dexmedetomidine pharmacokinetics due to gender was reported.

Elderly

The pharmacokinetic profile of dexmedetomidine was not altered by age. The elderly are more sensitive to the effects of dexmedetomidine. In clinical trials, there was a higher incidence of bradycardia and hypotension in elderly patients (>65 years of age).

Paediatric population

The pharmacokinetic profile of dexmedetomidine has not been studied in subjects less than 18 years.

Reported non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.

In the reported reproductive toxicity studies, dexmedetomidine had no effect on male or female fertility in the rat, and no teratogenic effects were reported in the rat or rabbit. In the rabbit study intravenous administration of the maximum dose, 96 µg/kg/day, produced exposures that are similar to those reported clinically. In the rat, subcutaneous administration at the maximum dose, 200 µg/kg/day, caused an increase in embryofetal death and reduced the fetal body weight. These effects were associated with clear maternal toxicity. Reduced fetal body weight was noted also in the rat fertility study at dose 18 µg/kg/day and was accompanied with delayed ossification at dose 54 µg/kg/day. The reported exposure levels in the rat are below the clinical exposure range.