SUFENTA Solution for injection / infusion Ref.[50458] Active ingredients: Sufentanil

Sufentanil is a synthetic opioid with µ-agonist pharmacological effects.

The pharmacokinetics of intravenous SUFENTA can be described as a three-compartment model with an average distribution time of 0,72 minutes, a redistribution time of 13,7 minutes and an elimination half-life of 148 minutes.

SUFENTA has an immediate onset of action. A dose dependent attenuation of the sympathetic response to surgical stress has been demonstrated at intravenous doses of 8–30 µg/kg.

Distribution

In studies with intravenous sufentanil doses ranging from 250 µg to 1 500 µg which allow prolonged blood sampling and drug measurements, the following were found: sequential distribution half-lives of 2,3–4,5 min and 35–73 min, a V_c (volume of distribution of the central compartment) of 14,2 L, a V_dss (distribution volume at steady state) of 344 L. The sequential distribution half-lives but not the terminal half-life (ranging from 4,1 h after 250 µg to 10–16 h after 500–1,500 µg) determines the decline of the sufentanil plasma concentrations from therapeutic to recovery levels. Sufentanil pharmacokinetics are linear within the dose range studied.

Peak plasma concentrations of sufentanil administered epidurally are reached within 10 minutes and are 4–6 times lower than those after intravenous administration. The addition of adrenaline (50–75 µg) further reduces the initial fast absorption by 25–50%.

Plasma protein binding is approximately 92,5%. Plasma protein binding in children is lower compared to adults and increases with age. In newborns sufentanil is about 80,5% bound to proteins compared to 88,5% in infants and 91,9% in children.

Metabolism

The liver and intestine are the major sites of biotransformation. Sufentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme.

Elimination

The mean (range) terminal elimination half-life of sufentanil is 13 (11–15) hours. Because of assay detection limitations, the sufentanil elimination half-life was significantly shorter (240 min) after the 250 µg dose than after 1,500 µg. The plasma clearance is 917 mL/min. Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged medicine.

Special populations

Hepatic impairment

The volume of distribution is increased and total clearance decreased in cirrhotic patients compared to controls. This results in a significant prolongation of half-life by about 30% which warrants a longer period of post-operative surveillance (see section 4.4).

Renal impairment

The volume of distribution at steady state, total clearance, and terminal elimination half-life in patients on dialysis and undergoing renal transplantation are not different from healthy controls. The free fraction of sufentanil in this population is not different from healthy patients.

Paediatric population

Pharmacokinetic information in children is limited.

Intravenous administration

Plasma protein binding in children is lower compared to adults and increases with age. In newborns sufentanil is about 80,5% bound to proteins compared to 88,5% in infants, 91,9% in children and 92,5% in adults.

After administration of an intravenous sufentanil bolus of 10–15 µg/kg in paediatric patients undergoing cardiac surgery, the pharmacokinetics of sufentanil can be described by a triexponential curve as in adults (Table 5). Clearance normalised to body mass was shown to be higher in infants and children compared to adolescents, whose clearance rates were comparable to that of adults. In neonates, clearance was significantly reduced and exhibited large variability (range 1,2 to 8,8 mL/min/kg and one outlying value of 21,4 mL/min/kg). Neonates were shown to have a greater distribution volume at steady state and a prolonged elimination half-life. Pharmacodynamic differences due to differences in the pharmacokinetic parameters may be greater if the unbound fraction is taken into account.

Table 5. Mean sufentanil pharmacokinetic parameters in children following administration of 10–15 μg/kg sufentanil as a single intravenous bolus (N=28):

Cl = clearance, normalised to body mass; N = number of patients included in analysis; SD = standard deviation; T_1/2β = elimination half-life; V_dss = volume of distribution at steady state. Age ranges stated are those of the children studied.

Epidural administration

After epidural administration of 0,75 µg/kg sufentanil in 15 children aged 4 to 12 years, plasma levels taken 30, 60, 120 and 240 min after injection ranged from 0,08 ± 0,01 ng/mL to 0,10 ± 0,1 ng/mL. In 6 children aged between 5 and 12 years receiving a 0,6 µg/kg sufentanil bolus followed by continuous epidural infusion containing 0,08 µg/kg/h sufentanil and bupivacaine 0,2 mg/kg/h for 48 h, maximum concentrations were reached at approximately 20 min after bolus injection and ranged from below the limit of quantification (<0,02 ng/mL) to 0,074 ng/mL.

Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.