FORTIVA Solution for injection Ref.[51236] Active ingredients: Remifentanil

Following administration of the recommended doses of remifentanil, the effective biological halflife is 3 to 10 minutes. The average clearance of remifentanil in young healthy adults is 40 ml/min/kg. Blood concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. For every 0,1 µg/kg/min increase in infusion rate, the blood concentration of remifentanil will rise 2,5 ng/ml. Remifentanil is approximately 70% bound to plasma proteins.

Metabolism: Remifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases.

The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (1/4 600^th as potent as remifentanil). The half-life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite.

Remifentanil is not a substrate for plasma cholinesterase.

Placental and milk transfer: Remifentanil crosses the placenta and appears in breast milk. In a human clinical trial, the concentration of remifentanil in foetal blood was approximately 50% of that in maternal blood.

The foetal arterio-venous ratio of remifentanil concentrations was approximately 30%, suggesting metabolism of remifentanil in the neonate.

Cardiac anaesthesia: The clearance of remifentanil is reduced by up to 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree Celsius.

Renal impairment: The pharmacokinetics of remifentanil after administration in the intensive care setting are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days.

The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment, the concentration of the carboxylic acid metabolite is expected to reach approximately 100-fold the level of remifentanil at steady state. Clinical data demonstrates that accumulation of the metabolite does not result in clinically relevant µ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.

There is no evidence that remifentanil is extracted during renal replacement therapy.

The carboxylic acid metabolite is extracted during haemodialysis by at least 30%.

Hepatic impairment: The pharmacokinetics of remifentanil are not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery.

Patients with severe hepatic impairment may be more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored, and the dose of remifentanil should be titrated to the individual patient need.

Paediatric patients: In paediatric patients 5 days to 17 years of age, the average clearance and steady state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The half-life of remifentanil is not significantly different in neonates suggesting that changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to that seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2 to 17 years of age are similar to those seen in adults after correcting for differences in body weight.

Elderly: The clearance of remifentanil is slightly reduced (approx. 25%) in elderly patients (>65 years) compared to young patients.

Elderly patients have a remifentanil EC50 for the formation of delta waves on the EEG that is 50% lower than young patients do; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient need.