Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Janssen-Cilag Limited 50-100 Holmers Farm Way High Wycombe Buckinghamshire HP12 4EG UK
The analgesic potency of Rapifen is one quarter that of fentanyl. The duration of action of Rapifen is one third that on an equianalgesic dose of fentanyl and is clearly dose-related. Its depressant effects on respiratory rate and alveolar ventilation are also of shorter duration than those of fentanyl.
The onset of action of Rapifen is four times more rapid than that of an equianalgesic dose of fentanyl. The peak analgesic and respiratory depressant effects occur within 90 seconds.
In man, alfentanil at therapeutic doses had no detrimental effects of myocardial performance. The cardiovascular stability is remarkable both in healthy and poor-risk patients. The only changes seen in blood pressure and heart rate are transient, slight decreases occurring immediately after induction. The incidence and degree of respiratory depression is less and of shorter duration after alfentanil than with fentanyl. Like other narcotic analgesics, alfentanil increases the amplitude of the EEG and reduces its frequency. Alfentanil reduces intraocular pressure by about 45%. It blocks increases in plasma cortisol and in plasma antidiuretic and growth hormones throughout surgery and prevents increases in plasma catecholamines up to but not during or after cardiopulmonary bypass in patients undergoing open heart surgery.
Alfentanil is a synthetic opioid with µ-agonist pharmacological effects.
After bolus injections ranging from 2.4 to 125 µg/kg, plasma levels in man decay triexponentially with a terminal half life of approximately 90 minutes. Total distribution volume varies from 0.4 to 1.0 L/kg, indicating a limited distribution of alfentanil to the tissues. Plasma clearance, varying from 3.3 to 8.3 ml/kg/min represents approximately one third of liver plasma flow indicating that elimination of alfentanil is not flow dependent. Since only 0.4% of the dose is excreted with the urine as unchanged drug, elimination of alfentanil occurs mainly by metabolism.
These main parameters in patients undergoing surgery are similar to those in healthy volunteers. Only when the drug was given as the sole anaesthetic in a continuous high infusion over about 5 hours was the clearance of alfentanil reduced resulting in a plasma half-life of about 200 minutes, the distribution volume not being markedly changed.
Plasma protein binding of alfentanil is 92%, mainly due to a strong binding to the ‘acute phase’ α1 acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. The elderly show a longer half-life for Rapifen after IV bolus doses.
Protein binding in newborns is 75% and increases in children to 85%. The plasma clearance in newborns is approximately 7.2 ± 3.2mL/kg/min and 4.7 ± 1.7 mL/kg/min in children between 4.5 to 7.75 years. The volume of distribution at steady state was 1230 ± 520 mL/kg in newborns and 163.5 ± 110 mL/kg in children. The half-life is 146 ± 57 minutes in newborns and 40.2 ± 8.9 minutes in children.
After administration of a single intravenous dose of 50 µg/kg, the terminal half-life in cirrhotic patients is significantly longer than in controls. The volume of distribution remains unchanged. The free fraction of alfentanil increases in cirrhotic patients to 18.5% compared with 11.5% in controls. This increase in free fraction together with a reduction in clearance from 3.06 mL/min/kg in controls to 1.60 mL/min/kg in cirrhotic patients will result in a more prolonged and pronounced effect (see Section 4.4.).
The volume of distribution and clearance of the free fraction is similar in renal failure patients and healthy controls. The free fraction of alfentanil in patients with renal failure is increased to 12.4 to 19 % compared with 10.3 to 11% in controls. This may result in an increase in clinical effects of alfentanil (see Section 4.4.).
Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
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