Durogesic Patch

Durogesic Patch Mechanism of Action





Full Prescribing Info
Pharmacotherapeutic group: Analgesics, opioids; phenylpiperidine derivatives. ATC code: N02AB03.
Pharmacology: Pharmacodynamics: Mechanism of action: Fentanyl is an opioid analgesic, interacting predominantly with the µ-opioid receptor. Its primary therapeutic actions are analgesia and sedation. Minimum effective analgesic serum concentrations of fentanyl in opioid-naive patients range from 0.3 to 1.5 ng/mL; side effects increase in frequency at serum concentrations above 2 ng/mL. Both the minimum effective concentration and the concentration at which toxicity occurs rise with increasing tolerance. The rate of development of tolerance varies widely among individuals.
Pharmacokinetics: Absorption: DUROGESIC provides continuous systemic delivery of fentanyl during the 72-hour application period. Fentanyl is released at a relatively constant rate. The concentration gradient existing between the system and the lower concentration in the skin drives drug release. After initial DUROGESIC application, serum fentanyl concentrations increase gradually, generally leveling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are proportional to the DUROGESIC patch size. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.
A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14% (range 0-26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.
Distribution: The plasma-protein binding of fentanyl is about 84%.
Metabolism: Fentanyl is a high clearance drug and is rapidly and extensively metabolized primarily by CYP3A4 in the liver. The major metabolite, norfentanyl, is inactive. Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.
Elimination: After DUROGESIC is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13-22) hours following a 24 hour application. Following a 72-hour application, the mean half-life ranges from 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours.
Within 72 hours of IV fentanyl administration, approximately 75% of the fentanyl dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the feces, primarily as metabolites.
Special populations: Pediatrics: DUROGESIC was not studied in children under 2 years of age. Studies conducted in older children found that when adjusting for body weight, clearance in pediatric patients was about 20% higher than that in adults. These findings have been taken into consideration in determining the dosing recommendations for pediatric patients. DUROGESIC should be administered only to opioid-tolerant children age 2 years or older (see Dosage & Administration, Precautions).
Elderly: Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half- life, and they may be more sensitive to the drug than younger patients. In a study conducted with DUROGESIC, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Precautions).
Renal impairment: Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population.
If patients with renal impairment receive DUROGESIC, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Precautions).
Hepatic impairment: In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 µg/hr application of DUROGESIC were assessed. Although tmax and t1/2 were not altered, the mean plasma Cmax and AUC values increased by approximately 35% and 73%, respectively, in these patients. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of DUROGESIC reduced if necessary (see Precautions).
Toxicology: Non-clinical information: Carcinogenicity and mutagenicity: In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays. In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 µg/kg/day in males or 100 µg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC0-24h comparison).
Fertility: Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. There was no evidence of teratogenic effects.
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