MATRIFEN Transdermal patch Ref.[7247] Active ingredients: Fentanyl

Absorption

The fentanyl transdermal patch provides continuous systemic delivery of fentanyl during the 72-hour application period. Following patch application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. The polymer matrix and the diffusion of fentanyl through the layers of the skin ensure that the release rate is relatively constant. The concentration gradient existing between the system and the lower concentration in the skin drives drug release. The average bioavailability of fentanyl after application of the transdermal patch is 92%.

After the first patch 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. 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. Due to accumulation, the AUC and C_max values over a dosing interval at steady state are approximately 40% higher than after a single application. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. High inter-subject variability in plasma concentrations has been observed.

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.

Skin temperature elevation may enhance the absorption of transdermally-applied fentanyl (see section 4.4). An increase in skin temperature through the application of a heating pad on low setting over the Matrifen system during the first 10 hours of a single application increased the mean fentanyl AUC value by 2.2-fold and the mean concentration at the end of heat application by 61%.

Distribution

Fentanyl is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (3 to 10 L/kg after intravenous dosing in patients). Fentanyl accumulates in skeletal muscle and fat and is released slowly into blood.

In a study in cancer patients treated with transdermal fentanyl, plasma protein binding was on average 95% (range 77-100%). Fentanyl crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.

Biotransformation

Fentanyl is a high clearance active substance and is rapidly and extensively metabolised primarily by CYP3A4 in the liver. The major metabolite, norfentanyl, and other metabolites are inactive. Skin does not appear to metabolise 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

Following a 72-hour patch application, the mean fentanyl half-life ranges from 20 to 27 hours. As a result of continued absorption of fentanyl from the skin depot after removal of the patch, the half-life of fentanyl after transdermal administration is about 2- to 3-fold longer than intravenous administration.

After intravenous administration, fentanyl mean total clearance values across studies range in general between 34 and 66 L/h.

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted into the urine and approximately 9% of the dose into the faeces. Excretion occurs primarily, as metabolites, with less than 10% of the dose excreted as unchanged active substance.

Linearity/non-Linearity

The serum fentanyl concentrations attained are proportional to the fentanyl transdermal patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated application.

harmacokinetic/Pharmacodynamic Relationships

There is a high inter-subject variability in fentanyl pharmacokinetics, in the relationships between fentanyl concentrations, therapeutic and adverse effects, and in opioid tolerance. The minimum effective fentanyl concentration depends on the pain intensity and the previous use of opioid therapy. Both the minimum effective concentration and the toxic concentration increase with tolerance. An optimal therapeutic concentration range of fentanyl can therefore not be established. Adjustment of the individual fentanyl dose must be based on the patient’s response and level of tolerance. A lag time of 12 to 24 hours after application of the first patch and after a dose increase must be taken into account.

Special populations

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 transdermal fentanyl, 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 section 4.4).

Renal impairment

The influence of renal impairment on the pharmacokinetics of fentanyl is expected to be limited because urinary excretion of unchanged fentanyl is less than 10% and there are no known active metabolites eliminated by the kidney. However, as the influence of renal impairment on the pharmacokinetics of fentanyl has not been evaluated, caution is advised (see sections 4.2 and 4.4).

Hepatic impairment

Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of transdermal fentanyl should be reduced if necessary (see section 4.4). Data in subjects with cirrhosis and simulated data in subjects with different grades of impaired liver function treated with transdermal fentanyl suggest that fentanyl concentrations may be increased, and fentanyl clearance may be decreased compared to subjects with normal liver function. The simulations suggest that the steady-state AUC of patients with Child-Pugh Grade B liver disease (Child-Pugh Score = 8) would be approximately 1.36 times larger compared with that of patients with normal liver function (Grade A; Child-Pugh Score = 5.5). As for patients with Grade C liver disease (Child-Pugh Score = 12.5), the results indicate that fentanyl concentration accumulates with each administration, leading these patients to have an approximately 3.72 times larger AUC at steady state.

Paediatric Population

Fentanyl concentrations were measured in more than 250 children aged 2 to 17 years who were applied fentanyl patches in the dose range of 12.5 to 300 mcg/h. Adjusting for body weight, clearance (L/h/kg) appears to be approximately 80% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are expected to have a similar clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients (see sections 4.2 and 4.4).

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Standard reproductive and developmental toxicity studies have been carried out using parenteral administration of fentanyl. In a rat study fentanyl did not influence male fertility. Some studies with female rats revealed reduced fertility and enhanced embryo mortality.

Effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the developing embryo. There was no indication of teratogenic effects in studies in two species (rats and rabbits). In a study on pre- and postnatal development the survival rate of offspring was significantly reduced at doses which slightly reduced maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour of the offspring were not observed.

Mutagenicity testing in bacteria and in rodents yielded negative results. Fentanyl induced mutagenic effects in mammalian cells in vitro, comparable to other opioid analgesics. A mutagenic risk for the use of therapeutic doses seems unlikely since effects appeared only at high concentrations.

A carcinogenicity study (daily subcutaneous injections of fentanyl hydrochloride for two years in Sprague Dawley rats) did not induce any findings indicative of oncogenic potential.