Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, Opioids: phenylpiperidine derivatives, ATC code: N02AB03
Mechanism of action
Fentanyl is an opioid analgesic, interacting predominantly with the mu opioid receptor. Its primary therapeutic actions are analgesia and sedation.
Paediatric population
The safety of fentanyl transdermal patch was evaluated in 3 open-label studies in 289 paediatric subjects with chronic pain, aged 2 to 17 years, inclusive. Eighty of the children were aged 2 to 6 years, inclusive. Of the 289 subjects enrolled in these 3 studies, 110 initiated fentanyl transdermal patch treatment with a dosage of 12.5 mcg/h(Fenta 12). Of these 110 subjects, 23 (20.9%) had previously been receiving <30 mg of oral morphine equivalents per day, 66 (60.0%) had been receiving 30 to 44 mg of oral morphine equivalents per day, and 12 (10.9%) had been receiving at least 45 mg of oral morphine equivalents per day (data not available for 9 [8.2%] subjects). Starting dosages of 25 mcg/h and higher were used by the remaining 179 subjects, 174 (97.2%) of whom had been on opioid doses of at least 45 mg of oral morphine equivalents per day. Among the remaining 5 subjects with a starting dosage of at least 25 mcg/h whose prior opioid doses were <45 mg of oral morphine equivalents per day, 1 (0.6%) had previously been receiving <30 mg of oral morphine equivalents per day and 4 (2.2%) had been receiving 30 to 44 mg of oral morphine equivalents per day (see section 4.8).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption
Fentanyl transdermal patch provides continuous systemic delivery of fentanyl during the 72-hour application period.
Following fentanyl transdermal 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 fentanyl transdermal 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 fentanyl transdermal patch 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 Fenta TDP patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated application.
Pharmacokinetic/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 fentanyl transdermal patch, 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 Fenta TDP 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).