Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system.
In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood levels of fentanyl may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope.
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination. At therapeutic dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting.
Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg.
(see graph and tables)
DURAGESIC® (fentanyl transdermal system) releases fentanyl from the reservoir at a nearly constant amount per unit time. The concentration gradient existing between the saturated solution of drug in the reservoir and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.
While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. The small amount of alcohol which has been incorporated into the system enhances the rate of drug flux through the rate-limiting copolymer membrane and increases the permeability of the skin to fentanyl.
Following DURAGESIC® 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. Serum fentanyl concentrations increase gradually following initial DURAGESIC® application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 24 and 72 hours after initial application (see Table A). Serum fentanyl concentrations achieved are proportional to the DURAGESIC® delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first few system applications. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl (see graph and Table B).
The kinetics of fentanyl in normal subjects following application of a 100 mcg/hr DURAGESIC® patch were bioequivalent with or without a BioclusiveTM overlay (polyurethane film dressing).
After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 17 (range 13-22) 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.
Serum Fentanyl Concentrations Following Multiple Applications of DURAGESIC® 100 mcg/h (n=10)
TABLE A: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF DURAGESIC®
NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in 17 hours.
| Mean (SD) Time to |
| Mean (SD) |
|DURAGESIC® 12 mcg/h ||27.5 (9.6) ||0.3 (0.2) |
|DURAGESIC® 25 mcg/h ||38.1 (18.0) ||0.6 (0.3) |
|DURAGESIC® 50 mcg/h ||34.8 (15.4) ||1.4 (0.5) |
|DURAGESIC® 75 mcg/h ||33.5 (14.5) ||1.7 (0.7) |
|DURAGESIC® 100 mcg/h ||36.8 (15.7) ||2.5 (1.2) |
TABLE B: RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
| Clearance |
| Volume of Distribution |
| Half-Life |
|Surgical Patients ||27 – 75 ||3 - 8 ||3 - 12 |
|Hepatically Impaired Patients ||3 - 80+ ||0.8 - 8+ ||4 - 12+ |
|Renally Impaired Patients ||30 – 78 ||– ||– |
Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8).
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.
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.
Hepatic or Renal Disease
Insufficient information exists to make recommendations regarding the use of DURAGESIC® in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.
In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to DOSAGE AND ADMINISTRATION section.
Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N=4) indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevance of these findings to DURAGESIC® (fentanyl transdermal system) is unknown at this time.
Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.
DURAGESIC® should be used with caution in elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see DOSAGE AND ADMINISTRATION).
The interaction between ritonavir, a CYP3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC0-∞. Coadministration of ritonavir in patients receiving DURAGESIC® has not been studied; however, an increase in fentanyl AUC is expected (see BOX WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore, potential interactions may occur when DURAGESIC® is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may reduce the efficacy of DURAGESIC®. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may also result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC® and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING , WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information).
Because of the risk for serious or life-threatening hypoventilation, DURAGESIC® is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with DURAGESIC®, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with DURAGESIC®.
While most adult and pediatric patients using DURAGESIC® chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation in addition to DURAGESIC®. The use of DURAGESIC® is contraindicated in patients who are not tolerant to opioid therapy.
The use of DURAGESIC® should be monitored by clinical evaluation, especially within the initial 24-72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. DURAGESIC® should be administered to children only if they are opioid-tolerant and 2 years of age or older.
See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation.
Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with DURAGESIC® was less than 1%.
Central nervous system effects increase with increasing serum fentanyl concentrations.