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Mechanism Of Action
Central Nervous System Effects
Fentanyl exerts its principal pharmacologic effects on the central nervous system. Central nervous system effects increase with increasing serum fentanyl concentrations.
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 concentrations 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.
In clinical trials of 357 non-opioid tolerant subjects treated with DURAGESIC, 13 subjects 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 subjects weighing less than 63 kg (9 of 13). Although subjects with prior 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.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of DURAGESIC is contraindicated in patients who are not tolerant to opioid therapy.
Gastrointestinal Tract And Other Smooth Muscle
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.
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.
DURAGESIC is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix 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 matrix 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.
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 20 and 72 hours after initial application (see Table 6). Serum fentanyl concentrations achieved are proportional to the DURAGESIC delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. 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 (see Figure 1). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.
After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 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.
A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the DURAGESIC system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.
Table 6: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING
FIRST 72-HOUR APPLICATION OF DURAGESIC
|Mean (SD) Time to Maximal Concentration Tmax (h)||Mean (SD) Maximal Concentration Cmax (ng/mL)|
|DURAGESIC 12 mcg/h||28.8 (13.7)||0.38 (0.13)*|
|DURAGESIC 25 mcg/h||31.7 (16.5)||0.85 (0.26)**|
|DURAGESIC 50 mcg/h||32.8 (15.6)||1.72 (0.53)**|
|DURAGESIC 75 mcg/h||35.8 (14.1)||2.32 (0.86)**|
|DURAGESIC 100 mcg/h||29.9 (13.3)||3.36 (1.28)**|
|*Cmax values dose normalized from 4 × 12.5 mcg/h: Study
2003-038 in healthy volunteers
**Cmax values: Study C-2002-048 dose proportionality study in healthy volunteers
NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours.
Figure 1 : Serum Fentanyl Concentrations Following
Single and Multiple Applications of DURAGESIC 100 mcg/h
Table 7: RANGE OF PHARMACOKINETIC PARAMETERS OF
INTRAVENOUS FENTANYL IN PATIENTS
|Clearance (L/h) Range [70 kg]||Volume of Distribution Vss (L/kg) Range||Half-Life t½ (h) Range|
|Renally Impaired Patients||30-78||-||-|
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
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.
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the DURAGESIC fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single DURAGESIC 100 μg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥ 65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥ 65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
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 [see DOSING AND ADMINISTRATION].
Information on the effect of hepatic impairment on the pharmacokinetics of DURAGESIC is limited. The pharmacokinetics of DURAGESIC delivering 50 μg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), Cmax and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.
Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of DURAGESIC, hepatic impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid use of DURAGESIC in patients with severe hepatic impairment [see DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use in Specific Populations].
Information on the effect of renal impairment on the pharmacokinetics of DURAGESIC is limited. The pharmacokinetics of intravenous injection of 25 μg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Because there is in-vivo evidence of renal contribution to the elimination of DURAGESIC, renal impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal impairment [see DOSING AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 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-∞. 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, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving DURAGESIC and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see BOXED WARNING and WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of DURAGESIC.
DURAGESIC as therapy for pain due to cancer has been studied in 153 patients. In this patient population, DURAGESIC has been administered in doses of 25 μg/h to 600 μg/h. Individual patients have used DURAGESIC continuously for up to 866 days. At one month after initiation of DURAGESIC therapy, patients generally reported lower pain intensity scores as compared to a prestudy analgesic regimen of oral morphine.
The duration of DURAGESIC use varied in cancer patients; 56% of patients used DURAGESIC for over 30 days, 28% continued treatment for more than 4 months, and 10% used DURAGESIC for more than 1 year.
In the pediatric population, the safety of DURAGESIC has been evaluated in 289 patients with chronic pain 2–18 years of age. The duration of DURAGESIC use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16–30 days; 16% for 31–60 days; and 17% for at least 61 days. Twenty-five patients were treated with DURAGESIC for at least 4 months and 9 patients for more than 9 months.
Last reviewed on RxList: 1/6/2017
This monograph has been modified to include the generic and brand name in many instances.
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