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Mechanism of Action
Fentanyl is an opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, codeine, and hydrocodone.
Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.
The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3-to 5-minute half-life).
In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of FENTORA should be individually titrated to achieve the desired effect [see DOSAGE AND ADMINISTRATION].
Central Nervous System
The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.
Fentanyl depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of another oral transmucosal fentanyl citrate (Actiq). Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl citrate product administration and may persist for several hours.
Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with oral transmucosal fentanyl products in clinical trials, fentanyl given rapidly by intravenous injection in large doses may interfere with respiration by causing rigidity in the muscles of respiration. Therefore, physicians and other healthcare providers should be aware of this potential complication. See BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and OVERDOSAGE.
Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.
Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of FENTORA is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract.
In a study that compared the absolute and relative bioavailability of FENTORA and Actiq (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with FENTORA) (Table 4).
Table 4: Pharmacokinetic
Parameters* in Adult Subjects Receiving FENTORA or Actiq
|Pharmacokinetic Parameter (mean)||FENTORA 400 mcg||Actiq 400 mcg (adjusted dose)***|
|Absolute Bioavailability||65% ± 20%||47% ± 10.5%|
|Fraction Absorbed Transmucosally||48% ± 31.8%||22% ± 17.3%|
|Tmax (minute)**||46.8 (20-240)||90.8 (35-240)|
|Cmax (ng/mL)||1.02 ± 0.42||0.63 ± 0.21|
|AUC0-tmax (ng•hr/mL)||0.40 ± 0.18||0.14 ± 0.05|
|AUC0-inf (ng•hr/mL)||6.48 ± 2.98||4.79 ± 1.96|
| * Based on venous blood samples.
** Data for Tmax presented as median (range).
*** Actiq (OTFC) data was dose adjusted (800 mcg to 400 mcg).
Similarly, in another bioavailability study exposure following administration of FENTORA was also greater (approximately 50%) compared to Actiq.
Due to differences in drug delivery, measures of exposure (Cmax, AUC0tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with FENTORA compared to Actiq (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for FENTORA.
Figure 1: Mean Plasma
Concentration Versus Time Profiles Following Single Doses of FENTORA and Actiq
in Healthy Subjects
Actiq data was dose adjusted (800 mcg to 400 mcg).
Mean pharmacokinetic parameters are presented in Table 5. Mean plasma concentration versus time profiles are presented in Figure 2.
Table 5: Pharmacokinetic
Parameters* Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in
|Pharmacokinetic Parameter (mean±SD)||100 mcg||200 mcg||400 mcg||800 mcg|
|Cmax (ng/mL)||0.25 ± 0.14||0.40 ± 0.18||0.97 ± 0.53||1.59 ± 0.90|
|Tmax minute** (range)||45.0 (25.0 -181.0)||40.0 (20.0 -180.0)||35.0 (20.0 -180.0)||40.0 (25.0 - 180.0)|
|AUC0-inf (ng•hr/mL)||0.98 ± 0.37||2.11 ± 1.13||4.72 ± 1.95||9.05 ± 3.72|
|AUC0-tmax (ng•hr/mL)||0.09 ± 0.06||0.13 ± 0.09||0.34 ± 0.23||0.52 ± 0.38|
|T½, hr**||2.63 (1.47 -13.57)||4.43 (1.85 -20.76)||11.09 (4.63 -20.59)||11.70 (4.63 - 28.63)|
|* Based on venous sampling.
** Data for Tmax presented as median (range).
Figure 2: Mean Plasma Concentration Versus Time
Profiles Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in
Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.
The effect of mucositis (Grade 1) on the pharmacokinetic profile of FENTORA was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected tmax where range was used) are presented in Table 6.
Table 6: Pharmacokinetic
Parameters in Patients with Mucositis
|Patient status||Cmax (ng/mL)||tmax (min)||AUC0-tmax (ng•hr/mL)||AUC0-8 (ng•hr/mL)|
|Mucositis||1.25 ± 0.78||25.0 (15 - 45)||0.21 ± 0.16||2.33 ± 0.93|
|No mucositis||1.24 ± 0.77||22.5 (10 - 121)||0.25 ± 0.24||1.86 ± 0.86|
Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.
Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80-85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.
The metabolic pathways following buccal administration of FENTORA have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active [see DRUG INTERACTIONS].
Disposition of fentanyl following buccal administration of FENTORA has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.
The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.
In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in US subjects (mean Cmax and AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).
The efficacy of FENTORA was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.
In this trial, patients were titrated in an open-label manner to a successful dose of FENTORA. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects.
Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of FENTORA and 3 being placebo. Patients used one tablet of study drug (either FENTORA or Placebo) per breakthrough pain episode.
Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45 and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.
Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 7. The median dose was 400 mcg.
Table 7: Successful Dose of FENTORA Following Initial
|FENTORA Dose||n (%)
|100 mcg||13 (16)|
|200 mcg||11 (14)|
|400 mcg||21 (26)|
|600 mcg||10 (13)|
|800 mcg||25 (31)|
The LS mean (SE) SPID30 for FENTORA-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).
Figure 3: Mean Pain
Intensity Differences (PID) at Each Time Point During the Double-Blind
Last reviewed on RxList: 3/12/2013
This monograph has been modified to include the generic and brand name in many instances.
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