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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 pure 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 pure 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 SUBSYS 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 SUBSYS. Peak respiratory depressive effects may be seen as early as 15 to 30 minutes from the start of oral transmucosal fentanyl 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 - WARNING: Importance Of Proper Patient Selection, Dosing, and Potential for Abuse, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE].
Following the single dose administration of SUBSYS, 400 mcg, the mean absolute bioavailability of fentanyl is 76% as measured by AUC0-∞. Fentanyl pharmacokinetic profile and bioavailability depend on the fraction of the dose that is absorbed through the sublingual mucosa and the fraction swallowed from the gastrointestinal tract.
In a study that compared the relative bioavailability of SUBSYS and oral transmucosal fentanyl citrate [OTFC]) in 21 healthy adult subjects, the rate and extent of fentanyl absorption were considerably greater with SUBSYS [34% greater maximum plasma concentration (Cmax) and 38% greater systemic exposure (AUCinf)] (Table 4 and Figure 1). [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 4 hours.
Table 4: Pharmacokinetic Parameters of Fentanyl in
Healthy Adult Subjects Receiving a Single Dose of SUBSYS or OTFC
|Pharmacokinetic Parameter (Mean (CV%))||SUBSYS 400 mcg||OTFC 400 mcg|
|Tmax (hour)*||1.5 (0.17, 2.00)||2.0 (0.5, 2.12)|
|Cmax (ng/mL)||0.813 (31.00)||0.607 (30.48)|
|AUC0-t (ng/mL X hr)||4.863 (35.12)||3.677 (39.16)|
|AUC0-∞ (ng/mL X hr)||5.761 (33.26)||4.182 (39.93)|
|* Data for Tmax presented as median (range)|
Figure 1 : Mean Fentanyl
Plasma Concentration-Time Profiles Following Single Dose Administration of
SUBSYS 400 mcg and OTFC 400mcg in Healthy Adult Subjects
Neither peak fentanyl concentration nor total exposure was appreciably affected by the pretreatment of oral cavity with hot water or refrigerated iced water, low or high pH beverages when SUBSYS was administered under fasted condition.
Dose proportionality among the five available strengths of SUBSYS (100, 200, 400, 600, and 800 mcg) has been evaluated in a crossover study in healthy subjects. Mean plasma fentanyl levels following these five dose levels of SUBSYS are shown in Figure 2. The curves for each dose level are similar in shape with increasing dose levels producing increasing plasma fentanyl levels. The Cmax and AUC0-∞ values increased in a dose-dependent manner that is approximately proportional to the SUBSYS doses administered.
Figure 2: Mean Fentanyl Plasma Concentration-Time
Profiles (36 hours) after Administration of SUBSYS 100 mcg, 200 mcg, 400 mcg,
600 mcg, and 800 mcg in Healthy Subjects
The pharmacokinetic parameters of the five strengths of SUBSYS tested are shown in Table 5. The mean Cmax ranged from 0.202 – 1.610 ng/mL. The median time of maximum plasma concentration (Tmax) across these five doses of SUBSYS varied from 0.67 -1.25 hours (range of 0.08 – 4.00 hours) as measured after the start of administration.
Table 5: Fentanyl Plasma
Pharmacokinetic Parameters in Healthy Adult Subjects Receiving Single Doses of
100, 200, 400, 600, 800 mcg of SUBSYS
|Pharmacokinetic Parameter (Mean (%CV))||100 mcg||200 mcg||400 mcg||600 mcg||800 mcg|
|Tmax (hr)*||1.25 (0.17-2.05)||1.25 (0.17-2.03)||1.00 (0.17-2.03)||0.67 (0.08-2.00)||0.69 (0.17-4.00)|
|Cmax (ng/mL)||0.202 (28.35)||0.378 (29.69)||0.800 (27.66)||1.17 (32.48)||1.610 (37.22)|
|AUClast (ng/mL X hr)||0.9776 (49.82)||1.985 (40.93)||4.643 (44.53)||6.682 (32.46)||9.450 (36.62)|
|AUC0-∞ (ng/mL X hr)||1.245 (53.82)||2.475 (46.48)||5.342 (44.16)||7.446 (81.54)||10.38 (35.60)|
|T½ (hr)||5.25 (89.92)||8.45 (77.94)||11.03 (62.20)||10.64 (41.73)||11.99 (32.15)|
|* Data for Tmax presented as median (range)|
The effect of mucositis (Grades 1 and 2) on the pharmacokinetics of SUBSYS was studied in a group of cancer patients with mucositis (N = 7 for Grade 1 and N = 2 for Grade 2) and without mucositis (N = 8). A single 100 mcg dose was administered. Mean summary statistics (standard deviation in parentheses) for patients with Grade 1 mucositis and patients without mucositis are presented in Table 6. Cancer patients with Grade 1 mucositis exhibited 73% greater Cmax and 52% greater AUClast values in comparison to patients without mucositis. The two cancer patients with Grade 2 mucositis had 4-and 7-fold higher Cmax and > 3- fold higher AUClast values compared to patients without mucositis.
Monitor patients with Grade 1 mucositis closely for signs of respiratory and central nervous system depression particularly during initiation of therapy with SUBSYS. As a result of the large and variable increase in exposure of fentanyl, use of SUBSYS should be avoided in patients with Grade 2 and more severe mucositis unless the benefits are expected to outweigh the risk of respiratory depression.
Table 6: Mean (%CV) Pharmacokinetic Parameters in
Patients with Mucositis
|Patient Status||N||Cmax (ng/mL)||Tmax (hr)*||AUC0-last (ng/mL X hr)|
|Mucositis Grade 1||7||0.45 (95.56)||0.25 (0.25, 2.00)||1.38 (44.93)|
|No Mucositis||8||0.26 (57.69)||0.38 (0.25, 2.00)||0.91 (14.29)|
|* Data for Tmax presented as median (range)|
Fentanyl is highly lipophilic. Animal data showed that following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. 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 free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (Vss) was 4 L/kg.
Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see DRUG INTERACTIONS].
Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the 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 was 0.5 L/hr/kg (range 0.3 - 0.7 L/hr/kg). The terminal half-life after SUBSYS administration is from 5 to 12 hours.
The efficacy of SUBSYS was demonstrated in a double-blind, placebo-controlled, crossover study in opioid tolerant adult patients with cancer and breakthrough pain. The dose range studied was from 100 mcg per dose to 1600 mcg per dose. Patients entering the trial must have had on average 1-4 episodes of pain per day not controlled on stable, chronic maintenance doses of opioid medication of at least 60 mg/day of morphine, 25 mcg/hr of transdermal fentanyl, or an equianalgesic dose of another opioid for at least 7 days.
The study began with an open-label dose titration period followed by a double-blind treatment period. The goal of titration was to find the dose of SUBSYS that provided adequate analgesia with acceptable side effects. Patients were titrated from a 100 mcg starting dose. Once a successful dose was established, patients were enrolled into the double-blind period and randomized to a sequence of 10 treatments; 7 with SUBSYS and 3 with placebo.
Patients assessed pain intensity on a 100 mm visual analog scale that rated the pain as 0=none to 100=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-100) was then measured at 5, 10, 15, 30, 45 and 60 minutes after the start of administration. The summed pain intensity difference from baseline to 30 minutes after dosing was the primary efficacy measure.
Out of 130 patients who entered the titration phase, 98 (75%) were able to titrate to a dose that adequately reduced pain with tolerable side effects and entered into the double-blind period.
The breakdown of successful dose for the patients entering the double-blind period of the study is as follows:
|SUBSYS Dose||Total No. (%)
|100 mcg||4 (4%)|
|200 mcg||7 (7%)|
|400 mcg||14 (15%)|
|600 mcg||15 (16%)|
|800 mcg||23 (24%)|
|1200 mcg (2 x 600 mcg)||20 (21%)|
|1600 mcg (2 x 800 mcg)||13 (14%)|
SUBSYS produced a statistically significantly greater reduction in pain intensity compared to placebo as measured by the Summed Pain Intensity Differences scale (SPID) at 30 minutes.
The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for SUBSYS than for placebo. The difference in mean pain intensity based on a 100 mm visual analog scale is displayed in Figure 3.
Figure 3 : Pain Intensity
Differences over Time
Last reviewed on RxList: 8/22/2013
This monograph has been modified to include the generic and brand name in many instances.
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