February 24, 2017
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CLINICAL PHARMACOLOGY

Mechanism Of Action

Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

Pharmacodynamics

Effects On The Central Nervous System

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 respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects On The Gastrointestinal Tract And Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed 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 biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects On The Cardiovascular System

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects On The Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].

Effects On The Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

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. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

Concentration-Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].

Respiratory System

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. 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. 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 [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

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 7 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 7: 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 400 mcg in Healthy Adult Subjects

Mean Fentanyl Plasma Concentration - Illustration

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

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 - Illustration

The pharmacokinetic parameters of the five strengths of SUBSYS tested are shown in Table 8. 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 8: Fentanyl Plasma Pharmacokinetic Parameters in Healthy Adult Subjects Receiving Single Doses of 100, 200, 400, 600, 800 mcg of SUBSYS

Pharm acokinetic 100 mcg 200 mcg 400 mcg 600 mcg 800 mcg
Parameter (Mean (%CV)) Tmax (hr)* 1.25 1.25 1.00 0.67 0.69
(0.17-2.05) (0.17-2.03) (0.17-2.03) (0.08-2.00) (0.17-4.00)
Cmax (ng/mL) 0.202 0.378 0.800 1.17 1.610
(28.35) (29.69) (27.66) (32.48) (37.22)
AUClast (ng/mL x hr) 0.9776 1.985 4.643 6.682 9.450
(49.82) (40.93) (44.53) (32.46) (36.62)
AUC0-∞ (ng/mL x hr) 1.245 2.475 5.342 7.446 10.38
(53.82) (46.48) (44.16) (81.54) (35.60)
T½ (hr) 5.25 8.45 11.03 10.64 11.99
(89.92) (77.94) (62.20) (41.73) (32.15)
* Data for Tmax presented as median (range)

Distribution

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.

Elimination

Metabolism

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].

Excretion

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.

Specific Population

Patients with Mucositis

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 9. 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 9: 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)

Clinical Studies

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. (%)
n=96
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

Pain Intensity Differences over Time - Illustration

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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