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Mechanism Of Action
Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.
Effects On The Central Nervous System
Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increase in carbon dioxide tension and 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, 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.
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 [see DOSAGE AND ADMINISTRATION].
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].
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 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 or nasal 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, ADVERSE REACTIONS, OVERDOSAGE].
In a study that compared the relative bioavailability of LAZANDA and an oral transmucosal fentanyl citrate product, the bioavailability of fentanyl from LAZANDA was approximately 20% higher. Fentanyl is absorbed from the nasal mucosa following intranasal administration of LAZANDA, with median Tmax values ranging from 15-21 min after administration of a single dose. Cmax and AUC values for fentanyl following administration of LAZANDA increase linearly over the 100- to 800-mcg dose range.
Mean plasma concentration versus time profiles are presented in Figure 1. Mean pharmacokinetic parameters are presented in Table 4.
Figure 1: Mean Plasma Fentanyl Concentration (pg/mL)
in Normal Subjects Receiving 100, 200, 400 and 800 mcg Lazanda or 200 mcg OTFC
Table 4: Pharmacokinetic
Parameters in Normal Subjects Receiving 100, 200, 400, and 800 mcg of LAZANDA
or 200 mcg OTFC
|100 mcg||200 mcg||400 mcg||800 mcg||200 mcg|
|Tmax, hours median (range)||0.33 (0.08-1.50)||0.25 (0.17-1.60)||0.35 (0.25-0.75)||0.34 (0.17-3.00)||1.50 (0.50-8.00)|
|Cmax, pg/mL Mean (%CV)||351.5 (51.3)||780.8 (48.4)||1552.1 (26.2)||2844.0 (56.0)||317.4 (29.9)|
|AUCinf, pg.hour/mL Mean (%CV)||2460.5 (17.9)||4359.9 (29.8)||7513.4 (26.7)||17272 (48.9)||3735.0 (32.8)|
|t½, hour Mean (%CV)||21.9 (13.6)||24.9 (51.3)||15.0 (24.7)||24.9 (92.5)||18.6 (31.4)|
A pharmacokinetic study evaluated the cerebrospinal fluid (CSF) concentrations of fentanyl administered via the intranasal (LAZANDA) route. As presented in Table 5, the maximum concentration of fentanyl in the CSF as delivered by LAZANDA was reached at 1.0 hour. Values for the Cmax and AUC0-6h of fentanyl are also presented in Table 5.
Table 5 : Cerebrospinal Pharmacokinetic Parameters in Normal Subjects Receiving 200 mcg of LAZANDA
|PHARMACOKINETICS PARAMETERS||LAZANDA (fentanyl nasal spray) 200 mcg|
|Tmax, hours Median (range)||1.01 (0.75-3.00)|
|Cmax, pg /mL Mean (%CV)||84.54 (55.7)|
|AUC0-6h,, pg.hour/mL Mean (%CV)||300.25 (40.6)|
In a pharmacokinetic study that evaluated multiple-dose pharmacokinetics of LAZANDA when two doses of LAZANDA are administered in the same nostril and are separated by a 1, 2 or 4 h time lapse, Cmax2 (Cmax after second administration) was greater than Cmax1 (Cmax after first administration), by 30% when LAZANDA was administered 1 h apart, by 25% when LAZANDA was administered 2 h apart and by 10% when LAZANDA was administered 4 h apart. Based on these results and based on Tmax range of LAZANDA observed across pharmacokinetic studies, and frequency of breakthrough pain episodes in a cancer population, a waiting period of 2 h between two consecutive doses of LAZANDA is recommended [see DOSAGE AND ADMINISTRATION].
In a pharmacokinetic study to evaluate differences in LAZANDA absorption in individuals with induced allergic (seasonal) rhinitis using Ragweed, no clinically meaningful differences were observed in rate or extent of exposure to fentanyl, when compared to the Asymptomatic (Unchallenged) state, indicating that presence of allergic rhinitis does not affect LAZANDA absorption. This study also assessed differences in Lazanda absorption, if any, when co-administered with oxymetazoline, a nasal decongestant in subjects undergoing treatment for seasonal allergic rhinitis. The mean Cmax and AUCt values for Treated arm (Rhinitis treated with oxymetazoline) were about 32% and 10% lower , respectively compared to the Asymptomatic arm. In addition, mean Tmax of LAZANDA in the Treated arm was 0.75 h (range 0.08-3 h) as compared to 0.25 h (0.17-1 h) for the Asymptomatic arm. These results indicate that co-administration with oxymetazoline in rhinitis leads to lower peak plasma concentrations and delayed Tmax of LAZANDA [see DRUG INTERACTIONS].
Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean volume of distribution at steady state (Vss) was 4 L/kg.
The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
The metabolic pathways following intranasal administration of LAZANDA 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.
The disposition of fentanyl following intranasal administration of LAZANDA 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 efficacy of LAZANDA was evaluated in one clinical trial in opioid tolerant adult patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg of oral morphine/day or an equianalgesic dose of another opioid (which could be fentanyl) for a week or longer. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain.
The clinical trial included an open-label titration phase where a dose was identified that provided adequate analgesia with tolerable side effects, within the range of 100 to 800 mcg. In the double-blind, placebo-controlled portion of the study, patients who were titrated to an adequate dose were randomized to a blinded sequence of 10 treatments with 7 being the identified dose of LAZANDA and 3 being placebo.
Of the patients who enrolled in the study, 73% achieved an adequate dose during the titration phase, 6% withdrew for lack of effective pain relief, and 5% withdrew due to adverse events. The distribution of final titrated doses is shown in Table 5. The final titrated dose of LAZANDA for breakthrough pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and, therefore, the dose was determined by titration starting at 100 mcg.
Table 6: Dose of LAZANDA Following Initial Titration
|LAZANDA Dose||(N=83) n (%)|
|100 mcg||12 (14)|
|200 mcg||7 (8)|
|400 mcg||27 (33)|
|800 mcg||37 (45)|
The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for LAZANDA than for placebo (see Figure 2).
Figure 2: Pain Intensity Differences (PID) following
LAZANDA or Placebo in Adult Patients with Breakthrough Cancer Pain
Last reviewed on RxList: 3/31/2017
This monograph has been modified to include the generic and brand name in many instances.
Additional Lazanda Information
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