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Mechanism of Action
Fentanyl is a pure 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, respiratory depression and death.
In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to any and all opioids.
The rate of development of tolerance varies widely among individuals. As a result, individually titrate the dose of Lazanda 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 a reduction in the responsiveness of the brain stem to increases in carbon dioxide 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 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 (e.g., 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.
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 Lazanda, in clinical trials, fentanyl given rapidly by intravenous injection in large doses has interfered with respiration by causing rigidity in the muscles of respiration. Physicians and other healthcare providers should be aware of this potential complication. [see BOXED WARNING- WARNING: Risk of Respiratory Depression, Medication Errors, Abuse Potential, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation].
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 3.
Figure 1: Mean Plasma Fentanyl Concentration (pg/mL) in
Normal Subjects Receiving 100, 200, 400 and 800 mcg Lazanda or 200 mcg OTFC
Table 3: 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)|
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, 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. Mean Cmax values for Treated arm (Rhinitis treated with oxymetazoline) were about 32% and 40% lower and mean AUCt values were about 10% and 17% lower for Ragweed and Tree pollen induced cohorts respectively as compared to the Asymptomatic arm in each cohort. In addition, mean Tmax of Lazanda in the Treated arm was 0.75 h (range 0.08-3 h) for the Ragweed pollen induced cohort and 1.25 h (range 0.08-3 h) for Tree pollen induced cohort as compared to 0.25 h (0.17-1 h) and 0.33 h (0.17-2 h) for the Asymptomatic arm in each cohort respectively. These results indicate that co-administration with oxymetazoline 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 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 total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
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 4. 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 4: Dose of Lazanda Following Initial Titration (ITT
|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: 6/14/2012
This monograph has been modified to include the generic and brand name in many instances.
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