"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
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 and respiratory depression.
Conditions which decrease fentanyl clearance including hepatic dysfunction and co-administration of CYP3A4 inhibitors may lead to increased duration of exposure. However, the duration of effect for the initial dose of fentanyl is largely determined by the rate of distribution of the drug. Diminished metabolic clearance may become significant with repeated dosing or at very high single doses.
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 ONSOLIS 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 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 a 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 in humans. They also stimulate prolactin secretion, growth hormone secretion, and pancreatic secretion of insulin and glucagon in humans and other species, e.g., rats and dogs. Thyroid stimulating hormone 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 ONSOLIS. 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 - WARNINGS: Importance of Proper Patient Selection and Potential for Abuse, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE].
The absorption pharmacokinetics of fentanyl from ONSOLIS is a combination of an initial rapid absorption from the buccal mucosa and a more prolonged absorption of swallowed fentanyl from the GI tract. Following buccal application of ONSOLIS, the absolute bioavailability of fentanyl was 71%. Approximately 51% of the total dose of ONSOLIS is absorbed from the buccal mucosa. The remaining 49% of the total dose is swallowed with the saliva and then slowly absorbed from the GI tract. Of the swallowed fentanyl, about 20% of the total dose escapes hepatic and intestinal first-pass elimination and becomes systemically available. An ONSOLIS film, if chewed and swallowed, will likely result in lower peak concentrations and lower bioavailability than when consumed as directed.
The absolute bioavailability study also demonstrated similar pharmacokinetics in the subsets of six male and six female adult normal volunteers.
In a study that compared the relative bioavailability of ONSOLIS and Actiq* (oral transmucosal fentanyl citrate [OTFC]) in 12 adult normal volunteers, the rate and extent of fentanyl absorption were considerably greater with ONSOLIS [62% greater maximum plasma concentration (Cmax) and 40% greater systemic exposure (AUCinf)] (Table 3 and Figure 1).
Table 3 : Fentanyl Plasma Pharmacokinetic Parameters
in Healthy Adult Subjects Receiving Single Doses of ONSOLIS or Actiq
|Pharmacokinetic Parameter *||ONSOLIS (800 mcg)||Actiq (800 mcg)|
|Cmax (ng/mL)||1.67 ± 0.75||1.03 ± 0.25|
|AUCmf (hr-ng/mL)||14.46 ± 5.4||10.30 ± 3.8|
|Tfirst (min)||9.0 ± 4.8||13.2 ± 10.8|
|Tmax (hr)||1.00 (0.75 - 4.00)||2.00 (0.50 - 4.00)|
|* Data for Tmax presented as median (range); other data are presented as mean ± SD|
Figure 1 : Mean Fentanyl Plasma Concentration versus Time Profiles Following Single Doses of ONSOLIS or Actiq in Healthy Adult Subjects
In another study, dose proportionality across the range of the available dosage strengths of ONSOLIS was demonstrated in a balanced crossover design comparing fentanyl plasma concentrations in three dosage strengths (200, 600, and 1200 mcg) in adult normal volunteers (n=12). Mean fentanyl plasma concentrations following these three doses of ONSOLIS are shown in Table 4. The curves for each dose level are similar in shape with increasing doses producing increasing fentanyl plasma concentrations. Cmax and AUCinf increased in a manner that is approximately proportional to the ONSOLIS dose administered. The mean Cmax ranged from 0.38 ng/mL to 2.19 ng/mL over this dose range.
Table 4 : Fentanyl Plasma Pharmacokinetic Parameters
in Healthy Adult Subjects Receiving Single Doses of 200-, 600-, and 1200-mcg of
|Pharmacokinetic Parameter *||ONSOLIS Dose (mcg)|
|Cmax (ng/mL)||0.38 ± 0.07||1.16 ± 0.19||2.19 ± 0.54|
|AUCinf (hr-ng/mL)||3.46 ± 0.72||11.72 ± 5.29||20.43 ± 4.52|
|* Based on venous blood samples.|
The effect of oral mucositis (Grade 1) on the pharmacokinetic profile of ONSOLIS was studied in a group of patients with cancer, with (n=7) and without (n=7) oral mucositis who were otherwise matched. A single 200 mcg ONSOLIS film was administered, followed by sampling at appropriate intervals. Summary results are presented in Table 5. Application of ONSOLIS on an active site of mucositis was associated with decreases in the Cmax and AUCinf that are not likely to be clinically relevant. The difference in Cmax is less than the intersubject variability and dose adjustment is not required.
Table 5 : Fentanyl Plasma
Pharmacokinetic Parameters in Adult Patients with or without Mucositis
Receiving Single Doses of ONSOLIS
|Patient status||Cmax (ng/mL)||Tmax (hr) *||AUC0-4 (hr-ng/mL)|
|Mucositis||0.47 ± 0.32||1.00
(0.50 - 4.00)
|1.14 ± 0.71|
|No mucositis||0.69 ± 0.54||1.00
(0.50 - 1.50)
|1.29 ± 0.87|
|* Data for Tmax presented as median (range); other data are presented as mean ± SD|
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 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 to 0.7 L/hr/kg). The terminal elimination half-life after ONSOLIS administration is about 14 hours.
The efficacy of ONSOLIS was investigated in a 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 with cancer experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg morphine/day, 50 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for 1 week or longer. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain.
A double-blind, placebo-controlled, crossover study was performed in patients with cancer to evaluate the effectiveness of ONSOLIS for the treatment of breakthrough cancer pain. Open-label titration identified a successful dose of ONSOLIS, within the range of 200 to 1200 mcg. A “successful” dose was defined as a dose in which a patient obtained adequate analgesia with tolerable side effects. Table 6 presents the successful dose for both the double-blind efficacy and open-label safety studies. In the double-blind efficacy study, patients who identified a successful dose were randomized to a sequence of nine treatments; six with the successful dose of ONSOLIS and three with placebo. Of the patients who entered the study, 54 percent achieved a successful dose during the titration phase and 4 percent withdrew for lack of effective pain relief. The final titrated dose of ONSOLIS for breakthrough cancer 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 200 mcg.
Table 6 : Dose of ONSOLIS Following Initial Titration
|ONSOLIS Dose||Double-blind Efficacy Study Total No. (%) (N=81)|
|200 mcg||4 (5%)|
|400 mcg||15 (19%)|
|600 mcg||23 (28%)|
|800 mcg||19 (23%)|
|1200 mcg||20 (25%)|
The primary outcome measure, the mean sum of pain intensity differences at 30 minutes (SPID30) for ONSOLIS-treated episodes was statistically significantly higher than for placebo-treated episodes (see Figure 2).
Figure 2 : Sum of Pain Intensity Differences (SPID)
Following ONSOLIS or Placebo in Adult Patients with Breakthrough Cancer Pain
Last reviewed on RxList: 1/26/2015
This monograph has been modified to include the generic and brand name in many instances.
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