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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.

Pharmacodynamics

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.

Analgesia

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).

Gastrointestinal System

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.

Cardiovascular System

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.

Endocrine System

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.

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. 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 - Warning: Risk of Respiratory Depression, Medication Errors, Abuse Potential, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE].

Pharmacokinetics

Absorption

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

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 Onsolis

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

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.

Metabolism

Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl was not found to be pharmacologically active in animal studies [see DRUG INTERACTIONS].

Elimination

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.

Clinical Studies

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

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

Patient Counseling Information

See FDA-Approved patient labeling (Medication Guide).

Patient/Caregiver Instructions

• Before initiating treatment with ONSOLIS, explain the statements below to patients and/or caregivers. Instruct patients to read the Medication Guide each time ONSOLIS is dispensed because new information may be available.
• TIRF REMS Access Program
  • Outpatients must be enrolled in the TIRF REMS Access program before they can receive Onsolis.
  • Allow patients the opportunity to ask questions and discuss any concerns regarding Onsolis or the TIRF REMS Access program.
  • As a component of the TIRF REMS Access program, prescribers must review the contents of the Onsolis Medication Guide with every patient before initiating treatment with Onsolis.
  • Advise the patient that Onsolis is available only from pharmacies that are enrolled in the TIRF REMS Access Program, and provide them with the telephone number and website for information on how to obtain the drug.
  • Patient must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of Onsolis.
  • Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access Program.
• Instruct patients and their caregivers that Onsolis contains medicine in an amount which can be fatal in children, in individuals for whom it is not prescribed, and in those who are not opioid tolerant. Patients and their caregivers must be instructed to keep Onsolis out of the reach of children. Patients and members of their household must be instructed to dispose of any unneeded films remaining from a prescription as soon as possible [see HOW SUPPLIED and Storage and Handling].
• Instruct patients not to take Onsolis for acute pain, postoperative pain, pain from injuries, headache, migraine, or any other short-term pain, even if they have taken other opioid analgesics for these conditions.
• Instruct patients on the meaning of opioid tolerance and Onsolis is only to be used as a supplemental pain medication for patients with pain requiring regular opioids, who have developed tolerance to the opioid medication and who need additional opioid treatment of breakthrough pain episodes.
• Instruct that if they are not taking an opioid medication on a regular around-the-clock basis, they must not take Onsolis.
• Instruct patients NOT to share Onsolis and that sharing Onsolis with anyone else could result in the other individual's death due to overdose.
• Advise patients that Onsolis contains fentanyl, which is a pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
• Instruct patients that they must wait at least 2 hours before treating a new episode of breakthrough pain with Onsolis.
• Advise patients that the active ingredient in Onsolis, fentanyl, is a drug that some people abuse. Onsolis is to be taken only by the patient for whom it was prescribed, and protected from theft or misuse in the work or home environments.
• Instruct patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking Onsolis.
• Instruct patients to use Onsolis exactly as prescribed by their doctor and not to take Onsolis more often than prescribed.
• Caution patients that Onsolis can affect a person's ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Warn patients taking Onsolis of these dangers and counsel accordingly.
• Warn patients not to combine Onsolis with alcohol, sleep aids, or tranquilizers except by order of the prescribing physician, because dangerous additive effects may occur resulting in serious injury or death.
• Inform female patients that if they become pregnant or plan to become pregnant during treatment with Onsolis to ask their doctor about the effects that Onsolis (or any medicine) may have on them and their unborn child.
• Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

Disposal of Unneeded Onsolis Films

Patients and members of their household must be instructed on the safe disposal of any unneeded films remaining from a prescription as soon as they are no longer needed.

1. To dispose of the unneeded Onsolis films:
2. Remove the Onsolis film from its foil package.
3. Drop the Onsolis film into the toilet.

Repeat steps 1 and 2 for each Onsolis film. Flush the toilet after all unneeded films have been put into the toilet.

Do not flush the Onsolis foil packages or cartons down the toilet [see HOW SUPPLIED and Storage and Handling].

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of Onsolis are provided in the Medication Guide. Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered.

In the event that a caregiver requires additional assistance in disposing of excess unneeded films that remain in the home after a patient has expired, instruct them to call Meda Pharmaceuticals Inc. at 1-800-526-3840 or seek assistance from their local Drug Enforcement Agency (DEA) office.

Last reviewed on RxList: 1/17/2012
This monograph has been modified to include the generic and brand name in many instances.