Fentora

Mechanism of Action

Fentanyl is an 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 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 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.

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 FENTORA should be individually titrated to achieve the desired effect [see DOSAGE AND ADMINISTRATION].

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 depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. 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, 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. 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 another oral transmucosal fentanyl citrate (Actiq). 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, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and OVERDOSAGE.

Pharmacokinetics

Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of FENTORA increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range.

Following buccal administration of FENTORA, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of FENTORA is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after buccal administration. Approximately 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the gastrointestinal tract.

In a study that compared the absolute and relative bioavailability of FENTORA and Actiq (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with FENTORA) (Table 4).

Table 4: Pharmacokinetic Parameters* in Adult Subjects Receiving FENTORA or Actiq

Similarly, in another bioavailability study exposure following administration of FENTORA was also greater (approximately 50%) compared to Actiq.

Due to differences in drug delivery, measures of exposure (Cmax, AUC0tmax, AUC0-inf) associated with a given dose of fentanyl were substantially greater with FENTORA compared to Actiq (see Figure 1). Therefore, caution must be exercised when switching patients from one product to another [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median Tmax for FENTORA.

Figure 1: Mean Plasma Concentration Versus Time Profiles Following Single Doses of FENTORA and Actiq in Healthy Subjects

Actiq data was dose adjusted (800 mcg to 400 mcg).

Mean pharmacokinetic parameters are presented in Table 5. Mean plasma concentration versus time profiles are presented in Figure 2.

Table 5: Pharmacokinetic Parameters* Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in Healthy Subjects

Figure 2: Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of FENTORA in Healthy Subjects

Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not appear to affect early systemic exposure to fentanyl.

The effect of mucositis (Grade 1) on the pharmacokinetic profile of FENTORA was studied in a group of patients with (N = 8) and without mucositis (N = 8) who were otherwise matched. A single 200 mcg tablet was administered, followed by sampling at appropriate intervals. Mean summary statistics (standard deviation in parentheses, expected tmax where range was used) are presented in Table 6.

Table 6: Pharmacokinetic Parameters in Patients with Mucositis

Following sublingual tablet placement, systemic exposure (as measured by AUC and Cmax) of fentanyl is equivalent to systemic exposure following buccal tablet placement.

Fentanyl is highly lipophilic. 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 mean oral volume of distribution at steady state (Vss/F) was 25.4 L/kg.

The metabolic pathways following buccal administration of FENTORA 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 [see DRUG INTERACTIONS].

Disposition of fentanyl following buccal administration of FENTORA 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.

Systemic exposure was higher for women than men (mean Cmax and AUC values were approximately 28% and 22% higher, respectively). The observed differences between men and women were largely attributable to differences in weight.

In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in US subjects (mean Cmax and AUC values were approximately 50% and 20% higher, respectively). The observed differences were largely attributed to the lower mean weight of the Japanese subjects compared to U.S. subjects (57.4 kg versus 73 kg).

Clinical Studies

The efficacy of FENTORA was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.

In this trial, patients were titrated in an open-label manner to a successful dose of FENTORA. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects.

Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of FENTORA and 3 being placebo. Patients used one tablet of study drug (either FENTORA or Placebo) per breakthrough pain episode.

Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45 and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.

Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 7. The median dose was 400 mcg.

Table 7: Successful Dose of FENTORA Following Initial Titration

The LS mean (SE) SPID30 for FENTORA-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).

Figure 3: Mean Pain Intensity Differences (PID) at Each Time Point During the Double-Blind Treatment Period

PID=pain intensity difference; SEM=standard error of the mean

Take fentanyl exactly as prescribed.

This medication comes in nasal spray, sublingual spray, sublingual tablet, lozenge, and transdermal patch forms. The dose and frequency of administration will vary with the indication and dosage form.

Instructions for use of nasal spray:

To use fentanyl nasal spray, begin by blowing your nose, if you have a runny nose. Remove the protective cap from the bottle tip and hold the bottle so that the nozzle is between your first and second fingers and your thumb is on the bottom. Sit upright and insert the tip of the bottle approximately 1/2 inch into one nostril, pointing the tip toward the bridge of your nose. Close your other nostril with your finger. Press down firmly on the finger grips until you hear a ''click'' sound. You may not feel the spray go into your nose, but as long as the number in the counting window increases by one, the spray has been given. Breathe in gently through your nose and out through your mouth one time after spraying. Do not sniff after spraying the medication into your nose. If your doctor wants you to use two sprays, repeat the adminsitration, using your other nostril. Stay sitting down for at least 1 minute after using fentanyl nasal spray. Do not blow your nose for at least 30 minutes after using fentanyl nasal spray.

Instructions for use of sublingual spray:

To use the sublingual spray, first remove the fentanyl sublingual spray unit from the blister package by cutting along the dashed line with a pair of scissors. Swallow any saliva in your mouth. Hold the fentanyl sublingual spray unit upright using your index and middle fingers and thumb. Point the nozzle into your mouth and under your tongue. Squeeze your fingers and thumb together to spray the medication under your tongue. Hold the medication under your tongue for 30 to 60 seconds. Do not spit out the medication or rinse your mouth. The fentanyl sublingual spray is a one-time use unit and will remain locked after use.

Instructions for use of sublingual tablets:

Place ABSTRAL (fentanyl) sublingual tablets on the floor of the mouth directly under the tongue immediately after removal from the blister pack. Do not chew, suck, or swallow ABSTRAL tablets. Allow ABSTRAL tablets to completely dissolve in the sublingual cavity. Do not eat or drink anything until the tablet is completely dissolved. If you have a dry mouth, use water to moisten the buccal mucosa before taking ABSTRAL.

Instructions for use of lozenges:

Place ACTIQ in your mouth between your cheeks and gums and actively suck on the medicine. Move the lozenge around in your mouth, especially along the inside of your cheeks. Twirl the handle often. Finish the ACTIQ unit completely in 15 minutes to get the most relief. If you finish ACTIQ too quickly, you will swallow more of the medicine and get less relief. Do not bite or chew ACTIQ. You will get less relief for your breakthrough cancer pain.

Instructions for use of transdermal patches:

A fentanyl transdermal system may be applied to the chest, back, flank, or upper arm in a place where there is no hair. Patches should not be placed on skin that is oily, burned, cut, irritated, or damaged. Avoid areas that are sensitive or that move around a lot. Do not shave the area where the patch will be placed.

A patch may be applied at any time of the day, but you should change the patch around the same time every 3 days. Do not wear more than one patch at a time, unless directed by your doctor. Before applying the patch, clean the skin and pat the area dry. Open the patch’s protective pouch and peel the plastic backing away from the patch. Take care not to touch the sticky side of the patch. Press the patch to the skin with the palm of your hand for at least 30 seconds. Make sure it sticks well, especially at the edges. Wash your hands after applying the patch. After 3 days, remove the patch and apply a new one in a different spot. If the patch falls off before 3 days, do not replace it with a new patch; wait until 3 days after you put it on to apply a new patch.

Injection:

This medication is also available in an injectable form to be given directly into a vein (IV) or the muscle (IM) by a healthcare professional.

• Store fentanyl at room temperature.
• Keep this and all medicines out of the reach of children.
• Special instructions for discarding used and unused fentanyl doses are provided in the medication guide you will receive with your medication. Follow these instructions carefully and ask your pharmacist for more information or if you are unclear how to dispose of fentanyl products safely.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Black, tarry stools
• blurred vision
• chest pain
• confusion
• convulsions
• cough
• decreased urine
• difficult or labored breathing
• dizziness
• dry mouth
• fainting
• fever or chills
• increased thirst
• irregular heartbeat
• lightheadedness
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea or vomiting
• nervousness
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pale skin
• pounding in the ears
• rapid breathing
• sneezing
• sore throat
• sunken eyes
• swelling of the hands, ankles, feet, or lower legs
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• wrinkled skin

• Abdominal or stomach pain
• change in walking and balance
• clumsiness or unsteadiness
• decreased awareness or responsiveness
• decreased frequency of urination
• headache
• muscle twitching or jerking
• pounding in the ears
• rhythmic movement of the muscles
• seeing, hearing, or feeling things that are not there
• seizures
• severe constipation
• severe sleepiness
• shakiness in the legs, arms, hands, or feet
• slow or fast heartbeat
• thinking abnormalities
• trembling or shaking of the hands or feet

Get emergency help immediately if any of the following symptoms of overdose occur:

• Extremely shallow or slow breathing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• diarrhea
• difficulty having a bowel movement (stool)
• difficulty with moving
• discouragement
• feeling sad or empty
• irritability
• lack or loss of strength
• loss of interest or pleasure
• muscle stiffness
• pain in the joints
• sleepiness or unusual drowsiness
• tiredness
• trouble concentrating
• trouble sleeping
• weight loss

• Changes in vision
• excessive muscle tone
• feeling of constant movement of self or surroundings
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• irritation, pain, or sores at the site of application
• itching skin
• muscle tension or tightness
• rash
• sensation of spinning
• sweating

• Tooth pain
• trouble with gums
• trouble with teeth

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Fentora, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Fentora.

To reduce the risk of respiratory depression, proper dosing and titration of Fentora are essential [see Dosage and Administration (2.3)]. Overestimating the Fentora dosage can result in a fatal overdose with the first dose. The substitution of Fentora for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.5)].

Fentora could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant.

Accidental ingestion of even one dose of Fentora, especially by children, can result in respiratory depression and death due to an overdose of fentanyl.

Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure

Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products.

Patients and their caregivers must be informed that Fentora contains a medicine in an amount which can be fatal to a child. Healthcare providers 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.

Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [see Patient Counseling Information (17)].

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

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Fentora with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.1)], particularly when an inhibitor is added after a stable dose of Fentora is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentora-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentora with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentora-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentora until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of Fentora with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using Fentora with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentora with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Fentora is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

Risk of Medication Errors

When prescribing, do not convert a patient to Fentora from any other fentanyl product on a mcg per mcg basis as Fentora and other fentanyl products are not equivalent on a microgram per microgram basis.

Fentora is not a generic version of other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute a Fentora prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and Fentora are not equivalent. Substantial differences exist in the pharmacokinetic profile of Fentora compared to other fentanyl products including other TIRF formulations that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of Fentora or any other fentanyl product may result in a fatal overdose.

There are no safe conversion directions available for patients on any other fentanyl products except ACTIQ (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Dosage and Administration (2.1)].Therefore, for opioid tolerant patients, the initial dose of Fentora should always be 100 mcg. Individually titrate each patient’s dose to provide adequate analgesia while minimizing side effects [see Dosage and Administration (2.3)].

Addiction, Abuse, and Misuse

Fentora contains fentanyl, a Schedule II controlled substance. As an opioid, Fentora exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Fentora. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Fentora, and monitor all patients receiving Fentora for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Fentora, but use in such patients necessitates intensive counseling about the risks and proper use of Fentora along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Fentora. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program

Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence (9)], Fentora is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of Fentora, patient and prescriber enrollment is not required.

Required components of the TIRF REMS Access program are:

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Fentora during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Fentora in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Fentora-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentora [see Warnings and Precautions (5.1)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.1)].

Monitor such patients closely, particularly when initiating and titrating Fentora and when Fentora is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.1)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Fentora with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Fentora if serotonin syndrome is suspected.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Fentora may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Fentora. In patients with circulatory shock, Fentora may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Fentora in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Fentora may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Fentora.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Fentora in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Fentora is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The fentanyl in Fentora may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The fentanyl in Fentora may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Fentora therapy.

Risks of Driving and Operating Machinery

Fentora may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Fentora and know how they will react to the medication.

Cardiac Disease

Intravenous fentanyl may produce bradycardia. Therefore, use Fentora with caution in patients with bradyarrhythmias.

Application Site Reactions

Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding [see Adverse Reactions (6)].

MAO Inhibitors

Fentora is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics [see Drug Interactions (7)].

The following serious adverse reactions are described, or described in greater detail, in other sections:

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Fentora has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months.

The clinical trials of Fentora were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain.

The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received Fentora for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of Fentora therapy or cancer-related symptoms.

Table 2 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.

Table 3 lists, by successful dose, adverse events with an overall frequency of ≥5% within the total population that occurred after a successful dose had been determined.

In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of Fentora. There was no evidence of excess toxicity in this subset of patients.

Application Site Reactions: In clinical trials, 10% of all patients exposed to Fentora reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients.

The duration of exposure to Fentora varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients (and not listed in Tables 2 and 3 above) from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving Fentora. Events are classified by system organ class.

Adverse Events (≥1%)

Blood and Lymphatic System Disorders: Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration

General Disorders and Administration Site Conditions: Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess

Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture

Investigations: Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

Metabolism and Nutrition Disorders: Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake

Musculoskeletal and Connective Tissue Disorders: Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain

Nervous System Disorders: Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy

Psychiatric Disorders: Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic and Mediastinal Disorders: Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing

Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat

Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis

Postmarketing Experience

The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders:

- Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Endocrine Disorders:

- Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

- Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Immune System Disorders:

- Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Fentora.

Clinical Presentation

Acute overdose with Fentora can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentora, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

The efficacy of Fentora was demonstrated in a double-blind, placebo-controlled, cross-over study in opioid tolerant patients with cancer and breakthrough pain. Patients considered opioid tolerant were those who were taking at least 60 mg of oral morphine daily, at least 25 mcg/hour of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer.

In this trial, patients were titrated in an open-label manner to a successful dose of Fentora. A successful dose was defined as the dose in which a patient obtained adequate analgesia with tolerable side effects. Patients who identified a successful dose were randomized to a sequence of 10 treatments with 7 being the successful dose of Fentora and 3 being placebo. Patients used one tablet of study drug (either Fentora or placebo) per breakthrough pain episode.

Patients assessed pain intensity on a scale that rated the pain as 0=none to 10=worst possible pain. With each episode of breakthrough pain, pain intensity was assessed first and then treatment was administered. Pain intensity (0-10) was then measured at 15, 30, 45, and 60 minutes after the start of administration. The sum of differences in pain intensity scores at 15 and 30 minutes from baseline (SPID30) was the primary efficacy measure.

Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg.

The LS mean (SE) SPID30 for Fentora-treated episodes was 3.0 (0.12) while for placebo-treated episodes it was 1.8 (0.18).

Figure 3. Mean Pain Intensity Differences (PID) at Each Time Point During the Double-Blind Treatment Period

PID=pain intensity difference; SEM=standard error of the mean

Fentora is supplied in individually sealed, child-resistant blister packages. Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with , and the other side of each dosage strength is uniquely identified by the debossing on the tablet as described in the table below. In addition, the dosage strength is indicated on the blister package and the carton. See blister package and carton for product information.

Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.

Storage and Handling

Store at 20 to 25°C (68 to 77°F) with excursions permitted between 15° and 30°C (59° to 86°F) until ready to use. (See USP Controlled Room Temperature.)

Protect Fentora from freezing and moisture. Do not use if the blister package has been tampered with.

Fentora® (fentanyl buccal tablet) CII 100 mcg, 4 Tablets X 7 Cards Carton Text

NDC 63459-541-28

CII

Fentora®

(fentanyl buccal tablet)

equivalent to 100 mcg fentanyl base

Information for Pharmacist:

WARNING: Keep out of the reach of children

PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY

DO NOT SUBSTITUTE Fentora FOR OTHER FENTANYL PRODUCTS

Fentora can be harmful or fatal if given to someone for whom it was not prescribed

For Buccal or Sublingual Administration.

Do NOT Split, Crush, Suck, Chew, or Swallow Tablet.