FENTORA^®     CII
(fentanyl buccal tablet)

FENTORA (fentanyl buccal tablet) is a potent opioid analgesic, intended for buccal mucosal administration. FENTORA is formulated as a flat-faced, round, beveled-edge white tablet. 

FENTORA is designed to be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet and absorption of fentanyl across the oral mucosa.   

FENTORA employs the OraVescent^® drug delivery technology, which generates a reaction that releases carbon dioxide when the tablet comes in contact with saliva. It is believed that transient pH changes accompanying the effervescent reaction may optimize dissolution (at a lower pH) and membrane permeation (at a higher pH) of fentanyl through the buccal mucosa.  

Active Ingredient: Fentanyl citrate, USP is N-(1-Phenethyl-4-piperidyl) propionanilide citrate (1:1). Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) that is freely soluble in organic solvents and sparingly soluble in water (1:40). The molecular weight of the free base is 336.5 (the citrate salt is 528.6). The pKa of the tertiary nitrogens are 7.3 and 8.4. The compound has the following structural formula:

All tablet strengths are expressed as the amount of fentanyl free base, e.g., the 100 microgram strength tablet contains 100 micrograms of fentanyl free base. 

Inactive Ingredients: Mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

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.

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.

The pharmacokinetics of FENTORA has not been studied in Special Populations.

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/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid 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 (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 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 of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 4. 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) (p<0.0001).

(See BOXED WARNING andCONTRAINDICATIONS)

FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg of oral morphine/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation could occur at any dose in patients not on a chronic regimen of opiates. For this reason, FENTORA is contraindicated in the management of acute or postoperative pain.

FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.

Because life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients, FENTORA is contraindicated in the management of acute or postoperative pain. This product must not be used in opioid non-tolerant patients.

FENTORA is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.

See BOXED WARNING

The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation, hypotension, and profound sedation may occur.

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.  

The safety and efficacy of FENTORA have not been established in pediatric patients below the age of 18 years.

Patients and their caregivers must be instructed that FENTORAcontains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children. (See SAFETY AND HANDLING, PRECAUTIONS, and MEDICATION GUIDE for specific patient instructions.)

FENTORA contains fentanyl, a mu-opioid agonist and a Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and is subject to misuse, and criminal diversion.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since FENTORA tablets may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of patients, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

FENTORA should be handled appropriately to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

The administration of FENTORA should be guided by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with cancer and chronic pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain.

Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine).

Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in FENTORA. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

The extent of fentanyl absorption with different formulations of transmucosal delivery systems can be substantially different; therefore, the same dose of fentanyl in two different formulations should not be viewed as equivalent. Therefore, caution must be exercised when switching patients from one product to another. (See DOSAGE AND ADMINISTRATION.)

For patients not previously using oral transmucosal fentanyl citrate, the initial dose of FENTORA should be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects.

Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients taking FENTORA should be warned of these dangers and should be counseled accordingly.

The use of concomitant CNS active drugs requires special patient care and observation. (See WARNINGS.)

Because potent opioids can cause respiratory depression, FENTORA should be titrated with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of FENTORA may further decrease respiratory drive to the point of respiratory failure.

FENTORA should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesia 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.

Intravenous fentanyl may produce bradycardia. Therefore, FENTORA should be used with caution in patients with bradyarrhythmias.

Insufficient information exists to make recommendations regarding the use of FENTORA in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

• Patients and their caregivers must be instructed that children, especially small children, exposed to FENTORA are at high risk of FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep FENTORA tablets out of the reach of children. (See SAFETY AND HANDLING, WARNINGS, and MEDICATION GUIDE for specific patient instructions.)
• Patients and their caregivers should be provided a Medication Guide each time FENTORA is dispensed because new information may be available.
• Patients should be aware that FENTORA contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
• Patients should be instructed that the active ingredient in FENTORA, fentanyl, is a drug that some people abuse. FENTORA should be taken only by the patient it was prescribed for, and it should be protected from theft or misuse in the work or home environment.
• Patients should be instructed that FENTORA tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. They are to be placed between the cheek and gum above a molar tooth and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.
• Patients should be cautioned to talk to their doctor if breakthrough pain is not alleviated or worsens after taking FENTORA.
• Patients should be cautioned that FENTORA can affect a person’s ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Patients taking FENTORA should be warned of these dangers and counseled accordingly.
• Patients should be warned to not combine FENTORA with alcohol, sleep aids, or tranquilizers except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
• Female patients should be informed that if they become pregnant or plan to become pregnant during treatment with FENTORA, they should ask their doctor about the effects that FENTORA (or any medicine) may have on them and their unborn children.
• Patients and caregivers should be advised that if they have been receiving treatment with FENTORA and the medicine is no longer needed they should flush any remaining product down the toilet, and if they then need further assistance, contact Cephalon at 1-800-896-5855.

Patients and members of their household must be advised to dispose of any unopened buler packages remaining from a prescription as soon as they are no longer needed.

To dispose of unused FENTORA, remove FENTORA tablets from buler packages and flush down the toilet. Do not flush the FENTORA buler packages or cartons down the toilet. (See SAFETY AND HANDLING.)

Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Patients should be encouraged to read this information in its entirety and be given an opportunity to have their questions answered.

In the event that a caregiver requires additional assistance in disposing of excess unusable tablets that remain in the home after a patient has expired, they should be instructed to call the Cephalon toll-free number (1-800-896-5855) or seek assistance from their local DEA office.

The effects of FENTORA on laboratory tests have not been evaluated.

See WARNINGS.

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when FENTORA is given concurrently with agents that affect CYP3A4 activity. The concomitant use of FENTORA with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression. Patients receiving FENTORA concomitantly with moderate or strong CYP 3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively. (See PHARMACOKINETICS, Drug Interactions and DOSAGE AND ADMINISTRATION.)

Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations, thus should be avoided.

Drugs that induce cytochrome P450 3A4 activity may have the opposite effects.

Concomitant use of FENTORA with an MAO inhibitor, or within 14 days of discontinuation, is not recommended.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl.

Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. tymphimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay.

Fentanyl impairs fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA.

There are no adequate and well-controlled studies in pregnant women. FENTORA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

Fentanyl is embryocidal as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA.

Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m² basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not teratogenic.

Fentanyl readily passes across the placenta to the fetus; therefore FENTORA is not recommended for analgesia during labor and delivery.

Fentanyl is excreted in human milk; therefore FENTORA should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using FENTORA.

See WARNINGS.

Of the 304 patients with cancer in clinical studies of FENTORA, 69 (23%) were 65 years of age and older.

Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients.

Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating FENTORA in elderly patients to provide adequate efficacy while minimizing risk.

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 most commonly observed adverse events seen with FENTORA are typical of opioid side effects. Opioid side effects should be expected and managed accordingly.

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 5 uls, 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 6 uls, 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.  

The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies uled below represent the ≥1% of patients 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: Anemia, Neutropenia, Thrombocytopenia, Leukopenia

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Nausea, Vomiting, Constipation, Abdominal Pain, Diarrhea, 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: Fatigue, Edema Peripheral, Asthenia, Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain

Hepatobiliary Disorders: Jaundice

Infections and Infestations: Pneumonia, 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 Weight, Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count

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

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

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

Psychiatric Disorders: Confusional State, Depression, Insomnia, Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness

Renal and Urinary Disorders: Renal Failure

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Cough, 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

Clinical Presentation

General

Treatment of Overdosage in the Opioid Non-Tolerant Person

Treatment of Overdose in Opioid-Tolerant Patients

General Considerations for Overdose

DOSAGE AND ADMINISTRATION

Patients With Hepatic and/or Renal Impairment

Patients Receiving CYP3A4 Inhibitors

Patients With Mucositis

Administration of FENTORA