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FENTORA®
(fentanyl) Buccal Tablets
WARNING
RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL
RESPIRATORY DEPRESSION
Fatal respiratory depression has occurred in patients treated with FENTORA, including following use in opioid non-tolerant patients and improper dosing. The substitution of FENTORA for any other fentanyl product may result in fatal overdose.
Due to the risk of respiratory depression, FENTORA is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see CONTRAINDICATIONS]
FENTORA must be kept out of reach of children. [see PATIENT INFORMATION and HOW SUPPLIED/Storage and Handling]
The concomitant use of FENTORA with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see DRUG INTERACTIONS].
MEDICATION ERRORS
Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.
ABUSE POTENTIAL
FENTORA contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. FENTORA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing FENTORA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.
Because of the risk for misuse, abuse, addiction, and overdose, FENTORA is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [see WARNINGS AND PRECAUTIONS] Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.
FENTORA (fentanyl buccal tablet) is a potent opioid analgesic, intended for buccal mucosal administration.
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 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-4piperidyl) 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.
FENTORA is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg/hr of transdermal fentanyl, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids while taking FENTORA.
This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. 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.
Limitations of Use
As a part of the TIRF REMS Access program, FENTORA may be dispensed only to outpatients enrolled in the program [see WARNINGS AND PRECAUTIONS]. For inpatient administration of FENTORA (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required.
Healthcare professionals who prescribe FENTORA on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of FENTORA [see WARNINGS AND PRECAUTIONS].
As with all opioids, the safety of patients using such products is dependent on health care professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.
It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose.
FENTORA is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) All patients should be titrated from the 100 mcg dose.
The initial dose of FENTORA is always 100 mcg with the only exception being patients already using Actiq.
a. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq table below (Table 1). The doses of FENTORA in this table are starting doses and not intended to represent equianalgesic doses to Actiq. Patients must be instructed to stop the use of Actiq and dispose of any remaining units.
Table 1: Initial Dosing Recommendations for Patients
on Actiq
| Current Actiq Dose (mcg) | Initial FENTORA Dose* |
| 200 | 100 mcg tablet |
| 400 | 100 mcg tablet |
| 600 | 200 mcg tablet |
| 800 | 200 mcg tablet |
| 1200 | 2 x 200 mcg tablets |
| 1600 | 2 x 200 mcg tablets |
| *From this initial dose, titrate patient to effective dose. | |
b. For patients converting from Actiq doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg FENTORA tablet and should proceed using multiples of this tablet strength.
The initial dose of FENTORA is 100 mcg.
Once the tablet is removed from the blister unit, the patient should immediately place the entire FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or place the entire FENTORA tablet under the tongue. Patients should not split the tablet.
The FENTORA tablet should not be crushed, sucked, chewed or swallowed whole, as this will result in lower plasma concentrations than when taken as directed.
The FENTORA tablet should be left between the cheek and gum or under the tongue until it has disintegrated, which usually takes approximately 14-25 minutes.
After 30 minutes, if remnants from the FENTORA tablet remain, they may be swallowed with a glass of water.
It is recommended that patients alternate sides of the mouth when administering subsequent doses of FENTORA in the buccal cavity.
For patients requiring discontinuation of opioids, a gradual downward titration is recommended because it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.
FENTORA tablets are flat-faced, round, beveled-edge in shape; are white in color; and are available in 100 mcg, 200 mcg, 400 mcg, 600 mcg and 800 mcg strengths as fentanyl base. Each tablet strength is marked with a unique identifier [see Storage and Handling].
FENTORA is supplied in individually sealed, child-resistant blister packages. The amount of fentanyl contained in FENTORA can be fatal to a child. Patients and their caregivers must be instructed to keep FENTORA out of the reach of children. [see BOXED WARNING, OVERDOSAGE, and PATIENT INFORMATION]
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.
Patients and members of their household must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed [see PATIENT INFORMATION]. If additional assistance is required, call Teva Pharmaceuticals at 1-800-896-5855.
To dispose of unused FENTORA, remove FENTORA tablets from blister packages and flush down the toilet. Do not flush FENTORA blister packages or cartons down the toilet. If you need additional assistance with disposal of FENTORA, call Teva Pharmaceuticals at 1-800896-5855.
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 'C', 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.
| Dosage Strength | Debossing | Carton/Blister Package Color | NDC Number |
| 100 mcg | 1 | Blue | NDC 63459-541-28 |
| 200 mcg | 2 | Orange | NDC 63459-542-28 |
| 400 mcg | 4 | Sage green | NDC 63459-544-28 |
| 600 mcg | 6 | Magenta (pink) | NDC 63459-546-28 |
| 800 mcg | 8 | Yellow | NDC 63459-548-28 |
Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing.
Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454. Revised: 02/2013
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 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 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 2: Adverse Events Which Occurred During
Titration at a Frequency of ≥ 5%
| System Organ Class MeDRA preferred term, n (%) | 100 mcg (N=45) |
200 mcg (N=34) |
400 mcg (N=53) |
600 mcg (N=56) |
800 mcg (N=113) |
Total (N=304)* |
| Gastrointestinal disorders | ||||||
| Nausea | 4 (9) | 5 (15) | 10 (19) | 13 (23) | 18 (16) | 50 (17) |
| Vomiting | 0 | 2 (6) | 2 (4) | 7 (13) | 3 (3) | 14 (5) |
| General disorders and administration site conditions | ||||||
| Fatigue | 3 (7) | 1 (3) | 9 (17) | 1 (2) | 5 (4) | 19 (6) |
| Nervous system disorders | ||||||
| Dizziness | 5 (11) | 2 (6) | 12 (23) | 18 (32) | 21 (19) | 58 (19) |
| Somnolence | 2 (4) | 2 (6) | 6 (12) | 7 (13) | 3 (3) | 20 (7) |
| Headache | 1 (2) | 3 (9) | 4 (8) | 8 (14) | 10 (9) | 26 (9) |
| * Three hundred and two (302) patients were included in the safety analysis. | ||||||
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.
Table 3: Adverse Events
Which Occurred During Long-Term Treatment at a Frequency of ≥ 5%
| System Organ Class MeDRA preferred term, n (%) | 100 mcg (N=19) |
200 mcg (N=31) |
400 mcg (N=44) |
600 mcg (N=48) |
800 mcg (N=58) |
Total (N=200) |
| Blood and lymphatic system disorders | ||||||
| Anemia | 6 (32) | 4 (13) | 4 (9) | 5 (10) | 7 (13) | 26 (13) |
| Neutropenia | 0 | 2 (6) | 1 (2) | 4 (8) | 4 (7) | 11 (6) |
| Gastrointestinal disorders | ||||||
| Nausea | 8 (42) | 5 (16) | 14 (32) | 13 (27) | 17 (31) | 57 (29) |
| Vomiting | 7 (37) | 5 (16) | 9 (20) | 8 (17) | 11 (20) | 40 (20) |
| Constipation | 5 (26) | 4 (13) | 5 (11) | 4 (8) | 6 (11) | 24 (12) |
| Diarrhea | 3 (16) | 0 | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Abdominal pain | 2 (11) | 1 (3) | 4 (9) | 7 (15) | 4 (7) | 18 (9) |
| General disorders and administration site conditions | ||||||
| Edema peripheral | 6 (32) | 5 (16) | 4 (9) | 5 (10) | 3 (5) | 23 (12) |
| Asthenia | 3 (16) | 5 (16) | 2 (5) | 3 (6) | 8 (15) | 21 (11) |
| Fatigue | 3 (16) | 3 (10) | 9 (20) | 9 (19) | 8 (15) | 32 (16) |
| Infections and infestations | ||||||
| Pneumonia | 1 (5) | 5 (16) | 1 (2) | 1 (2) | 4 (7) | 12 (6) |
| Investigations | ||||||
| Weight decreased | 1 (5) | 1 (3) | 3 (7) | 2 (4) | 6 (11) | 13 (7) |
| Metabolism and nutrition disorders | ||||||
| Dehydration | 4 (21) | 0 | 4 (9) | 6 (13) | 7 (13) | 21 (11) |
| Anorexia | 1 (5) | 2 (6) | 4 (9) | 3 (6) | 6 (11) | 16 (8) |
| Hypokalemia | 0 | 2 (6) | 0 | 1 (2) | 8 (15) | 11 (6) |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 2 (11) | 0 | 2 (5) | 3 (6) | 2 (4) | 9 (5) |
| Arthralgia | 0 | 1 (3) | 3 (7) | 4 (8) | 3 (5) | 11 (6) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||||
| Cancer pain | 3 (16) | 1 (3) | 3 (7) | 2 (4) | 1 (2) | 10 (5) |
| Nervous system disorders | ||||||
| Dizziness | 5 (26) | 3 (10) | 5 (11) | 6 (13) | 6 (11) | 25 (13) |
| Headache | 2 (11) | 1 (3) | 4 (9) | 5 (10) | 8 (15) | 20 (10) |
| Somnolence | 0 | 1 (3) | 4 (9) | 4 (8) | 8 (15) | 17 (9) |
| Psychiatric disorders | ||||||
| Confusional state | 3 (16) | 1 (3) | 2 (5) | 3 (6) | 5 (9) | 14 (7) |
| Depression | 2 (11) | 1 (3) | 4 (9) | 3 (6) | 5 (9) | 15 (8) |
| Insomnia | 2 (11) | 1 (3) | 3 (7) | 2 (4) | 4 (7) | 12 (6) |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Cough | 1 (5) | 1 (3) | 2 (5) | 4 (8) | 5 (9) | 13 (7) |
| Dyspnea | 1 (5) | 6 (19) | 0 | 7 (15) | 4 (7) | 18 (9) |
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 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.
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
Fentanyl is metabolized mainly via the human CYP3A4 isoenzyme system; therefore potential interactions may occur when FENTORA is given concurrently with agents that affect CYP3A4 activity.
The concomitant use of FENTORA with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving FENTORA who begin therapy with, or increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs of opioid toxicity over an extended period of time. Dosage increase should be done cautiously [see WARNINGS AND PRECAUTIONS]. The concomitant use of FENTORA with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of FENTORA. Patients receiving FENTORA who stop therapy with, or decrease the dose of, CYP3A4 inducers should be monitored for signs of increased FENTORA activity and the dose of FENTORA should be adjusted accordingly.
FENTORA contains fentanyl, a mu-opioid agonist and a Schedule II controlled substance with high potential for abuse similar to other opioids including hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and is subject to misuse and criminal diversion.
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.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated abuse of a prescription drug and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, and sometimes tolerance and/or physical dependence.
Abuse and addiction are separate and distinct from physical dependence and tolerance (see section 9.3). Physicians should be aware that addiction may not be accompanied by concurrent tolerance and physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Proper assessment of patients, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Abuse of FENTORA poses a risk of overdose and death. This risk is increased with concurrent abuse of FENTORA with alcohol and other substances.
FENTORA, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Both tolerance and physical dependence can develop during chronic opioid therapy.
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug constitute evidence of physical dependence. 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). Clinically significant physical dependence may not occur until after several days to weeks of continued opioid usage.
FENTORA should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If FENTORA is abruptly discontinued, or the dosage is rapidly reduced, in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea; increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].
Included as part of the PRECAUTIONS section.
See BOXED WARNING
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.
FENTORA is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) For patients being converted from Actiq, it is necessary to follow the instructions found in Table 1 in Section 2.1, as Actiq and FENTORA are not equivalent on a microgram per microgram basis. FENTORA is NOT a generic version of Actiq. All patients should be titrated from the 100 mcg dose.
The initial dose of FENTORA should be 100 mcg. Titrate each patient individually to provide adequate analgesia while minimizing side effects. [see DOSAGE AND ADMINISTRATION]
When dispensing, DO NOT substitute a FENTORA prescription for an Actiq prescription under any circumstances. FENTORA and Actiq are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products including Actiq that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of FENTORA for the same dose of Actiq or any other fentanyl product may result in a fatal overdose.
Patients and their caregivers must be instructed that FENTORA contains 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 HOW SUPPLIED/Storage and Handling]
The concomitant use of FENTORA with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see DRUG INTERACTIONS].
Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of FENTORA if warranted.
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). Warn patients taking FENTORA of these dangers and counsel them accordingly.
Because potent opioids can cause respiratory depression, titrate FENTORA 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.
Administer FENTORA 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, use FENTORA with caution in patients with bradyarrhythmias.
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.
Because of the risk for misuse, abuse, addiction, and overdose [see Drug Abuse and Dependence], 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:
Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.
See FDA-approved patient labeling (Medication Guide).
Patients and members of their household must be advised to dispose of any unopened blister packages remaining from a prescription as soon as they are no longer needed.
To dispose of unused FENTORA, remove FENTORA tablets from blister packages and flush down the toilet. Do not flush the FENTORA blister packages or cartons down the toilet.
Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of FENTORA are provided in the FENTORA Medication Guide. Instruct patients to read this information in its entirety and provide 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, instruct them to call the Teva Pharmaceuticals toll-free number (1-800-8965855) or seek assistance from their local DEA office.
Fentanyl was evaluated for carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg in females were administered subcutaneously and no treatment-related neoplasms were observed (doses are equivalent to 2.3- and 3.4-times the exposure of a single human dose of 800 mcg per pain episode, respectively, based on an AUC comparison). In mice, at topical doses up to 50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms was observed.
Fentanyl citrate was not mutagenic in the Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay.
In a fertility study, female rats were administered fentanyl subcutaneously for 14 days prior to mating with untreated males at doses up to 300 mcg/kg and no effects on female fertility were observed. The systemic exposure at the dose of 300 mcg/kg was approximately 8.6-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison. Males were administered fentanyl subcutaneously for 28 days prior to mating with untreated females at doses up to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected fertility, were observed. These effects included decreased percent mobile sperm, decreased sperm concentrations as well as an increase in the percent abnormal sperm. The dose in males at which no effects on fertility were observed was 100 mcg/kg, which is approximately 5.7- times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.
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 (25, 50 or 100 mcg/kg) was administered subcutaneously to pregnant rats during the period of organogenesis (Gestation Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl (50, 100 or 250 mcg/kg) was also administered subcutaneously to pregnant rabbits during the period of organogenesis (GD 6-18). Maternal toxicity was noted at doses > 100 mcg/kg. No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to 7.5times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison).
Published studies concur with the conducted studies regarding the lack of teratogenic potential for fentanyl. One literature report showed that administration of fentanyl (10, 100, or 500 mcg/kg) to pregnant rats from GD 7-21, via implanted microosmotic minipumps, was not teratogenic (the high dose was approximately 6-times the single human dose of 800 mcg per pain episode on a mg/m² basis). Another report showed that intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant rats from GD 6-18 was embryotoxic in the 30 mcg/kg group, but was not teratogenic. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA.
In a postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20 with subcutaneous doses of fentanyl (25, 50, 100 and 400 mcg/kg). Maternal toxicity was noted at doses > 100 mcg/kg. A reduction in pup growth and delayed attainment of developmental indices were observed at > 100 mcg/kg. No difference in the number of live pups/litter was seen at birth, however, pup survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation, fentanyl-related clinical signs (decreased activity, skin cold to touch, and moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg group. Pups from this group also had significantly reduced body weights throughout the lactation period. The dose of fentanyl administered to rats at which no developmental toxicity in the F1 generation was seen was 50 mcg/kg which is approximately equal the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison.
Fentanyl readily passes across the placenta to the fetus; therefore, do not use FENTORA for analgesia during labor and delivery (including caesarean section) since it may cause respiratory depression in the fetus or in the newborn infant.
Fentanyl is excreted in human milk; therefore do not use FENTORA 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.
The safety and efficacy of FENTORA have not been established in pediatric patients below the age of 18 years.
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.
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.
Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant gender differences were noted either in dosage requirement or in observed adverse reactions.
The pharmacokinetic effects of race with the use of FENTORA have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.
The manifestations of FENTORA overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation [see CLINICAL PHARMACOLOGY].
Immediate management of opioid overdose includes removal of the FENTORA tablet, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, as well as ventilatory and circulatory status.
Provide ventilatory support, obtain intravenous access, and employ naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use.
Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.
Management of severe FENTORA overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient's airway is secure. In the presence of hypoventilation or apnea, ventilation should be assisted or controlled and oxygen administered as indicated.
Patients with overdose should be carefully observed and appropriately managed until their clinical condition is well-controlled.
Although muscle rigidity interfering with respiration has not been seen following the use of FENTORA, this is possible with fentanyl and other opioids. If it occurs, manage by the use of assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.
FENTORA is contraindicated in opioid non-tolerant patients.
FENTORA is contraindicated in the management of acute or postoperative pain including headache/migraine and dental pain. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients.
Patients considered opioid tolerant are those who are taking around-theclock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid daily for a week or longer.
FENTORA is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl.
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.
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.
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
| Pharmacokinetic Parameter (mean) | FENTORA 400 mcg | Actiq 400 mcg (adjusted dose)*** |
| Absolute Bioavailability | 65% ± 20% | 47% ± 10.5% |
| Fraction Absorbed Transmucosally | 48% ± 31.8% | 22% ± 17.3% |
| Tmax (minute)** | 46.8 (20-240) | 90.8 (35-240) |
| Cmax (ng/mL) | 1.02 ± 0.42 | 0.63 ± 0.21 |
| AUC0-tmax (ng•hr/mL) | 0.40 ± 0.18 | 0.14 ± 0.05 |
| AUC0-inf (ng•hr/mL) | 6.48 ± 2.98 | 4.79 ± 1.96 |
| * Based on venous blood samples. ** Data for Tmax presented as median (range). *** Actiq (OTFC) data was dose adjusted (800 mcg to 400 mcg). |
||
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
| Pharmacokinetic Parameter (mean±SD) | 100 mcg | 200 mcg | 400 mcg | 800 mcg |
| Cmax (ng/mL) | 0.25 ± 0.14 | 0.40 ± 0.18 | 0.97 ± 0.53 | 1.59 ± 0.90 |
| Tmax minute** (range) | 45.0 (25.0 -181.0) | 40.0 (20.0 -180.0) | 35.0 (20.0 -180.0) | 40.0 (25.0 - 180.0) |
| AUC0-inf (ng•hr/mL) | 0.98 ± 0.37 | 2.11 ± 1.13 | 4.72 ± 1.95 | 9.05 ± 3.72 |
| AUC0-tmax (ng•hr/mL) | 0.09 ± 0.06 | 0.13 ± 0.09 | 0.34 ± 0.23 | 0.52 ± 0.38 |
| T½, hr** | 2.63 (1.47 -13.57) | 4.43 (1.85 -20.76) | 11.09 (4.63 -20.59) | 11.70 (4.63 - 28.63) |
| * Based on venous sampling. ** Data for Tmax presented as median (range). |
||||
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
| Patient status | Cmax (ng/mL) | tmax (min) | AUC0-tmax (ng•hr/mL) | AUC0-8 (ng•hr/mL) |
| Mucositis | 1.25 ± 0.78 | 25.0 (15 - 45) | 0.21 ± 0.16 | 2.33 ± 0.93 |
| No mucositis | 1.24 ± 0.77 | 22.5 (10 - 121) | 0.25 ± 0.24 | 1.86 ± 0.86 |
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).
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
| FENTORA Dose | n (%) (N=80) |
| 100 mcg | 13 (16) |
| 200 mcg | 11 (14) |
| 400 mcg | 21 (26) |
| 600 mcg | 10 (13) |
| 800 mcg | 25 (31) |
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
MEDICATION GUIDE
FENTORA®
(fen-tor-a)
(fentanyl) Buccal Tablets 100 mcg, 200 mcg, 400 mcg, 600 mcg,
800 mcg
IMPORTANT:
Do not use FENTORA unless you are regularly using another opioid pain medicine around-the-clock for your cancer pain and your body is used to these medicines (this means you are opioid tolerant). You can ask your healthcare provider if you are opioid tolerant.
Keep FENTORA in a safe place away from children.
Get emergency help right away if:
These are medical emergencies that can cause death. If possible, try to remove FENTORA from the mouth.
Read this Medication Guide completely before you start using FENTORA, and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household and other caregivers.
What is the most important information I should know about FENTORA?
FENTORA can cause life-threatening breathing problems which can lead to death.
1. Do not use FENTORA if you are not opioid tolerant.
2. If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using FENTORA. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain.
3. Use FENTORA exactly as prescribed by your healthcare provider.
4. Do not switch from FENTORA to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of FENTORA is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of FENTORA that may be different than other fentanyl containing medicines you may have been taking.
5. Do not use FENTORA for short-term pain that you would expect to go away in a few days, such as:
6. Never give FENTORA to anyone else, even if they
have the same symptoms you have. It may harm them or even cause death.
FENTORA is a federally controlled substance (CII) because it is a strong opioid
(narcotic) pain medicine that can be misused by people who abuse prescription
medicines or street drugs.
7. FENTORA is available only through a program called the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access program. To receive FENTORA, you must:
What is FENTORA?
It is not known if FENTORA is safe and effective in children under 18 years of age.
Who should not use FENTORA?
Do not use FENTORA:
What should I tell my healthcare provider before using FENTORA?
Before using FENTORA, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may cause serious or life-threatening side effects when taken with FENTORA. Sometimes, the doses of certain medicines and FENTORA need to be changed if used together.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I use FENTORA?
Before you can begin to use FENTORA:
Using FENTORA:
What should I avoid while using FENTORA?
What are the possible side effects of FENTORA?
FENTORA can cause serious side effects, including:
1. Breathing problems that can become life-threatening. See “What is the most important information I should know about FENTORA?”
Call your healthcare provider or get emergency medical help right away if you:
1. These symptoms can be a sign that you have taken too much FENTORA or the dose is too high for you. These symptoms may lead to serious problems or death if not treated right away. If you have any of these symptoms, do not take any more FENTORA until you have talked to your healthcare provider.
2. Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.
3. Physical dependence. Do not stop using FENTORA or taking any other opioid without talking to your healthcare provider. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Physical dependency is not the same as drug addiction.
4. A chance of abuse or addiction. This chance is higher if you are or have been addicted to or abused other medicines, street drugs, or alcohol, or if you have a history of mental health problems.
5. Pain, irritation, or sores at the application site (on your gum, on the inside of your cheek, or under your tongue). Tell your healthcare provider if this is a problem for you.
The most common side effects of FENTORA are:
Constipation (not often enough or hard bowel movements) is a very common side effect of pain medicines (opioids) including FENTORA and is unlikely to go away without treatment. Talk to your healthcare provider about dietary changes, and the use of laxatives (medicines to treat constipation) and stool softeners to prevent or treat constipation while taking FENTORA.
Talk to your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of FENTORA. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1Â800-FDA-1088.
How should I store FENTORA?
How should I dispose of unused FENTORA tablets when they are no longer needed?
General information about FENTORA
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use FENTORA only for the purpose for which it was prescribed. Do not give FENTORA to other people, even if they have the same symptoms you have. FENTORA can harm other people and even cause death. Sharing FENTORA is against the law.
This Medication Guide summarizes the most important information about FENTORA. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about FENTORA that is written for health professionals.
For more information about the TIRF REMS Access program, go to www.TIRFREMSAccess.com or call 1-866-822-1483.
What are the ingredients in FENTORA?
Active Ingredient: fentanyl citrate
Inactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.
Instructions for Use
Before you use FENTORA, it is important that you read the Medication Guide and these Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use FENTORA the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use FENTORA.
When you get an episode of breakthrough cancer pain, use the dose of FENTORA prescribed by your healthcare provider as follows:
Figure 1
 |
Figure 2
 |
Figure 3
 |
OR,
Figure 4a
 |
Figure 4b
 |
 Figure 4c
 |
Figure 4d
 |
This Medication Guide has been approved by the U.S. Food and Drug Administration.
