FENTORA

Cephalon, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use FENTORA safely and effectively. See full prescribing information for FENTORA. Initial U.S. Approval: [1968]RECENT MAJOR CHANGESDosage and Administration, Maintenance Dosing (2.3) 02/2013Dosage and Administration, Administration of FENTORA (2.4) 02/2013Dosage and Administration, Discontinuation of FENTORA (2.5) 02/2013BOXED WARNINGWARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL See full prescribing information for complete boxed warning Due to the risk of fatal respiratory depression, FENTORA is contraindicated in opioid non-tolerant patients (1) and in management of acute or postoperative pain, including headache/migraines. (4) Keep out of reach of children. (5.3) Use with CYP3A4 inhibitors may cause fatal respiratory depression. (7) When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to FENTORA. (2.1, 5.2) When dispensing, do not substitute with any other fentanyl products. (5.1) Contains fentanyl, a Schedule II controlled substance with abuse liability similar to other opioid analgesics. (9.1) FENTORA is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program. (5.11) INDICATIONS AND USAGEFENTORA is an opioid agonist 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. (1)Limitations of Use: FENTORA may be dispensed only to patients enrolled in the TIRF REMS Access program. (1)DOSAGE AND ADMINISTRATION Patients must remain on around-the-clock opioids when taking FENTORA. (1) Initial dose of FENTORA: 100 mcg. (2.1) Initiate titration using multiples of 100 mcg FENTORA tablet. Limit patient access to only one strength of FENTORA at any one time. (2.1) Individually titrate to a tolerable dose that provides adequate analgesia using single FENTORA tablet. (2.1) No more than two doses can be taken per breakthrough pain episode. (2.1) Wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. (2.1) Place entire tablet in buccal cavity or under the tongue; tablet is not to be split, crushed, sucked, chewed or swallowed whole. (2.4) DOSAGE FORMS AND STRENGTHS Tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. (3) CONTRAINDICATIONS Opioid non-tolerant patients. (4) Management of acute or postoperative pain, including headache/migraine. (4) Intolerance or hypersensitivity to fentanyl or components of FENTORA. (4) WARNINGS AND PRECAUTIONS Clinically significant respiratory and CNS depression can occur. Monitor patients accordingly. (5.1) Fentora is not bioequivalent to other fentanyl products. Do not convert from other fentanyl products on a mcg per mcg basis. (5.2) Use with other CNS depressants and cytochrome P450 3A4 inhibitors may increase depressant effects including hypoventilation, hypotension, and profound sedation. Consider dosage adjustments if warranted. (5.4) Titrate FENTORA cautiously in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression and in patients susceptible to intracranial effects of CO2 retention. (5.6, 5.7) Application site reactions occurred in 10% of patients in clinical trials and ranged from paresthesia to ulceration and bleeding. (5.8) Side EffectsMost common (frequency ≥10%): nausea, dizziness, vomiting, fatigue, anemia, constipation, edema peripheral, asthenia, dehydration and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals, at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .DRUG INTERACTIONS See Boxed Warning and Warnings and Precautions. (5.4, 7) USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) Administer FENTORA with caution to patients with hepatic or renal impairment. (8.6)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL
• 1 FENTORA INDICATIONS AND USAGE
• 2 FENTORA DOSAGE AND ADMINISTRATION
  • 2.1 Initial Dose
  • 2.2 Dose Titration
  • 2.3 Maintenance Dosing
  • 2.4 Administration of FENTORA
  • 2.5 Discontinuation of FENTORA
• 3 DOSAGE FORMS AND STRENGTHS
• 4 FENTORA CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Respiratory Depression
  • 5.2 Important Information Regarding Prescribing and Dispensing
  • 5.3 Patient/Caregiver Instructions
  • 5.4 Additive CNS Depressant Effects
  • 5.5 Effects on Ability to Drive and Use Machines
  • 5.6 Chronic Pulmonary Disease
  • 5.7 Head Injuries and Increased Intracranial Pressure
  • 5.8 Application Site Reactions
  • 5.9 Cardiac Disease
  • 5.10 MAO Inhibitors
  • 5.11 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
• 6 FENTORA ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Patients with Renal or Hepatic Impairment
  • 8.7 Gender
  • 8.8 Race
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
  • 9.3 Dependence
• 10 OVERDOSAGE
  • 10.1 Clinical Presentation
  • 10.2 Immediate Management
  • 10.3 Treatment of Overdosage (Accidental Ingestion) in the Opioid Non-Tolerant Person
  • 10.4 Treatment of Overdose in Opioid Tolerant Patients
  • 10.5 General Considerations for Overdose
• 11 FENTORA DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 Storage and Handling
  • 16.2 Disposal of FENTORA
  • 16.3 How Supplied
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Patient/Caregiver Instructions
  • 17.2 Disposal of Unopened FENTORA Blister Packages When No Longer Needed
• MEDICATION GUIDE
• Blister for NDC 63459-541-04
• BLISTER FOR NDC 63459-542-04
• BLISTER FOR NDC 63459-544-04
• BLISTER FOR NDC 63459-546-04
• BLISTER FOR NDC 63459-548-04
• CARTON FOR NDC 63459-541-28
• CARTON FOR NDC 63459-542-28
• CARTON FOR NDC 63459-544-28
• CARTON FOR NDC 63459-546-28
• CARTON FOR NDC 63459-548-28

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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 (5.11)]. 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.

2 DOSAGE AND ADMINISTRATION

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 (5.11)] .

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.

2.1 Initial Dose

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.

Patients on Actiq

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

*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.

All Other Patients

The initial dose of FENTORA is 100 mcg.

Repeat Dosing

a. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of FENTORA for any episode of breakthrough pain.

b. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA.

2.2 Dose Titration

a. From an initial dose, patients should be closely followed by the prescriber and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of FENTORA  over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted.

b. Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200 mcg FENTORA tablet for doses  above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously.

c. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of FENTORA for any breakthrough pain episode. During titration, one dose of FENTORA  may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg).

d. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. To reduce the risk of overdose during titration, patients should have only one strength of FENTORA tablets available at any time.

e. Patients should be strongly encouraged to use all of their FENTORA tablets of one strength prior to being prescribed the next strength. If this is not practical, unused FENTORA should be disposed of safely [see How Supplied/Storage and Handling (16.2)]. Dispose of any unopened FENTORA tablets remaining from a prescription as soon as they are no longer needed.

2.3 Maintenance Dosing

a. Once titrated to an effective dose, patients should generally use only ONE FENTORA tablet of the appropriate strength per breakthrough pain episode.

b. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode.

c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA.

d. Dosage adjustment of FENTORA may be required in some patients. Generally, the FENTORA  dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes

e. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the around-the-clock opioid used for persistent pain should be re-evaluated.

f. Once an effective dose is determine during the titration scheme outlined above, an alternate route of administration is sublingual (placing the tablet under the tongue).

2.4 Administration of FENTORA

Opening the Blister Package

• Instruct patients not to open the blister until ready to administer FENTORA.
• Separate a single blister unit from the blister card by bending and tearing apart at the perforations.
• Bend the blister unit along the line where indicated.
• Peel back the blister backing to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet.
• Do not store the tablet once it has been removed from the blister package as the tablet integrity may be compromised and, more importantly, because this increases the risk of accidental exposure to the tablet.

Tablet Administration:

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.

2.5 Discontinuation of FENTORA

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.

3 DOSAGE FORMS AND STRENGTHS

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 How Supplied/Storage and Handling (16.3)] .

4 CONTRAINDICATIONS

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-the-clock 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.

5 WARNINGS AND PRECAUTIONS

See Boxed Warning

5.1 Respiratory Depression

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.

5.2 Important Information Regarding Prescribing and Dispensing

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 (2.1)]

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.

5.3 Patient/Caregiver Instructions

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  (16.1)  ]

5.4 Additive CNS Depressant Effects

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 (7)] .

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.

5.5 Effects on Ability to Drive and Use Machines

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.

5.6 Chronic Pulmonary Disease

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.

5.7 Head Injuries and Increased Intracranial Pressure

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.

5.8 Application Site Reactions

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.

5.9 Cardiac Disease

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

5.10 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.

5.11 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:

• Healthcare professionals, who prescribe FENTORA for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
• To receive FENTORA, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
• Pharmacies that dispense FENTORA must enroll in the program and agree to comply with the REMS requirements.
• Wholesalers and distributors that distribute FENTORA must enroll in the program, and distribute only to authorized pharmacies.

Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483.

6 ADVERSE REACTIONS

6.1 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 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%

 * 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%

 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.

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

7 DRUG INTERACTIONS

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 (5.4)]. 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Category C

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 c25, 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 7.5-times 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.

8.2 Labor and Delivery

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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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

8.5 Geriatric Use

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.

8.6 Patients with Renal or Hepatic Impairment

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.

8.7 Gender

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.

8.8 Race

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.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

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.

9.2 Abuse

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 re-evaluation 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.

9.3 Dependence

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 (2.5)] .  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 (8.1)] .

10 OVERDOSAGE

10.1 Clinical Presentation

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 (12.2)] .

10.2 Immediate Management

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.

10.3 Treatment of Overdosage (Accidental Ingestion) in the Opioid Non-Tolerant Person

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.

10.4 Treatment of Overdose in Opioid Tolerant Patients

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.

10.5 General Considerations for Overdose

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.

11 DESCRIPTION

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-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.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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.

Analgesia

The analgesic effects of fentanyl are related to the blood level of the drug, if proper allowance is made for the delay into and out of the CNS (a process with a 3- to 5-minute half-life).

In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance with any and all opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of FENTORA should be individually titrated to achieve the desired effect [see Dosage and Administration (2.1)].

Central Nervous System

The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.

Fentanyl 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).

Gastrointestinal System

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (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.

Respiratory System

All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. During the titration phase of the clinical trials, somnolence, which may be a precursor to respiratory depression, did increase in patients who were treated with higher doses of 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 (4)  , Warnings and Precautions (5.2)  and Overdosage (10).

12.3 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.

Absorption

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

 * Based on venous blood samples.

** Data for T_max presented as median (range). 

***Actiq 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 (C_max, AUC_0-tmax, AUC_0-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 (2.1) and Warnings and Precautions (5.1)]. Figure 1 includes an inset which shows the mean plasma concentration versus time profile to 6 hours. The vertical line denotes the median T_max for FENTORA.

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

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

 * Based on venous sampling.

** Data for T_max 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 t_max 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 C_max) of fentanyl is equivalent to systemic exposure following buccal tablet placement.

 Distribution

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.

Metabolism

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 (7)] .

Elimination

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.

Gender

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

Race

In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in US subjects (mean C_max 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).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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.

Mutagenesis

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.

Impairment of Fertility

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.

14 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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 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 (10), and Patient Counseling Information (17.1)]

Store at 20 to 25ºC (68 to 77ºF) 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.

16.2 Disposal of FENTORA

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 Counseling Information (17.2)]. 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 1-800-896-5855.

16.3 How Supplied

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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling ( Medication Guide).

17.1 Patient/Caregiver Instructions

• Before initiating treatment with FENTORA, explain the statements below to patients and/or caregivers. Instruct patients to read the Medication Guide each time FENTORA is dispensed because new information may be available.
• TIRF REMS Access Program
  • Outpatients must be enrolled in the TIRF REMS Access program before they can receive FENTORA.
  • Allow patients the opportunity to ask questions and discuss any concerns regarding FENTORA or the TIRF REMS Access program.
  • As a component of the TIRF REMS Access program, prescribers must review the contents of the FENTORA Medication Guide with every patient before initiating treatment with FENTORA.
  • Advise the patient that FENTORA is available only from pharmacies that are enrolled in the TIRF REMS Access program, and provide them with the telephone number and website for information on how to obtain the drug.
  • Advise the patient that only enrolled healthcare providers may prescribe FENTORA.
  • Patient must sign the Patient-Prescriber Agreement to acknowledge that they understand the risks of FENTORA.
  • Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the TIRF REMS Access program.
• 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 How Supplied/Storage and Handling (16.1), and Warnings and Precautions (5.3)  ]
• Instruct patients not to take FENTORA for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short-term pain, even if they have taken other opioid analgesics for these conditions.
• Instruct patients on the meaning of opioid tolerance and that FENTORA is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes.
• Instruct patients that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take FENTORA.
• Instruct patients that the titration phase is the only period in which they may take more than ONE tablet to achieve a desired dose (e.g., two 100 mcg tablets for a 200 mcg dose).
• Instruct patients that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF FENTORA USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of FENTORA for any breakthrough pain episode.
• Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA.
• Instruct patients NOT to share FENTORA and that sharing FENTORA with anyone else could result in the other individual’s death due to overdose.
• Make patients aware that FENTORA contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone.
• Instruct patients 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.
• Instruct patients not to open the blister until ready to use FENTORA and not to store the tablet in a temporary container such as a pill box, once it has been removed from the blister package.
• Instruct patients that FENTORA tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. Tablets are to be placed between the cheek and gum above a molar tooth or under the tongue and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water.
• Caution patients to talk to their doctor if breakthrough pain is not alleviated or worsens after taking FENTORA.
• Instruct patients to use FENTORA exactly as prescribed by their doctor and not to take FENTORA more often than prescribed.
• Caution patients 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). Warn patients taking FENTORA of these dangers and counsel them accordingly.
• Warn patients 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.
• Inform female patients 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.
• Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure.

17.2 Disposal of Unopened FENTORA Blister Packages When No Longer Needed

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 (1-800-896-5855) or seek assistance from their local DEA office.

MEDICATION GUIDE

FENTORA^® (fen-tor-a) CII

(fentanyl buccal tablet)

100 mcg, 200 mcg, 400 mcg, 600 mcg, 800 mcg

 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.

• You must not use more than 2 doses of FENTORA for each episode of breakthrough cancer pain.
• You must wait at least 4 hours before treating a new episode of breakthrough pain with FENTORA. See the Medication Guide section “How should I use FENTORA?” and the Instructions for Use at the end of this Medication Guide for detailed information about how to use FENTORA the right way.

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:

• pain after surgery
• headache or migraine
• dental pain

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.

• Prevent theft, misuse or abuse. Keep FENTORA in a safe place to protect it from being stolen. FENTORA can be a target for people who abuse (narcotic) medicines or street drugs.
• Selling or giving away this medicine is against the law.

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:

• talk to your healthcare provider
• understand the benefits and risks of FENTORA
• agree to all of the instructions
• sign the Patient-Prescriber Agreement form.

What is FENTORA?

• FENTORA is a prescription medicine that contains the medicine fentanyl.  

• FENTORA is used to manage breakthrough pain in adults with cancer who are already routinely taking other opioid pain medicines around-the-clock for cancer pain.
• FENTORA is started only after you have been taking other opioid pain medicines and your body has become used to them (you are opioid tolerant). Do not use FENTORA if you are not opioid tolerant. 
• You must stay under your healthcare provider’s care while using FENTORA.
• FENTORA is only:
  • available through the TIRF REMS Access program
  • given to people who are opioid tolerant

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:

• if you are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for your cancer pain, and your body is used to these medicines.
• for short-term pain that you would expect to go away in a few days, such as:
  • pain after surgery
  • headaches or migraines
  • dental pain
• if you are allergic to any of the ingredients in FENTORA. See the end of this Medication Guide for a complete list of ingredients in FENTORA.

What should I tell my healthcare provider before starting FENTORA?

Before using FENTORA, tell your healthcare provider if you:

• have trouble breathing or lung problems such as asthma, wheezing, or shortness of breath
• have or had a head injury or brain problem
• have liver or kidney problems
• have seizures
• have a slow heart rate or other heart problems
• have low blood pressure
• have mental problems including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)
• have a past or present drinking problem (alcoholism), or a family history of drinking problems
• have a past or present drug abuse problem or addiction problem, or a family history of a drug abuse problem or addiction problem
• have any other medical conditions
• are pregnant or plan to become pregnant.  FENTORA may cause serious harm to your unborn baby.
• are breastfeeding or plan to breastfeed. FENTORA passes into your breast milk. It can cause serious harm to your baby. You should not take FENTORA while breastfeeding.

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.

• Do not take any medicine while using FENTORA until you have talked to your healthcare provider. Your healthcare provider will tell you if it is safe to take other medicines while you are using FENTORA.
• Be very careful about taking other medicines that may make you sleepy, such as other pain medicines, anti-depressant medicines, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers.

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:

• Your healthcare provider will explain the TIRF REMS Access program to you.
• You will sign the TIRF REMS Access program Patient-Prescriber Agreement form.
• FENTORA is only available at pharmacies that are part of the TIRF REMS Access program. Your healthcare provider will let you know the pharmacy closest to your home where you can have your FENTORA prescription filled.

Using FENTORA:

• Use FENTORA exactly as prescribed. Do not use FENTORA more often than prescribed.
• Your healthcare provider will change the dose until you and your healthcare provider find the right dose for you.
• See the detailed Instructions for Use at the end of this Medication Guide for information about how to use FENTORA the right way.
• Use FENTORA tablets whole.
• Do not crush, split, suck, or chew FENTORA tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.
• Wait 30 minutes after using FENTORA. If there is any of the FENTORA tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine.
• You must not use more than 2 doses of FENTORA for each episode of breakthrough cancer pain.
  • Use 1 dose of FENTORA for an episode of breakthrough cancer pain.
  • If your breakthrough cancer pain does not get better 30 minutes after taking the first dose of FENTORA, you can use only 1 more dose of FENTORA as instructed by your healthcare provider.
  • If your breakthrough pain does not get better after the second dose of FENTORA, call your healthcare provider for instructions. Do not use another dose of FENTORA at this time.
• Wait at least 4 hours before treating a new episode of breakthrough cancer pain with FENTORA.
  • If you only need to take 1 dose of FENTORA for an episode of breakthrough pain, you must wait 4 hours from the time of that dose to take a dose of FENTORA for a new episode of  breakthrough pain.
  • If you need to use 2 doses of FENTORA for an episode of breakthrough pain, you must wait 4 hours after the second dose to take a dose of FENTORA for a new episode of breakthrough pain.
• It is important for you to keep taking your around-the-clock opioid pain medicine while using FENTORA.
• Talk to your healthcare provider if your dose of FENTORA does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of FENTORA needs to be changed.
• Talk to your healthcare provider if you have more than 4 episodes of breakthrough cancer pain per day.  The dose of your around-the-clock opioid pain medicine may need to be adjusted.
• If you begin to feel dizzy, sick to your stomach, or very sleepy before the tablet is completely dissolved, rinse your mouth with water and spit the remaining pieces of the tablet into a sink or toilet right away. Rinse the sink or flush the toilet to dispose of any remaining tablet pieces.
• If you use too much FENTORA or overdose, you or your caregiver should call for emergency medical help or have someone take you to the nearest hospital emergency room.

What should I avoid while taking FENTORA?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how FENTORA affects you. FENTORA can make you sleepy. Ask your healthcare provider when it is okay to do these activities.
• Do not drink alcohol while using FENTORA. It can increase your chance of getting dangerous side effects.

What are the possible side effects of FENTORA?

FENTORA can cause serious side effects, including:

• 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:

  • have trouble breathing
  • have drowsiness with slowed breathing
  • have slow, shallow breathing (little chest movement with breathing)
  • feel faint, very dizzy, confused, or have unusual symptoms

  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.

• Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down.
• 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.
• 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.
• 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:

• nausea
• vomiting
• dizziness
• low red blood cell count
• tiredness
• swelling of the arms, hands, legs and feet
• headache

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 1-800-FDA-1088.

How should I store FENTORA?

• Always keep FENTORA in a safe place away from children and from anyone for whom it has not been prescribed. Protect FENTORA from theft.
• Store FENTORA at room temperature, 59^oF  to 86^oF (15^o C to 30^oC)  until ready to use. Do not freeze FENTORA.
• Keep FENTORA in the original blister unit. Do not remove FENTORA from its blister packaging for storage in a temporary container, such as a pill box.
• Keep FENTORA dry.

 How should I dispose of unused FENTORA tablets when they are no longer needed?

• Dispose of any unused FENTORA tablets remaining from a prescription as soon as they are no longer needed.
  • Remove FENTORA tablets from blister packages and flush down the toilet.
• Do not flush the FENTORA packaging (card, blister units, or cartons) down the toilet.
• If you need help with disposal of FENTORA, call Teva Pharmaceuticals at 1-800-896-5855 or call your local Drug Enforcement Agency (DEA) office.

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 doctor. 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 of 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:

• FENTORA comes packaged as a blister card containing 4 blister units. Each blister unit contains 1 FENTORA tablet. Do not open a blister unit until ready to use.
• Separate one of the blister units from the blister card by tearing apart at the perforations. Bend the blister unit along the line where indicated. The product strength of your FENTORA tablets will be printed in the boxed area shown as (See Figure 1).

• Peel back foil on blister unit to expose tablet (See Figure 2).

• Do not push the tablet through the foil on the blister unit because this could damage the tablet.
• When removed from the blister unit, FENTORA tablet must be used right away.
• Use FENTORA tablets whole.
• Do not crush, split, suck, or chew FENTORA tablets, or swallow the tablets whole. You will get less relief for your breakthrough cancer pain.
• You can place a FENTORA tablet:
  • in your mouth above a rear molar tooth between the upper cheek and gum (See Figure 3). Switch (alternate) sides of your mouth for each dose.

OR,

•  on the floor of your mouth, under your tongue (See Figures 4a, 4b, 4c, 4d).
• When placing the tablet under your tongue, first lift your tongue (4b), then place the tablet under your tongue (4c), and lower your tongue over the tablet (4d).

Figure 4a

Figure 4b

Figure 4c

Figure 4d

• Leave the tablet in place until it dissolves. A FENTORA tablet generally takes between 14 to 25 minutes to dissolve.
• After 30 minutes, if there is any FENTORA left in your mouth, you may drink a glass of water to help you swallow the left over medicine.
• If you cannot use FENTORA in this manner, tell your healthcare provider. Your healthcare provider will tell you what to do.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed By:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Revised February 2013

FENT-008

FENTMG-007

FENTORA is a trademark of Cephalon, Inc. or its affiliates.

©2006-2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

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