Fentanyl Buccal

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Life-Threatening Respiratory Depression [see Warnings and Precautions (5.1) ] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4) ] Addiction, Abuse, and Misuse [see Warnings and Precautions (5.6) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8) ] Serotonin Syndrome [see Warnings and Precautions (5.10) ] Adrenal Insufficiency [see Warnings and Precautions (5.11) ] Severe Hypotension [see Warnings and Precautions (5.12) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14) ] Seizures [see Warnings and Precautions (5.15) ] Most 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 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 fentanyl buccal tablets has been evaluated in 304 opioid-tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months. The clinical trials of fentanyl buccal tablets 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 fentanyl buccal tablets 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 fentanyl buccal tablets 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) Three hundred and two (302) patients were included in the safety analysis. 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) 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 fentanyl buccal tablets. There was no evidence of excess toxicity in this subset of patients. Application Site Reactions: In clinical trials, 10% of all patients exposed to fentanyl buccal tablets reported application site reactions. These reactions ranged from paresthesias to ulceration and bleeding. Application site reactions occurring in ≥1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients. The duration of exposure to fentanyl buccal tablets 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 fentanyl buccal tablets. 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders: - Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Endocrine Disorders: - Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. - Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] . Immune System Disorders: - Anaphylaxis : Anaphylaxis has been reported with ingredients contained in fentanyl buccal tablet. General Disorders and Administration Site Conditions: Drug withdrawal syndrome

4 CONTRAINDICATIONS Fentanyl Buccal Tablet is contraindicated in: Opioid non-tolerant patients: Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1) ; Warnings and Precautions (5.1) ]. Significant respiratory depression [see Warnings and Precautions (5.1) ]. Acute or postoperative pain including headache/migraine and dental pain, or acute pain in the emergency department [see Indications and Usage (1) ] . Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14) ]. Known hypersensitivity (e.g. anaphylaxis) to fentanyl or components of fentanyl buccal tablet (e.g., anaphylaxis) [see Adverse Reactions (6.2) ] . Opioid non-tolerant patients. ( 4 ) Management of acute or postoperative pain, including headache/migraine and dental pain. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Known hypersensitivity to fentanyl or components of fentanyl buccal tablet. ( 4 )

11 DESCRIPTION Fentanyl buccal tablet is an opioid agonist, intended for buccal mucosal administration. Fentanyl buccal tablet 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. Fentanyl buccal tablet 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. Chemical Structure

2 DOSAGE AND ADMINISTRATION Patients must require and use around-the-clock opioids when taking fentanyl buccal tablet. ( 1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with fentanyl buccal tablet. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2 , 5.1 , 5.4 , 5.6 ) Initial dose of fentanyl buccal tablet: 100 mcg. ( 2.3 ) Initiate titration using multiples of 100 mcg fentanyl buccal tablet. Limit patient access to only one strength of fentanyl buccal tablet at any one time. ( 2.4 ) Individually titrate to a tolerable dose that provides adequate analgesia using a single fentanyl buccal tablet. ( 2.5 ) No more than two doses can be taken per breakthrough pain episode. ( 2.3 ) Wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. ( 2.3 ) Place entire tablet in buccal cavity or under the tongue; tablet is not to be split, crushed, sucked, chewed or swallowed whole. ( 2.6 ) When opioid therapy is no longer required, consider discontinuing fentanyl buccal tablet along with a gradual downward of other opioids to minimize possible withdrawal effects. ( 2.7 ) 2.1 Important Dosage and Administration Instructions Healthcare professionals who prescribe fentanyl buccal tablet for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of fentanyl buccal tablet [see Warnings and Precautions (5.7) ] . Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.6) ] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with fentanyl buccal tablet and adjust the dosage accordingly [see Warnings and Precautions (5.1) ] . Instruct patients and caregivers to take steps to store fentanyl buccal tablet securely and to properly dispose of unused fentanyl buccal tablet as soon as no longer needed [see Warnings and Precautions (5.2 , 5.6) , Patient Counseling Information (17) ]. Fentanyl buccal tablet 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.) [see Warnings and Precautions (5.5) ]. Fentanyl buccal tablet is NOT a generic version of any other transmucosal fentanyl product [see Warnings and Precautions (5.5) ] . 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with fentanyl buccal tablet [see Warnings and Precautions (5.1) , Patient Counseling Information (17) ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1 , 5.4 , 5.6) ]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose . 2.3 Initial Dosage The initial dose of fentanyl buccal tablet is always 100 mcg with the only exception being patients already using ACTIQ. Patients on ACTIQ For patients being converted from ACTIQ, prescribers must use the Initial Dosing Recommendations for Patients on ACTIQ t able below (Table 1). The doses of fentanyl buccal tablet 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 Fentanyl Buccal Tablet Dose From this initial dose, titrate patient to effective dose. 200 100 mcg tablet 400 100 mcg tablet 600 200 mcg tablet 800 200 mcg tablet 1200 2 × 200 mcg tablets 1600 2 × 200 mcg tablets For patients converting from ACTIQ doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg fentanyl buccal tablet and should proceed using multiples of this tablet strength. Repeat Dosing 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 fentanyl buccal tablet for any episode of breakthrough pain. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. 2.4 Dose Titration From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of fentanyl buccal tablet/s over several episodes of breakthrough pain and discuss their experience with their healthcare provider to determine if a dosage adjustment is warranted. 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 fentanyl buccal tablet for doses above 400 mcg (600 mcg and 800 mcg). Note: Do not use more than 4 tablets simultaneously. 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 fentanyl buccal tablet for any breakthrough pain episode. During titration, one dose of fentanyl buccal tablet may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg). Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. To reduce the risk of overdose during titration, patients should have only one strength of fentanyl buccal tablet/s available at any time. Patients should be strongly encouraged to use all of their fentanyl buccal tablets of one strength prior to being prescribed the next strength. If this is not practical, unused fentanyl buccal tablets should be disposed of safely [see How Supplied/Storage and Handling (16) ]. Dispose of any unopened fentanyl buccal tablets remaining from a prescription as soon as they are no longer needed. 2.5 Maintenance Dosing Once titrated to an effective dose, patients should generally use only ONE fentanyl buccal tablet of the appropriate strength per breakthrough pain episode. 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. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. Dosage adjustment of fentanyl buccal tablet may be required in some patients. Generally, the fentanyl buccal tablet 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. 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. Once an effective dose is determined using the titration scheme outlined above, an alternate route of administration is sublingual (placing the tablet under the tongue). 2.6 Administration of Fentanyl Buccal Tablet Opening the Blister Package: Instruct patients not to open the blister until ready to administer fentanyl buccal tablet. 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 fentanyl buccal tablet in the buccal cavity (above a rear molar, between the upper cheek and gum) or place the entire fentanyl buccal tablet under the tongue. Patients should not split the tablet . The fentanyl buccal tablet should not be crushed, sucked, chewed or swallowed whole, as this will result in lower plasma concentrations than when taken as directed. The fentanyl buccal 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 fentanyl buccal 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 fentanyl buccal tablet/s in the buccal cavity. 2.7 Discontinuation of Fentanyl Buccal Tablet For patients no longer requiring opioid therapy, consider discontinuing fentanyl buccal tablet along with a gradual downward tapering (titration) of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, fentanyl buccal tablet therapy can usually be discontinued immediately. [see Drug Abuse and Dependence (9.3) ] 2.8 Disposal of Fentanyl Buccal Tablets To dispose of unused fentanyl buccal tablets, remove fentanyl buccal tablets from blister packages and flush down the toilet. Do not flush fentanyl buccal tablets blister packages or cartons down the toilet. If you need additional assistance with disposal of fentanyl buccal tablets, call Teva Pharmaceuticals at 1-888-483-8279.

1 INDICATIONS AND USAGE Fentanyl buccal tablet 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, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg per hour of transdermal fentanyl, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking fentanyl buccal tablet. Fentanyl buccal tablet 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 ) Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg per hour of transdermal fentanyl, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg of oral hydrocodone per day, or an equianalgesic dose of another opioid. Patients must remain on around-the-clock opioids while taking fentanyl buccal tablet. Limitations of Use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine, or dental pain. As a part of the TIRF REMS, fentanyl buccal tablet may be dispensed by outpatient pharmacies only to patients enrolled in the program ( 5.7 ). For inpatient administration of fentanyl buccal tablet, patient and prescriber enrollment are not required. Limitations of Use: Not for use in opioid non-tolerant patients. Not for use in the management of acute or postoperative pain, including headache/migraine, and dental pain [see Contraindications (4) ] . As a part of the TIRF REMS, fentanyl buccal tablet may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions (5.7) ] . For inpatient administration of fentanyl buccal tablet, patient and prescriber enrollment are not required.

9.2 Abuse Fentanyl buccal tablet contains fentanyl, a substance with high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Fentanyl buccal tablet can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.6) ] . 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 substance use and includes: 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, increased tolerance, and sometimes physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance [see Drug Abuse and Dependence (9.3) ] . Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Fentanyl buccal tablet, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of Fentanyl Buccal Tablet Fentanyl buccal tablet is for oral transmucosal use only. Abuse of fentanyl buccal tablet poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl buccal tablet with alcohol and other central nervous system depressants.

9.1 Controlled Substance Fentanyl buccal tablet contains fentanyl, a Schedule II controlled substance.

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 results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Fentanyl buccal tablet contains fentanyl, a Schedule II controlled substance. 9.2 Abuse Fentanyl buccal tablet contains fentanyl, a substance with high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Fentanyl buccal tablet can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.6) ] . 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 substance use and includes: 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, increased tolerance, and sometimes physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance [see Drug Abuse and Dependence (9.3) ] . Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Fentanyl buccal tablet, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of Fentanyl Buccal Tablet Fentanyl buccal tablet is for oral transmucosal use only. Abuse of fentanyl buccal tablet poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl buccal tablet with alcohol and other central nervous system depressants. 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 results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .

10 OVERDOSAGE Clinical Presentation Acute overdose with fentanyl buccal tablet can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] . Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl buccal tablet, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Table 4 includes clinically significant drug interactions with fentanyl buccal tablet. Table 4. Clinically Significant Drug Interactions with Fentanyl Buccal Tablet Inhibitors of CYP3A4 Clinical Impact: The concomitant use of fentanyl buccal tablet and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of fentanyl buccal tablet is achieved [see Warnings and Precautions (5.3) ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl buccal tablet/s until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl buccal tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of fentanyl buccal tablet and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3) ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the fentanyl buccal tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl buccal tablet dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.4 , 5.6) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.10) ] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl buccal tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10) ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1) ]. Intervention: The use of fentanyl buccal tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of fentanyl buccal tablet and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphrine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl buccal tablet and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.4) ]. Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl buccal tablet is used concomitantly with anticholinergic drugs. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with fentanyl buccal tablet because they may reduce analgesic effect of fentanyl buccal tablet or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fentanyl is an opioid agonist whose principal therapeutic action is analgesia. 12.2 Pharmacodynamics Effects on the 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 a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and to electrical stimulation. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle 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 in the small intestine is delayed 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 biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2] ) . Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships 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 [see Dosage and Administration (2.1) ] . The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration-Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4 , 2.5) ] . 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. 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. 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 [see Warnings and Precautions (5.1) ] . 12.3 Pharmacokinetics Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of fentanyl buccal tablet increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range. Absorption Following buccal administration of fentanyl buccal tablet, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of fentanyl buccal tablet 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 fentanyl buccal tablet and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with fentanyl buccal tablet) (Table 5). Table 5. Pharmacokinetic Parameters Based on venous blood samples. in Adult Subjects Receiving Fentanyl Buccal Tablet or ACTIQ Pharmacokinetic Parameter (mean) Fentanyl Buccal Tablet 400 mcg ACTIQ 400 mcg (adjusted dose) ACTIQ data was dose adjusted (800 mcg to 400 mcg). Absolute Bioavailability 65% ± 20% 47% ± 10.5% Fraction Absorbed Transmucosally 48% ± 31.8% 22% ± 17.3% T max (minute) Data for T max presented as median (range). 46.8 (20-240) 90.8 (35-240) C max (ng/mL) 1.02 ± 0.42 0.63 ± 0.21 AUC 0-tmax (ng∙hr/mL) 0.40 ± 0.18 0.14 ± 0.05 AUC 0-inf (ng∙hr/mL) 6.48 ± 2.98 4.79 ± 1.96 Similarly, in another bioavailability study exposure following administration of fentanyl buccal tablet 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 fentanyl buccal tablet compared to ACTIQ (see Figure 1 ). Therefore, caution must be exercised when switching patients from one product to another [see Dosage and Administration (2.3) and Warnings and Precautions (5.5) ] . 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 fentanyl buccal tablet. Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of Fentanyl Buccal Tablet and ACTIQ in Healthy Subjects ACTIQ data were dose adjusted (800 mcg to 400 mcg). Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2. Table 6. Pharmacokinetic Parameters Based on venous sampling. Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects Pharmacokinetic Parameter (mean±SD) 100 mcg 200 mcg 400 mcg 800 mcg C max (ng/mL) 0.25 ± 0.14 0.40 ± 0.18 0.97 ± 0.53 1.59 ± 0.90 T max , minute Data for T max presented as median (range). (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) AUC 0-inf (ng∙hr/mL) 0.98 ± 0.37 2.11 ± 1.13 4.72 ± 1.95 9.05 ± 3.72 AUC 0-tmax (ng∙hr/mL) 0.09 ± 0.06 0.13 ± 0.09 0.34 ± 0.23 0.52 ± 0.38 T 1/2 , 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) Figure 2. Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets 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 fentanyl buccal tablet 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 7. Table 7. Pharmacokinetic Parameters in Patients with Mucositis Patient status C max (ng/mL) t max (min) AUC 0-tmax (ng∙hr/mL) AUC 0-8 (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 C max ) of fentanyl is equivalent to systemic exposure following buccal tablet placement. Figure 1 Figure 2 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. Elimination Metabolism The metabolic pathways following buccal administration of fentanyl buccal tablet 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) ] . Excretion Disposition of fentanyl following buccal administration of fentanyl buccal tablet 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. Sex 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 U.S. 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).

12.1 Mechanism of Action Fentanyl is an opioid agonist whose principal therapeutic action is analgesia.

12.2 Pharmacodynamics Effects on the 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 a reduction in the responsiveness of the brain stem to both increases in carbon dioxide and to electrical stimulation. Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle 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 in the small intestine is delayed 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 biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2] ) . Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships 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 [see Dosage and Administration (2.1) ] . The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration-Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4 , 2.5) ] . 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. 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. 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 [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics Fentanyl exhibits linear pharmacokinetics. Systemic exposure to fentanyl following administration of fentanyl buccal tablet increases linearly in an approximate dose-proportional manner over the 100- to 800-mcg dose range. Absorption Following buccal administration of fentanyl buccal tablet, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of fentanyl buccal tablet 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 fentanyl buccal tablet and ACTIQ (oral transmucosal fentanyl citrate), the rate and extent of fentanyl absorption were considerably different (approximately 30% greater exposure with fentanyl buccal tablet) (Table 5). Table 5. Pharmacokinetic Parameters Based on venous blood samples. in Adult Subjects Receiving Fentanyl Buccal Tablet or ACTIQ Pharmacokinetic Parameter (mean) Fentanyl Buccal Tablet 400 mcg ACTIQ 400 mcg (adjusted dose) ACTIQ data was dose adjusted (800 mcg to 400 mcg). Absolute Bioavailability 65% ± 20% 47% ± 10.5% Fraction Absorbed Transmucosally 48% ± 31.8% 22% ± 17.3% T max (minute) Data for T max presented as median (range). 46.8 (20-240) 90.8 (35-240) C max (ng/mL) 1.02 ± 0.42 0.63 ± 0.21 AUC 0-tmax (ng∙hr/mL) 0.40 ± 0.18 0.14 ± 0.05 AUC 0-inf (ng∙hr/mL) 6.48 ± 2.98 4.79 ± 1.96 Similarly, in another bioavailability study exposure following administration of fentanyl buccal tablet 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 fentanyl buccal tablet compared to ACTIQ (see Figure 1 ). Therefore, caution must be exercised when switching patients from one product to another [see Dosage and Administration (2.3) and Warnings and Precautions (5.5) ] . 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 fentanyl buccal tablet. Figure 1. Mean Plasma Concentration Versus Time Profiles Following Single Doses of Fentanyl Buccal Tablet and ACTIQ in Healthy Subjects ACTIQ data were dose adjusted (800 mcg to 400 mcg). Mean pharmacokinetic parameters are presented in Table 6. Mean plasma concentration versus time profiles are presented in Figure 2. Table 6. Pharmacokinetic Parameters Based on venous sampling. Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets in Healthy Subjects Pharmacokinetic Parameter (mean±SD) 100 mcg 200 mcg 400 mcg 800 mcg C max (ng/mL) 0.25 ± 0.14 0.40 ± 0.18 0.97 ± 0.53 1.59 ± 0.90 T max , minute Data for T max presented as median (range). (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) AUC 0-inf (ng∙hr/mL) 0.98 ± 0.37 2.11 ± 1.13 4.72 ± 1.95 9.05 ± 3.72 AUC 0-tmax (ng∙hr/mL) 0.09 ± 0.06 0.13 ± 0.09 0.34 ± 0.23 0.52 ± 0.38 T 1/2 , 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) Figure 2. Mean Plasma Concentration Versus Time Profiles Following Single 100, 200, 400, and 800 mcg Doses of Fentanyl Buccal Tablets 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 fentanyl buccal tablet 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 7. Table 7. Pharmacokinetic Parameters in Patients with Mucositis Patient status C max (ng/mL) t max (min) AUC 0-tmax (ng∙hr/mL) AUC 0-8 (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 C max ) of fentanyl is equivalent to systemic exposure following buccal tablet placement. Figure 1 Figure 2 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. Elimination Metabolism The metabolic pathways following buccal administration of fentanyl buccal tablet 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) ] . Excretion Disposition of fentanyl following buccal administration of fentanyl buccal tablet 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. Sex 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 U.S. 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).

20230329

10

3 DOSAGE FORMS AND STRENGTHS Fentanyl buccal 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) ] . Buccal Tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg strengths as fentanyl base. ( 3 )

Fentanyl Buccal Fentanyl Citrate MANNITOL SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM BICARBONATE SODIUM CARBONATE ANHYDROUS CITRIC ACID MAGNESIUM STEARATE FENTANYL CITRATE FENTANYL 1;C Fentanyl Buccal Fentanyl Citrate MANNITOL SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM BICARBONATE SODIUM CARBONATE ANHYDROUS CITRIC ACID MAGNESIUM STEARATE FENTANYL CITRATE FENTANYL 2;C Fentanyl Buccal Fentanyl Citrate MANNITOL SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM BICARBONATE SODIUM CARBONATE ANHYDROUS CITRIC ACID MAGNESIUM STEARATE FENTANYL CITRATE FENTANYL 4;C Fentanyl Buccal Fentanyl Citrate MANNITOL SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM BICARBONATE SODIUM CARBONATE ANHYDROUS CITRIC ACID MAGNESIUM STEARATE FENTANYL CITRATE FENTANYL 6;C Fentanyl Buccal Fentanyl Citrate MANNITOL SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM BICARBONATE SODIUM CARBONATE ANHYDROUS CITRIC ACID MAGNESIUM STEARATE FENTANYL CITRATE FENTANYL 8;C

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 a 26-week transgenic mice model (Tg.AC), 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. Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for fentanyl buccal tablet.

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 a 26-week transgenic mice model (Tg.AC), 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. Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg subcutaneously. Conversion to the human equivalent doses indicates that this is within the range of the human recommended dosing for fentanyl buccal tablet.

NDA021947

Fentanyl Buccal

Fentanyl Citrate

51862-638

HUMAN PRESCRIPTION DRUG

BUCCAL,SUBLINGUAL

PRINCIPAL DISPLAY PANEL - 100 mcg Tablet Blister Pack Carton NDC 51862-634-28 FENTANYL Buccal Tablets CII Equivalent to 100 mcg fentanyl base 28 Buccal Tablets (4 tablets x 7 cards) Information for Pharmacist: Counsel the patient about the use of this product including maximum dosing during a single breakthrough pain episode Instruct patients to read the enclosed fentanyl buccal tablets Medication Guide Fentanyl buccal tablets must only be supplied through the TIRF REMS Access restricted program. For more information call 1-866-822-1483 or visit www.TIRFREMSAccess.com. WARNING: Keep out of the reach of children PATIENTS MUST BE TOLERANT TO AROUND-THE-CLOCK OPIOID THERAPY DO NOT SUBSTITUTE FENTANYL BUCCAL TABLETS FOR OTHER FENTANYL PRODUCTS Fentanyl buccal tablets can be harmful or fatal if given to someone for whom it was not prescribed For Buccal or Sublingual Administration. Do NOT Split, Crush, Suck, Chew, or Swallow Tablet. Distributed by: Mayne Pharma Raleigh, NC 27609 mayne pharma PRINCIPAL DISPLAY PANEL - 100 mcg Tablet Blister Pack Carton

Dispense with Medication Guide available at: products.maynepharma.com 400-33-100054.05 Distributed By: Mayne Pharma Raleigh, NC 27609

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) . Storage and Disposal of Unused and Used Fentanyl Buccal Tablets [see Medication Guide / Instructions for Use ]. Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl buccal tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1 , 5.6) , Drug Abuse and Dependence (9.2) ] . Inform patients that leaving fentanyl buccal tablets unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl buccal tablets should be disposed of by removing fentanyl buccal tablets from the blister cards and flushing the unused medication down the toilet (if a drug take-back option is not readily available). Do not flush the fentanyl buccal tablet blister packages or cartons down the toilet. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Disposal of Unopened Fentanyl Buccal Tablet Blister Packages When No Longer Needed: Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of fentanyl buccal tablet are provided in the Fentanyl Buccal Tablet 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 (1-888-483-8279) or seek assistance from their local DEA office. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl buccal tablet or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.1) ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl buccal tablet. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10) ] . If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Increased Risk of Overdose and Death in Children Due to Accidental Ingestion Healthcare providers and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure [see Warnings and Precautions (5.2) ] . Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2) ] . Instruct patients to take steps to store fentanyl buccal tablet securely and to dispose of unused fentanyl buccal tablet [see Dosage and Administration (2.8) , Patient Counseling Information; Disposal of Unopened Fentanyl Buccal Tablet Blister Packages When No Longer Needed (17) ]. Instruct patients and caregivers to keep both used and unused fentanyl buccal tablet out of the reach of children [see Warnings and Precautions (5.2) ] . Interactions with Benzodiazepines and Other CNS Depressants (including Alcohol) Inform patients that potentially fatal additive effects may occur if fentanyl buccal tablet is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.4) , Drug Interactions (7) ] . Addiction, Abuse, and Misuse Inform patients that the use of fentanyl buccal tablet, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.6) ] . Instruct patients not to share fentanyl buccal tablet with others and to take steps to protect fentanyl buccal tablet from theft or misuse. Transmucosal Immediate-Release Fentanyl (TIRF) REMS Fentanyl buccal tablet is available only through a restricted program called the Transmucosal Immediate Release Fentanyl (TIRF) REMS [see Warnings and Precautions (5.7) ] . Inform the patient of the following notable requirements: Outpatients must be enrolled in the REMS program Patients must be opioid-tolerant to receive fentanyl buccal tablet. Fentanyl buccal tablet is available only from certified pharmacies participating in this program. Therefore, provide patients with the telephone number and website for information on how to obtain the product. Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients are required to enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require fentanyl buccal tablet while hospitalized [see Warnings and Precautions (5.7) ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.10) , Drug Interactions (7) ] . MAOI Interaction Inform patients to avoid taking fentanyl buccal tablet while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl buccal tablet [see Warnings and Precautions (5.10) ; Drug Interactions (7) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.11) ] . Important Administration Instructions [see Dosage and Administration (2) ] Instruct patients not to take fentanyl buccal tablet 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 fentanyl buccal tablet 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 fentanyl buccal tablet. 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 FENTANYL BUCCAL TABLET USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of fentanyl buccal tablet for any breakthrough pain episode. Instruct patients that they MUST wait at least 4 hours before treating another episode of breakthrough pain with fentanyl buccal tablet. Instruct patients NOT to share fentanyl buccal tablet and that sharing fentanyl buccal tablet with anyone else could result in the other individual's death due to overdose. Make patients aware that fentanyl buccal tablet contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Instruct patients not to open the blister until ready to use fentanyl buccal tablet 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 fentanyl buccal tablet is not to be swallowed whole; this will reduce the effectiveness of the medication. The tablet is 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 fentanyl buccal tablet. Instruct patients to use fentanyl buccal tablet exactly as prescribed by their doctor and not to take fentanyl buccal tablet more often than prescribed. Provide patients and their caregivers with a Medication Guide each time fentanyl buccal tablet is dispensed because new information may be available. Hypotension Inform patients that fentanyl buccal tablet may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12) ]. Anaphylaxis Inform patients that anaphylaxis have been reported with ingredients contained in fentanyl buccal tablet. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6) ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform patients that prolonged use of fentanyl buccal tablet can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that fentanyl buccal tablet can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ] . Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2) ] . Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3) ]. Driving or Operating Heavy Machinery Inform patients that fentanyl buccal tablet may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16) ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ] .

Patient Instructions for Use Before you use fentanyl buccal tablet, 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 fentanyl buccal tablet the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use fentanyl buccal tablet. When you get an episode of breakthrough cancer pain, use the dose of fentanyl buccal tablet prescribed by your healthcare provider as follows: Fentanyl buccal tablets come packaged as a blister card containing 4 blister units. Each blister unit contains 1 fentanyl buccal tablet. Do not open a blister 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 fentanyl buccal tablets will be printed in the boxed area shown as (See Figure 1 ). Figure 1 Peel back foil on blister unit to expose tablet (See Figure 2 ). 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, fentanyl buccal tablet must be used right away. Use fentanyl buccal tablet whole. Do not crush, split, suck, or chew fentanyl buccal tablet, or swallow the tablet whole. You will get less relief for your breakthrough cancer pain. You can place a fentanyl buccal 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. Figure 3 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 fentanyl buccal tablet generally takes between 14 to 25 minutes to dissolve. After 30 minutes, if there is any fentanyl buccal tablet left in your mouth, you may drink a glass of water to help you swallow the left over medicine. If you cannot use fentanyl buccal tablet in this manner, tell your healthcare provider. Your healthcare provider will tell you what to do. Distributed by: Mayne Pharma Raleigh, NC 27609 call 1-844-825-8500 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 01/2023 400-33-100054.05 Printed in USA Figure Figure 1 Figure 2 Figure 3 Figure 4a Figure 4b Figure 4c Figure 4d

Dispense with Medication Guide available at: products.maynepharma.com Medication Guide Fentanyl Buccal Tablet, CII IMPORTANT: Do not use fentanyl buccal tablet unless you are regularly using another opioid pain medicine around-the-clock for at least one week or longer 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 fentanyl buccal tablets in a safe place away from children. Get emergency help right away if: a child takes fentanyl buccal tablet. Fentanyl buccal tablet can cause an overdose and death in any child who takes it. an adult who has not been prescribed fentanyl buccal tablet uses it. an adult who is not already taking opioids around-the-clock, uses fentanyl buccal tablet. These are medical emergencies that can cause death. If possible, try to remove fentanyl buccal tablet from the mouth. Fentanyl buccal tablet is: A strong prescription pain medicine that contains an opioid (narcotic) that 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. Fentanyl buccal tablet 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 fentanyl buccal tablet if you are not opioid tolerant. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about fentanyl buccal tablet: Get emergency help or call 911 right away if you take too much fentanyl buccal tablet (overdose). When you first start taking fentanyl buccal tablet, when your dose is changed, or if you take too much (overdose), serious life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking fentanyl buccal tablet with other medicines that may make you sleepy, such as other pain medicines, anti-depressants, sleeping pills, anti-anxiety medicines, antihistamines, or tranquilizers, or with alcohol or street drugs can cause severe drowsiness, confusion, breathing problems, coma, and death. Never give anyone else your fentanyl buccal tablets. They could die from taking it. Selling or giving away fentanyl buccal tablets is against the law. Store fentanyl buccal tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. If you stop taking your around-the-clock opioid pain medicine for your cancer pain, you must stop using fentanyl buccal tablet. You may no longer be opioid tolerant. Talk to your healthcare provider about how to treat your pain. Fentanyl buccal tablets are available only through a program called the T ransmucosal I mmediate R elease F entanyl (TIRF) R isk E valuation and M itigation S trategy (REMS). To receive fentanyl buccal tablets, you must: talk to your healthcare provider understand the benefits and risks of fentanyl buccal tablet agree to all of the instructions sign the Patient Enrollment Form Fentanyl buccal tablets are only available at pharmacies that are part of the TIRF REMS. Your healthcare provider can help you locate a pharmacy closest to your home where you can have your fentanyl buccal tablet prescription filled. 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. Do not take fentanyl buccal tablet if: You are not opioid tolerant. Opioid tolerant means that you are already taking other opioid pain medicines around-the-clock for at least one week or longer for your cancer pain, and your body is used to these medicines. You have severe asthma, trouble breathing, or other lung problems. You have a bowel blockage or have narrowing of the stomach or intestines. You are allergic to any of the ingredients in fentanyl buccal tablet . See the end of this Medication Guide for a complete list of ingredients in fentanyl buccal tablet. You have short-term pain that you would expect to go away in a few days, such as: pain after surgery headache or migraine dental pain Before taking fentanyl buccal tablet, tell your healthcare provider if you have a history of: Troubled breathing or lung problems such as asthma, wheezing, or shortness of breath head injury, seizures slow heart rate or other heart problems low blood pressure mental problems [including major depression, schizophrenia or hallucinations (seeing or hearing things that are not there)] problems urinating liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems Tell your healthcare provider if you are: pregnant or planning to become pregnant. Prolonged use of fentanyl buccal tablet during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Fentanyl passes into breast milk and may harm your baby. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl buccal tablet with certain other medicines can cause serious side effects that could lead to death. When taking fentanyl buccal tablet: Do not change your dose. Take fentanyl buccal tablet exactly as prescribed by your healthcare provider. 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 fentanyl buccal tablet. Use fentanyl buccal tablet whole. Do not crush, split, suck, or chew fentanyl buccal tablet, or swallow the tablet whole. You will get less relief for your breakthrough cancer pain. Wait 30 minutes after using fentanyl buccal tablet. If there is any of the fentanyl buccal 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 fentanyl buccal tablet for each episode of breakthrough cancer pain. Use 1 dose of fentanyl buccal tablet for an episode of breakthrough cancer pain. If your breakthrough cancer pain does not get better 30 minutes after taking the first dose of fentanyl buccal tablet, you can use only 1 more dose of fentanyl buccal tablet as instructed by your healthcare provider. If your breakthrough pain does not get better after the second dose of fentanyl buccal tablet, call your healthcare provider for instructions. Do not use another dose of fentanyl buccal tablet at this time. Wait at least 4 hours before treating a new episode of breakthrough cancer pain with fentanyl buccal tablet. If you only need to take 1 dose of fentanyl buccal tablet for an episode of breakthrough pain, you must wait 4 hours from the time of that dose to take a dose of fentanyl buccal tablet for a new episode of breakthrough pain. If you need to use 2 doses of fentanyl buccal tablet for an episode of breakthrough pain, you must wait 4 hours after the second dose to take a dose of fentanyl buccal tablet for a new episode of breakthrough pain. It is important for you to keep taking your around-the-clock opioid pain medicine while using fentanyl buccal tablets. Talk to your healthcare provider if your dose of fentanyl buccal tablets does not relieve your breakthrough cancer pain. Your healthcare provider will decide if your dose of fentanyl buccal tablets 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. Do not stop taking fentanyl buccal tablets 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. After you stop taking, or when fentanyl buccal tablet is no longer needed, see " How should I dispose of unused fentanyl buccal tablets when they are no longer needed? " for proper disposal of fentanyl buccal tablets. Dispose of expired, unwanted, or unused fentanyl buccal tablets by removing the product from the blister cards and promptly flushing down the toilet (if a drug take-back option is not readily available.) Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. DO NOT Drive or operate heavy machinery, until you know how fentanyl buccal tablet affects you. Fentanyl buccal tablet can make you sleepy, dizzy, or lightheaded. DO NOT Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with fentanyl buccal tablet may cause you to overdose and die. DO NOT Switch from fentanyl buccal tablet to other medicines that contain fentanyl without talking with your healthcare provider. The amount of fentanyl in a dose of fentanyl buccal tablet is not the same as the amount of fentanyl in other medicines that contain fentanyl. Your healthcare provider will prescribe a starting dose of fentanyl buccal tablet that may be different than other fentanyl containing medicines you may have been taking. The possible side effects of fentanyl buccal tablet: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, low red blood cell count, swelling of the arms, hands, legs and feet. Call your healthcare provider if you have any of these symptoms and they are severe. Decreased blood pressure. This can make you feel dizzy or lightheaded if you get up too fast from sitting or lying down. 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. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These symptoms can be a sign that you have taken too much fentanyl buccal tablet 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 fentanyl buccal tablet until you have talked to your healthcare provider. These are not all the possible side effects of fentanyl buccal tablet. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov How should I store fentanyl buccal tablets? Always keep fentanyl buccal tablets in a safe place away from children and from anyone for whom it has not been prescribed. Protect fentanyl buccal tablets from theft. Store fentanyl buccal tablets at room temperature, 59°F to 86°F (15° C to 30°C) until ready to use. Do not freeze fentanyl buccal tablets. Keep fentanyl buccal tablets in the original blister unit. Do not remove fentanyl buccal tablets from its blister packaging for storage in a temporary container, such as a pill box. Keep fentanyl buccal tablets dry. How should I dispose of unused fentanyl buccal tablets when they are no longer needed? Dispose of any unused fentanyl buccal tablets remaining from a prescription as soon as they are no longer needed. Remove the tablets from blister packages and flush them down the toilet. Do not flush the fentanyl buccal tablets packaging (card, blister units or cartons) down the toilet. If you need help with disposal of fentanyl buccal tablets, call Teva Pharmaceuticals at 1-888-483-8279 or call your local Drug Enforcement Agency (DEA) office. General information about fentanyl buccal tablet Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Use fentanyl buccal tablet only for the purpose for which it was prescribed. Do not give fentanyl buccal tablet to other people, even if they have the same symptoms you have. Fentanyl buccal tablet can harm other people and even cause death. Sharing fentanyl buccal tablet is against the law. This Medication Guide summarizes the most important information about fentanyl buccal tablet. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information about fentanyl buccal tablet 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 fentanyl buccal tablet? Active Ingredient: fentanyl citrate Inactive Ingredients: mannitol, sodium starch glycolate, sodium bicarbonate, sodium carbonate, citric acid, and magnesium stearate.

14 CLINICAL STUDIES The efficacy of fentanyl buccal tablet 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 fentanyl buccal tablet. 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 fentanyl buccal tablet and 3 being placebo. Patients used one tablet of study drug (either fentanyl buccal tablet 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 (SPID 30 ) was the primary efficacy measure. Sixty-five percent (65%) of patients who entered the study achieved a successful dose during the titration phase. The distribution of successful doses is shown in Table 8. The median dose was 400 mcg. Table 8. Successful Dose of Fentanyl Buccal Tablet Following Initial Titration Fentanyl Buccal Tablet 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) SPID 30 for fentanyl buccal tablet-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 Figure 3

8.5 Geriatric Use Of the 304 patients with cancer in clinical studies of fentanyl buccal tablets, 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 fentanyl buccal tablet in elderly patients to provide adequate efficacy while minimizing risk. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl buccal tablet slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ] . Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.4 Pediatric Use The safety and efficacy of fentanyl buccal tablet have not been established in pediatric patients below the age of 18 years.

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8) ] . Available data with fentanyl buccal tablet in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl buccal tablet is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl buccal tablet, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data 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 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of fentanyl buccal tablet on a mg/m 2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of fentanyl buccal tablet based on a mg/m 2 basis). No evidence of teratogenicity was reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg fentanyl buccal tablet per pain episode on a mg/m 2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean C max observed following administration of 800 mcg dose of fentanyl buccal tablet in humans. 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 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation : Not recommended. ( 8.2 ) Renal and Hepatic Impairment : Administer fentanyl buccal tablet with caution. ( 8.6 ) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.8) ] . Available data with fentanyl buccal tablet in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl buccal tablet is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl buccal tablet, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data 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 7.5-times the exposure of a single human dose of 800 mcg per pain episode, based on an AUC comparison). Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of fentanyl buccal tablet on a mg/m 2 basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of fentanyl buccal tablet based on a mg/m 2 basis). No evidence of teratogenicity was reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg fentanyl buccal tablet per pain episode on a mg/m 2 basis and produced mean steady-state plasma levels that are approximately 5 times higher than the mean C max observed following administration of 800 mcg dose of fentanyl buccal tablet in humans. 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 Lactation Risk Summary Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl buccal tablet. Clinical Considerations Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) Clinical Pharmacology (12.2) , Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and efficacy of fentanyl buccal tablet 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 fentanyl buccal tablets, 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 fentanyl buccal tablet in elderly patients to provide adequate efficacy while minimizing risk. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl buccal tablet slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ] . Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Patients with Renal or Hepatic Impairment Insufficient information exists to make recommendations regarding the use of fentanyl buccal tablet 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 Sex Both male and female opioid tolerant patients with cancer were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in dosage requirement or in observed adverse reactions. 8.8 Race The pharmacokinetic effects of race with the use of fentanyl buccal tablet have not been systematically evaluated. In studies conducted in healthy Japanese subjects, systemic exposure was generally higher than that observed in U.S. subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING Fentanyl buccal tablets are supplied in individually sealed, child-resistant blister packages. Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child-resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with , and the other side of each dosage strength is uniquely identified by the debossing on the tablet as described in the table below. In addition, the dosage strength is indicated on the blister package and the carton. See blister package and carton for product information. Dosage Strength Debossing Carton/Blister Package Color NDC Number 100 mcg 1 Blue NDC 51862-634-28 200 mcg 2 Orange NDC 51862-635-28 400 mcg 4 Sage green NDC 51862-636-28 600 mcg 6 Magenta (pink) NDC 51862-637-28 800 mcg 8 Yellow NDC 51862-638-28 Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing. Figure Storage and Handling 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 fentanyl buccal tablet from freezing and moisture. Do not use if the blister package has been tampered with. Store fentanyl buccal tablet securely and dispose of properly [see Patient Counseling Information (17) ].

Storage and Handling 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 fentanyl buccal tablet from freezing and moisture. Do not use if the blister package has been tampered with. Store fentanyl buccal tablet securely and dispose of properly [see Patient Counseling Information (17) ].

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME See full prescribing information for complete boxed warning . Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. Due to the risk of fatal respiratory depression, fentanyl buccal tablet is contraindicated in opioid non-tolerant patients ( 1 ) and in management of acute or postoperative pain, including headache/migraines. ( 5.1 ) Accidental ingestion of fentanyl buccal tablet, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal. ( 5.2 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl. ( 5.3 , 7 , 12.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.4 , 7 ) When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl product to fentanyl buccal tablet. ( 5.5 ) When dispensing, do not substitute with any other fentanyl products. ( 5.5 ) Fentanyl buccal tablet exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for these behaviors and conditions. ( 5.6 ) Fentanyl buccal tablet is available only through a restricted program called the TIRF REMS. Pharmacies, outpatients, and healthcare professionals who prescribe to outpatients, are required to enroll in the program. Patients must be opioid tolerant to receive a TIRF medicine. ( 5.7 ) Prolonged use of fentanyl buccal tablet during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.8 ) Life-Threatening Respiratory Depression Serious life-threatening and/or fatal respiratory depression has occurred in patients treated with fentanyl buccal tablet, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of fentanyl buccal tablet or following a dose increase. The substitution of fentanyl buccal tablet for any other fentanyl product may result in fatal overdose [see Warnings and Precautions (5.1) ] . Due to the risk of respiratory depression, fentanyl buccal tablet is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [see Contraindications (4) ]. Accidental Ingestion Accidental ingestion of even one dose of fentanyl buccal tablet, especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions (5.2) ]. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. Fentanyl buccal tablet must be kept out of reach of children [see Warnings and Precautions (5.2) ]. Cytochrome P450 3A4 Interaction The concomitant use of fentanyl buccal tablet with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl buccal tablet and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4) , Drug Interactions (7) ] . Reserve concomitant prescribing of fentanyl buccal tablet and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Risk of Medication Errors Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablet compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration (2.1) , Warnings and Precautions (5.5) ]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to fentanyl buccal tablet [see Dosage and Administration (2.1) ]. When dispensing, do not substitute a fentanyl buccal tablet prescription for other fentanyl products. Addiction, Abuse, and Misuse Fentanyl buccal tablet exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing fentanyl buccal tablet, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.6) ]. Risk Evaluation and Mitigation Strategy (REMS) Because of the risk for accidental exposure, misuse, abuse, addiction, and overdose, fentanyl buccal tablets are 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, pharmacies, outpatients, and healthcare professionals who prescribe to outpatients must enroll in the program. Inpatient pharmacies must develop policies and procedures to verify opioid tolerance in inpatients who require fentanyl buccal tablet while hospitalized [see Warnings and Precautions (5.7) ]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483. Neonatal Opioid Withdrawal Syndrome Prolonged use of fentanyl buccal tablet during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.8) ].