FENTANYL CITRATE

Oral Transmucosal Fentanyl Citrate (OTFC) (fentanyl citrate) oral transmucosal lozenge is a solid formulation of fentanyl, an opioid agonist, intended for oral transmucosal administration. OTFC is formulated as a white to off-white solid drug matrix on a handle that is fracture resistant (ABS plastic) under normal conditions when used as directed. OTFC is designed to be dissolved slowly in the mouth to facilitate transmucosal absorption. The handle allows the OTFC unit to be removed from the mouth if signs of excessive opioid effects appear during administration. 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: Inactive Ingredients: Hydrated dextrates, citric acid, dibasic sodium phosphate, artificial berry flavor, magnesium stearate, and edible glue (modified food starch and confectioner’s sugar). chemical-structure

Oral Transmucosal Fentanyl Citrate (OTFC) is indicated for the management of breakthrough pain in cancer patients 16 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 of transdermal fentanyl per hour, 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 when taking OTFC. 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, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program [see Warnings and Precautions ( 5.7 )] . For inpatient administration of OTFC, patient and prescriber enrollment are not required. OTFC is an opioid agonist indicated for the management of breakthrough pain in cancer patients 16 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 of transdermal fentanyl per hour, 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 OTFC. 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. ( 4 ) As a part of the TIRF REMS, OTFC may be dispensed by outpatient pharmacies only to outpatients enrolled in the program. ( 5.7 ) For inpatient administration of OTFC, patient and prescriber enrollment are not required.

Patients must require and use around-the-clock opioids when taking OTFC. ( 1 ) OTFC should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver both when initiating and renewing treatment with OTFC, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose of OTFC: 200 mcg. Prescribe an initial supply of six 200 mcg OTFC units. ( 2.3 ) Individually titrate to a tolerable dose that provides adequate analgesia using single OTFC dosage unit per breakthrough cancer pain episode. ( 2.4 ) No more than two doses can be taken per breakthrough pain episode. ( 2.4 , 2.5 ) Wait at least 4 hours before treating another episode of breakthrough pain with OTFC. ( 2.4 , 2.5 ) Limit consumption to four or fewer units per day once successful dose is found. ( 2.5 ) Periodically reassess patients receiving OTFC to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.5 ) When opioid therapy is no longer required, consider discontinuing OTFC 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 Oral Transmucosal Fentanyl Citrate (OTFC) for outpatients must enroll in the TIRF REMS and comply with the requirements of the REMS to ensure safe use of OTFC [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 )]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OTFC for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OTFC. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. Instruct patients and caregivers to take steps to store OTFC securely and to properly dispose of unused OTFC as soon as no longer needed [see Warnings and Precautions ( 5.1 , 5.3 )]. Other TIRF formulations and OTFC are not equivalent. DO NOT substitute an OTFC prescription for any other TIRF formulation under any circumstances. Do not convert patients on a mcg per mcg basis from any other fentanyl product to OTFC [see Warnings and Precautions ( 5.5 )] . 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose . The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 )]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Individually titrate OTFC to a dose that provides adequate analgesia and minimizes side effects. The initial dose of OTFC to treat episodes of breakthrough cancer pain is always 200 mcg . The OTFC unit should be consumed over 15 minutes. Patients should be prescribed an initial titration supply of six 200 mcg OTFC units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose to prevent confusion and possible overdose. Repeat Dosing In cases where the breakthrough pain episode is not relieved after 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of OTFC for any episode of breakthrough pain. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with OTFC. 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 using a single OTFC dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient’s mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of OTFC over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted. In cases where the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit (30 minutes after the start of the unit), patients may take ONLY ONE additional dose of the same strength for that episode. Thus, patients should take a maximum of two doses of OTFC for any breakthrough pain episode. Patients must wait at least 4 hours before treating another episode of breakthrough pain with OTFC. To reduce the risk of overdosing during titration, patients should have only one strength of OTFC available at any one time. titration-process 2.5 Maintenance Dosing Once titrated to an effective dose, patients should generally use ONLY ONE OTFC unit of the appropriate strength per breakthrough pain episode. On those occasions when the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit, patient 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 OTFC. Once a successful dose has been found (i.e., an average episode is treated with a single unit), patients should limit consumption to four or fewer units per day. Dosage adjustment of OTFC may be required in some patients in order to continue to provide adequate relief of breakthrough pain. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Generally, the OTFC 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 maintenance (around-the-clock) opioid used for persistent pain should be re-evaluated. 2.6 Administration of OTFC Open the blister package with scissors immediately prior to product use. The patient should place the OTFC unit in his or her mouth between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. The OTFC unit should be sucked, not chewed. A unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed [see Clinical Pharmacology ( 12.3 )] . The OTFC unit should be consumed over a 15-minute period. Longer or shorter consumption times may produce less efficacy than reported in OTFC clinical trials. If signs of excessive opioid effects appear before the unit is consumed, remove the drug matrix from the patient’s mouth immediately and decrease future doses. 2.7 Discontinuation of OTFC When opioid therapy is no longer required, consider discontinuing OTFC 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, OTFC therapy can usually be discontinued immediately [see Drug Abuse and Dependence ( 9.3 )]. 2.8 Disposal of OTFC After consumption of the unit is complete and the matrix is totally dissolved, throw away the handle in a trash container that is out of the reach of children. If any of the drug matrix remains on the handle, place the handle under hot running tap water until all of the drug matrix is dissolved, and then dispose of the handle in a place that is out of the reach of children. Dispose of handles in the child-resistant container (as described in steps 1 and 2) at least once a day. If the temporary storage bottle provided as part of the OTFC Child Safety Kit is available, partially consumed units may be stored in the specially provided child-resistant container out of the reach of children until proper disposal is possible. Unopened units remaining from a prescription must be properly disposed as soon as they are no longer needed. To dispose of the unused OTFC units: Remove the OTFC unit from its blister package using scissors, and hold OTFC by its handle over the toilet bowl. Using wire-cutting pliers cut off the drug matrix end so that it falls into the toilet. Dispose of the handle in a place that is out of the reach of children. Repeat steps 1, 2, and 3 for each OTFC unit. Flush the toilet twice after 5 units have been cut and deposited into the toilet. Do not flush the entire OTFC units, OTFC handles, blister packages, or cartons down the toilet. Dispose of the handle where children cannot reach it. In the event that a caregiver requires additional assistance in disposing of excess unusable units that remain in the home after a patient has expired, instruct them to call the toll-free number for Teva Pharmaceuticals (1-888-483-8279) or seek assistance from their local DEA office.

Oral Transmucosal Fentanyl Citrate (OTFC) 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 ( 5.2 )]. Significant respiratory depression [see Warnings and Precautions ( 5.2 )]. 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 ( 5.11 )]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )]. Known hypersensitivity to fentanyl or components of OTFC (e.g., anaphylaxis, hypersensitivity) [see Adverse Reactions ( 6.2 )]. Opioid non-tolerant patients. ( 4 ) Significant respiratory depression. ( 4 ) Management of acute or postoperative pain, including headache/migraine and dental pain. ( 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 OTFC. ( 4 )

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Seizures [see Warnings and Precautions ( 5.16 )] Most common (frequency ≥5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache, dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia. ( 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 Oral Transmucosal Fentanyl Citrate (OTFC) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days. The most serious adverse reactions associated with OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Because the clinical trials of OTFC were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received OTFC for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of OTFC therapy, or cancer-related symptoms. Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system. Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients) Dose Group Percentage of Patients Reporting Event 200- 600 mcg (n=230) 800- 1400 mcg (n=138) 1600 mcg (n=54) >1600 mcg (n=41) Any Dose Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. (n=254) Body As A Whole Asthenia 6 4 0 7 9 Headache 3 4 6 5 6 Accidental Injury 1 1 4 0 2 Digestive Nausea 14 15 11 22 23 Vomiting 7 6 6 15 12 Constipation 1 4 2 0 4 Nervous Dizziness 10 16 6 15 17 Somnolence 9 9 11 20 17 Confusion 1 6 2 0 4 Anxiety 3 0 2 0 3 Abnormal Gait 0 1 4 0 2 Dry Mouth 1 1 2 0 2 Nervousness 1 1 0 0 2 Vasodilatation 2 0 2 0 2 Hallucinations 0 1 2 2 1 Insomnia 0 1 2 0 1 Thinking Abnormal 0 1 2 0 1 Vertigo 1 0 0 0 1 Respiratory Dyspnea 2 3 6 5 4 Skin Pruritus 1 0 0 5 2 Rash 1 1 0 2 2 Sweating 1 1 2 2 2 Special Senses Abnormal Vision 1 0 2 0 2 The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection Digestive: Diarrhea, dyspepsia, flatulence Metabolic and Nutritional: Peripheral edema, dehydration Nervous: Hypesthesia, migraine Respiratory: Pharyngitis, cough increased The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system. Body as a Whole: Bone pain Cardiovascular: Deep thrombophlebitis, hypertension, hypotension Digestive: Anorexia, eructation, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis Hemic and Lymphatic: Anemia, leukopenia Metabolic and Nutritional: Edema, hypercalcemia, weight loss Musculoskeletal: Myalgia, pathological fracture, myasthenia Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased Skin and Appendages: Alopecia, exfoliative dermatitis Special Senses: Taste perversion Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study. Adverse reactions are listed in descending order of frequency within each body system. Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients) Dose Group Percentage of Patients Reporting Event 200- 600 mcg (n=98) 800- 1400 mcg (n=83) 1600 mcg (n=53) >1600 mcg (n=27) Any Dose Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once. (n=152) Body As A Whole Asthenia 25 30 17 15 38 Headache 12 17 13 4 20 Accidental Injury 4 6 4 7 9 Hypertonia 2 2 2 0 3 Digestive Nausea 31 36 25 26 45 Vomiting 21 28 15 7 31 Constipation 14 11 13 4 20 Intestinal Obstruction 0 2 4 0 3 Cardiovascular Hypertension 1 1 0 0 1 Nervous Dizziness 12 10 9 0 16 Anxiety 9 8 8 7 15 Somnolence 8 13 8 7 15 Confusion 2 5 13 7 10 Depression 9 4 2 7 9 Insomnia 5 1 8 4 7 Abnormal Gait 5 1 0 0 4 Dry Mouth 3 1 2 4 4 Nervousness 2 2 0 4 3 Stupor 4 1 0 0 3 Vasodilatation 1 1 4 0 3 Thinking Abnormal 2 1 0 0 2 Abnormal Dreams 1 1 0 0 1 Convulsion 0 1 2 0 1 Myoclonus 0 0 4 0 1 Tremor 0 1 2 0 1 Vertigo 0 0 4 0 1 Respiratory Dyspnea 15 16 8 7 22 Skin Rash 3 5 8 4 8 Sweating 3 2 2 0 4 Pruritus 2 0 2 0 2 Special Senses Abnormal Vision 2 2 0 0 3 Urogenital Urinary Retention 1 2 0 0 2 The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain Cardiovascular: Deep thrombophlebitis, palpitation, vascular disorder Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder, migraine Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased Skin and Appendages: Skin ulcer, alopecia Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, mucous membrane disorder, neck rigidity Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder Hemic and Lymphatic: Bleeding time increased Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma Respiratory : Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration Skin and Appendages : Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash Special Senses : Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of OTFC. 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. Digestive: - Dental decay : Dental decay, including dental caries, tooth loss, and gum line erosion. 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. - Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )] . 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 use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Immune System Disorders: - Anaphylaxis : Anaphylaxis has been reported with ingredients contained in OTFC. General Disorders and Administration Site Conditions: - Application site reactions including irritation, pain, ulcer, and drug withdrawal syndrome. Metabolic and Nutritional Disorders: - Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Gastrointestinal Disorders: - Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.15 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

Table 3 includes clinically significant drug interactions with Oral Transmucosal Fentanyl Citrate (OTFC). Table 3: Clinically Significant Drug Interactions with OTFC Inhibitors of CYP3A4 Clinical Impact: The concomitant use of OTFC 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 OTFC is achieved [see Warnings and Precautions ( 5.6 )] . 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 OTFC until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Evaluate 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 OTFC 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 ( 5.6 )] . 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 OTFC dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC 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 ( 5.2 )]. Intervention: The use of OTFC 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 OTFC and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of OTFC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )]. Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate 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: Evaluate patients for signs of urinary retention or reduced gastric motility when OTFC is used concomitantly with anticholinergic drugs. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid the use of mixed agonist/antagonist or partial agonist analgesics in patients who are already receiving a full opioid agonist analgesic (including OTFC) because they may reduce analgesic effect of OTFC or precipitate withdrawal symptoms. ( 7 )