Fentanyl system

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Accidental Exposure [see Warnings and Precautions ( 5.3 )] Interactions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions ( 5.4 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Serotonin Syndrome [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.13 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.19 )] Seizures [see Warnings and Precautions ( 5.20 )] Withdrawal [see Warnings and Precautions ( 5.21 )] Most common adverse reactions (≥5%) are nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, anorexia, headache, and diarrhea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, call Alvogen, Inc. at 1-866-770-3024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical practice. The safety of fentanyl transdermal system was evaluated in 216 patients who took at least one dose of fentanyl transdermal system in a multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal system. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement. The most common adverse reactions (≥5%) in a double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (≥5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for ≥1% of fentanyl transdermal system-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3 . The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in ≥1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue. Table 3: Adverse Reactions Reported by ≥1% of Fentanyl Transdermal System-Treated Patients and With an Incidence Greater Than Placebo-Treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal System System/Organ Class Adverse Reaction Fentanyl Transdermal System % (N=216) Placebo % (N=200) Cardiac disorders Palpitations 4 1 Ear and labyrinth disorders Vertigo 2 1 Gastrointestinal disorders Nausea 41 17 Vomiting 26 3 Constipation 9 1 Abdominal pain upper 3 2 Dry mouth 2 0 General disorders and administration site conditions Fatigue 6 3 Feeling cold 6 2 Malaise 4 1 Asthenia 2 0 Edema peripheral 1 1 Metabolism and nutrition disorders Anorexia 5 0 Musculoskeletal and connective tissue disorders Muscle spasms 4 2 Nervous system disorders Somnolence 19 3 Dizziness 10 4 Psychiatric disorders Insomnia 10 7 Depression 1 0 Skin and subcutaneous tissue disorders Hyperhidrosis 6 1 Pruritus 3 2 Rash 2 1 Adverse reactions not reported in Table 3 that were reported by ≥1% of fentanyl transdermal system-treated adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of fentanyl transdermal system used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4 . Table 4: Adverse Reactions Reported by ≥1% of Fentanyl Transdermal System-Treated Patients in 11 Clinical Trials of Fentanyl Transdermal System System/Organ Class Adverse Reaction Fentanyl Transdermal System % (N=1854) Gastrointestinal disorders Diarrhea 10 Abdominal pain 3 Immune system disorders Hypersensitivity 1 Nervous system disorders Headache 12 Tremor 3 Paresthesia 2 Psychiatric disorders Anxiety 3 Confusional state 2 Hallucination 1 Renal and urinary disorders Urinary retention 1 Skin and subcutaneous tissue disorders Erythema 1 The following adverse reactions occurred in adult and pediatric patients with an overall frequency of <1% and are listed in descending frequency within each System/Organ Class: Cardiac disorders : cyanosis Eye disorders : miosis Gastrointestinal disorders : subileus General disorders and administration site conditions : application site reaction, influenza-like illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis Musculoskeletal and connective tissue disorders : muscle twitching Nervous system disorders : hypoesthesia Psychiatric disorders : disorientation, euphoric mood Reproductive system and breast disorders : erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders : respiratory depression Skin and subcutaneous tissue disorders : eczema, dermatitis allergic, dermatitis contact Pediatrics The safety of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥1% of fentanyl transdermal system-treated pediatric patients are shown in Table 5 . Table 5: Adverse Reactions Reported by ≥1% of Fentanyl Transdermal System-Treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal System System/Organ Class Adverse Reaction Fentanyl Transdermal System % (N=289) Gastrointestinal disorders Vomiting 34 Nausea 24 Constipation 13 Diarrhea 13 Abdominal pain 9 Abdominal pain upper 4 Dry mouth 2 General disorders and administration site conditions Edema peripheral 5 Fatigue 2 Application site reaction 1 Asthenia 1 Immune system disorders Hypersensitivity 3 Metabolism and nutrition disorders Anorexia 4 Musculoskeletal and connective tissue disorders Muscle spasms 2 Nervous system disorders Headache 16 Somnolence 5 Dizziness 2 Tremor 2 Hypoesthesia 1 Psychiatric disorders Insomnia 6 Anxiety 4 Depression 2 Hallucination 2 Renal and urinary disorders Urinary retention 3 Respiratory, thoracic and mediastinal disorders Respiratory depression 1 Skin and subcutaneous tissue disorders Pruritus 13 Rash 6 Hyperhidrosis 3 Erythema 3 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of fentanyl transdermal system. 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. Cardiac Disorders : tachycardia, bradycardia Eye Disorders : vision blurred Gastrointestinal Disorders : ileus, dyspepsia General Disorders and Administration Site Conditions : pyrexia, application site erosion and application site ulcer Investigations : weight decreased Nervous System Disorders : convulsions (including clonic convulsions and grand mal convulsion), amnesia, depressed level of consciousness, loss of consciousness Psychiatric Disorders : agitation Respiratory, Thoracic, and Mediastinal Disorders : respiratory distress, apnea, bradypnea, hypoventilation, dyspnea Vascular Disorders : hypotension, hypertension Serotonin syndrome : cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Androgen deficiency : cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology ( 12.2 ) ] Hyperalgesia and Allodynia : cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.10 ) ]

4 CONTRAINDICATIONS Fentanyl transdermal system is contraindicated in: patients who are not opioid-tolerant. the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time. the management of post-operative pain, including use after outpatient or day surgeries, (e.g., tonsillectomies). the management of mild pain. patients with significant respiratory depression [see Warnings and Precautions ( 5.12 ) ]. patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.12 ) ]. patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.19 ) ]. patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system [see Adverse Reactions ( 6.2 ) ]. Opioid non-tolerant patients. ( 4 ) Acute or intermittent pain, postoperative pain, mild 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 any of the components of the transdermal system. ( 4 )

11 DESCRIPTION The system contains fentanyl, an opioid agonist, for transdermal administration. The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per 9.44 cm 2 ). The composition per unit area of all transdermal system sizes is identical. * Nominal delivery rate is 12.5 mcg/hour per hour ** Nominal delivery rate per hour Strength (mcg/hour) Size (cm²) Fentanyl Content (mg) 12* 4.72 1.33 25** 9.44 2.66 50** 18.88 5.32 75** 28.32 7.99 100** 37.76 10.65 The molecular weight of fentanyl base is 336.5, and the molecular formula is C 22 H 28 N 2 O. The n-octanol: water partition coefficient is 860:1. The pKa is 8.4. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is: Fentanyl transdermal system is a rectangular translucent system with rounded corners. The product name, “FENTANYL” and dosage strength are printed in green on each system. Each system is comprised of a clear fluoropolymer coated polyethylene terephthalate (PET) release liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these functional layers are: 1) a translucent backing layer of ethylene vinyl acetate/polyethylene terephthalate (EVA/PET) film with green print; 2) a drug-in-adhesive layer containing fentanyl. Before use, a clear fluoropolymer coated PET release liner covering the drug-in-adhesive layer is removed and discarded. Structural Formula Parts of the Fentanyl Transdermal System Patch

2 DOSAGE AND ADMINISTRATION Fentanyl transdermal system should be prescribed only by healthcare providers who are knowledgeable about the use of extended-release/long-acting 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. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of fentanyl transdermal system 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, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with fentanyl transdermal system. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) 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 transdermal system. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose selection: consult conversion instructions. ( 2.3 ) Each transdermal system is intended to be worn for 72 hours. ( 2.3 ) Adhere to instructions concerning administration and disposal of fentanyl transdermal system. ( 2.7 , 2.8 ) Mild to moderate hepatic and renal impairment: Initiate treatment with one half the usual starting dose, titrate slowly, and regularly evaluate for signs of respiratory and central nervous system depression. ( 2.5 , 2.6 ) Do not abruptly discontinue fentanyl transdermal system in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.9 ) 2.1 Important Dosage and Administration Instructions Fentanyl transdermal system should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid [see Indications and Usage ( 1 ) ]. Use the lowest effective dosage for the shortest duration of time 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 fentanyl transdermal system 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. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, 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 fentanyl transdermal system. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 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 transdermal system [see Warnings and Precautions ( 5.2 ), 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. However, 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 , 5.2 , 5.4 ) ]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. 2.3 Initial Dosage Do not initiate treatment with fentanyl transdermal system in opioid nontolerant patients [see Contraindications ( 4 ) ]. The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose. When fentanyl transdermal system therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed bases for breakthrough pain when appropriate. While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient's 24-hour fentanyl requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which could result in adverse reactions. In a fentanyl transdermal system clinical trial, patients were converted from their prior opioid to fentanyl transdermal system using Table 1 as a guide for the initial fentanyl transdermal system dose. Each fentanyl transdermal system is worn continuously for up to 72 hours [see Dosage and Administration ( 2.7 ) ]. When converting patients from oral or parenteral opioids to fentanyl transdermal system, use Table 1 (alternatively use Table 2 for adult and pediatric patients taking opioids or doses not listed in Table 1 ) and consider the following: These are not tables of equianalgesic doses. The conversion doses in these tables are only for the conversion from one of the listed oral or parenteral opioid analgesics to fentanyl transdermal system. The tables cannot be used to convert from fentanyl transdermal system to another opioid because these conversions will result in an overestimation of the dose of the new opioid (these conversions are conservative) and may result in fatal overdosage. Table 1 1 : Dose Conversion from Other Opioids to Fentanyl Transdermal System 1 Table 1 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration ( 2.9 ) ]. Current Analgesic Daily Dosage (mg/day) Oral morphine 60-134 135-224 225-314 315-404 Intramuscular or Intravenous morphine 10-22 23-37 38-52 53-67 Oral oxycodone 30-67 67.5-112 112.5-157 157.5-202 Oral codeine 150-447 Oral hydromorphone 8-17 17.1-28 28.1-39 39.1-51 Intravenous hydromorphone 1.5-3.4 3.5-5.6 5.7-7.9 8-10 Intramuscular meperidine 75-165 166-278 279-390 391-503 Oral methadone 20-44 45-74 75-104 105-134 ⇓ ⇓ ⇓ ⇓ Recommended fentanyl transdermal system dose 25 mcg/hour 50 mcg/hour 75 mcg/hour 100 mcg/hour Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1 , use the following methodology when converting patients from oral or parenteral opioids to fentanyl transdermal system: Calculate the previous 24-hour analgesic requirement. Convert this amount to the equianalgesic oral morphine dose using a reliable reference. Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding recommended initial fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained. A 37.5 mcg/hour dose may also be used. For patients that require more than 100 mcg/hour, several transdermal systems may be used. Do not use Table 2 to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent. Table 2 1 : Recommended Initial Fentanyl Transdermal System Dose based upon Daily Oral Morphine Dose NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal system. 1 Table 2 should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration ( 2.9 ) ]. Oral 24 - hour Morphine (mg/day) Fentanyl Transdermal System Dose (mcg/hour) 60-134 25 135-224 50 225-314 75 315-404 100 405-494 125 495-584 150 585-674 175 675-764 200 765-854 225 855-944 250 945-1034 275 1035-1124 300 An additional intermediate strength 37.5 mcg/hour fentanyl transdermal system is available and may be considered during conversion from prior opioids or dose titration. For example, the 37.5 mcg/hour system could be used before converting or titrating to a 50 mcg/hour system. The additional 37.5 mcg/hour system was not used in the clinical studies. For delivery rates in excess of 100 mcg/hour, multiple systems may be used. 2.4 Titration and Maintenance of Therapy Individually titrate fentanyl transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal system to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 ) ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics. Patients who experience breakthrough pain may require a dosage adjustment of fentanyl transdermal system, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the fentanyl transdermal system dosage. The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl transdermal system dose for the first time until at least 3 days after the initial application. Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application. It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose [see Clinical Pharmacology ( 12.3 ) ]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made. Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal system dose. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. A small proportion of adult patients may not achieve adequate analgesia using a 72-hour dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen. Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended. 2.5 Dosage Modifications in Patients with Hepatic Impairment Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions ( 5.17 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. 2.6 Dosage Modifications in Patients with Renal Impairment Avoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions ( 5.18 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 ) ]. 2.7 Administration of Fentanyl Transdermal System FENTANYL TRANSDERMAL SYSTEM PATCHES ARE FOR TRANSDERMAL USE ONLY. Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions ( 5.3 ) ]. Application and Handling Instructions Patients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application. Patients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged. The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. Each fentanyl transdermal system patch may be worn continuously for 72 hours. The next patch is applied to a different skin site after removal of the previous transdermal system. If problems with adhesion of the fentanyl transdermal system patch occur, the edges of the patch may be taped with first-aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing. If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site. Patients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system. Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of a fentanyl transdermal system patch from an adult's body to a child while hugging, sharing the same bed as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver's skin to the medication in the patch while applying or removing the patch. Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed. Avoidance of Heat Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions ( 5.8 ) ]. 2.8 Disposal Instructions Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures and deaths, including deaths of children [see Warnings and Precautions ( 5.3 ) ]. Instruct patients to dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet. Instruct patients to remove unused patches from their pouches, remove the release liners, fold the patches so that the adhesive side of the patch adheres to itself, and to immediately flush the patches down the toilet. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed. 2.9 Safe Reduction or Discontinuation of Fentanyl Transdermal System Do not abruptly discontinue fentanyl transdermal system in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking fentanyl transdermal system, there are a variety of factors that should be considered, including the dose of fentanyl transdermal system the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on fentanyl transdermal system who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.21 ), Drug Abuse and Dependence ( 9.3 ) ].

1 INDICATIONS AND USAGE Fentanyl transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60 mg morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration , and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions ( 5.1 ) ], reserve fentanyl transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Fentanyl transdermal system is not indicated as an as-needed (prn) analgesic. Fentanyl transdermal system, an opioid agonist, is indicated for the management of severe and persistent pain that requires an extended treatment period with daily opioid analgesic and for which alternative treatment options are inadequate. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. ( 2.1 ) Limitations of use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, [see Warnings and Precautions ( 5.1 ) ] , reserve fentanyl transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Fentanyl transdermal system is not indicated as an as-needed (prn) analgesic.

9.2 Abuse Fentanyl transdermal system contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 ) ]. Misuse is the intentional use, for the therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing use despite harmful consequences, giving a higher priority given to drug use than to other activities and obligations), and possible tolerance, or physical dependence. Misuse and abuse of fentanyl transdermal system increases risk of overdosage, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl transdermal system abuse include those with a history of prolonged use of products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl transdermal system in combination with other abused drugs. “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 healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may 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 transdermal system, 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 reevaluation 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 Transdermal System Fentanyl transdermal system is intended for transdermal use only. Abuse of fentanyl transdermal system poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants [see Warnings and Precautions ( 5.4 ), and Drug Interactions ( 7 ) ]. Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1 ) ]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system.

9.1 Controlled Substance Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), 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 use. Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids. Rapid tapering of fentanyl transdermal system in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing fentanyl transdermal system, gradually taper the dosage using a patient-specific plan that considers the following: the dose of fentanyl transdermal system the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.9 ), and Warnings and Precautions ( 5.21 ) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations ( 8.1 ) ].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance. 9.2 Abuse Fentanyl transdermal system contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 ) ]. Misuse is the intentional use, for the therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing use despite harmful consequences, giving a higher priority given to drug use than to other activities and obligations), and possible tolerance, or physical dependence. Misuse and abuse of fentanyl transdermal system increases risk of overdosage, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl transdermal system abuse include those with a history of prolonged use of products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl transdermal system in combination with other abused drugs. “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 healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may 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 transdermal system, 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 reevaluation 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 Transdermal System Fentanyl transdermal system is intended for transdermal use only. Abuse of fentanyl transdermal system poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants [see Warnings and Precautions ( 5.4 ), and Drug Interactions ( 7 ) ]. Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1 ) ]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), 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 use. Do not abruptly discontinue fentanyl transdermal system in a patient physically dependent on opioids. Rapid tapering of fentanyl transdermal system in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing fentanyl transdermal system, gradually taper the dosage using a patient-specific plan that considers the following: the dose of fentanyl transdermal system the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.9 ), and Warnings and Precautions ( 5.21 ) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations ( 8.1 ) ].

10 OVERDOSAGE Clinical Presentation Acute overdose with fentanyl transdermal system 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 Give primary attention to the reestablishment of a patent 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. Once stable, examine the patient and ensure that all fentanyl transdermal systems have been removed. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid 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 transdermal system, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose. 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 initiated with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Table 6 includes clinically significant drug interactions with fentanyl transdermal system. Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal System Inhibitors of CYP3A4 Clinical Impact: The concomitant use of fentanyl transdermal system 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 transdermal system is achieved [see Warnings and Precautions ( 5.7 ) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system 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 transdermal system 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 fentanyl transdermal system dosage until stable drug effects are achieved. Assess 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 transdermal system 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 ( 5.7 ) ]. 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 transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system 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, can increase the risk of hypotension, 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, educate them on the signs and symptoms of respiratory depression (including 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 , 5.2 , 5.4 ) ]. 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 ( 5.11 ) ]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system 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 ( 5.11 ) ] or opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of fentanyl transdermal system 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 transdermal system and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression that may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system 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 ( 5.2 , 5.4 ) ]. 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 fentanyl transdermal system is used concomitantly with anticholinergic drugs. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with fentanyl transdermal system because they may reduce analgesic effect of fentanyl transdermal system or precipitate withdrawal symptoms. ( 5.21 , 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues. 12.2 Pharmacodynamics Effects on the Central Nervous System 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 respiratory centers to both increases in carbon dioxide tension and 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO 2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive postoperative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system. Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy. 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 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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of 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, sweating, and/or orthostatic hypotension. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. 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 , 2.4 ) ]. 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 ) ]. 12.3 Pharmacokinetics Absorption Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin, drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin. While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 7 ). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 1 ). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%. Table 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of Fentanyl Transdermal System * C max values dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers ** C max values: Study C-2002-048 dose proportionality study in healthy volunteers NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours. Mean (SD) Time to Maximal Concentration T max (h) Mean (SD) Maximal Concentration C max (ng/mL) Fentanyl Transdermal System 12 mcg/hour 28.8 (13.7) 0.38 (0.13) * Fentanyl Transdermal System 25 mcg/hour 31.7 (16.5) 0.85 (0.26) ** Fentanyl Transdermal System 50 mcg/hour 32.8 (15.6) 1.72 (0.53) ** Fentanyl Transdermal System 75 mcg/hour 35.8 (14.1) 2.32 (0.86) ** Fentanyl Transdermal System 100 mcg/hour 29.9 (13.3) 3.36 (1.28) ** Figure 1: Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/h Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl in Patients + Estimated NOTE: Information on volume of distribution and half-life not available for renally impaired patients. Clearance (L/h) Range [70 kg] Volume of Distribution Vss (L/kg) Range Half-Life t 1/2 (h) Range Surgical Patients 27-75 3-8 3-12 Hepatically Impaired Patients 3-80 + 0.8-8 + 4-12 + Renally Impaired Patients 30-78 - - Figure 1 Distribution Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8). Elimination Metabolism Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. Excretion Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13% and 21%. Specific Populations Age: Geriatric Population Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single fentanyl transdermal system 100 mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean C max and AUC ∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC ∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions ( 5.12 ) and Use in Specific Populations ( 8.5 ) ]. Age: Pediatric Population In 1.5 to 5-year-old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration ( 2.3 ) ]. Hepatic Impairment Information on the effect of hepatic impairment on the pharmacokinetics fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C max and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.17 ) and Use in Specific Populations ( 8.6 ) ]. Renal Impairment Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.18 ) and Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies CYP3A4 Inhibitors Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in 11 healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg three times a day on Day 1 and 300 mg three times a day on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC 0-∞ . The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions ( 5.7 ), and Drug Interactions ( 7 ) ]. CYP3A4 Inducers Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.

12.1 Mechanism of Action Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

12.2 Pharmacodynamics Effects on the Central Nervous System 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 respiratory centers to both increases in carbon dioxide tension and 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO 2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive postoperative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system. Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy. 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 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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of 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, sweating, and/or orthostatic hypotension. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. 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 , 2.4 ) ]. 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 ) ].

12.3 Pharmacokinetics Absorption Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin, drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin. While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 7 ). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 1 ). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%. Table 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of Fentanyl Transdermal System * C max values dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers ** C max values: Study C-2002-048 dose proportionality study in healthy volunteers NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours. Mean (SD) Time to Maximal Concentration T max (h) Mean (SD) Maximal Concentration C max (ng/mL) Fentanyl Transdermal System 12 mcg/hour 28.8 (13.7) 0.38 (0.13) * Fentanyl Transdermal System 25 mcg/hour 31.7 (16.5) 0.85 (0.26) ** Fentanyl Transdermal System 50 mcg/hour 32.8 (15.6) 1.72 (0.53) ** Fentanyl Transdermal System 75 mcg/hour 35.8 (14.1) 2.32 (0.86) ** Fentanyl Transdermal System 100 mcg/hour 29.9 (13.3) 3.36 (1.28) ** Figure 1: Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/h Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl in Patients + Estimated NOTE: Information on volume of distribution and half-life not available for renally impaired patients. Clearance (L/h) Range [70 kg] Volume of Distribution Vss (L/kg) Range Half-Life t 1/2 (h) Range Surgical Patients 27-75 3-8 3-12 Hepatically Impaired Patients 3-80 + 0.8-8 + 4-12 + Renally Impaired Patients 30-78 - - Figure 1 Distribution Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8). Elimination Metabolism Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. Excretion Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13% and 21%. Specific Populations Age: Geriatric Population Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single fentanyl transdermal system 100 mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean C max and AUC ∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC ∞ was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions ( 5.12 ) and Use in Specific Populations ( 8.5 ) ]. Age: Pediatric Population In 1.5 to 5-year-old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration ( 2.3 ) ]. Hepatic Impairment Information on the effect of hepatic impairment on the pharmacokinetics fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C max and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.17 ) and Use in Specific Populations ( 8.6 ) ]. Renal Impairment Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.18 ) and Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies CYP3A4 Inhibitors Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in 11 healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg three times a day on Day 1 and 300 mg three times a day on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%-420%) increase in fentanyl AUC 0-∞ . The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions ( 5.7 ), and Drug Interactions ( 7 ) ]. CYP3A4 Inducers Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.

20230606

21

3 DOSAGE FORMS AND STRENGTHS Transdermal system: Fentanyl Transdermal System 12 mcg/hour* Transdermal System (system size 4.72 cm 2 ) Fentanyl Transdermal System 25 mcg/hour Transdermal System (system size 9.44 cm 2 ) Fentanyl Transdermal System 50 mcg/hour Transdermal System (system size 18.88 cm 2 ) Fentanyl Transdermal System 75 mcg/hour Transdermal System (system size 28.32 cm 2 ) Fentanyl Transdermal System 100 mcg/hour Transdermal System (system size 37.76 cm 2 ) This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems. Transdermal system : 12 mcg/hour, 25 mcg/hour, 50 mcg/hour, 75 mcg/hour, 100 mcg/hour. ( 3 )

Fentanyl system Fentanyl METHYL LAURATE FENTANYL FENTANYL Fentanyl system Fentanyl METHYL LAURATE FENTANYL FENTANYL Fentanyl system Fentanyl METHYL LAURATE FENTANYL FENTANYL Fentanyl system Fentanyl METHYL LAURATE FENTANYL FENTANYL Fentanyl system Fentanyl METHYL LAURATE FENTANYL FENTANYL

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC 0-24h comparison). Mutagenesis There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays. Impairment of Fertility The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.

ANDA202097

Fentanyl system

Fentanyl

47781-427

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

Principal Display Panel - 12 mcg/h Patch Carton 12 mcg/h NDC 47781- 423 -47 FENTANYL Transdermal System CII In vivo delivery of 12 mcg/h fentanyl for 72 hours Because serious or life-threatening breathing problems could result, DO NOT USE FENTANYL TRANSDERMAL SYSTEM: for pain that can be treated with immediate-release opioids or non-opioid analgesics for intermittent (on an as-needed basis) pain for any postoperative pain unless you are opioid tolerant (have been using other narcotic opioid medicines) Each transdermal system contains: 1.33 mg fentanyl DO NOT USE IF SEAL ON POUCH IS BROKEN KEEP OUT OF REACH OF CHILDREN Read enclosed Medication Guide for important safety information. Rx Only Alvogen ® five (12 mcg/h) systems For Opioid-Tolerant Patients Only Principal Display Panel - 12 mcg/h Patch Carton

Indications and Usage ( 1 ) 05/2023 Dosage and Administration ( 2.1 , 2.3 ) 05/2023 Warnings and Precautions ( 5.10 ) 05/2023

13 NON-CLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC 0-24h comparison). Mutagenesis There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays. Impairment of Fertility The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl transdermal system 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 , 5.3 ), Drug Abuse and Dependence ( 9.2 ) ]. Inform patients that leaving fentanyl transdermal system 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 transdermal system should be disposed of by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [see Instructions for Use ]. Inform patients that they can visit www.fda.gov/drugsdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 ) ]. Instruct patients not to share fentanyl transdermal system with others and to take steps to protect fentanyl transdermal system from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl transdermal system 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 ( 5.2 ) ]. Accidental Exposure Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3 ) ]. Fentanyl transdermal system can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children. Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if fentanyl transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 ) ]. 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 transdermal system. 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 ( 5.2 ) ]. 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. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.10 ), Postmarketing Experience ( 6.2 ) ]. 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 and signs 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 ( 5.11 ) and Drug Interactions ( 7 ) ]. MAOI Interaction Inform patients to avoid taking fentanyl transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl transdermal system [see Drug Interactions ( 7 )] . Important Administration Instructions Advise patients never to change the dose of fentanyl transdermal system or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional. Warnings About Heat Warn patients of the potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl. Instruct patients to contact their healthcare provider if they develop a high fever. Instruct patients to: avoid strenuous exertion that can increase body temperature while wearing the patch. avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources including heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.9 ) ]. Driving or Operating Heavy Machinery Inform patients that fentanyl transdermal system 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 ( 5.22 ) ]. 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 ) ]. 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 ( 5.13 ) ]. Hypotension Inform patients that fentanyl transdermal system 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 ( 5.14 ) ]. Anaphylaxis Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. 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 female patients of reproductive potential that prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 ) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that fentanyl transdermal system can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations ( 8.1 ) ]. Lactation Advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system [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 ) ]. Manufactured by: Kindeva Drug Delivery L.P. Northridge, CA 91324 USA Distributed by: Alvogen, Inc. Pine Brook, NJ 07058 USA Revised: 05/2023 3200000610

Instructions for Use Fentanyl (fen' ta nil) Transdermal System CII Be sure that you read, understand, and follow these Instructions for Use before you apply fentanyl transdermal system (patch). Talk to your healthcare provider or pharmacist if you have any questions. Important information about the fentanyl transdermal system (patch) appearance: Fentanyl transdermal system is a rectangular, see-through patch with rounded corners. Fentanyl transdermal system comes in 5 different dosage strengths and sizes: 12 mcg/hour 25 mcg/hour 50 mcg/hour 75 mcg/hour 100 mcg/hour The product name, “FENTANYL”, and dosage strength are printed in green on each patch. Parts of the Fentanyl Transdermal System patch: BEFORE APPLYING FENTANYL TRANSDERMAL SYSTEM Each fentanyl transdermal system patch is sealed in its own protective pouch. Do not remove a fentanyl transdermal system patch from the pouch until you are ready to use it. Do not use a fentanyl transdermal system patch if the pouch seal is broken or the patch is cut, damaged or changed in any way. Fentanyl transdermal system patches are available in 5 different dosage strengths and patch sizes. Make sure you have the right dose patch or patches that have been prescribed for you. APPLYING A FENTANYL TRANSDERMAL PATCH Skin areas where the fentanyl transdermal system patch may be applied: For adults: Put the patch on the chest, back, flank (sides of the waist), or upper arm in a place where there is no hair (See Figures A-D ). For children (and adults with mental impairment): Put the patch on the upper back (See Figure B ). This will lower the chances that the child will remove the patch and put it in their mouth. For adults and children Do not put a fentanyl transdermal system patch on skin that is very oily, burned, broken out, cut, irritated, or damaged in any way. Avoid sensitive areas or those that move around a lot. If there is hair, do not shave (shaving irritates the skin). Instead, clip hair as close to the skin as possible (See Figure E ). Talk to your healthcare provider if you have questions about skin application sites. Figure A Figure B Figure C Figure D Figure E Prepare to apply a fentanyl transdermal system patch: Choose the time of day that is best for you to apply fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider. Do not wear more than one fentanyl transdermal system patch at a time unless your healthcare provider tells you to do so. Before applying a new fentanyl transdermal system patch, remove the patch you have been wearing. Clean the skin area with clear water only. Pat skin completely dry . Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied. Open the pouch: Fold and tear at slit, or cut at slit taking care not to cut the patch. Remove the fentanyl transdermal system patch. Each fentanyl transdermal system patch is sealed in its own protective pouch. Do not remove the fentanyl transdermal system patch from the pouch until you are ready to use it (See Figure F ). Peel: Peel off both parts of the release liner from the patch. Each fentanyl transdermal system patch has a clear plastic release liner that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this release liner off and throw the pieces away. Touch the sticky side of the fentanyl transdermal system patch as little as possible (See Figure G ). Figure F Figure G Press: Press the patch onto the chosen skin site with the palm of your hand and hold there for at least 30 seconds (See Figure H ). Make sure it sticks well, especially at the edges. Fentanyl transdermal system may not stick to all people. You need to check the patch often to make sure that they are sticking well to the skin. If the patch falls off right away after applying, throw it away and put a new one on at a different skin site. See the section below called “ Disposing of a fentanyl transdermal system patch. ” If you have a problem with the patch not sticking Apply first-aid tape only to the edges of the patch. If you continue to have problems with the patch not sticking, you may cover the patch with a transparent adhesive film dressing such as Bioclusive™ or Tegaderm™. These are special see-through adhesive dressings. Never cover a fentanyl transdermal system patch with any other bandage or tape. Remove the backing from the Bioclusive™ or Tegaderm™ dressing and place it carefully over the fentanyl transdermal system patch, smoothing it over the patch and your skin. If your patch falls off before 3 days (72 hours) of use, dispose of (throw away) properly. See the section below “ Disposing of a fentanyl transdermal system patch. ” Apply a new fentanyl transdermal system patch on at a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider). Wash your hands when you have finished applying a fentanyl transdermal system patch. Remove a fentanyl transdermal system patch after wearing it for 3 days (72 hours). Dispose of the used patch right away. See the section below “ Disposing of a fentanyl transdermal system patch. ” Choose a different skin site to apply a new fentanyl transdermal system patch. Repeat Steps 2 through 6 above when applying a new fentanyl transdermal system patch. Do not apply the new patch to the same place as the last one. WATER AND FENTANYL TRANSDERMAL SYSTEM You can bathe, swim or shower while you are wearing a fentanyl transdermal system patch. If the patch falls off before 3 days (72 hours) after application, dispose of properly. See the section below “ Disposing of a fentanyl transdermal system patch. ” Apply a new fentanyl transdermal system patch on a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider). DISPOSING OF A FENTANYL TRANSDERMAL SYSTEM PATCH Fold the used fentanyl transdermal system patch in half so that the sticky side sticks to itself (See Figure I ). Flush the used fentanyl transdermal system patch down the toilet right away (See Figure J ). A used fentanyl transdermal system patch can be very dangerous for or lead to death in babies, children, pets, and adults who have not been prescribed fentanyl transdermal system. Throw away any fentanyl transdermal system patches that are left over from your prescription as soon as they are no longer needed. Remove the leftover patches from their protective pouch and remove the release liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet. Do not flush the pouch or the release liner down the toilet. These items can be thrown away in a trash can. Figure H Figure I Figure J This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Kindeva Drug Delivery L.P. Northridge, CA 91324 Distributed by: Alvogen, Inc. Pine Brook, NJ 07058 USA Revised: 05/2023 Bioclusive™ is a trademark of Ethicon, Inc. Tegaderm™ is a trademark of 3M Parts of the Fentanyl Transdermal System Patch Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2023 Medication Guide Fentanyl (fen' ta nil) Transdermal System, CII Fentanyl Transdermal System is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine, in people who are already regularly using opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them. A long-acting (extended-release) 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. Not to be used on an “as needed” basis. Important information about Fentanyl Transdermal System: Get emergency help or call 911 right away if you use too much fentanyl transdermal system (overdose) . When you first start taking fentanyl transdermal system, when your dose is changed, or if you take too much (overdose), serious or 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 transdermal system with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) may cause severe drowsiness, decreased awareness, breathing difficulties, with slow or shallow breathing, coma, and death. Never give anyone else your fentanyl transdermal system. They could die from taking it. Selling or giving away fentanyl transdermal system is against the law. Store fentanyl transdermal system, securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems. Dispose of expired, unwanted, or unused fentanyl transdermal system, by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [see Instructions for Use ]. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Do not use Fentanyl Transdermal System if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. Before applying Fentanyl Transdermal System, tell your healthcare provider if you have a history of: head injury, seizures 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: have a fever are pregnant or planning to become pregnant. Use of fentanyl transdermal system for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. are breastfeeding. Not recommended during treatment with fentanyl transdermal system. It may harm your baby. are living in a household where there are small children or someone who has abused street or prescription drugs. are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl transdermal system with certain other medicines can cause serious side effects that could lead to death. notice your pain getting worse. If your pain gets worse after you use fentanyl transdermal system, do not use more of fentanyl transdermal system without first talking to your doctor. Talk to your doctor if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after using fentanyl transdermal system. When using Fentanyl Transdermal System: Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system patch. Do not apply more than 1 patch at the same time unless your healthcare provider tells you to. You should wear the fentanyl transdermal system patch continuously for 3 days, unless advised otherwise by your healthcare provider. Do not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die. Call your healthcare provider if the dose you are using does not control your pain. Do not stop using fentanyl transdermal system without talking to your healthcare provider. While using Fentanyl Transdermal System DO NOT: Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated water beds, or tanning lamps, or engage in exercise that increases your body temperature. These can cause an overdose that can lead to death. Drive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with fentanyl transdermal system may cause you to overdose and die. The possible side effects of Fentanyl Transdermal System are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, itching, redness, or rash where the patch is applied. Call your healthcare provider if you have any of these symptoms and they are severe. 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 are not all the possible side effects of fentanyl transdermal system. 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. Manufactured by: Kindeva Drug Delivery L.P., Northridge, CA 91324 USA; Distributed by: Alvogen, Inc., Pine Brook, NJ 07058 USA, www.Alvogen.com or call Alvogen, Inc. at 1-866-770-3024.

14 CLINICAL STUDIES Fentanyl transdermal system as therapy for pain due to cancer has been studied in 153 patients. In this patient population, fentanyl transdermal system has been administered in doses of 25 mcg/h to 600 mcg/h. Individual patients have used fentanyl transdermal system continuously for up to 866 days. At one month after initiation of fentanyl transdermal system therapy, patients generally reported lower pain intensity scores as compared to a pre-study analgesic regimen of oral morphine. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year. In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 289 patients with chronic pain 2-18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤15 days; 46% for 16-30 days; 16% for 31-60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.

8.5 Geriatric Use Clinical studies of fentanyl transdermal system did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology ( 12.3 ) ]. 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 transdermal system slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12 ) ]. 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 of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. The safety and effectiveness of fentanyl transdermal system in children under 2 years of age have not been established. To guard against excessive exposure to fentanyl transdermal system by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal system application and disposal instructions [see Dosage and Administration ( 2.7 ), ( 2.8 ) and Warnings and Precautions ( 5.3 ) ].

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 ) ]. Available data with fentanyl transdermal system 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 and developmental delays 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 Use of opioid analgesics for an extended period of time 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, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 ) ]. 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 transdermal system is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl transdermal system, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data 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 2 times the daily human dose administered by a 100 mcg/h patch on a mg/m 2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m 2 basis). There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis). The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from Day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Day 28 which recovered by Day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis.

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Not recommended. ( 8.2 ) Severe Hepatic and Renal Impairment : Use not recommended. ( 8.6 , 8.7 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 ) ]. Available data with fentanyl transdermal system 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 and developmental delays 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 Use of opioid analgesics for an extended period of time 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, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 ) ]. 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 transdermal system is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl transdermal system, can prolong labor through actions that 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data 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 2 times the daily human dose administered by a 100 mcg/h patch on a mg/m 2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m 2 basis). There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis). The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from Day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Day 28 which recovered by Day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 basis. 8.2 Lactation Risk Summary Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for use in nursing women because of the possibility of effects in their infants. 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 transdermal system. Clinical Considerations Monitor infants exposed to fentanyl transdermal system 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 breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time 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 of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. The safety and effectiveness of fentanyl transdermal system in children under 2 years of age have not been established. To guard against excessive exposure to fentanyl transdermal system by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal system application and disposal instructions [see Dosage and Administration ( 2.7 ), ( 2.8 ) and Warnings and Precautions ( 5.3 ) ]. 8.5 Geriatric Use Clinical studies of fentanyl transdermal system did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology ( 12.3 ) ]. 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 transdermal system slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12 ) ]. 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 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.17 ) and Clinical Pharmacology 12.3 ) ]. 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.18 ) and Clinical Pharmacology ( 12.3 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems. See chart for information regarding individual systems. * This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a 125 mcg/hour strength that could be prescribed by using multiple transdermal systems. Fentanyl Transdermal System Strength (mcg/hour) System Size (cm 2 ) Fentanyl Content (mg) NDC Number Fentanyl transdermal system – 12 * 4.72 1.33 47781-423-47 Fentanyl transdermal system – 25 9.44 2.66 47781-424-47 Fentanyl transdermal system – 50 18.88 5.32 47781-426-47 Fentanyl transdermal system – 75 28.32 7.99 47781-427-47 Fentanyl transdermal system – 100 37.76 10.65 47781-428-47 Store in original unopened pouch. Store up to 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Store fentanyl transdermal system securely and dispose of properly [see Patient Counseling Information ( 17 ) ].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF FENTANYL TRANSDERMAL SYSTEM WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF FENTANYL TRANSDERMAL SYSTEM See full prescribing information for complete boxed warning. Fentanyl transdermal system exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing, and monitor regularly for these behaviors or conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.2 ) Accidental exposure to fentanyl transdermal system, especially in children, can result in fatal overdose of fentanyl. ( 5.3 ) 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 ) Prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 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. ( 5.5 ) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. ( 5.6 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl. ( 5.7 ) Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. ( 5.8 ) Addiction, Abuse, and Misuse Because the use of fentanyl transdermal system 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 ) ]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl transdermal system, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal system are essential [see Warnings and Precautions ( 5.2 ) ]. Accidental Exposure Accidental exposure of even one dose of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.3 )] . Deaths due to an overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure [see Warnings and Precautions ( 5.3 ) ] . 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. Reserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 ) ]. Neonatal Opioid Withdrawal Syndrome If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [ see Warnings and Precautions ( 5.5 ) ]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.6 ) ]. Cytochrome P450 3A4 Interaction The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects 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 transdermal system and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 ) ]. Risk of Increased Fentanyl Absorption with Application of External Heat Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources [see Warnings and Precautions ( 5.8 ) ].