FDA label fb2aefbc-5cfb-4e56-a617-5297e441e784

WARNING: ABUSE POTENTIAL, RESPIRATORY DEPRESSION AND DEATH, ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4 INTERACTION, AND EXPOSURE TO HEAT Abuse Potential Fentanyl transdermal system contains fentanyl, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for their clinical risks for opioid abuse or addiction prior to prescribing fentanyl transdermal system and then routinely monitor all patients for signs of misuse, abuse and addiction during treatment [see Warnings and Precautions ( 5.1 ) and Drug Abuse and Dependence ( 9 )]. Respiratory Depression and Death Respiratory depression and death may occur with use of fentanyl transdermal system, even when fentanyl transdermal system has been used as recommended and not misused or abused. Proper dosing and titration are essential and fentanyl transdermal system should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Fentanyl transdermal system is contraindicated for use in conditions in which the risk of life-threatening respiratory depression is significantly increased, including use as an as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain. Monitor for respiratory depression, especially during the first two applications following initiation of dosing, or following an increase in dosage [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Accidental Exposure Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure [see Dosage and Administration ( 2.3 ) ( 2.4 ) and Warnings and Precautions ( 5.3 )]. 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. Monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor [see Warnings and Precautions ( 5.8 ), and Clinical Pharmacology ( 12.3 )] . Exposure To Heat The fentanyl transdermal system application site and surrounding area must not be exposed 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. Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat ( 5.9 ) . Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an adjustment in the dose of fentanyl transdermal system to avoid overdose and death ( 5.10 ) . WARNING: ABUSE POTENTIAL, RESPIRATORY DEPRESSION AND DEATH, ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4 INTERACTION, AND EXPOSURE TO HEAT See full prescribing information for complete boxed warning. Contains a high concentration of fentanyl, a Schedule II controlled substance, which is subject to misuse, abuse, addiction, and criminal diversion. ( 9 ) Fatal respiratory depression could occur in patients who are not opioid‑tolerant and in patients that are opioid‑tolerant even if fentanyl transdermal system is not misused or abused. ( 5 ) Accidental exposure of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl. ( 5 ) CYP 3A4 inhibitors can result in a fatal overdose of fentanyl from fentanyl transdermal system. ( 5 ) Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. Temperature dependent increases in fentanyl release from the system may result in overdose and death. ( 5 )

5 WARNINGS AND PRECAUTIONS Fentanyl transdermal system can be abused. Use caution when prescribing if there is an increased risk of misuse, abuse, or diversion. ( 5.1 ) Fatal respiratory depression can occur with fentanyl transdermal system. Monitor patients accordingly. Use with extreme caution in patients at risk of respiratory depression. ( 5.2 ) Accidental exposure of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl. ( 5.3 ) Use fentanyl transdermal system with extreme caution in patients susceptible to intracranial effects of CO 2 retention. ( 5.6 ) Fentanyl transdermal system may have additive effects when used in conjunction with other CNS depressants, alcohol, and drugs of abuse. ( 5.7 ) Use of fentanyl transdermal system with a CYP3A4 inhibitor may result in an increase in fentanyl plasma concentrations. Monitor patients accordingly and adjust dosage if necessary. ( 5.8 ) Fentanyl transdermal system may produce bradycardia. Administer with caution to patients with bradyarrhythmias. ( 5.11 ) Use fentanyl transdermal system with caution in patients with pancreatic/biliary disease. ( 5.14 ) 5.1 Abuse Potential Fentanyl transdermal system contains fentanyl, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing fentanyl transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence ( 9 )] . Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Respiratory Depression and Death Respiratory depression is the chief hazard of fentanyl transdermal system. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Fentanyl transdermal system has a narrow indication and should be prescribed only by healthcare professionals who are knowledgeable in the administration of potent opioids and management of chronic pain [see Indications and Usage ( 1 )] . Fentanyl transdermal system is contraindicated for use in conditions in which the risk of life-threatening respiratory depression is significantly increased, including use as an as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain [see Contraindications ( 4 )]. Proper dosing and titration of fentanyl transdermal system are essential [see Dosage and Administration ( 2.3 )] . Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication, can result in fatal overdose with the first dose. However, respiratory depression has also been reported with use of fentanyl transdermal system in patients who are opioid-tolerant, even when fentanyl transdermal system has been used as recommended and not misused or abused. The mean half-life of fentanyl when delivered by fentanyl transdermal system is approximately 20 to 27 hours. Serum fentanyl concentrations continue to rise for the first two system applications. In addition, significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed [see Clinical Pharmacology ( 12.3 )] . Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening or fatal respiratory depression can occur at any time during the use of fentanyl transdermal system, the potential for serious, life-threatening, or fatal respiratory depression is greatest during the first two applications following initiation of dosing, or following an increase in dosage. Closely monitor patients for respiratory depression when initiating therapy with fentanyl transdermal system, especially within the initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Because significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed, respiratory depression may persist beyond the removal of fentanyl transdermal system. Monitor patients for respiratory depression after patch removal to ensure that the patient’s respiration has stabilized for at least 24 to 72 hours or longer as clinical symptoms dictate. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdose ( 10.2 )]. 5.3 Accidental Exposure A considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal system (see Dosage and Administration ( 2.4 ) ( 2.5 )]. 5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance. Therefore, monitor these patients closely, particularly when initiating therapy with fentanyl transdermal system and when given in conjunction with other drugs that depress respiration [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 )] . 5.5 Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy with fentanyl transdermal system, as in these patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea [see Warnings and Precautions ( 5.2 )]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.6 Head Injuries and Increased Intracranial Pressure Avoid use of fentanyl transdermal system in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma [see Warnings and Precautions ( 5.2 )] . In addition, opioids may obscure the clinical course of patients with head injury. Monitor patients with brain tumors who may be susceptible to the intracranial effects of CO 2 retention for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal system, as fentanyl transdermal system may reduce respiratory drive and CO 2 retention can further increase intracranial pressure. 5.7 Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse The concomitant use of fentanyl transdermal system with other central nervous system depressants, including, but not limited to, other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or coma. Monitor patients prescribed concomitant CNS active drugs for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal system, and reduce the dose of one or both agents [see Warnings and Precautions ( 5.2 )]. 5.8 Interactions with CYP3A4 Inhibitors The concomitant use of fentanyl transdermal system with a CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil) 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 sedation and respiratory depression for an extended period of time, and make dosage adjustments if warranted [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 5.9 Application of External Heat Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased fentanyl exposure [see Clinical Pharmacology ( 12.3 )]. Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources [see Dosage and Administration ( 2.4 )]. 5.10 Patients with Fever Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing fentanyl transdermal systems who develop fever closely for opioid side effects and reduce the fentanyl transdermal system dose if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl transdermal system to avoid the risk of potential overdose and death. 5.11 Cardiac Disease Fentanyl transdermal system may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal system. 5.12 Hepatic Impairment A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as fentanyl transdermal system and hepatic metabolism of fentanyl, avoid use of fentanyl transdermal system in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase. [see Dosing and Administration ( 2.2 ),Use in Specific Populations (8.6) and Clinical Pharmacology ( 12.3 )]. 5.13 Renal Impairment 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 of the long half-life of fentanyl when administered as fentanyl transdermal system, avoid the use of fentanyl transdermal system in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosing and Administration ( 2.2 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. 5.14 Use in Pancreatic/Biliary Tract Disease Fentanyl transdermal system may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsened symptoms. Fentanyl transdermal system may cause increases in the serum amylase concentration. 5.15 Avoidance of Withdrawal Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion to another opioid or when decreasing or discontinuing fentanyl transdermal system. Gradual reduction of the dose of fentanyl transdermal system is recommended [see Dosage and Administration ( 2.3 ) and Drug Abuse and Dependence ( 9 )] . 5.16 Driving and Operating Machinery Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the fentanyl transdermal system.

5.1 Abuse Potential Fentanyl transdermal system contains fentanyl, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing fentanyl transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence ( 9 )] . Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.3 Accidental Exposure A considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal system (see Dosage and Administration ( 2.4 ) ( 2.5 )].

5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance. Therefore, monitor these patients closely, particularly when initiating therapy with fentanyl transdermal system and when given in conjunction with other drugs that depress respiration [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Abuse Potential [see Warnings and Precautions ( 5.1 )] Respiratory Depression [see Warnings and Precautions ( 5.2 )] Accidental Exposure [see Warnings and Precautions ( 5.3 )] Elderly, Cachetic, and Debilitated Patients [see Warnings and Precautions ( 5.4 )] Chronic Pulmonary Disease [see Warnings and Precautions ( 5.5 )] Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions ( 5.6 )] Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse [see Warnings and Precautions ( 5.7 )] Interactions with CYP3A4 Inhibitors [see Warnings and Precautions ( 5.8 )] Application of External Heat [see Warnings and Precautions ( 5.9 )] Patients with Fever [see Warnings and Precautions ( 5.10 )] Cardiac Disease [see Warnings and Precautions ( 5.11 )] Hepatic Impairment [see Warnings and Precautions (5.12)] Renal Impairment [see Warnings and Precautions ( 5.13 )] Use in Pancreatic/Biliary Tract Disease [see Warnings and Precautions ( 5.14 )] Avoidance of Withdrawal [see Warnings and Precautions ( 5.15 )] Driving and Operating Machinery [see Warnings and Precautions ( 5.16 )] 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 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. (6.0) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Cardiac Disorders: Tachycardia, Bradycardia Eye Disorders: Vision blurred Gastrointestinal Disorders: Ileus, Dyspepsia General Disorders and Administration Site Conditions: Feeling of body temperature change Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction Investigations: Weight decreased Nervous System Disorders: Convulsions (including Clonic convulsions and Grand mal convulsion), Amnesia Psychiatric Disorders: Agitation Respiratory, Thoracic, and Mediastinal Disorders: Respiratory distress, Apnea, Bradypnea, Hypoventilation, Dyspnea Vascular Disorders: Hypotension, Hypertension

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. Cardiac Disorders: Tachycardia, Bradycardia Eye Disorders: Vision blurred Gastrointestinal Disorders: Ileus, Dyspepsia General Disorders and Administration Site Conditions: Feeling of body temperature change Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction Investigations: Weight decreased Nervous System Disorders: Convulsions (including Clonic convulsions and Grand mal convulsion), Amnesia Psychiatric Disorders: Agitation Respiratory, Thoracic, and Mediastinal Disorders: Respiratory distress, Apnea, Bradypnea, Hypoventilation, Dyspnea Vascular Disorders: Hypotension, Hypertension