FDA label dbcfeb48-a9f0-4d74-8a63-8d1c3ce7182f

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED FENTANYL ABSORPTION WITH APPLICATION OF EXTERNAL HEAT; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse 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 fentanyl transdermal system, and monitor 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. Monitor for respiratory depression, especially during initiation of fentanyl transdermal system or following a dose increase. Because of the risk of respiratory depression, fentanyl transdermal system is contraindicated for use as an as-needed analgesic, in non-opioid tolerant patients, in acute pain, and in postoperative pain [see Contraindications (4) and Warnings and Precautions (5.2) ]. Accidental Exposure Accidental exposure to even one dose of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl. 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) ]. Neonatal Opioid Withdrawal Syndrome 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, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4) ]. 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 (5.5) 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 waterbeds 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 (5.6) ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.7) , Drug Interactions (7) ]. Reserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit treatment to the minimum effective dosages and durations. Follow patients for signs and symptoms of respiratory depression and sedation. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED FENTANYL ABSORPTION WITH APPLICATION OF EXTERNAL HEAT; and RISKS FROM CONCOMITANT USE OF BENZODIAZEPINES OR OTHER CNS DEPRESSANTS 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 ) 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. ( 5.4 ) Concomitant use with CYP 3A4 inhibitors (or discontinuation of CYP 3A4 inducers) can result in a fatal overdose of fentanyl. ( 5.5 ) 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. ( 5.6 ) 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. ( 5.7 , 7 )

5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of fentanyl transdermal system with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2) ] , particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl transdermal system-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl transdermal system with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl transdermal system-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved [see Dosage and Administration (2.3) , Drug Interactions (7) ] . Concomitant use of fentanyl transdermal system with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl transdermal system plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using fentanyl transdermal system with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7) ] .

5.6 Risk of Increased Fentanyl Absorption with 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 (2.6) ] .

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl transdermal system with benzodiazepines and/or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when fentanyl transdermal system is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) , Patient Counseling Information (17) ] .

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of fentanyl transdermal system in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Fentanyl transdermal system-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of fentanyl transdermal system [see Warnings and Precautions (5.2) ] . Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2) ] . Monitor such patients closely, particularly when initiating and titrating fentanyl transdermal system and when fentanyl transdermal system is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2) ] . Alternatively, consider the use of non-opioid analgesics in these patients.

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) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Interactions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions (5.7) ] Serotonin Syndrome [see Warnings and Precautions (5.10) ] Adrenal Insufficiency [see Warnings and Precautions (5.11) ] Severe Hypotension [see Warnings and Precautions (5.12) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.17) ] Seizures [see Warnings and Precautions (5.18) ] Withdrawal [see Warnings and Precautions (5.19) ] 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, contact Mallinckrodt at 1-800-778-7898 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 Postmarketing 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 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 chronic use of opioids [see Clinical Pharmacology (12.2) ] .

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 Postmarketing 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 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 chronic use of opioids [see Clinical Pharmacology (12.2) ] .

<table> <col width="223.7pt"/> <col width="111.85pt"/> <col width="112pt"/> <thead> <tr> <td colspan="3" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Table 3.</content> <content styleCode="bold">Adverse Reactions Reported by &#x2265;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</content> </paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="bottom"> <paragraph> <content styleCode="bold">System/Organ Class </content> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Fentanyl Transdermal System</content> <content styleCode="bold"> % </content> <content styleCode="bold">(N=216)</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Placebo % (N=200)</content> </paragraph> </td> </tr> </thead> <tbody> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Cardiac disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Palpitations</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Ear and labyrinth disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Vertigo</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>41</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Constipation</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Abdominal pain upper</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Dry mouth</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">General disorders and administration site conditions</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Fatigue</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="bottom"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Feeling cold</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="bottom"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Malaise</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="bottom"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Edema peripheral</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and nutrition disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Anorexia</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Muscle spasms</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Nervous system disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Somnolence</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Psychiatric disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Depression </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"/> <td/> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Hyperhidrosis</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Pruritus</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>Rash</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode=" Botrule Toprule Lrule Rrule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table>