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warnings and cautions
5 WARNINGS AND PRECAUTIONS Risk of Increased Fentanyl Absorption with Elevated Body Temperature: Monitor patients with fever closely for sedation and respiratory depression and reduce the dose if necessary. Warn patients to avoid strenuous exertion that may lead to increased body temperature ( 5.9 ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.10 ) Serotonin Syndrome with Concomitant Use of Serotonergic Drugs: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue DURAGESIC immediately if serotonin syndrome is suspected. ( 5.11 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.12 ) Severe Hypotension: Monitor during dose initiation and titration. Avoid the use of DURAGESIC in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of DURAGESIC in patients with impaired consciousness or coma. ( 5.14 ) 5.1 Addiction, Abuse, and Misuse DURAGESIC contains fentanyl, an opioid agonist and a Schedule II controlled substance. As an opioid, DURAGESIC exposes users to the risks of addiction, abuse, and misuse . Because modified-release products such as DURAGESIC deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of fentanyl present [see Drug Abuse and Dependence (9) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed DURAGESIC. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing DURAGESIC, and monitor all patients receiving DURAGESIC for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as DURAGESIC, but use in such patients necessitates intensive counseling about the risks and proper use of DURAGESIC along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of DURAGESIC by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death [see Overdosage (10) ]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing DURAGESIC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ]. 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 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) 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. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG . Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. DURAGESIC is indicated only in opioid tolerant patients because of the risk for respiratory depression and death. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of DURAGESIC, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression within the first 24–72 hours of initiating therapy with and following dosage increases of DURAGESIC. To reduce the risk of respiratory depression, proper dosing and titration of DURAGESIC are essential [see Dosage and Administration (2) ] . Overestimating the DURAGESIC dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental exposure to DURAGESIC, especially in children, can result in respiratory depression and death due to an overdose of fentanyl. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.8) ] . 5.4 Accidental Exposure A considerable amount of active fentanyl remains in DURAGESIC even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to DURAGESIC. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression, and has resulted in deaths. Placing DURAGESIC 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. Improper disposal of DURAGESIC in the trash has resulted in accidental exposures and deaths. Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to DURAGESIC [see Dosage and Administration (2.6) , (2.7) ]. Exposure to DURAGESIC patches discarded in the trash by children have been reported and have resulted in deaths. 5.5 Neonatal Opioid Withdrawal Syndrome Prolonged use of DURAGESIC during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ] . 5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of DURAGESIC 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 (5.3) ] , particularly when an inhibitor is added after a stable dose of DURAGESIC is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DURAGESIC-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using DURAGESIC with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DURAGESIC-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of DURAGESIC until stable drug effects are achieved [see Dosage and Administration (2.3) , Drug Interactions (7) ] . Concomitant use of DURAGESIC with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease DURAGESIC plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using DURAGESIC 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) ] . 5.7 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 DURAGESIC system increased fentanyl exposure [see Clinical Pharmacology (12.3) ] . Warn patients to avoid exposing the DURAGESIC application site and surrounding area to direct external heat sources [see Dosage and Administration (2.6) ] . 5.8 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of DURAGESIC 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 DURAGESIC 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 Risk of Increased Fentanyl Absorption with Elevated Body Temperature 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 DURAGESIC systems who develop fever closely for sedation and respiratory depression and reduce the DURAGESIC dose, if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing DURAGESIC to avoid the risk of potential overdose and death. 5.10 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of DURAGESIC 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 : DURAGESIC-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 DURAGESIC [see Warnings and Precautions (5.3) ] . 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 (5.3) ] . Monitor such patients closely, particularly when initiating and titrating DURAGESIC and when DURAGESIC is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.11 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of DURAGESIC with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7) ] . This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue DURAGESIC immediately if serotonin syndrome is suspected. 5.12 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.13 Severe Hypotension DURAGESIC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7) ]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of DURAGESIC. In patients with circulatory shock, DURAGESIC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of DURAGESIC in patients with circulatory shock. 5.14 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DURAGESIC may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with DURAGESIC. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DURAGESIC in patients with impaired consciousness or coma. 5.15 Cardiac Disease DURAGESIC may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with DURAGESIC. 5.16 Hepatic Impairment A clinical pharmacology study with DURAGESIC 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 DURAGESIC and hepatic metabolism of fentanyl, avoid use of DURAGESIC in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of DURAGESIC 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 DURAGESIC. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase. [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 5.17 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 DURAGESIC, avoid the use of DURAGESIC in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of DURAGESIC 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 DURAGESIC. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration (2.5) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 5.18 Risks of Use in Patients with Gastrointestinal Conditions DURAGESIC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in DURAGESIC may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. 5.19 Increased Risk of Seizures in Patients with Seizure Disorders The fentanyl in DURAGESIC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during DURAGESIC therapy. 5.20 Withdrawal Do not abruptly discontinue DURAGESIC in a patient physically dependent on opioids. When discontinuing DURAGESIC in a physically dependent patient, gradually taper the dosage. Rapid tapering of DURAGESIC in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.8) , Drug Abuse and Dependence (9.3) ] . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including DURAGESIC. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7) ] . 5.21 Risks of Driving and Operating Machinery DURAGESIC may impair the mental or physical abilities required for the performance of potentially dangerous activities, 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 DURAGESIC and know how they will react to the medication [see Patient Counseling Information (17) ] .