Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1)], reserve DURAGESIC 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.
• DURAGESIC is not indicated as an as-needed (prn) analgesic.

2.1 Important Dosage and Administration Instructions

DURAGESIC should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, DURAGESIC is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning DURAGESIC therapy. As DURAGESIC is only for use in opioid-tolerant patients, do not begin any patient on DURAGESIC as the first opioid [see Indications and Usage (1)].

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with DURAGESIC when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.3)].

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 DURAGESIC [see Warnings and Precautions (5.3), 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, 5.3, 5.8)].

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 DURAGESIC in opioid nontolerant patients [see Contraindications (4)].

The recommended starting dose when converting from other opioids to DURAGESIC is intended to minimize the potential for overdosing patients with the first dose.

Discontinue all other around-the-clock opioid drugs when DURAGESIC therapy is initiated.

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 DURAGESIC clinical trial, patients were converted from their prior opioid to DURAGESIC using Table 1 as a guide for the initial DURAGESIC dose.

Each DURAGESIC 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 DURAGESIC, 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 DURAGESIC.
• The tables cannot be used to convert from DURAGESIC 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.

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 DURAGESIC:

1. Calculate the previous 24-hour analgesic requirement.
2. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.
3. Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each DURAGESIC dose. Use this table to find the calculated 24-hour morphine dose and the corresponding recommended initial DURAGESIC dose.
4. Initiate DURAGESIC 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. The 37.5 mcg/hour strength is not available as DURAGESIC. It is available as Fentanyl Transdermal System. For patients that require more than 100 mcg/hour, several transdermal systems may be used.
5. Do not use Table 2 to convert from DURAGESIC to other therapies because this conversion to DURAGESIC is conservative and will overestimate the dose of the new agent.

An additional intermediate strength 37.5 mcg/hour DURAGESIC 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 DURAGESIC to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DURAGESIC to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring 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 chronic therapy, periodically reassess the continued need for opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of DURAGESIC, 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 DURAGESIC dosage.

The dosing interval for DURAGESIC is 72 hours. Do not increase the DURAGESIC 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 DURAGESIC 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 DURAGESIC 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 DURAGESIC in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of DURAGESIC. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions (5.16), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.6 Dosage Modifications in Patients with Renal Impairment

Avoid the use of DURAGESIC in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of DURAGESIC. 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 (8.7), and Clinical Pharmacology (12.3)].

2.7 Administration of DURAGESIC

DURAGESIC PATCHES ARE FOR TRANSDERMAL USE ONLY.

Proper handling of DURAGESIC is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to DURAGESIC [see Warnings and Precautions (5.4)].

2.8 Disposal Instructions

Failure to properly dispose of DURAGESIC has resulted in accidental exposures and deaths, including deaths of children [see Warnings and Precautions (5.4)].

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 DURAGESIC

Do not abruptly discontinue DURAGESIC 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 DURAGESIC, there are a variety of factors that should be considered, including the dose of DURAGESIC 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 DURAGESIC 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, monitor 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 a long duration 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 (5.20), Drug Abuse and Dependence (9.3)].

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. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

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 (CO2) 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.

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 Patient Counseling Information (17)].

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 (2.9)].

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 (2.7), (2.8)]. 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 (2.4), 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 (2.7)].

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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

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.

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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), DURAGESIC may reduce respiratory drive, and the resultant CO2 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 (2.5), 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 (2.6), 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 (2.9), 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)].

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 DURAGESIC was evaluated in 216 patients who took at least one dose of DURAGESIC in a multicenter, double-blind, randomized, placebo-controlled clinical trial of DURAGESIC. 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 DURAGESIC-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.

Adverse reactions not reported in Table 3 that were reported by ≥1% of DURAGESIC-treated adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of DURAGESIC used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4.

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

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of DURAGESIC. 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 DURAGESIC.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety of DURAGESIC 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 DURAGESIC 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 DURAGESIC in children under 2 years of age have not been established.

To guard against excessive exposure to DURAGESIC by young children, advise caregivers to strictly adhere to recommended DURAGESIC application and disposal instructions [see Dosage and Administration (2.7), (2.8) and Warnings and Precautions (5.4)].

8.5 Geriatric Use

Clinical studies of DURAGESIC 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 DURAGESIC 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 DURAGESIC slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.10)].

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 DURAGESIC has not been fully evaluated. A clinical pharmacology study with DURAGESIC 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 DURAGESIC, hepatic impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid use of DURAGESIC in patients with severe hepatic impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.16) and Clinical Pharmacology 12.3)].

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of DURAGESIC 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 DURAGESIC, renal impairment would be expected to have significant effects on the pharmacokinetics of DURAGESIC. Avoid the use of DURAGESIC in patients with severe renal impairment [see Dosage and Administration (2.6), Warnings and Precautions (5.17) and Clinical Pharmacology (12.3)].

9.1 Controlled Substance

DURAGESIC contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

DURAGESIC contains fentanyl, a substance with a high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. DURAGESIC can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in long-acting formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes physical withdrawal.

"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 providers. "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor 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.

DURAGESIC, 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), 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 opioid usage.

Do not abruptly discontinue DURAGESIC in a patient physically dependent on opioids. Rapid tapering of DURAGESIC 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 DURAGESIC, gradually taper the dosage using a patient-specific plan that considers the following: the dose of DURAGESIC 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 a long duration 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), Warnings and Precautions (5.20)].

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)].

Clinical Presentation

Acute overdose with DURAGESIC 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 DURAGESIC 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 DURAGESIC, carefully monitor the patient until spontaneous respiration is reliably reestablished. After DURAGESIC 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.

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 DURAGESIC securely and dispose of properly [see Patient Counseling Information (17)].

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store DURAGESIC 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, 5.4), Drug Abuse and Dependence (9.2)]. Inform patients that leaving DURAGESIC 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 DURAGESIC 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/drugdisposal 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 DURAGESIC, 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 DURAGESIC with others and to take steps to protect DURAGESIC 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 DURAGESIC 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 (5.3)].

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 DURAGESIC. 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 (5.3)].

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.

Accidental Exposure

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.4)].

DURAGESIC 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 DURAGESIC 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 (5.8), Drug Interactions (7)].

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 DURAGESIC while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DURAGESIC [see Drug Interactions (7)].

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 (5.12)].

Important Administration Instructions

Advise patients never to change the dose of DURAGESIC or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue DURAGESIC without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.9)].

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 DURAGESIC 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.

Hypotension

Inform patients that DURAGESIC 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 (5.13)].

Anaphylaxis

Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in DURAGESIC. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Lactation

Advise patients that breastfeeding is not recommended during treatment with DURAGESIC [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)].

Driving or Operating Heavy Machinery

Inform patients that DURAGESIC 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 (5.21)].

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)].