Drug Safety-related Labeling Changes (SrLC)

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DURAGESIC-100 (NDA-019813)

(FENTANYL)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/04/2021 (SUPPL-81)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… 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)].

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Accidental ingestion of even one dose of DURAGESIC, especially by 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)].

Newly added information:

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. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

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. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.2, 5.7), Patient Counseling Information (17)].

5.8 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… 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)].

7 Drug Interactions

Table 6: Clinically Significant Drug Interactions with DURAGESIC

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.8)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.8)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Important information about DURAGESIC:

Additions and/or revisions underlined:

• Get emergency help or call 911 right away if you take too much DURAGESIC (overdose). When you first start taking DURAGESIC, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.

Before taking DURAGESIC, tell your healthcare provider if you have a history of:

• abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

• living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have: …

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

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)].

Newly added information:

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 Administrations (2.2), Warnings and Precautions (5.4)].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.

10/07/2019 (SUPPL-79)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

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.

Additions and/or revisions underlined:

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).

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.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Table 6: Clinically Significant Drug Interactions with DURAGESIC

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about DURAGESIC:

• Store DURAGESIC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

• Dispose of expired, unwanted, or unused DURAGESIC®, 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). Visit additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

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. 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 flushing the unused medication down the toilet if a drug take-back option is not readily available. 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.

Newly added titled section:

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.

09/18/2018 (SUPPL-76)

Approved Drug Label (PDF)

Boxed Warning

In the boxed warning title, the following underlined language was added after “ADDICTION, ABUSE, AND MISUSE”: RISK EVALUATION AND MITIGATION STRATEGY (REMS)

Addition of the following information:

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

• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety.

5 Warnings and Precautions

Addition of the following subsection after the warning regarding addiction, abuse and misuse:

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.

12/16/2016 (SUPPL-69)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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

 

Addiction, Abuse, and Misuse

…Assess each patient’s risk prior to prescribing DURAGESIC, and monitor all patients regularly for the development of these behaviors and conditions

 

Accidental Exposure

Accidental exposure to even one dose of DURAGESIC, especially in children, can result in a fatal overdose of fentanyl…

 

Risk of Increased Fentanyl Absorption with Application of External Heat

…Warn patients to avoid exposing the application site   and   surrounding   area   to   direct   external   heat   sources.

 

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• Reserve concomitant prescribing of DURAGESIC 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.

4 Contraindications

(Additions and/or revisions are underlined)

DURAGESIC is contraindicated in:

• patients with significant respiratory depression
• in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• in patients with known or suspected gastrointestinal obstruction, including paralytic ileus
• in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system.

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(Additions and/or revisions are underlined)

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…

5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

(Newly added subsection)

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), 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). 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.

5.11 Adrenal Insufficiency

(Newly added subsection)

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.

5.12 Severe Hypotension

(Revised subsection title; Additions and/or revisions are underlined)

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.

5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

(Revised subsection title)

5.17 Risks of Use in Patients with Gastrointestinal Conditions

(Revised subsection title; Additions and/or revisions are underlined)

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.

5.18 Increased Risk of Seizures in Patients with Seizure Disorders

(Newly added subsection)

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.

5.19 Withdrawal

(Revised subsection title; Additions and/or revisions are underlined)

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.

5.2 Life-Threatening Respiratory Depression

(Additions and/or revisions are underlined)

Monitor patients closely for respiratory depression within the first 24-72 hours of initiating therapy with and following dosage increases of DURAGESIC.

5.20 Risks of Driving and Operating Machinery

(Revised subsection title; Additions and/or revisions are underlined)

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.

5.3 Accidental Exposure

(Additions and/or revisions are underlined)

Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression, and has resulted in deaths.

 

…Exposure to DURAGESIC patches discarded in the trash by children have been reported and have resulted in deaths.

5.4 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions are underlined)

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.

5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

(Revised subsection title; Additions and/or revisions are underlined)

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)], 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.

Concomitant use of DURAGEISC 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.

5.6 Risk of Increased Fentanyl Absorption with Application of External Heat

(Revised subsection title)

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Revised subsection title; Additions and/or revisions are underlined)

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.

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.

5.8 Risk of Increased Fentanyl Absorption with Elevated Body Temperature

(Newly added subsection title; Additions and/or revisions are underlined)

Monitor patients wearing DURAGESIC systems who develop fever closely for sedation and respiratory depression and reduce the DURAGESIC dose, if necessary.

5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(Revised subsection title; Additions and/or revisions are underlined)

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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are discussed elsewhere in the labeling:

• Interactions  with  Benzodiazepines or Other  Central  Nervous  System  Depressants
• Serotonin Syndrome
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal

6.2 Post-Marketing Experience

(Additions and/or revisions are underlined)

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.

 

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.

7 Drug Interactions

(Additions and/or revisions are underlined)

Table 6 includes clinically significant drug interactions with DURAGESIC. (Table has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with DURAGESIC in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing.   When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

 

Clinical Considerations

Labor or Delivery

…An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate…Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

 

Data

Animal Data

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy…In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m2 basis).

8.2 Lactation

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Risk Summary

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with DURAGESIC.

 

Clinical Considerations

Monitor infants exposed to DURAGESIC through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Infertility

Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

 

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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.

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Accidental Exposure

Inform patients that accidental exposure, especially in   children, may result in respiratory depression or death. Instruct patients to take steps store DURAGESIC securely and to dispose of unused DURAGESIC by flushing down the toilet.

Inform   patients   that   deaths   have   occurred   from   accidental   exposure   to   DURAGESIC Transdermal Systems discarded in the trash.

Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed.

 

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

 

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.

MAOI Interaction

Inform patients to avoid taking DURAGESIC while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking DURAGESIC.

 

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.

 

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).

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.

 

Pregnancy

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that DURAGESIC can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy.

 

Lactation

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

 

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

 

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.

 

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Medication Guide

(Additions and/or revisions are underlined)

Important information about DURAGESIC:

• Taking DURAGESIC with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) may cause severe drowsiness, decreased awareness, breathing difficulties, with slow or shallow breathing, coma, and death.

Tell your healthcare provider if you:

• are breastfeeding. Not recommended during treatment with DURAGESIC…

When using DURAGESIC:

• Do not change your dose. Apply DURAGESIC® exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
• Do not cut, break, chew, crush, dissolve, snort, or inject DURAGESIC because this may cause you to overdose and die.

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headed ness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.