label

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

DURAGESIC



safely and effectively. See full prescribing information for

DURAGESIC.

DURAGESIC



(fentanyl transdermal system), CII

Initial U.S. Approval: 1968

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK

EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-

THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL

EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME;

CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED

FENTANYL ABSORPTION WITH APPLICATION OF

EXTERNAL HEAT; and RISKS FROM CONCOMITANT USE OF

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

 DURAGESIC exposes users to risks of addiction, abuse, and

misuse, which can lead to overdose and death. Assess patient’s

risk before prescribing, and monitor regularly for these

behaviors or conditions. (5.1)

 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. (5.2)

 Serious, life-threatening, or fatal respiratory depression may

occur. Monitor closely, especially upon initiation or following a

dose increase. (5.3)

 Accidental exposure to DURAGESIC, especially in children, can

result in fatal overdose of fentanyl. (5.4)

 Prolonged use of DURAGESIC during pregnancy can result in

neonatal opioid withdrawal syndrome, which may be life-

threatening if not recognized and treated. If opioid use is

required for a prolonged period in a pregnant woman, advise the

patient of the risk of neonatal opioid withdrawal syndrome and

ensure that appropriate treatment will be available. (5.5)

 Concomitant use with CYP3A4 inhibitors (or discontinuation of

CYP3A4 inducers) can result in a fatal overdose of fentanyl. (5.6)

 Exposure of the DURAGESIC application site and surrounding

area to direct external heat sources has resulted in fatal overdose

of fentanyl. Warn patients to avoid exposing the DURAGESIC

application site and surrounding area to direct external heat

sources. (5.7)

 Concomitant use of opioids with benzodiazepines or other

central nervous system (CNS) depressants, including alcohol,

may result in profound sedation, respiratory depression, coma,

and death. Reserve concomitant prescribing for use in patients

for whom alternative treatment options are inadequate; limit

dosages and durations to the minimum required; and follow

patients for signs and symptoms of respiratory depression and

sedation. (5.8, 7)

----------------------------RECENT MAJOR CHANGES-------------------------

Dosage and Administration (2.2) 03/2021

Warnings and Precautions (5.1, 5.3, 5.8) 03/2021

----------------------------INDICATIONS AND USAGE----------------------------

DURAGESIC contains fentanyl, an opioid agonist, and is indicated for the

management of pain in opioid-tolerant patients, severe enough to require

daily, around-the-clock, long-term opioid treatment and for which alternative

treatment options are inadequate. (1)

Patients considered opioid-tolerant are those taking, for one week or longer, at

least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour,

30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral

oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic

dose of another opioid. (2.1)

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 opioid formulations, 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. (1)

 DURAGESIC is not indicated as an as-needed (prn) analgesic

-----------------------DOSAGE AND ADMINISTRATION---------------------

 To be prescribed only by healthcare providers knowledgeable in use of

potent opioids for management of chronic pain. (2.1)

 Use the lowest effective dosage for the shortest duration consistent with

individual patient treatment goals (2.1).

 Individualize dosing based on the severity of pain, patient response,

prior analgesic experience, and risk factors for addiction, abuse, and

misuse. (2.1)

 Discuss availability of naloxone with the patient and caregiver and

assess each patient’s need for access to naloxone, both when initiating

and renewing treatment with DURAGESIC. Consider prescribing

naloxone based on the patient’s risk factors for overdose. (2.2, 5.1, 5.3,

5.8)

 Initial dose selection: consult conversion instructions. (2.3)

 Each transdermal system is intended to be worn for 72 hours. (2.3)

 Adhere to instructions concerning administration and disposal of

DURAGESIC. (2.7, 2.8)

 Mild to moderate hepatic and renal impairment: Initiate treatment with

one half the usual starting dose, titrate slowly, and monitor for signs of

respiratory and central nervous system depression. (2.5, 2.6)

 Do not abruptly discontinue DURAGESIC in a physically-dependent

patient because rapid discontinuation of opioid analgesics has resulted in

serious withdrawal symptoms, uncontrolled pain, and suicide. (2.9)

--------------------DOSAGE FORMS AND STRENGTHS----------------------

Transdermal system: 12 mcg/hour, 25 mcg/hour, 37.5 mcg/hour, 50 mcg/hour,

75 mcg/hour, 100 mcg/hour. (3)

-------------------------------CONTRAINDICATIONS-------------------------------

 Opioid non-tolerant patients. (4)

 Acute or intermittent pain, postoperative pain, mild pain. (4)

 Significant respiratory depression. (4)

 Acute or severe bronchial asthma in an unmonitored setting or in

absence of resuscitative equipment. (4)

 Known or suspected gastrointestinal obstruction, including paralytic

ileus. (4)

 Known hypersensitivity to fentanyl or any of the components of the

transdermal system. (4)

---------------------------WARNINGS AND PRECAUTIONS--------------------

 Risk of Increased Fentanyl Absorption with Elevated Body

Temperature: Monitor patients with fever closely for sedation and

respiratory depression and reduce the dose if necessary. Warn patients

to avoid strenuous exertion that may lead to increased body temperature

(5.9).

 Life-Threatening Respiratory Depression in Patients with Chronic

Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:

Monitor closely, particularly during initiation and titration. (5.10)

 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs:

Potentially life-threatening condition could result from concomitant

serotonergic drug administration. Discontinue DURAGESIC

immediately if serotonin syndrome is suspected. (5.11)

 Adrenal Insufficiency: If diagnosed, treat with physiologic replacement

of corticosteroids, and wean patient off of the opioid. (5.12)

 Severe Hypotension: Monitor during dose initiation and titration. Avoid

the use of DURAGESIC in patients with circulatory shock. (5.13)

 Risks of Use in Patients with Increased Intracranial Pressure, Brain

Tumors, Head Injury or Impaired Consciousness: Monitor for sedation

and respiratory depression. Avoid use of DURAGESIC in patients with

impaired consciousness or coma. (5.14)

------------------------------ADVERSE REACTIONS------------------------------

Most common adverse reactions (≥5%) are nausea, vomiting, somnolence,

dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold,

anorexia, headache, and diarrhea. (6)

To report SUSPECTED ADVERSE REACTIONS, call Janssen

Pharmaceuticals Inc.1-800-526-7736 or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

Reference ID: 4756459

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For current labeling information, please visit https://www.fda.gov/drugsatfda

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---------------------------------DRUG INTERACTIONS----------------------------

 Lactation: Not recommended. (8.2)

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use

 Severe Hepatic and Renal Impairment: Use not recommended. (8.6, 8.7)

with DURAGESIC because they may reduce analgesic effect of

DURAGESIC or precipitate withdrawal symptoms. (5.20, 7)

See 17 for PATIENT COUNSELING INFORMATION and Medication

Guide.

-----------------------USE IN SPECIFIC POPULATIONS-----------------------

Revised: 03/2021

 Pregnancy: May cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK

EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-

THREATENING RESPIRATORY DEPRESSION: ACCIDENTAL

EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME;

CYTOCHROME P450 3A4 INTERACTION; EXPOSURE TO HEAT;

and RISKS FROM CONCOMITANT USE OF BENZODIAZEPINES

OR OTHER CNS DEPRESSANTS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Patient Access to Naloxone for the Emergency

Treatment of Opioid Overdose

2.3 Initial Dosage

2.4 Titration and Maintenance of Therapy

2.5 Dosage Modifications in Patients with Hepatic

Impairment

2.6 Dosage Modifications in Patients with Renal

Impairment

2.7 Administration of DURAGESIC

2.8 Disposal Instructions

2.9 Safe Reduction or Discontinuation of

DURAGESIC

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

5.2 Opioid Analgesic Risk Evaluation and Mitigation

Strategy (REMS)

5.3 Life-Threatening Respiratory Depression

5.4 Accidental Exposure

5.5 Neonatal Opioid Withdrawal Syndrome

5.6 Risks of Concomitant Use or Discontinuation of

Cytochrome P450 3A4 Inhibitors and Inducers

5.7 Risk of Increased Fentanyl Absorption with

Application of External Heat

5.8 Risks from Concomitant Use with

Benzodiazepines or Other CNS Depressants

5.9 Risk of Increased Fentanyl Absorption with

Elevated Body Temperature

5.10 Life-Threatening Respiratory Depression in

Patients with Chronic Pulmonary Disease or in

Elderly, Cachectic, or Debilitated Patients

5.11 Serotonin Syndrome with Concomitant Use of

Serotonergic Drugs

5.12 Adrenal Insufficiency

5.13 Severe Hypotension

5.14 Risks of Use in Patients with Increased

Intracranial Pressure, Brain Tumors, Head Injury,

or Impaired Consciousness

5.15 Cardiac Disease

5.16 Hepatic Impairment

5.17 Renal Impairment

5.18 Risks of Use in Patients with Gastrointestinal

Conditions

5.19 Increased Risk of Seizures in Patients with

Seizure Disorders

5.20 Withdrawal

5.21 Risks of Driving and Operating Machinery

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of

Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not

listed.

Reference ID: 4756459

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FULL PRESCRIBING INFORMATION

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND

MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL

SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED

FENTANYL ABSORPTION WITH APPLICATION OF EXTERNAL HEAT; and

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS

DEPRESSANTS

Addiction, Abuse, and Misuse

DURAGESIC exposes patients and other users to the risks of opioid addiction, abuse, and

misuse, which can lead to overdose and death. Assess each patient’s risk prior to

prescribing DURAGESIC, and monitor all patients regularly for the development of these

behaviors and conditions [see Warnings and Precautions (5.1)].

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 REMS for these

products [see Warnings and Precautions (5.2)]. 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.

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of

DURAGESIC. Monitor for respiratory depression, especially during initiation of

DURAGESIC or following a dose increase. Because of the risk of respiratory depression,

DURAGESIC is contraindicated for use as an as-needed analgesic, in non-opioid tolerant

Reference ID: 4756459

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patients, in acute pain, and in postoperative pain [see Contraindications (4) and Warnings

and Precautions (5.3)].

Accidental Exposure

Accidental exposure to even one dose of DURAGESIC, especially in children, can result

in a fatal overdose of fentanyl. Deaths due to an overdose of fentanyl have occurred when

children and adults were accidentally exposed to DURAGESIC. Strict adherence to the

recommended handling and disposal instructions is of the utmost importance to prevent

accidental exposure [see Warnings and Precautions (5.4)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of DURAGESIC during pregnancy can result in neonatal opioid

withdrawal syndrome, which may be life-threatening if not recognized and treated, and

requires management according to protocols developed by neonatology experts. If opioid

use is required for a prolonged period in a pregnant woman, advise the patient of the risk

of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be

available [see Warnings and Precautions (5.5)].

Cytochrome P450 3A4 Interaction

The concomitant use of DURAGESIC with all cytochrome P450 3A4 inhibitors may result

in an increase in fentanyl plasma concentrations, which could increase or prolong adverse

drug effects and may cause potentially fatal respiratory depression. In addition,

discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an

increase in fentanyl plasma concentration. Monitor patients receiving DURAGESIC and

any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.6) and Clinical

Pharmacology (12.3)].

Risk of Increased Fentanyl Absorption with Application of External Heat

Exposure of the DURAGESIC application site and surrounding area to direct external

heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing,

hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and

has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application

site and surrounding area to direct external heat sources [see Warnings and

Precautions (5.7)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression,

coma, and death [see Warnings and Precautions (5.8), Drug Interactions (7)].

Reference ID: 4756459

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 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.

1 INDICATIONS AND USAGE

DURAGESIC is indicated for the management of pain in opioid-tolerant patients, severe enough

to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment

options are inadequate.

Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60 mg

morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg

oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day,

or an equianalgesic dose of another opioid.

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 DOSAGE AND ADMINISTRATION

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)].

Reference ID: 4756459

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 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

Reference ID: 4756459

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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.

Table 1

: Dose Conversion from Other Opioids to DURAGESIC

Current Analgesic Daily Dosage (mg/day)

Oral morphine 60

–

134 135

–

224 225

–

314 315

–

404

Intramuscular or Intravenous morphine 10

–

22 23

–

37 38

–

52 53

–

Oral ox

codone 30

–

67 67.5

–

112 112.5

–

157 157.5

–

202

Oral codeine 150

–

447

Oral h

dromorphone 8

–

17 17.1

–

28 28.1

–

39 39.1

–

Intravenous h

dromorphone 1.5

–

3.4 3.5

–

5.6 5.7

–

7.9 8

–

Intramuscular meperidine 75

–

165 166

–

278 279

–

390 391

–

503

Oral methadone 20

–

44 45

–

74 75

–

104 105

–

134

   

Recommended DURAGESIC Dose 25 mc

/hou

50 mc

/hou

75 mc

/hou

100 mc

/hou

Table 1 should not be used to convert from DURAGESIC to other therapies because this conversion to

DURAGESIC is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate

the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and

dministration (2.9)].

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.

Reference ID: 4756459

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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.

Table 2

: Recommended Initial DURAGESIC Dose based upon Daily Oral Morphine Dose

Oral 24-hour DURAGESIC

Morphine Dose

(mg/day) (mcg/hour)

–

134 25

135

–

224 50

225

–

314 75

315

–

404 100

405

–

494 125

495

–

584 150

585

–

674 175

675

–

764 200

765

–

854 225

855

–

944 250

945

–

1034 275

1035

–

1124 300

NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to

DURAGESIC.

Table 2 should not be used to convert from DURAGESIC to other therapies because this conversion to

DURAGESIC is conservative. Use of Table 2 for conversion to other analgesic therapies can

overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage

and Administration (2.9)].

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

Reference ID: 4756459

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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)].

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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)].

Application and Handling Instructions

 Patients should apply DURAGESIC to intact, non-irritated, and non-irradiated skin on a

flat surface such as the chest, back, flank, or upper arm. In young children and persons with

cognitive impairment, adhesion should be monitored and the upper back is the preferred

location to minimize the potential of inappropriate patch removal. Hair at the application

site may be clipped (not shaved) prior to system application. If the site of DURAGESIC

application must be cleansed prior to application of the patch, do so with clear water. Do

not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter

its characteristics. Allow the skin to dry completely prior to patch application.

 Patients should apply DURAGESIC immediately upon removal from the sealed package.

The patch must not be altered (e.g., cut) in any way prior to application. DURAGESIC

should not be used if the pouch seal is broken or if the patch is cut or damaged.

 The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds,

making sure the contact is complete, especially around the edges.

 Each DURAGESIC patch may be worn continuously for 72 hours. The next patch is

applied to a different skin site after removal of the previous transdermal system.

 If problems with adhesion of the DURAGESIC patch occur, the edges of the patch may be

taped with first aid tape. If problems with adhesion persist, the patch may be overlayed

with a transparent adhesive film dressing.

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 If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the

toilet. A new patch may be applied to a different skin site.

 Patients (or caregivers who apply DURAGESIC) should wash their hands immediately

with soap and water after applying DURAGESIC.

 Contact with unwashed or unclothed application sites can result in secondary exposure to

DURAGESIC and should be avoided. Examples of accidental exposure include transfer of

a DURAGESIC patch from an adult’s body to a child while hugging, sharing the same bed

as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s

skin to the medication in the patch while applying or removing the patch.

 Instruct patients, family members, and caregivers to keep patches in a secure location out

of the reach of children and of others for whom DURAGESIC was not prescribed.

Avoidance of Heat

Instruct patients to avoid exposing the DURAGESIC application site and surrounding area to direct

external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing,

hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and

Precautions (5.7)].

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,

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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)].

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3 DOSAGE FORMS AND STRENGTHS

Transdermal system:

 DURAGESIC 12 mcg/hour

(system size 5.5 cm

 DURAGESIC 25 mcg/hour (system size 11 cm

 DURAGESIC 37.5 mcg/hour (system size 16.5 cm

 DURAGESIC 50 mcg/hour (system size 22 cm

 DURAGESIC 75 mcg/hour (system size 33 cm

 DURAGESIC 100 mcg/hour (system size 44 cm

This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish

it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.

The 12 mcg/hour system has a solid green border and the 25, 37.5, 50, 75 and 100 mcg/hour

systems have a green background with translucent diagonal stripes that alternate in direction and

increase in number with each sequential increasing dosage strength.

4 CONTRAINDICATIONS

DURAGESIC is contraindicated in:

 patients who are not opioid-tolerant.

 the management of acute or intermittent pain, or in patients who require opioid analgesia

for a short period of time.

 the management of post-operative pain, including use after out-patient or day surgeries,

(e.g., tonsillectomies).

 the management of mild pain.

 patients with significant respiratory depression [see Warnings and Precautions (5.10)].

 in patients with acute or severe bronchial asthma in an unmonitored setting or in the

absence of resuscitative equipment [see Warnings and Precautions (5.10)].

 in patients with known or suspected gastrointestinal obstruction, including paralytic ileus

[see Warnings and Precautions (5.18)].

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 in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the

transdermal system [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

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

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(REMS) for these products. Under the requirements of the REMS, drug companies with approved

opioid analgesic products must make REMS-compliant education programs available to healthcare

providers. Healthcare providers are strongly encouraged to do all of the following:

 Complete a REMS-compliant education program offered by an accredited provider of

continuing education (CE) or another education program that includes all the elements of

the FDA Education Blueprint for Health Care Providers Involved in the Management or

Support of Patients with Pain.

 Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics

with patients and/or their caregivers every time these medicines are prescribed. The Patient

Counseling Guide (PCG) can be obtained at this link:

www.fda.gov/OpioidAnalgesicREMSPCG.

 Emphasize to patients and their caregivers the importance of reading the Medication Guide

that they will receive from their pharmacist every time an opioid analgesic is dispensed to

them.

 Consider using other tools to improve patient, household, and community safety, such as

patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS

CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint

can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.3 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids,

even when used as recommended. Respiratory depression, if not immediately recognized and

treated, may lead to respiratory arrest and death. Management of respiratory depression may

include close observation, supportive measures, and use of opioid antagonists, depending on the

patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO

) 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.

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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)].

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.

However, 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 exposure or overdose. If naloxone

is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and

Precautions (5.1, 5.8), Patient Counseling Information (17)].

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

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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

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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)].

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Advise both patients and caregivers about the risks of respiratory depression and sedation when

DURAGESIC is used with benzodiazepines or other CNS depressants (including alcohol and illicit

drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant

use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk

of substance use disorders, including opioid abuse and misuse, and warn them of the risk for

overdose and death associated with the use of additional CNS depressants including alcohol and

illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

5.9 Risk of Increased Fentanyl Absorption with Elevated Body Temperature

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by

approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-

dependent increases in fentanyl released from the system and increased skin permeability. Monitor

patients wearing DURAGESIC systems who develop fever closely for sedation and respiratory

depression and reduce the DURAGESIC dose, if necessary. Warn patients to avoid strenuous

exertion that leads to increased core body temperature while wearing DURAGESIC to avoid the

risk of potential overdose and death.

5.10 Life-Threatening Respiratory Depression in Patients with Chronic

Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of DURAGESIC in patients with acute or severe bronchial asthma in an unmonitored

setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease

DURAGESIC-treated patients with significant chronic obstructive pulmonary disease or cor

pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or

pre-existing respiratory depression are at increased risk of decreased respiratory drive including

apnea, even at recommended dosages of DURAGESIC [see Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated

patients because they may have altered pharmacokinetics or altered clearance compared to younger,

healthier patients [see Warnings and Precautions (5.3)].

Monitor such patients closely, particularly when initiating and titrating DURAGESIC and when

DURAGESIC is given concomitantly with other drugs that depress respiration [see Warnings and

Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients.

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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.

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5.14 Risks of Use in Patients with Increased Intracranial Pressure, Brain

Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO

retention (e.g., those with

evidence of increased intracranial pressure or brain tumors), DURAGESIC may reduce respiratory

drive, and the resultant CO

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)].

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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 ADVERSE REACTIONS

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

 Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

 Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]

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 Accidental Exposure [see Warnings and Precautions (5.4)]

 Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]

 Interactions with Benzodiazepines or Other Central Nervous System Depressants [see

Warnings and Precautions (5.8)]

 Serotonin Syndrome [see Warnings and Precautions (5.11)]

 Adrenal Insufficiency [see Warnings and Precautions (5.12)]

 Severe Hypotension [see Warnings and Precautions (5.13)]

 Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.18)]

 Seizures [see Warnings and Precautions (5.19)]

 Withdrawal [see Warnings and Precautions (5.20)]

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.

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Table 3: Adverse Reactions Reported by ≥1% of DURAGESIC-treated Patients and With an Incidence

Greater Than Placebo-treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of

DURAGESIC

DURAGESIC Placebo

System/Organ Class % %

Adverse Reaction (N=216) (N=200)

Cardiac disorders

Palpitations 4 1

Ear and labyrinth disorders

Verti

o 2 1

Gastrointestinal disorders

ausea 41 17

Vomitin

26 3

Constipation 9 1

Abdominal pain uppe

3 2

mouth 2 0

General disorders and administration site conditions

Fati

ue 6 3

Feelin

col

6 2

Malaise 4 1

Asthenia 2 0

Edema peripheral 1 1

Metabolism and nutrition disorders

Anorexia 5 0

Musculoskeletal and connective tissue disorders

Muscle spasms 4 2

Nervous system disorders

Somnolence 19 3

Dizziness 10 4

Psychiatric disorders

Insomnia 10 7

Depression 1 0

Skin and subcutaneous tissue disorders

perhidrosis 6 1

Pruritus 3 2

Rash 2 1

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.

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Table 4: Adverse Reactions Reported by ≥1% of DURAGESIC-treated Patients in 11 Clinical Trials of

DURAGESIC

System/Organ Class %

Adverse Reaction (N=1854)

Gastrointestinal disorders

Diarrhea 10

Abdominal pain 3

Immune system disorders

persensitivit

Nervous system disorders

Headache 12

Tremo

Paresthesia 2

Psychiatric disorders

Anxiet

Confusional state 2

Hallucination 1

Renal and urinary disorders

Urinar

retention 1

Skin and subcutaneous tissue disorders

thema 1

The following adverse reactions occurred in adult and pediatric patients with an overall frequency

of <1% and are listed in descending frequency within each System/Organ Class:

Cardiac disorders: cyanosis

Eye disorders: miosis

Gastrointestinal disorders: subileus

General disorders and administration site conditions: application site reaction, influenza-like

illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis

Musculoskeletal and connective tissue disorders: muscle twitching

Nervous system disorders: hypoesthesia

Psychiatric disorders: disorientation, euphoric mood

Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: respiratory depression

Skin and subcutaneous tissue disorders: eczema, dermatitis allergic, dermatitis contact

Pediatrics

The safety of DURAGESIC was evaluated in three open-label trials in 289 pediatric patients with

chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥1% of

DURAGESIC-treated pediatric patients are shown in Table 5.

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Table 5: Adverse Reactions Reported by ≥1% of DURAGESIC-treated Pediatric Patients in 3 Clinical

Trials of DURAGESIC

DURAGESIC

System/Organ Class %

Adverse Reaction (N=289)

Gastrointestinal disorders

Vomitin

ausea 24

Constipation 13

Diarrhea 13

Abdominal pain 9

Abdominal pain uppe

mouth 2

General disorders and administration site conditions

Edema

eripheral 5

Fati

ue 2

Application site reaction 1

Asthenia 1

Immune system disorders

persensitivit

Metabolism and nutrition disorders

Anorexia 4

Musculoskeletal and connective tissue disorders

Muscle spasms 2

Nervous system disorders

Headache 16

Somnolence 5

Dizziness 2

Tremo

poesthesia 1

Psychiatric disorders

Insomnia 6

Anxiet

Depression 2

Hallucination 2

Renal and urinary disorders

Urinar

retention 3

Respiratory, thoracic and mediastinal disorders

Respirator

depression 1

Skin and subcutaneous tissue disorders

Pruritus 13

Rash 6

perhidrosis 3

thema 3

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

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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)].

7 DRUG INTERACTIONS

Table 6 includes clinically significant drug interactions with DURAGESIC.

Table 6: Clinically Significant Drug Interactions with DURAGESIC

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of DURAGESIC and CYP3A4 inhibitors can increase the plasma

concentration of fentanyl, resulting in increased or prolonged opioid effects particularly

when an inhibitor is added after a stable dose of DURAGESIC is achieved [see

Warnings and Precautions (5.6)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the

DURAGESIC plasma concentration will decrease [see Clinical Pharmacology (12.3)],

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resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had

developed physical dependence to fentanyl.

Intervention: If concomitant use is necessary, consider dosage reduction of DURAGESIC until stable

drug effects are achieved. Monitor patients for respiratory depression and sedation at

frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the DURAGESIC dosage

until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole),

protease inhibitors (e.g., ritonavir), grapefruit juice

CYP3A4 Inducers

Clinical Impact: The concomitant use of DURAGESIC and CYP3A4 inducers can decrease the plasma

concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased

efficacy or onset of a withdrawal syndrome in patients who have developed physical

dependence to fentanyl [see Warnings and Precautions (5.6)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl

plasma concentration will increase [see Clinical Pharmacology (12.3)], which could

increase or prolong both the therapeutic effects and adverse reactions, and may cause

serious respiratory depression.

Intervention: If concomitant use is necessary, consider increasing the DURAGESIC dosage until

stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4

inducer is discontinued, consider DURAGESIC dosage reduction and monitor for signs

of respiratory depression.

Examples: Rifampin, carbamazepine, phenytoin

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other

CNS depressants, including alcohol, can increase the risk of hypotension, respiratory

depression, profound sedation, coma, and death.

Intervention:

Reserve concomitant prescribing of these drugs for use in patients for whom alternative

treatment options are inadequate. Limit dosages and durations to the minimum

required. Follow patients closely for signs of respiratory depression and sedation [see

Warnings and Precautions (5.8)]. If concomitant use is warranted, consider prescribing

naloxone for the emergency treatment of opioid overdose [see Dosage and

dministration (2.2), Warnin

s and Precautions (5.1, 5.3, 5.8)].

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

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Serotonergic Drugs

Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic

neurotransmitter system has resulted in serotonin syndrome [see Warnings and

Precautions (5.11)].

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during

treatment initiation and dose adjustment. Discontinue DURAGESIC if serotonin

syndrome is suspected.

Examples:

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).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings

and Precautions (5.11)] or opioid toxicity (e.g., respiratory depression, coma).

Intervention: The use of DURAGESIC is not recommended for patients taking MAOIs or within 14

days of stopping such treatment.

Examples: phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact: May reduce the analgesic effect of DURAGESIC and/or precipitate withdrawal

symptoms.

Intervention: Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact: DURAGESIC may enhance the neuromuscular blocking action of skeletal muscle

relaxants and produce an increased degree of respiratory depression.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise

expected and decrease the dosage of DURAGESIC and/or the muscle relaxant as

necessary. 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)].

Diuretics

Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic

hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and

increase the dosage of the diuretic as needed.

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Anticholinergic Drugs

Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention

and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when

DURAGESIC is used concomitantly with anticholinergic drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal

syndrome [see Warnings and Precautions (5.5)]. 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 [see Data].

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

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can

result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly

after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and

abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the

specific opioid used, duration of use, timing and amount of last maternal use, and rate of

elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid

withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)].

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Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects

in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-

induced respiratory depression in the neonate. DURAGESIC is not recommended for use in

pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or

other analgesic techniques are more appropriate. Opioid analgesics, including DURAGESIC, can

prolong labor through actions that temporarily reduce the strength, duration, and frequency of

uterine contractions. However, this effect is not consistent and may be offset by an increased rate

of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics

during labor for signs of excess sedation and respiratory depression.

Data

Human Data

There are no adequate and well-controlled studies in pregnant women. DURAGESIC should be

used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient

respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence

syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were

no more frequent than expected in most studies of infants born to women treated acutely during

labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed

in infants whose mothers were treated with intravenous fentanyl.

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. The high dose was approximately 2 times the daily human dose

administered by a 100 mcg/h patch on a mg/m

basis).

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/m

basis). There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg)

via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease

in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity.

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Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on

embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose

administered by a 100 mcg/hour patch on a mg/m

basis).

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat

model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via

intravenous infusion from Day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment

(0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased

survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated

alterations in some physical landmarks of development (delayed incisor eruption and eye opening)

and transient behavioral development (decreased locomotor activity at Day 28 which recovered by

Day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered

by a 100 mcg/hour patch on a mg/m

basis.

8.2 Lactation

Risk Summary

Fentanyl is excreted in human milk; therefore, DURAGESIC is not recommended for use in

nursing women because of the possibility of effects in their infants.

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

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

[see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

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

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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.

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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 DRUG ABUSE AND DEPENDENCE

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.

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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.

Risks Specific to the Abuse of DURAGESIC

DURAGESIC is intended for transdermal use only. Abuse of DURAGESIC poses a risk of

overdose and death. This risk is increased with concurrent abuse of DURAGESIC with alcohol

and other central nervous system depressants [see Warnings and Precautions (5.8) and Drug

Interactions (7)]. Intentional compromise of the transdermal delivery system may result in the

uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in

overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the

transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting

fentanyl extracted from the transdermal system.

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

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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)].

10 OVERDOSAGE

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)].

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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.

11 DESCRIPTION

The system contains fentanyl, an opioid agonist, for transdermal administration. The amount of

fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per

11 cm

). The composition per unit area of all transdermal system sizes is identical.

Strength

(mcg/hour)

37.5

100

Nominal delivery rate is 12.5 mcg/hour per hour

ominal deliver

rate

er hour

Size

(cm

)

5.5

16.5

Fentanyl

Content

(mg)

1.55

3.1

4.65

6.2

9.3

12.4

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

The molecular weight of fentanyl base is 336.5, and the empirical formula is C

O. The

n-octanol: water partition coefficient is 860:1. The pKa is 8.4.

The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural

formula is:

DURAGESIC is a rectangular translucent system with rounded corners. The product name and

dosage strength are printed in green in the center of each system. The 12 mcg/hour system has a

solid green border and the 25, 37.5, 50, 75 and 100 mcg/hour systems have a green background

with translucent diagonal stripes that alternate in direction and increase in number with each

sequential increasing dosage strength.

Each system is comprised of a siliconized polyethylene terephthalate (PET) release liner and two

functional layers. Proceeding from the outer surface toward the surface adhering to skin, these

functional layers are:

1) a transparent backing layer of ethylene vinyl acetate/polyethylene terephthalate (EVA/PET)

film with green print; 2) a drug-in-adhesive layer containing fentanyl, polyacrylate adhesive, and

isopropyl myristate. Before use, a siliconized PET release liner covering the drug-in-adhesive layer

is removed and discarded.

Release Liner

Drug Containing Layer

Backing Layer

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12 CLINICAL PHARMACOLOGY

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

Effects on the Central Nervous System

Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The

respiratory depression involves a reduction in the responsiveness of the brain stem respiratory

centers to both increases in carbon dioxide tension and electrical stimulation.

Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but

are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce

similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose

situations.

In clinical trials of 357 non-opioid tolerant subjects treated with DURAGESIC, 13 subjects

experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than

8 breaths/minute or a pCO

greater than 55 mm Hg. In these studies, the incidence of

hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing

less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in

the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been

received that describe opioid-naive post-operative patients who have experienced clinically

significant hypoventilation and death with DURAGESIC.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations,

especially for patients who have an underlying pulmonary condition or who receive concomitant

opioids or other CNS drugs associated with hypoventilation. The use of DURAGESIC is

contraindicated in patients who are not tolerant to opioid therapy.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the

antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and

propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased,

while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced

effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi,

and transient elevations in serum amylase.

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Effects on the Cardiovascular System

Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing,

red eyes, sweating, and/or orthostatic hypotension.

Histamine assays and skin wheal testing in clinical studies indicate that clinically significant

histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically

significant histamine release in dosages up to 50 mcg/kg.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing

hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth

hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to

androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea,

or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown

because the various medical, physical, lifestyle, and psychological stressors that may influence

gonadal hormone levels have not been adequately controlled for in studies conducted to date [see

Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in

in-vitro and animal models. The clinical significance of these findings is unknown. Overall, the

effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially

among patients who have been previously treated with potent agonist opioids. The minimum

effective analgesic concentration of fentanyl for any individual patient may increase over time due

to an increase in pain, the development of a new pain syndrome, and/or the development of

analgesic tolerance [see Dosage and Administration (2.1, 2.4)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing fentanyl plasma concentration and increasing frequency

of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory

depression. In opioid-tolerant patients, the situation may be altered by the development of

tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.3, 2.4)].

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12.3 Pharmacokinetics

Absorption

DURAGESIC is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the

matrix at a nearly constant amount per unit time. The concentration gradient existing between the

matrix and the lower concentration in the skin, drives drug release. Fentanyl moves in the direction

of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through

the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour

application period, each system is labeled with a nominal flux which represents the average amount

of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (12.5,

25, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual

titration of dosage for a given patient.

Following DURAGESIC application, the skin under the system absorbs fentanyl, and a depot of

fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic

circulation. Serum fentanyl concentrations increase gradually following initial DURAGESIC

application, generally leveling off between 12 and 24 hours and remaining relatively constant, with

some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations

of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 6).

Serum fentanyl concentrations achieved are proportional to the DURAGESIC delivery rate. With

continuous use, serum fentanyl concentrations continue to rise for the first two system applications.

By the end of the second 72-hour application, a steady-state serum concentration is reached and is

maintained during subsequent applications of a patch of the same size (see Figure 1). Patients reach

and maintain a steady-state serum concentration that is determined by individual variation in skin

permeability and body clearance of fentanyl.

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in

approximately 20–27 hours. Continued absorption of fentanyl from the skin accounts for a slower

disappearance of the drug from the serum than is seen after an IV infusion, where the apparent

half-life is approximately 7 (range 3–12) hours.

A clinical pharmacology study conducted in healthy adult subjects has shown that the application

of heat over the DURAGESIC system increased mean overall fentanyl exposure by 120% and

average maximum fentanyl level by 61%.

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Table 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of DURAGESIC

Mean (SD) Time to Mean (SD)

Maximal Maximal

Concentration Concentration

max

(h) (n

/mL)

DURAGESIC 12 mcg/hour 28.8 (13.7) 0.38 (0.13)*

DURAGESIC 25 mcg/hour 31.7 (16.5) 0.85 (0.26)**

DURAGESIC 50 mcg/hour 32.8 (15.6) 1.72 (0.53)**

DURAGESIC 75 mcg/hour 35.8 (14.1) 2.32 (0.86)**

DURAGESIC 100 mcg/hour 29.9 (13.3) 3.36 (1.28)**

* C

max

values dose normalized from 4 × 12.5 mcg/h: Study 2003-038 in healthy volunteers

** C

max

values: Study C-2002-048 dose proportionality study in healthy volunteers

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that

serum concentrations fall 50%, on avera

e, in approximatel

20-27 hours.

Figure 1: Serum Fentanyl Concentrations

Following Single and Multiple Applications of DURAGESIC 100 mcg/h

Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl In Patients

Clearance Volume of Distribution Half-Life

(L/h) V

1/2

Range (L/kg) (h)

[70 kg] Range Range

Surgical Patients 27–75 3–8 3–12

Hepatically Impaired Patients 3–80

0.8–8

4–12

Renall

Impaired Patients 30

–

Estimated

NOTE: Information on volume of distribution and half-life not available for renall

impaired patients.

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Distribution

Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug.

Alterations in pH may affect its distribution between plasma and the central nervous system.

Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The

average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8).

Elimination

Metabolism

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans,

the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other

inactive metabolites that do not contribute materially to the observed activity of the drug.

Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a

human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the

system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Excretion

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine,

mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the

dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of

fentanyl in plasma are estimated to be between 13 and 21%.

Specific Populations

Age: Geriatric Population

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 fentanyl transdermal

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. In this study, a single

DURAGESIC 100 mcg/hour patch was applied to a skin site on the upper outer arm in a group of

healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The

mean C

max

and AUC

∞

values were approximately 8% lower and 7% higher, respectively, in the

elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC

∞

was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%,

respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to

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45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.10) and Use in

Specific Populations (8.5)].

Age: Pediatric Population

In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were

approximately twice as high as that of adult patients. In older pediatric patients, the

pharmacokinetic parameters were similar to that of adults. However, these findings have been

taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric

patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and

Administration (2.3)].

Hepatic Impairment

Information on the effect of hepatic impairment on the pharmacokinetics of DURAGESIC is

limited. The pharmacokinetics of DURAGESIC delivering 50 mcg/hour of fentanyl for 72 hours

was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C

max

and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.

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 Dosing and Administration (2.5), Warnings and Precautions (5.16), and Use in

Specific Populations (8.6)].

Renal Impairment

Information on the effect of renal impairment on the pharmacokinetics of DURAGESIC is limited.

The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients

(n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen

level and fentanyl clearance was found.

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

Dosing and Administration (2.6), Warnings and Precautions (5.17) and Use in Specific

Populations (8.7)].

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Drug Interaction Studies

CYP3A4 Inhibitors

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system

(CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated

in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or

placebo for 3 days. The ritonavir dose was 200 mg three times a day on Day 1 and 300 mg three

times a day on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was

given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo.

Naloxone was administered to counteract the side effects of fentanyl. The results suggested that

ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%–420%)

increase in fentanyl AUC

0-∞

. The concomitant use of transdermal fentanyl with all CYP3A4

inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin,

nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,

fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma

concentrations, which could increase or prolong adverse drug effects and may cause potentially

fatal respiratory depression. Carefully monitor patients receiving DURAGESIC and any CYP3A4

inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage

if warranted [see Boxed Warning and Warnings and Precautions (5.6), and Drug Interactions (7)].

CYP3A4 Inducers

Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of

DURAGESIC.

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an

increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or

100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the

100 mcg/h patch based on AUC

0-24h

comparison).

Mutagenesis

There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary

rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the

human lymphocyte and CHO chromosomal aberration in vitro assays.

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Impairment of Fertility

The potential effects of fentanyl on male and female fertility were examined in the rat model via

two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025,

0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats

were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1

or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of

pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated

that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone

produced no effects on fertility (this dose is approximately 1.6 times the daily human dose

administered by a 100 mcg/hour patch on a mg/m

basis). In a separate study, a single daily bolus

dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times

the human dose for a period of 12 days.

14 CLINICAL STUDIES

DURAGESIC as therapy for pain due to cancer has been studied in 153 patients. In this patient

population, DURAGESIC has been administered in doses of 25 mcg/h to 600 mcg/h. Individual

patients have used DURAGESIC continuously for up to 866 days. At one month after initiation of

DURAGESIC therapy, patients generally reported lower pain intensity scores as compared to a

pre-study analgesic regimen of oral morphine.

The duration of DURAGESIC use varied in cancer patients; 56% of patients used DURAGESIC

for over 30 days, 28% continued treatment for more than 4 months, and 10% used DURAGESIC

for more than 1 year.

In the pediatric population, the safety of DURAGESIC has been evaluated in 289 patients with

chronic pain 2–18 years of age. The duration of DURAGESIC use varied; 20% of pediatric

patients were treated for ≤ 15 days; 46% for 16–30 days; 16% for 31–60 days; and 17% for at least

61 days. Twenty-five patients were treated with DURAGESIC for at least 4 months and 9 patients

for more than 9 months.

16 HOW SUPPLIED/STORAGE AND HANDLING

DURAGESIC (fentanyl transdermal system) is supplied in cartons containing 5 individual child-

resistant packaged systems. See chart for information regarding individual systems.

DURAGESIC Strength

(mcg/hour)

DURAGESIC-12

DURAGESIC-25

DURAGESIC-37.5

System

Size

(cm

)

5.5

11.5

16.5

Fentanyl

Content

(mg)

1.55

3.1

4.65

NDC

Number

50458-101-05

50458-102-05

50458-103-05

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DURAGESIC-50 22 6.2 50458-104-05

DURAGESIC-75 33 9.3 50458-105-05

DURAGESIC-100 44 12.4 50458-106-05

This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to

distinguish it from a 125 mcg/hour strength that could be prescribed by using multiple transdermal systems.

The 37.5 mcg/hour strength is not available as DURAGESIC. It is available as Fentanyl Transdermal

stem.

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)].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions

for Use).

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.

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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.

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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:

Reference ID: 4756459

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

 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

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of DURAGESIC during

pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if

not recognized and treated [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].

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 [see Use in Specific Populations

(8.1)].

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)].

Reference ID: 4756459

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

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)].

Manufactured by:

ALZA Corporation

Vacaville, CA 95688

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560

Revised 03/2021

 2018 Janssen Pharmaceuticals, Inc.

Reference ID: 4756459

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

Medication Guide

DURAGESIC

(Dur-ah-GEE-zik) (fentanyl) Transdermal System, CII

DURAGESIC

is:

 A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough

to require daily around-the-clock, long-term treatment with an opioid, in people who are already regularly using

opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid

medicines do not treat your pain well enough or you cannot tolerate them.

 A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you

take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to

death.

 Not for use to treat pain that is not around-the-clock.

Important information about DURAGESIC

 Get emergency help or call 911 right away if you use 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.

 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.

 Never give anyone else your DURAGESIC

. They could die from taking it. Selling or giving away DURAGESIC

against the law.

 Store DURAGESIC

, securely, out of sight and reach of children, and in a location not accessible by others,

including visitors to the home.

 If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with

water, and get emergency help right away because an accidental exposure to DURAGESIC

can lead to death or