FENTANYL - fentanyl patch, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FENTANYL (UNII: UF599785JZ) (FENTANYL - UNII:UF599785JZ)
Available from:
Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC
INN (International Name):
FENTANYL
Composition:
FENTANYL 7.5 mg in 72 h
Administration route:
TRANSDERMAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Fentanyl transdermal system is indicated for management of persistent , moderate to severe chronic pain that: - requires continuous, around-the-clock opioid administration for an extended period of time, and requires continuous, around-the-clock opioid administration for an extended period of time, and - cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids. cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids. Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/h (see DOSAGE AND ADMINISTRATION ). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg
Product summary:
Fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems. See chart for information regarding individual systems. Fentanyl transdermal system is supplied in sealed transdermal systems which pose little risk of exposure to health care workers. If the gel from the drug reservoir accidentally contacts the skin, the area should be washed with copious amounts of water. Do not use soap, alcohol, or other solvents to remove the gel because they may enhance the drug’s ability to penetrate the skin. Do not use a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal. KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND PETS. Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature.] Apply immediately after removal from individually sealed package. Do not use if the seal is broken. For transdermal use only. A SCHEDULE CII NARCOTIC. DEA ORDER FORM REQUIRED. Manufactured by: Watson Laboratories, Inc Corona, CA 92880 USA Distributed by: Watson Pharma, Inc. Corona, CA 92880 USA Revised: August 2008
Authorization status:
Abbreviated New Drug Application
Authorization number:
49999-833-05

FENTANYL - fentanyl patch, extended release

Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

----------

Fentanyl Transdermal System C-II

Revised: August 2008

Rx only

Full Prescribing Information

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid

agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone,

methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse

and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused

and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl

transdermal system) may be a particular target for abuse and diversion.

Fentanyl transdermal system is indicated for management of persistent, moderate to severe

chronic pain that:

requires continuous, around-the-clock opioid administration for an extended period of

time, and

cannot be managed by other means such as non-steroidal analgesics, opioid

combination products, or immediate-release opioids

Fentanyl transdermal system should ONLY be used in patients who are already receiving

opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose

at least equivalent to fentanyl transdermal system 25 mcg/h. Patients who are considered

opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of

morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral

hydromorphone daily or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal

system is contraindicated:

in patients who are not opioid-tolerant

in the management of acute pain or in patients who require opioid analgesia for a short

period of time

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

surgeries (e.g., tonsillectomies)

in the management of mild pain

in the management of intermittent pain [e.g., use on an as needed basis (prn)]

(See CONTRAINDICATIONS for further information.)

Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers

should be aware that serious or life threatening hypoventilation may occur, even in opioid-

tolerant patients, during the initial application period.

The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4

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

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

fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in

fentanyl plasma concentrations, which could increase or prolong adverse drug effects and

may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal

system and potent any CYP3A4 inhibitor should be carefully monitored for an extended

period of time and dosage adjustments should be made if warranted. (See CLINICAL

PHARMACOLOGY – Drug Interactions, WARNINGS, PRECAUTIONS and DOSAGE

AND ADMINISTRATION for further information).

The safety of fentanyl transdermal system has not been established in children under 2

years of age. Fentanyl transdermal system should be administered to children only if they

are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use.)

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid

therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal

respiratory depression. Overestimating the fentanyl transdermal system dose when

converting patients from another opioid medication can result in fatal overdose with the

first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system,

patients who are thought to have had a serious adverse event, including overdose, will

require monitoring and treatment for at least 24 hours.

Fentanyl transdermal system can be abused in a manner similar to other opioid agonists,

legal or illicit. This risk should be considered when administering, prescribing, or

dispensing fentanyl transdermal system in situations where the healthcare professional is

concerned about increased risk of misuse, abuse or diversion.

Persons at increased risk for opioid abuse include those with a personal or family history of

substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g.,

major depression). Patients should be assessed for their clinical risks for opioid abuse or

addiction prior to being prescribed opioids. All patients receiving opioids should be

routinely monitored for signs of misuse, abuse and addiction. Patients at increased risk of

opioid abuse may still be appropriately treated with modified-release opioid formulations;

however, these patients will require intensive monitoring for signs of misuse, abuse, or

addiction.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do

not use a fentanyl transdermal system patch if the seal is broken or the patch is cut,

damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way

can expose the patient or caregiver to the contents of the patch, which can result in an

overdose of fentanyl that may be fatal.

Avoid exposing the fentanyl transdermal system application site and surrounding area to

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

lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot

baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl

released from the system resulting in possible overdose and death. Patients wearing

fentanyl transdermal systems who develop fever or increased core body temperature due to

strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal

system dose should be adjusted if necessary.

DESCRIPTION

Fentanyl transdermal system is a transdermal system providing continuous systemic delivery of fentanyl,

a potent opioid analgesic, for 72 hours. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-

piperidinyl) propanamide. The structural formula is:

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

H N O. The n-

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

System Components and Structure

The amount of fentanyl released from each system per hour is proportional to the surface area (25

mcg/h per 10 cm ). The composition per unit area of all system sizes is identical. Each system also

contains 0.1 mL of alcohol USP per 10 cm .

Dose*

(mcg/h)

Size

(cm )

Fentanyl

Content

(mg)

*Nominal delivery rate per hour

Fentanyl transdermal system is a rectangular transparent unit comprising a protective liner and four

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

layers are:

1) a backing layer of polyester film; 2) a drug reservoir of fentanyl and alcohol USP gelled with

hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of

fentanyl delivery to the skin surface; and 4) a fentanyl containing silicone adhesive. Before use, a

protective liner covering the adhesive layer is removed and discarded.

The active component of the system is fentanyl. The remaining components are pharmacologically

inactive. Less than 0.2 mL of alcohol is also released from the system during use.

CLINICAL PHARMACOLOGY

Pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid mu-receptor. These

mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical

settings, fentanyl exerts its principal pharmacologic effects on the central nervous system.

In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur.

Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.

Analgesic blood levels of fentanyl may cause nausea and vomiting directly by stimulating the

chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than

in recumbent patients, as is postural syncope.

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the

gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for

the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients

with biliary colic may experience worsening rather than relief of pain.

While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be

2

variable, in some cases producing urinary urgency, in others, difficulty in urination. At therapeutic

dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some

patients may exhibit orthostatic hypotension and fainting.

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.

Pharmacokinetics (see graph and tables)

Fentanyl transdermal system releases fentanyl from the reservoir at a nearly constant amount per unit

time. The concentration gradient existing between the saturated solution of drug in the reservoir 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 copolymer release membrane 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 (25, 50, 75,

and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a

given patient. The small amount of alcohol which has been incorporated into the system enhances the

rate of drug flux through the rate-limiting copolymer membrane and increases the permeability of the

skin to fentanyl.

Following fentanyl transdermal system 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 fentanyl transdermal

system 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 24 and 72 hours after initial application (see Table A). Serum

fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With

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

After several sequential 72-hour applications, patients reach and maintain a steady state serum

concentration that is determined by individual variation in skin permeability and body clearance of

fentanyl (see graph and Table B).

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

approximately 17 (range 13 to 22) 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 to 12) hours.

TABLE A FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-

HOUR APPLICATION OF A FENTANYL TRANSDERMAL SYSTEM

Mean (SD) Time to Maximal

Concentration

T

(h)

Mean (SD)

Maximal Concentration

C

(ng/mL)

Fentanyl Transdermal System 25 mcg/h

38.1 (18.0)

0.6 (0.3)

Fentanyl Transdermal System 50 mcg/h

34.8 (15.4)

1.4 (0.5)

Fentanyl Transdermal System 75 mcg/h

33.5 (14.5)

1.7 (0.7)

Fentanyl Transdermal System 100 mcg/h

36.8 (15.7)

2.5 (1.2)

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

so that serum concentrations fall 50%, on average, in 17 hours.

TABLE B RANGE OF PHARMACOKINETIC PARAMETERS OF

INTRAVENOUS FENTANYL IN PATIENTS

Clearance

(L/h)

Range

[70 kg]

Volume of Distribution

V

(L/kg)

Range

Half-life

T

(h)

Range

+Estimated

Surgical Patients

27 – 75

3 – 8

3 – 12

Hepatically Impaired Patients

3 – 80+

0.8 – 8+

4 – 12+

Renally Impaired Patients

30 – 78

NOTE: Information on volume of distribution and half-life not available for renally impaired patients.

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 to 8; N=8).

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. 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%.

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.

Special Populations

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of fentanyl transdermal

system in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human

cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these

patients, it should be used with caution because of the hepatic metabolism and renal excretion of

fentanyl.

Pediatric Use

max

max

SS

1/2

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 DOSAGE AND ADMINISTRATION section.

Geriatric Use

Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N=4)

indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60.

The relevance of these findings to fentanyl transdermal system is unknown at this time.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large

initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that

depress respiration.

Fentanyl transdermal systems should be used with caution in elderly, cachectic or debilitated patients as

they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance

(see DOSAGE AND ADMINISTRATION).

Drug Interactions

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 tid on Day 1 and 300 mg tid 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% to 420%) increase in fentanyl AUC

. Coadministration of ritonavir in patients

receiving fentanyl transdermal system has not been studied; however, an increase in fentanyl AUC is

expected. (see BOX WARNING, WARNINGS, PRECAUTIONS and DOSAGE AND

ADMINISTRATION).

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4),

therefore, potential interactions may occur when fentanyl transdermal system is given concurrently with

agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may

reduce the efficacy of fentanyl transdermal systems. The concomitant use of transdermal fentanyl with

all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin,

nelfinavir, nefazadone, amiodarmone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,

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

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

respiratory depression. Patients receiving fentanyl transdermal systems and any CYP3A4 inhibitor

should be carefully monitored for an extended period of time and dosage adjustments should be made if

warranted (see BOX WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND

ADMINISTRATION for further information).

Pharmacodynamics

Ventilatory Effects

Because of the risk for serious or life-threatening hypoventilation, fentanyl transdermal system is

CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not

opioid-tolerant. In clinical trials of 357 patients with acute pain treated with fentanyl transdermal system,

13 patients 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 patients weighing less than

63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had

0-∞

higher rates of hypoventilation. In addition, post-marketing reports have been received that describe

opioid-naïve post-operative patients who have experienced clinically significant hypoventilation and

death with fentanyl transdermal system.

While most adult and pediatric patients using fentanyl transdermal system chronically develop tolerance

to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during

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

especially for patients who have an underlying pulmonary condition or who receive usual doses of

opioids or other CNS drugs associated with hypoventilation in addition to fentanyl transdermal system.

The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid

therapy.

The use of fentanyl transdermal system should be monitored by clinical evaluation, especially within the

initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following

increases in dosage. Fentanyl transdermal system should be administered to children only if they are

opioid-tolerant and 2 years of age or older.

See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE

REACTIONS, and OVERDOSAGE for additional information on hypoventilation.

Cardiovascular Effects

Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with

fentanyl transdermal system was less than 1%.

CNS Effects

Central nervous system effects increase with increasing serum fentanyl concentrations.

INDICATIONS AND USAGE

Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain

that:

requires continuous, around-the-clock opioid administration for an extended period of time, and

cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or

immediate-release opioids.

Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy,

who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to

fentanyl transdermal system 25 mcg/h (see DOSAGE AND ADMINISTRATION). Patients who are

considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of

morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone

daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is

contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute

pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of

time. (see BOX WARNING and CONTRAINDICATIONS).

An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is

advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize

treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid

analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of

pain management such as outlined by the World Health Organization, the Agency for Health Research

and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being

prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse,

abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family

history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major

depression). Patients at increased risk may still be appropriately treated with modified-release opioid

formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or

addiction.

CONTRAINDICATIONS

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is

contraindicated:

in patients who are not opioid-tolerant

in the management of acute pain or in patients who require opioid analgesia for a short period

of time

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

(e.g., tonsillectomies)

in the management of mild pain

in the management of intermittent pain (e.g., use on an as needed basis [prn])

in situations of significant respiratory depression, especially in unmonitored settings where

there is a lack of resuscitative equipment

in patients who have acute or severe bronchial asthma

Fentanyl transdermal system is contraindicated in patients who have or are suspected of having

paralytic ileus.

Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to

fentanyl or any components of this product.

WARNINGS

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use

a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged, or

changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the

patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that

may be fatal.

The safety of fentanyl transdermal system has not been established in children under 2 years of

age. Fentanyl transdermal system should be administered to children only if they are opioid-

tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid

therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory

depression. Overestimating the fentanyl transdermal system dose when converting patients from

another opioid medication can result in fatal overdose with the first dose. The mean elimination

half-life of fentanyl transdermal system is 17 hours. Therefore, patients who have experienced

serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl

transdermal system removal since serum fentanyl concentrations decline gradually and reach an

approximate 50% reduction in serum concentrations 17 hours after system removal.

Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous

administration of potent opioids, in the management of patients receiving potent opioids for treatment of

pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal

system application site to direct external heat sources, such as heating pads or electric blankets,

heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system.

Patients should be advised against taking hot baths or sunbathing. There is a potential for

temperature-dependent increases in fentanyl released from the system resulting in possible

overdose and death.

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. Patients

wearing fentanyl transdermal systems who develop fever or increased core body temperature

due to strenuous exertion should be monitored for opioid side effects and the fentanyl

transdermal system dose should be adjusted if necessary.

Death and other serious medical problems have occurred when people were accidentally exposed to

fentanyl transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal

system from an adult’s body to a child while hugging, accidental sitting on a patch and possible

accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was

applying or removing the patch.

Placing fentanyl transdermal system 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.

Misuse, Abuse and Diversion of Opioids

Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people

with addiction disorders and are subject to criminal diversion.

Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered

when prescribing or dispensing fentanyl transdermal system in situations where the physician or

pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Fentanyl transdermal system has been reported as being abused by other methods and routes of

administration. These practices will result in uncontrolled delivery of the opioid and pose a significant

risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND

ADDICTION).

Concerns about abuse, addiction and diversion should not prevent the proper management of pain.

However, all patients treated with opioids require careful monitoring for signs of abuse and addiction,

since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their state professional licensing board or state controlled

substances authority for information on how to prevent and detect abuse or diversion of this product.

Hypoventilation (Respiratory Depression)

Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal

system especially during the initial 24 to 72 hours following initiation of therapy and following

increases in dose.

Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch

is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system.

Consequently, patients with hypoventilation should be carefully observed for degree of sedation and

their respiratory rate monitored until respiration has stabilized.

The use of concomitant CNS active drugs requires special patient care and observation.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in

fentanyl transdermal system. Respiratory depression is more likely to occur in elderly or debilitated

patients, usually following large initial doses in non-tolerant patients, or when opioids are given in

conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of

respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by

abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can

exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative

properties and opioids especially dangerous.

Fentanyl transdermal system should be used with extreme caution in patients with significant chronic

obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased

respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even

usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of

apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be

employed only under careful medical supervision at the lowest effective dose.

Chronic Pulmonary Disease

Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal

system should be administered with caution to patients with pre-existing medical conditions

predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further

decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure

Fentanyl transdermal system should not be used in patients who may be particularly susceptible to the

intracranial effects of CO retention such as those with evidence of increased intracranial pressure,

impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury.

Fentanyl transdermal system should be used with caution in patients with brain tumors.

Interactions with other CNS Depressants

The concomitant use of fentanyl transdermal system with other central nervous system depressants,

including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines),

general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory

depression, hypotension, and profound sedation or potentially result in coma. When such combined

therapy is contemplated, the dose of one or both agents should be significantly reduced.

Interactions with Alcohol and Drugs of Abuse

Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with

alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Interactions with CYP3A4 Inhibitors

The concomitant use of fentanyl transdermal system with all CYP3A4 inhibitors (such as ritonavir,

ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone, amiodarone,

amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and

verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong

adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl

transdermal system and any CYP3A4 inhibitors should be carefully monitored for an extended period of

time and dosage adjustments should be made if warranted. (see BOX WARNING, CLINICAL

PHARMACOLOGY – Drug Interactions, PRECAUTIONS and DOSAGE AND

ADMINISTRATION for further information.)

PRECAUTIONS

General

Fentanyl transdermal system should not be used to initiate opioid therapy in patients who are not opioid-

tolerant. Children converting to fentanyl transdermal system should be opioid-tolerant and 2 years of age

or older (see BOX WARNING.)

Patients, family members and caregivers should be instructed to keep patches (new and used) out of the

reach of children and others for whom fentanyl transdermal system was not prescribed. A considerable

amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Accidental

or deliberate application or ingestion by a child or adolescent will cause respiratory depression that

could result in death.

Cardiac Disease

Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with

bradyarrhythmias.

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of fentanyl transdermal

system in patients with impaired renal or hepatic function. If the drug is used in these patients, it should

be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Use in Pancreatic/Biliary Tract Disease

Fentanyl transdermal system may cause spasm of the sphincter of Oddi and should be used with caution

in patients with biliary tract disease, including acute pancreatitis. Opioids like fentanyl transdermal

system may cause increases in the serum amylase concentration.

Tolerance

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution

of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired

effects of drugs, and may develop at different rates for different effects.

Physical Dependence

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal

syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the

drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is

characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning,

perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness,

abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,

respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE

AND ADMINISTRATION - Discontinuation of fentanyl transdermal system).

Ambulatory Patients

Strong opioid analgesics impair the mental or physical abilities required for the performance of

potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given

fentanyl transdermal system should not drive or operate dangerous machinery unless they are tolerant to

the effects of the drug.

Information for Patients

Patients and their caregivers should be provided with a Medication Guide each time fentanyl

transdermal system is dispensed because new information may be available.

Patients receiving fentanyl transdermal systems should be given the following instructions by the

physician:

1. Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid

pain medicine similar to

morphine, hydromorphone, methadone, oxycodone, and oxymorphone.

2. Patients should be advised that each fentanyl transdermal system may be worn continuously

for 72 hours, and that each patch should be applied to a different skin site after removal of the

previous transdermal patch.

3. Patients should be advised that fentanyl transdermal systems should be applied to intact, non-irritated,

and non-irradiated skin

on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should be advised

of the following:

In young children or persons with cognitive impairment, the patch should be put on the upper

back to lower the chances that the patch will be removed and placed in the mouth.

Hair at the application site should be clipped (not shaved) prior to patch application.

If the site of fentanyl transdermal system 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.

4. Patients should be advised that fentanyl transdermal system

should be applied immediately upon removal from the sealed package and after removal of the

protective liner. Additionally the patient should be advised of the following:

The fentanyl transdermal system should not be used if the seal is broken, or if the patch is cut,

damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can

expose the patient or caregiver to the contents of the patch, which can result in an overdose of

fentanyl that may be fatal.

The transdermal patch should be pressed firmly in place with the palm of the hand for 30

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

The patch should not be folded so that only part of the patch is exposed.

5. Patients should be advised that the dose of fentanyl transdermal system or the number of patches

applied to the skin should NEVER be adjusted without the prescribing healthcare professional’s

instruction.

6. Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl

transdermal system application site to direct external heat sources, such as:

heating pads,

electric blankets,

sunbathing

heat or tanning lamps,

saunas,

hot tubs, or hot baths, and

heated water beds, etc.

7. Patients should also be advised of a potential for temperature-dependent increase in fentanyl release

from the patch that could result in an overdose of fentanyl; therefore, if patients who develop a high

fever or increased body temperature due to strenuous exertion while wearing the patch they should

contact their physician.

8. Patients should be advised that if they experience problems with adhesion of the fentanyl

transdermal system, they may tape the edges of the patch with first aid tape.

9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a

different skin site.

10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush

down the toilet used fentanyl transdermal patches after removal from the skin.

11. Patients should be instructed that, if the gel from the drug reservoir accidentally contacts the skin,

the area should be washed clean with clear water and not soap, alcohol, or other chemicals, because

these products may increase the ability of fentanyl to go through the skin.

12. Patients should be advised that fentanyl transdermal system may impair mental and/or physical ability

required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).

13. Patients should be advised to refrain from any potentially dangerous activity when starting on

fentanyl transdermal system or when their dose is being adjusted, until it is established that they have

not been adversely affected.

14. Patients should be advised that fentanyl transdermal system should not be combined with alcohol or

other CNS depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects

may occur, resulting in serious injury or death.

15. Patients should be advised to consult their physician or pharmacist if other medications are being or

will be used with fentanyl transdermal system.

16. Patients should be advised of the potential for severe constipation.

17. Patients should be advised that if they have been receiving treatment with fentanyl transdermal

system and cessation of therapy is indicated, it may be appropriate to taper the fentanyl transdermal

system dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal

symptoms.

18. Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with a high

potential for abuse.

19. Patients, family members and caregivers should be advised to protect fentanyl transdermal system

from theft or misuse in the work or home environment.

20. Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach

of children due to the high risk of fatal respiratory depression.

21. Patients should be advised that fentanyl transdermal system should never be given to anyone other

than the individual for whom it was prescribed because of the risk of death or other serious medical

problems to that person for whom it was not intended.

22. Patients should be informed that, if the patch dislodges and accidentally sticks to skin of another

person, they should immediately take the patch off, wash the exposed area with water and seek

medical attention for the accidentally exposed individual

23. When fentanyl transdermal system is no longer needed, the unused patches should be removed from

their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the

to ilet.

24. Women of childbearing potential who become, or are planning to become pregnant, should be

advised to consult a physician prior to initiating or continuing therapy with fentanyl transdermal

system.

25. Patients should be informed that accidental exposure or misuse may lead to death or other serious

medical problems.

Drug Interactions

Agents Affecting Cytochrome P450 3A4 Isoenzyme System

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4),

therefore potential interactions may occur when fentanyl transdermal system is given concurrently with

agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity may

reduce the efficacy of fentanyl transdermal system. The concomitant use of transdermal fentanyl with all

CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin,

nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,

fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma

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

depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be

carefully monitored for an extended period of time, and dosage adjustments should be made if warranted

(see BOX WARNING, CLINICAL PHARMACOLOGY – Drug Interactions, WARNINGS, and

DOSAGE AND ADMINISTRATION for further information).

Central Nervous System Depressants

The concomitant use of fentanyl transdermal system with other central nervous system depressants,

including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines),

general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory

depression, hypotension, and profound sedation, or potentially result in coma or death. When such

combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

MAO Inhibitors

Fentanyl transdermal system is not recommended for use in patients who have received MAOI within 14

days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid

analgesics.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in animals to evaluate the carcinogenic potential of fentanyl HCl have not been conducted.

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.

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/hr 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.

Pregnancy - Pregnancy Category C

No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl

during pregnancy have been reported.

The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit

models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 µg/kg/day) to

pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not

produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose

administered by a 100 mcg/hr patch on a mg/m basis). In contrast, the intravenous administration of

fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of

embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. 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. 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/hr patch on a mg/m basis).

There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system

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

Nonteratogenic Effects

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.

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 though 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/hr patch on a mg/m basis.

Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl transdermal system is not

recommended for analgesia during labor and delivery.

Nursing Mothers

Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for use in

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

Pediatric Use

The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 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 or

oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system

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. Approximately 90% of the total daily

opioid requirement (fentanyl transdermal system plus rescue medication) was provided by fentanyl

transdermal system.

Fentanyl transdermal system was not studied in children under 2 years of age.

Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2

years of age or older (see DOSAGE AND ADMINISTRATION and BOX WARNING).

To guard against accidental ingestion by children, use caution when choosing the application site for

fentanyl transdermal system (see DOSAGE AND ADMINISTRATION) and monitor adhesion of the

system closely.

Geriatric Use

Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N=4)

indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60.

The relevance of these findings to fentanyl transdermal system is unknown at this time.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large

initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that

depress respiration.

Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as

they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see

DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

In post-marketing experience, deaths from hypoventilation due to inappropriate use of fentanyl

transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS).

Pre-marketing Clinical Trial Experience

Although fentanyl transdermal system use in post-operative or acute pain and in patients who are not

opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was originally

evaluated in 357 post-operative adult patients for 1 to 3 days and 153 cancer patients for a total of 510

patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used

fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10%

used fentanyl transdermal system for more than 1 year.

Hypoventilation was the most serious adverse reaction observed in 13 (4%) post-operative patients and

in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of

the opioid-naïve patients.

Various adverse events were reported; a causal relationship to fentanyl transdermal system was not

always determined. The frequencies presented here reflect the actual frequency of each adverse effect

in patients who received fentanyl transdermal system. There has been no attempt to correct for a placebo

effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated

patients in controlled trials.

Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in

Table 1; similar reactions were seen in the 357 post-operative patients.

In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients

with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of

pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17%

for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4

months and 9 patients for more than 9 months.

There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in

children as young as 2 years old when used as directed. The most common adverse events were fever

(35%), vomiting (33%), and nausea (24%).

Adverse events reported in pediatric patients at a rate of ≥ 1% are presented in Table 1.

TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%) Adult (N=380) and Pediatric (N=291) Clinical

Trial Experience

Body System Adults

Pediatrics

Body as a

Whole

Abdominal pain*, headache*, fatigue*,back pain,

fever, influenza-like symptoms*, accidental injury,

rigors

Pain*, headache*, fever,

syncope, abdominal pain, allergic

reaction, flushing

Cardiovascular Arrhythmia, chest pain

Hypertension, tachycardia

Digestive

Nausea**, vomiting**, constipation**, dry mouth**,

anorexia*, diarrhea*, dyspepsia*, flatulence

Nausea**, vomiting**,

constipation*, dry mouth, diarrhea

Nervous

Somnolence**, insomnia, confusion**, asthenia**,

dizziness*, nervousness*, hallucinations*, anxiety*,

depression*, euphoria*, tremor, abnormal

coordination, speech disorder, abnormal thinking,

abnormal gait, abnormal dreams, agitation,

paresthesia, amnesia, syncope, paranoid reaction

Somnolence*, nervousness**,

insomnia*, asthenia*,

hallucinations, anxiety,

depression, convulsions,

dizziness, tremor, speech

disorder, agitation, stupor,

confusion, paranoid reaction

Respiratory

Dyspnea*, hypoventilation*, apnea*, hemoptysis,

pharyngitis*, hiccups, bronchitis, rhinitis, sinusitis,

upper respiratory tract infection*

Dyspnea, respiratory depression,

rhinitis, coughing

Skin and

Appendages

Sweating**, pruritus*, rash, application site

reaction-erythema, papules, itching, edema

Pruritus*, application site

reaction*, sweating increased,

* Reactions occurring in 3% to 10% of fentanyl transdermal system patients

** Reactions occurring in 10% or more of fentanyl transdermal system patients

rash, rash erythematous, skin

reaction localized

Urogenital

Urinary retention* Micturition disorder

Urinary retention

The following adverse effects have been reported in less than 1% of the 510 adult post-operative and

cancer patients studied:

Cardiovascular: bradycardia

Digestive: abdominal distention

Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility

Respiratory: stertorous breathing, asthma, respiratory disorder

Skin and Appendages, General: exfoliative dermatitis, pustules

Special Senses: amblyopia

Urogenital: bladder pain, oliguria, urinary frequency

Post-Marketing Experience - Adults

The following adverse reactions have been reported in association with the use of fentanyl transdermal

system and not reported in the pre-marketing adverse reactions section above:

Body as a Whole: Edema

Cardiovascular: tachycardia

Metabolic and Nutritional: weight loss

Special Senses: blurred vision

Urogenital: decreased libido, anorgasmia, ejaculatory difficulty

DRUG ABUSE AND DEPENDENCE

Fentanyl transdermal system contains a high concentration of fentanyl, a potent Schedule II opioid

agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine,

oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to

respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and

is subject to criminal diversion.

The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for

abuse and diversion.

Addiction is a primary, chronic neurobiologic disease, with genetic, psychosocial, and environmental

factors influencing its development and manifestations. It is characterized by behaviors that include one

or more of the following: impaired control over drug use, compulsive use, continued use despite harm,

and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is

common.

“Drug seeking” behavior is very common in addicts and drug abusers. 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 physician(s). “Doctor shopping”

to obtain additional prescriptions is common among drug abusers and people suffering from untreated

addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians

should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical

dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized

by misuse for non-medical purposes, often in combination with other psychoactive substances. Since

fentanyl transdermal system may be diverted for non-medical use, careful record keeping of prescribing

information, including quantity, frequency, and renewal requests 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.

Fentanyl transdermal systems are intended for transdermal use (to be applied on the skin) only. Do not

use a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in

any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver

to the contents of the patch, which can result in an overdose of fentanyl that may be fatal.

OVERDOSAGE

Clinical Presentation

The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most

serious significant effect being hypoventilation.

Treatment

For the management of hypoventilation, immediate countermeasures include removing the fentanyl

transdermal system and physically or verbally stimulating the patient. These actions can be followed by

administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation

following an overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of

naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully

chosen because of the possibility of re-narcotization after system removal; repeated administration of

naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the

release of catecholamines.

Always ensure a patent airway is established and maintained, administer oxygen and assist or control

respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate

body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and

managed with appropriate parenteral fluid therapy.

DOSAGE AND ADMINISTRATION

Special Precautions

Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid

agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone,

methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and

associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is

subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal

system) may be a particular target for abuse and diversion.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. The

fentanyl transdermal system patch should not be used if the seal is broken, or the patch is cut,

damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can

expose the patient or caregiver to the contents of the patch, which can result in an overdose of

fentanyl that may be fatal.

Each fentanyl transdermal system patch may be worn continuously for 72 hours. The next patch should

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

If problems with adhesion of the fentanyl transdermal system patch occur, the edges of the patch may be

taped with first aid tape.

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.

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid

therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory

depression. Overestimating the fentanyl transdermal system dose when converting patients from

another opioid medication can result in fatal overdose with the first dose. Due to the mean

elimination half-life of 17 hours of fentanyl transdermal system, patients who are thought to have

had a serious adverse event, including overdose, will require monitoring and treatment for at

least 24 hours.

The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors

(such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and

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

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

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

fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4

inhibitor should be carefully monitored for an extended period of time and dosage adjustments

should be made if warranted. (See BOX WARNING, WARNINGS, CLINICAL

PHARMACOLOGY – Drug Interactions, WARNINGS and PRECAUTIONS for further

information.)

Pediatric patients converting to fentanyl transdermal system with a 25 mcg/h patch should be opioid-

tolerant and receiving at least 60 mg of oral morphine or the equivalent per day. The dose conversion

schedule described in Table C, and method of titration described below are recommended in opioid-

tolerant pediatric patients over 2 years of age with chronic pain (see PRECAUTIONS – Pediatric

Us e).

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large

initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that

depress respiration.

Fentanyl transdermal systems should be used with caution in elderly, cachectic, or debilitated patients as

they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance

(see CLINICAL PHARMACOLOGY – Special Populations, Geriatric Use).

General Principles

Fentanyl transdermal system is indicated for management of persistent, moderate to severe

chronic pain that:

requires continuous, around-the-clock opioid administration for an extended period of time

cannot be managed by other means such as non-steroidal analgesics, opioid combination

products, or immediate-release opioids

Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid

therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least

equivalent to fentanyl transdermal system 25 mcg/h. Patients who are considered opioid-tolerant

are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least

30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic

dose of another opioid.

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is

contraindicated:

in patients who are not opioid-tolerant

in the management of acute pain or in patients who require opioid analgesia for a short period

of time.

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

(e.g., tonsillectomies)

in the management of mild pain

in the management of intermittent pain (e.g., use on an as needed basis [prn])

(See CONTRAINDICATIONS for further information.)

Safety of fentanyl transdermal system has not been established in children under 2 years of

age.Fentanyl transdermal system should be administered to children only if they are opioid-

tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

Prescribers should individualize treatment using a progressive plan of pain management such as outlined

by the World Health Organization, the Agency for Health Research and Quality, the Federation of State

Medical Boards Model Policy, or the American Pain Society.

With all opioids, the safety of patients using the products is dependent on health care practitioners

prescribing them in strict conformity with their approved labeling with respect to patient selection,

dosing, and proper conditions for use.

As with all opioids, dosage should be individualized. The most important factor to be considered in

determining the appropriate dose is the extent of pre-existing opioid-tolerance (see BOX WARNING

and CONTRAINDICATIONS). Initial doses should be reduced in elderly or debilitated patients (see

PRECAUTIONS).

Fentanyl transdermal system should be applied 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 should be clipped (not shaved)

prior to system application. If the site of fentanyl transdermal system 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.

Fentanyl transdermal system should be applied immediately upon removal from the sealed package. Do

not use if the seal is broken. Do not alter the patch (e.g., cut) in any way prior to application and do not

use cut or damaged patches.

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

making sure the contact is complete, especially around the edges. If the gel from the drug reservoir

accidentally contacts the skin of the patient or caregiver, the skin should be washed with copious

amounts of water. Do not use soap, alcohol, or other solvents to remove the gel because they may

enhance the drug’s ability to penetrate the skin.

Fentanyl transdermal system should be kept out of the reach of children. Used patches should be folded

so that the adhesive side of the patch adheres to itself, then the patch should be flushed down the toilet

immediately upon removal. Patients should dispose of any patches remaining from a prescription as

soon as they are no longer needed. Unused patches should be removed from their pouches, folded so

that the adhesive side of the patch adheres to itself, and flushed down the toilet.

Dose Selection

Doses must be individualized based upon the status of each patient and should be assessed at

regular intervals after fentanyl transdermal system application. Reduced doses of fentanyl

transdermal system are suggested for the elderly and other groups discussed in precautions.

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid

therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory

depres s ion.

In selecting an initial fentanyl transdermal system dose, attention should be given to 1) the daily dose,

potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a

pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to

calculate the fentanyl transdermal system dose needed (potency estimates may vary with the route of

administration), 3) the degree of opioid tolerance and 4) the general condition and medical status of the

patient. Each patient should be maintained at the lowest dose providing acceptable pain control.

Initial Fentanyl Transdermal System Dose Selection

Overestimating the fentanyl transdermal system dose when converting patients from another

opioid medication can result in fatal overdose with the first dose. Due to the mean elimination

half-life of 17 hours of fentanyl transdermal system, patients who are thought to have had a

serious adverse event, including overdose, will require monitoring and treatment for at least 24

hours .

There has been no systematic evaluation of fentanyl transdermal system as an initial opioid analgesic in

the management of chronic pain, since most patients in the clinical trials were converted to fentanyl

transdermal system from other narcotics. The efficacy of fentanyl transdermal system 12 mcg/h as an

initiating dose has not been determined. In addition, patients who are not opioid-tolerant have

experienced hypoventilation and death during use of fentanyl transdermal system. Therefore, fentanyl

transdermal system should be used only in patients who are opioid-tolerant.

To convert adult and pediatric patients from oral or parenteral opioids to fentanyl transdermal system

use Table C:

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table C, use the

following methodology:

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose using Table D.

3. Table E displays the range of 24-hour oral morphine doses that are recommended for conversion to

each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose

and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system

treatment using the recommended dose and titrate patients upwards (no more frequently than every 3

days after the initial dose or than every 6 days thereafter) until analgesic efficacy is attained. The

recommended starting dose when converting from other opioids to fentanyl transdermal system is

likely too low for 50% of patients. This starting dose is recommended to minimize the potential for

overdosing patients with the first dose. For delivery rates in excess of 100 mcg/h, multiple systems

may be used.

Table C1 Dose Conversion Guidelines

Current Analgesic

Daily Dosage(mg/d)

Oral morphine

60-134

135-224 225-314

315-404

IM/IV morphine

10-22

23-37

38-52

53-67

Oral oxycodone

30-67

67.5-112 112.5-157 157.5-202

IM/IV oxycodone

15-33

33.1-56

56.1-78

78.1-101

Oral codeine

150-447 448-747 748-1047 1048-1347

Oral hydromorphone

8-17

17.1-28

28.1-39

39.1-51

IV hydromorphone

1.5-3.4

3.5-5.6

5.7-7.9

8-10

IM meperidine

75-165

166-278 279-390

391-503

Oral methadone

20-44

45-74

75-104

105-134

IM methadone

10-22

23-37

38-52

53-67

Recommended fentanyl

transdermal system dose

25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table C, use the

conversion methodology outlined above with Table D.

1 Table C should not be used to convert from fentanyl transdermal system to other therapies

because this conversion to fentanyl transdermal system is conservative. Use of table C 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-Discontinuation

of Fentanyl Transdermal System).

TABLE D EQUIANALGESIC POTENCY CONVERSION

Name

Equianalgesic

Dose (mg)

¹Table D should not be used to convert from fentanyl transdermal system to other therapies

because this conversion to fentanyl transdermal system is conservative. Use of table D 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–Discontinuation

of Fentanyl Transdermal System).

All IM and PO doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic

effect. IM denotes intramuscular, PO oral, and PR rectal.

Based on single-dose studies in which an intramuscular dose of each drug listed was compared with

morphine to establish the relative potency. Oral doses are those recommended when changing from

parenteral to an oral route. Reference: Foley, K.M. (1985) The treatment of cancer pain. NEJM

313(2):84-95.

Although controlled studies are not available, in clinical practice it is customary to consider the

doses of opioid given IM, IV, or subcutaneously to be equivalent. There may be some differences in

pharmacokinetic parameters such as C

and T

The conversion ratio of 10 mg parenteral morphine = 30 mg oral morphine is based on clinical

experience in patients with chronic pain. The conversion ratio of 10 mg parenteral morphine = 60 mg

oral morphine is based on a potency study in acute pain. Reference: Ashburn and Lipman (1993)

Management of pain in the cancer patient.

Anesth Analg 76:402-416.

Morphine

60 (30)

Hydromorphone (Dilaudid

Methadone (Dolophine

Oxycodone

Levorphanol (Levo-Dromoran )

Oxymorphone (Numorphan )

10 (PR)

Meperidine (Demerol

Codeine

TABLE E¹ RECOMMENDED INITIAL

FENTANYL TRANSDERMAL

SYSTEM DOSE BASED UPON DAILY

ORAL MORPHINE DOSE

a

Oral 24-hour

Morphine

(mg/day)

Fentanyl Transdermal System

Dose

(mcg/h)

60-134²

135-224

225-314

315-404

405-494

495-584

585-674

675-764

765-854

855-944

945-1034

1035-1124

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

to fentanyl transdermal system.

Table E should not be used to convert from fentanyl transdermal system to other therapies

because this conversion to fentanyl transdermal system is conservative. Use of table E 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 Discontinuation

of Fentanyl Transdermal System).

The majority of patients are adequately maintained with fentanyl transdermal system administered every

72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require

systems to be applied every 48 hours rather than every 72 hours. An increase in the fentanyl transdermal

system 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.

Because of the increase in serum fentanyl concentration over the first 24 hours following initial system

application, the initial evaluation of the maximum analgesic effect of fentanyl transdermal system cannot

be made before 24 hours of wearing. The initial fentanyl transdermal system dose may be increased

after 3 days (see DOSAGE AND ADMINISTRATION – Dose Titration).

During the initial application of fentanyl transdermal system, patients should use short-acting analgesics

as needed until analgesic efficacy with fentanyl transdermal system is attained. Thereafter, some patients

still may require periodic supplemental doses of other short-acting analgesics for “breakthrough” pain.

Dose Titration

The recommended initial fentanyl transdermal system dose based upon the daily oral morphine dose is

conservative, and 50% of patients are likely to require a dose increase after initial application of

fentanyl transdermal system. The initial fentanyl transdermal system dose may be increased after 3 days

based on the daily dose of supplemental opioid analgesics required by the patient in the second or third

day of the initial application.

Physicians are advised that it may take up to 6 days after increasing the dose of fentanyl transdermal

system for the patient to reach equilibrium on the new dose (see graph in CLINICAL

PHARMACOLOGY). Therefore, patients should wear a higher dose through two applications before

any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic.

Appropriate dose increments should be based on the daily dose of supplementary opioids, using the

1

ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/h increase in fentanyl transdermal system dose.

Fentanyl transdermal system -12 delivers 12.5 mcg/h of fentanyl.

Discontinuation of fentanyl transdermal system

To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new

analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system

removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Opioid

withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some

patients after conversion or dose adjustment. For patients requiring discontinuation of opioids, a gradual

downward titration is recommended since it is not known at what dose level the opioid may be

discontinued with producing the signs and symptoms of abrupt withdrawal.

Tables, C, D, and E should not be used to convert from fentanyl transdermal system to other

therapies. Because the conversion to fentanyl transdermal system is conservative, use of tables

C, D and E for conversion to other analgesic therapies can overestimate the dose of the new

agent. Overdosage of the new analgesic agent is possible.

HOW SUPPLIED

Fentanyl transdermal system is supplied in cartons containing 5 individually packaged systems. See chart

for information regarding individual systems.

Fentanyl Transdermal System Dose

(mcg/h)

System Size

(cm )

Fentanyl Content

(mg)

Fentanyl Transdermal System-25

Fentanyl Transdermal System-50

Safety and Handling

Fentanyl transdermal system is supplied in sealed transdermal systems which pose little risk of exposure

to health care workers. If the gel from the drug reservoir accidentally contacts the skin, the area should

be washed with copious amounts of water. Do not use soap, alcohol, or other solvents to remove the

gel because they may enhance the drug’s ability to penetrate the skin. Do not use a fentanyl transdermal

system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that

is cut, damaged, or changed in any way can expose the patient or caregiver to thecontents of the patch,

which can result in an overdose of fentanyl that may be fatal.

KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND

PETS.

Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature.] Apply immediately after

removal from individually sealed package. Do not use if the seal is broken. For transdermal use only.

A SCHEDULE CII NARCOTIC. DEA ORDER FORM REQUIRED.

Manufactured by:

Watson Laboratories, Inc

Corona, CA 92880 USA

Distributed by:

Watson Pharma, Inc.

Corona, CA 92880 USA

Revised: August 2008

image of label

2

FENTANYL

fentanyl patch, extended release

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:49 9 9 9 -

8 33(NDC:0 59 1-3213)

Route of Administration

TRANSDERMAL

DEA Sche dule

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

FENTANYL (UNII: UF59 9 78 5JZ) (FENTANYL - UNII:UF59 9 78 5JZ)

FENTANYL

7.5 mg in 72 h

Inactive Ingredients

Ingredient Name

Stre ng th

ALCO HO L (UNII: 3K9 9 58 V9 0 M)

Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:49 9 9 9 -8 33-0 5

5 in 1 CARTON

1

1 in 1 POUCH

1

72 h in 1 PATCH

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 70 9

12/0 9 /20 11

Labeler -

Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC (831276758)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Lake Erie Medical & Surgical Supply DBA Quality Care Pro ducts LLC

8 31276 758

RELABEL, REPACK

Revised: 1/2012

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