fentanyl 25 MCG/HR 3 Day Transdermal Patch

Details

WARNINGS

Fentanyl transdermal system is intended for transdermal use (on intact skin) only.

Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.

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 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, 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 40ºC (104ºF) 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 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 a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting 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 preexisting 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 2 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 with all CYP3A4 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 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) .

DRUG INTERACTIONS

Drug Interactions

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.

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-piperidyl] propanamide.

The structural formula is: C 22 H 28 N 2 O M.W.

336.5 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/hr per 10.7 cm 2 ).

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

Dose Nominal delivery rate per hour (mcg/hr) Size (cm 2 ) Fentanyl Content (mg) 25 10.7 2.76 50 21.4 5.52 75 32.1 8.28 100 42.8 11.04 Fentanyl transdermal system is a rectangular unit comprising a protective liner and two functional layers.

Proceeding from the outer surface toward the surface adhering to skin, these layers are: A BACKING LAYER OF POLYESTER FILM; FENTANYL IN A POLYISOBUTENE ADHESIVE MATRIX THAT CONTROLS THE RATE OF FENTANYL DELIVERY TO THE SKIN SURFACE; AND A PROTECTIVE POLYESTER RELEASE LINER.

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.

Structural formula for fentanyl Graphic 1

HOW SUPPLIED

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

See chart for information regarding individual systems: Label Strength (mcg/hr) Patch Size (cm 2 ) Fentanyl Content (mg) 25 10.7 2.76 50 21.4 5.52 75 32.1 8.28 100 42.8 11.04 They are supplied by Dispensing Solutions Inc.

as follows: NDC Strength Quantity/Form Source NDC 68258-3023-1 25 ug/1 h 5 BLISTER PACK 0093-6900-45 68258-3024-1 75 ug/1 h 5 BLISTER PACK 0093-6902-45 68258-3025-1 100 ug/1 h 5 BLISTER PACK 0093-6903-45 Safety and Handling Fentanyl transdermal systems are supplied in sealed blister packages which pose little risk of exposure to health care workers.

If the drug matrix accidentally contacts the skin, the area should be washed with copious amounts of water.

Do not use soap, alcohol, or other solvents because they may enhance the drug’s ability to penetrate the skin.

Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.

KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND PETS.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Apply immediately after removal from individually sealed blister package.

Do not use if the seal is broken.

For transdermal use only.

A SCHEDULE CII NARCOTIC.

DEA ORDER FORM REQUIRED.

Bioclusive™ is a trademark of Ethicon, Inc.

Dilaudid ® is a registered trademark of Abbott Laboratories.

Dolophine ® is a registered trademark of Roxane Laboratories, Inc.

Levo-Dromoran ® is a registered trademark of Valeant Pharmaceuticals International.

Numorphan ® is a registered trademark of Endo Pharmaceuticals.

Demerol ® is a registered trademark of Sanofi-Aventis U.S.

Manufactured By: Aveva Drug Delivery Systems A Nitto Denko Company Miramar, FL 33025 Distributed By: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 And Relabeled By: Dispensing Solutions Inc.

3000 West Warner Ave Santa Ana, CA 92704 United States

GERIATRIC USE

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 transdermal fentanyl 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 ).

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/hr (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.

PEDIATRIC USE

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/hr and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid.

Initiation of 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.

PREGNANCY

Pregnancy

NUSRING MOTHERS

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.

BOXED WARNING

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/hr.

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 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.

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 if the seal is broken or the patch is cut, damaged, or changed in any way.

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.

INFORMATION FOR PATIENTS

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: Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.

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.

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.

Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from the sealed blister 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.

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.

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.

Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermal system application site and surrounding area 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.

Patients should also be advised of a potential for temperature dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician.

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.

If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive™).

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 systems after removal from the skin.

11.

Patients should be instructed that, if the drug matrix 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 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 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 the 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 blisters, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

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.

26.

MRI : Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI).

Because this fentanyl transdermal system contains aluminum, it is recommended to remove the patch before undergoing any MRI procedures.

DOSAGE AND ADMINISTRATION

Special Precautions Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.

Fentanyl can be abused and is subject to criminal diversion.

The high content of fentanyl in 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 should not be used if the seal is broken, or the patch is cut, damaged, or changed in any way.

Each fentanyl transdermal system 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 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 (e.g., Bioclusive™).

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.

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, 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 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/hr patch should be opiod-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 PRCAUTIONS , Pediatric Use ).

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 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/hr.

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

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 preexisting 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 blister 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 drug matrix 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 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 blisters, 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 depression .

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.

There has been no systemic 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/hr 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: Calculate the previous 24 hour analgesic requirement.

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

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/hr, multiple systems may be used.

TABLE C 1 DOSE CONVERSION GUIDELINES Current Analgesic Daily Dosage (mg/d) Oral morphine 60 to 134 135 to 224 225 to 314 315 to 404 IM/IV morphine 10 to 22 23 to 37 38 to 52 53 to 67 Oral oxycodone 30 to 67 67.5 to 112 112.5 to 157 157.5 to 202 IM/IV oxycodone 15 to 33 33.1 to 56 56.1 to 78 78.1 to 101 Oral codeine 150 to 447 448 to 747 748 to 1047 1048 to 1347 Oral hydromorphone 8 to 17 17.1 to 28 28.1 to 39 39.1 to 51 IV hydromorphone 1.5 to 3.4 3.5 to 5.6 5.7 to 7.9 8 to 10 IM meperidine 75 to 165 166 to 278 279 to 390 391 to 503 Oral methadone 20 to 44 45 to 74 75 to 104 105 to 134 IM methadone 10 to 22 23 to 37 38 to 52 53 to 67 ↓ ↓ ↓ ↓ Recommended fentanyl transdermal system dose 25 mcg/hr 50 mcg/hr 75 mcg/hr 100 mcg/hr 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 , Discontinuation of Fentanyl Transdermal System).

TABLE D TABLE 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 , 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.

EQUIANALGESIC POTENCY CONVERSION Name Equianalgesic Dose (mg) IM 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 max and T max .

PO Morphine 10 60 (30) 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.

Hydromorphone (Dilaudid ® ) 1.5 7.5 Methadone (Dolophine ® ) 10 20 Oxycodone 15 30 Levorphanol (Levo-Dromoran ® ) 2 4 Oxymorphone (Numorphan ® ) 1 10 (PR) Meperidine (Demerol ® ) 75 – Codeine 130 200 TABLE E 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 , Discontinuation of Fentanyl Transdermal System).

RECOMMENDED INITIAL FENTANYL TRANSDERMAL SYSTEM DOSE BASED UPON DAILY ORAL MORPHINE DOSE Oral 24 hour Morphine (mg/day) Fentanyl Transdermal System Dose (mcg/hr) 60 to 134 25 135 to 224 50 225 to 314 75 315 to 404 100 405 to 494 125 495 to 584 150 585 to 674 175 675 to 764 200 765 to 854 225 855 to 944 250 945 to 1034 275 1035 to 1124 300 NOTE: In clinical trials, these ranges of daily oral morphine doses were used as a basis for conversion to 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 , 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 dosage 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 dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hr increase in fentanyl transdermal system dose.

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 without 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 of 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.