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Fentanyl Transdermal System

DEA Controlled Substance Schedule C-II

TABLE OF CONTENTS

1. DESCRIPTION 8. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 9. DRUG ABUSE AND DEPENDENCE
3. DOSAGE AND ADMINISTRATION 10. OVERDOSAGE
4. CONTRAINDICATIONS 11. DRUG INTERACTIONS
5. MECHANISM OF ACTION 12. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. WARNINGS AND PRECAUTIONS  

 


WARNING: ABUSE POTENTIAL , RESPIRATORY DEPRESSION and DEATH, ACCIDENTAL EXPOSURE, CYTOCHROME P450 3A4 INTERACTION, AND EXPOSURE TO HEAT

Abuse Potential

Fentanyl patches contains fentanyl, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Fentanyl patches can be abused in a manner similar to other opioid agonists, legal or illicit. 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). Assess patients for their clinical risks for opioid abuse or addiction prior to prescribing fentanyl patches and then routinely monitor all patients for signs of misuse, abuse and addiction during treatment [see Warnings and Precautions and Drug Abuse and Dependence].

Respiratory Depression and Death

Respiratory depression and death may occur with use of fentanyl patches, even when fentanyl patches has been used as recommended and not misused or abused. Proper dosing and titration are essential and fentanyl patches should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Fentanyl patches is contraindicated for use in conditions in which the risk of life-threatening respiratory depression is significantly increased, including use as an as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain. Monitor for respiratory depression, especially during the first two applications following initiation of dosing, or following an increase in dosage [see Contraindications and Warnings and Precautions].

Accidental Exposure

Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl patches. Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure [see Dosage and Administration and Warnings and Precautions].

Cytochrome P450 3A4 Interaction

The concomitant use of fentanyl patches with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Monitor patients receiving fentanyl patches and any CYP3A4 inhibitor [see Warnings and Precautions].

Exposure To Heat

The fentanyl patches application site and surrounding area must not be exposed to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds. Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. Patients wearing fentanyl patches systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased fentanyl exposure and may require an adjustment in the dose of fentanyl patches to avoid overdose and death.



1. 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 empirical formula is C22H28N2O. 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 10.5 cm2). The composition per unit area of all system sizes is identical.

* Nominal delivery rate per hour

** Nominal delivery rate is 12.5 mcg/hr

Fentanyl transdermal patch is a rectangular transparent unit comprising a protective liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:

1) a backing layer of polyester/ethyl vinyl acetate film;

2) a drug-in-adhesive layer. Before use, a protective liner covering the adhesive layer is removed and discarded.

2. INDICATIONS AND USAGE

Fentanyl transdermal patch is a transdermal formulation of fentanyl indicated for the management of persistent, moderate to severe chronic pain in opioid-tolerant patients 2 years of age and older when a continuous, around-the-clock opioid analgesic is required for an extended period of time, and the patient cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.

Patients considered opioid-tolerant are those who are taking 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 for a week or longer.

3. DOSAGE AND ADMINISTRATION

3.1 Proper Patient Selection

Abuse Potential

Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribing fentanyl transdermal patch [see Warnings and Precautions].

Opioid Tolerance

Opioid tolerance to an opioid of comparable potency must be established before prescribing fentanyl transdermal patch [see Warnings and Precautions].

Patients considered opioid-tolerant are those who are taking 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 for a week or longer.

3.2 Dosing

Conversion to Fentanyl Transdermal Patch in Opioid-Tolerant Patients

The recommended starting dose when converting from other opioids to fentanyl transdermal patch is intended to minimize the potential for overdosing patients with the first dose. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with fentanyl transdermal patch [see Warnings and Precautions (5.2)].

In selecting an initial fentanyl transdermal patch dose, take the following factors into account:

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 patch dose needed (potency estimates may vary with the route of administration);

3. the degree of opioid tolerance;

4. the general condition and medical status of the patient.

To convert adult and pediatric patients from oral or parenteral opioids to fentanyl transdermal patch, use Table 1. Do not use Table 1 to convert from fentanyl transdermal patch to other therapies because this conversion to fentanyl transdermal patch is conservative and will overestimate the dose of the new agent.

TABLE 11. DOSE CONVERSION GUIDELINES

Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the conversion methodology outlined above with Table 2.

1 Table 1 should not be used to convert from fentanyl transdermal patch to other therapies because this conversion to fentanyl transdermal patch is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration].

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Alternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology:

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose using a reliable reference.

Refer to Table 2 for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal patch dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal patch dose. Initiate fentanyl transdermal patch treatment using the recommended dose and titrate patients upwards (no more frequently than 3 days after the initial dose and every 6 days thereafter) until analgesic efficacy is attained.

3. Do not use Table 2 to convert from fentanyl transdermal patch to other therapies because this conversion to fentanyl transdermal patch is conservative and will overestimate the dose of the new agent.

TABLE 21. RECOMMENDED INITIAL FENTANYL TRANSDERMAL PATCH DOSE BASED UPON DAILY ORAL MORPHINE DOSE

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

1 Table 2 should not be used to convert from fentanyl transdermal patch to other therapies because this conversion to fentanyl transdermal patch is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration].

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For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Hepatic Impairment

Avoid the use of fentanyl transdermal patch in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal patch. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions, Use in Specific Populations].

Renal Impairment

Avoid the use of fentanyl transdermal patch in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal patch. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Warnings and Precautions, Use in Specific Populations].

3.3 Titration and Maintenance of Therapy

Once therapy is initiated, assess pain intensity and opioid adverse reactions frequently, especially respiratory depression [see Warnings and Precautions]. Routinely monitor all patients for signs of misuse, abuse and addiction [see Warnings and Precautions].

The initial fentanyl transdermal patch dose may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.

It may take up to 6 days for fentanyl levels to reach equilibrium on a new dose. Therefore, evaluate patients for further titration after no less than two 3day applications before any further increase in dosage is made.

Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12 mcg/hour increase in fentanyl transdermal patch dose.

The majority of patients are adequately maintained with fentanyl transdermal patch administered every 72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using a 72-hour regimen. An increase in the fentanyl transdermal patch 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.

Discontinuation of Fentanyl Transdermal Patch

To convert patients to another opioid, remove fentanyl transdermal patch 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. Withdrawal symptoms are possible in some patients after conversion or dose adjustment [see Warnings and Precautions].

Do not use Tables 1 and 2 to convert from fentanyl transdermal patch to other therapies to avoid overestimating the dose of the new agent potentially resulting in overdose of the new analgesic and death.

When discontinuing fentanyl transdermal patch and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of withdrawal symptoms [see Warnings and Precautions]. It is not known at what dose level fentanyl transdermal patch may be discontinued without producing the signs and symptoms of opioid withdrawal.

3.4 Administration of Fentanyl Transdermal Patches

Fentanyl transdermal patches are for transdermal use, only.

Proper handling of fentanyl transdermal patches is advised in order to prevent adverse reactions, including death, associated with accidental secondary exposure to fentanyl transdermal patches [see Warnings and Precautions].

Application and Handling Instructions

• Patients should apply fentanyl transdermal patch to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal patch application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application.

• Patients should apply fentanyl transdermal patch immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. fentanyl transdermal patch should not be used if the pouch seal is broken or if the patch is cut or damaged.

• The transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.

• Each fentanyl transdermal patch may be worn continuously for 72 hours. The next patch is applied to a different skin site after removal of the previous transdermal system.

• If problems with adhesion of the fentanyl transdermal patch occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with a transparent adhesive film dressing.

• If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site.

• Patients (or caregivers who apply fentanyl transdermal patch) should wash their hands immediately with soap and water after applying fentanyl transdermal patch.

• Contact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal patch and should be avoided. Examples of accidental exposure include transfer of a fentanyl transdermal patch from an adult’s body to a child while hugging, sharing the same bed as the patient, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while applying or removing the patch.

• Instruct patients, family members, and caregivers to keep patches in a secure location out of the reach of children and of others for whom fentanyl transdermal patch was not prescribed.

Avoidance of Heat

Instruct patients to avoid exposing the fentanyl transdermal patch application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions].

3.5 Disposal Instructions

Proper disposal of fentanyl transdermal patches is advised in order to prevent adverse reactions, including death, associated with accidental secondary exposure to fentanyl transdermal patches [see Warnings and Precautions].

Patients should dispose of used patches by folding the adhesive side of the patch to itself, then flush the patch 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, fold so that the adhesive side of the patch adheres to itself, and flush down the toilet.

4. CONTRAINDICATIONS

Fentanyl transdermal patch is contraindicated in the following patients and situations due to the risk of fatal respiratory depression:

• in patients who are not opioid-tolerant [see Warnings and Precautions].

• in the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time [see Warnings and Precautions].

• in the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies) [see Warnings and Precautions].

• in the management of mild pain [see Warnings and Precautions].

• in patients with significant respiratory compromise, especially if adequate monitoring and resuscitative equipment are not readily available [see Warnings and Precautions].

• in patients who have acute or severe bronchial asthma [see Warnings and Precautions].

Fentanyl transdermal patch is also contraindicated:

• in patients who have or are suspected of having paralytic ileus Reference ID:

• in patients with known hypersensitivity to fentanyl or any components of the transdermal system. Severe hypersensitivity reactions, including anaphylaxis have been observed with fentanyl transdermal patches [see Adverse Reactions].

5. MECHANISM OF ACTION

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid μ-receptor. These μ-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. Its primary actions of therapeutic value are analgesia and sedation. Fentanyl may increase the patient’s tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized.

In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers and the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting by directly 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 opioids. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal patches should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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/m2 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/m2 basis).

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 through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis.

6.2 Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl is not recommended for analgesia during labor and delivery.

6.3 Nursing Mothers

Fentanyl is excreted in human milk; therefore, fentanyl is not recommended for use in nursing women because of the possibility of sedation and/or respiratory depression in their infants.

6.4 Pediatric Use

The safety of fentanyl transdermal patches was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal patch therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials.

The safety and effectiveness of fentanyl transdermal patches in children under 2 years of age have not been established.

To guard against excessive exposure to fentanyl transdermal patches by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal patch application and disposal instructions [see Dosage and Administration and Warnings and Precautions].

6.5 Geriatric Use

Clinical studies of fentanyl transdermal patches did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.

Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal patch and when given in conjunction with other drugs that depress respiration [see Warnings and Precautions].

6.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal patch has not been fully evaluated. A clinical pharmacology study with fentanyl transdermal patch in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal patch, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal patch. Avoid use of fentanyl transdermal patch in patients with severe hepatic impairment [see Dosing and Administration, Warnings and Precautions].

6.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of fentanyl transdermal patch has not been fully evaluated. A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal patch, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal patch. Avoid the use of fentanyl transdermal patch in patients with severe renal impairment [see Dosing and Administration, Warnings and Precautions].

6.8 Neonatal Opioid Withdrawal Syndrome

Chronic maternal use of fentanyl can affect the neonate with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dosage of last maternal use, and rate of elimination of the drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

7. WARNINGS AND PRECAUTIONS

7.1 Abuse Potential

Fentanyl is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl transdermal patches can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing fentanyl transdermal patches in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence].

Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. 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. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

7.2 Respiratory Depression and Death

Respiratory depression is the chief hazard of fentanyl transdermal patches. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

Fentanyl transdermal patch has a narrow indication and should be prescribed only by healthcare professionals who are knowledgeable in the administration of potent opioids and management of chronic pain [see Indications and Usage]. Fentanyl transdermal patch is contraindicated for use in conditions in which the risk of life-threatening respiratory depression is significantly increased, including use as an as-needed analgesic, use in non-opioid tolerant patients, acute pain, and postoperative pain [see Contraindications]. Proper dosing and titration of fentanyl transdermal patches are essential [see Dosage and Administration]. Overestimating the fentanyl transdermal patch dose when converting patients from another opioid medication, can result in fatal overdose with the first dose. However, respiratory depression has also been reported with use of fentanyl transdermal patches in patients who are opioid-tolerant, even when fentanyl transdermal patch has been used as recommended and not misused or abused.

The mean half-life of fentanyl when delivered by fentanyl transdermal patch is approximately 20-27 hours. Serum fentanyl concentrations continue to rise for the first two system applications. In addition, significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “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.

While serious, life-threatening or fatal respiratory depression can occur at any time during the use of fentanyl transdermal patch, the potential for serious, life threatening, or fatal respiratory depression is greatest during the first two applications following initiation of dosing, or following an increase in dosage. Closely monitor patients for respiratory depression when initiating therapy with fentanyl transdermal patch, especially within the initial 24-72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Because significant amounts of fentanyl continue to be absorbed from the skin for 24 hours or more after the patch is removed, respiratory depression may persist beyond the removal of fentanyl transdermal patch. Monitor patients for respiratory depression after patch removal to ensure that the patient’s respiration has stabilized for at least 24 to 72 hours or longer as clinical symptoms dictate.

Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdose].

7.3 Accidental Exposure

A considerable amount of active fentanyl remains in fentanyl transdermal patch even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal patch. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Placing fentanyl transdermal patch 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.

Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal patch (see Dosage and Administration].

7.4 Elderly, Cachectic, and Debilitated Patients

Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance. Therefore, monitor these patients closely, particularly when initiating therapy with fentanyl transdermal patch and when given in conjunction with other drugs that depress respiration [see Warnings and Precautions and Use in Specific Populations].

7.5 Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy with fentanyl transdermal patch, as in these patients, even usual therapeutic doses of fentanyl transdermal patches may decrease respiratory drive to the point of apnea [see Warnings and Precautions]. Consider the use of alternative non-opioid analgesics in these patients if possible.

7.6 Head Injuries and Increased Intracranial Pressure

Avoid use of fentanyl transdermal patches in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma [see Warnings and Precautions]. In addition, opioids may obscure the clinical course of patients with head injury. Monitor patients with brain tumors who may be susceptible to the intracranial effects of CO2 retention for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal patch, as fentanyl transdermal patch may reduce respiratory drive and CO2 retention can further increase intracranial pressure.

7.7 Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse

The concomitant use of fentanyl transdermal patches 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 coma. Monitor patients prescribed concomitant CNS active drugs for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal patch, and reduce the dose of one or both agents [see Warnings and Precautions].

7.8 Interactions with CYP3A4 Inhibitors

The concomitant use of fentanyl transdermal patch with a CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, 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. Carefully monitor patients receiving fentanyl transdermal patch and any CYP3A4 inhibitor for signs of sedation and respiratory depression for an extended period of time, and make dosage adjustments if warranted [see Warnings and Precautions, Drug Interactions].

7.9 Application of External Heat

Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as a result of exposure to heat. A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal patch system increased fentanyl exposure.

Warn patients to avoid exposing the fentanyl transdermal patch application site and surrounding area to direct external heat sources [see Dosage and Administration].

7.10 Patients with Fever

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing fentanyl transdermal patch systems who develop fever closely for opioid side effects and reduce the fentanyl transdermal patch dose if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl transdermal patch to avoid the risk of potential overdose and death.

7.11 Cardiac Disease

Fentanyl transdermal patch may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal patch.

7.12 Hepatic Impairment

A clinical pharmacology study with fentanyl transdermal patch in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as fentanyl transdermal patch and hepatic metabolism of fentanyl, avoid use of fentanyl transdermal patch in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal patch in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal patch. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase. [see Dosing and Administration, Use in Specific Populations].

7.13 Renal Impairment

A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because of the long half-life of fentanyl when administered as fentanyl transdermal patch, avoid the use of fentanyl transdermal patch in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal patch in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of a dose, start with one half of the usual dosage of fentanyl transdermal patch. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosing and Administration, Use in Specific Populations].

7.14 Use in Pancreatic/Biliary Tract Disease

Fentanyl transdermal patch may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsened symptoms. Fentanyl transdermal patch may cause increases in the serum amylase concentration.

7.15 Avoidance of Withdrawal

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion to another opioid or when decreasing or discontinuing fentanyl transdermal patch. Gradual reduction of the dose of fentanyl transdermal patch is recommended [see Dosage and Administration and Drug Abuse and Dependence].

7.16 Driving and Operating Machinery

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. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the fentanyl transdermal patch.

8. ADVERSE REACTIONS

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

• Abuse Potential [see Warnings and Precautions]

• Respiratory Depression [see Warnings and Precautions]

• Accidental Exposure [see Warnings and Precautions]

• Elderly, Cachetic, and Debilitated Patients [see Warnings and Precautions]

• Chronic Pulmonary Disease [see Warnings and Precautions]

• Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions]

• Interactions with Other CNS Depressants, Alcohol, and Drugs of Abuse [see Warnings and Precautions]

• Interactions with CYP3A4 Inhibitors [see Warnings and Precautions]

• Application of External Heat [see Warnings and Precautions]

• Patients with Fever [see Warnings and Precautions]

• Cardiac Disease [see Warnings and Precautions]

• Hepatic Impairment [see Warnings and Precautions]

• Renal Impairment [see Warnings and Precautions]

• Use in Pancreatic/Biliary Tract Disease [see Warnings and Precautions]

• Avoidance of Withdrawal [see Warnings and Precautions]

• Driving and Operating Machinery [see Warnings and Precautions]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

8.1 Clinical Trial Experience

The safety of fentanyl transdermal patch was evaluated in 216 patients who took at least one dose of fentanyl transdermal patch in a multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal patch. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.

The most common adverse reactions (≥5%) in a double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (≥5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for ≥1% of fentanyl transdermal patch-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3.

The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in ≥1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.

Table 3. Adverse Reactions Reported by ≥1% of Fentanyl-transdermal-patch-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal Patch

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

Table 4. Adverse Reactions Reported by ≥1% of Fentanyl-transdermal-patch-treated Patients in 11 Clinical Trials of Fentanyl Transdermal Patch

The following adverse reactions occurred in adult and pediatric patients with an overall frequency of < 1% and are listed in descending frequency within each System/Organ Class:

Cardiac disorders: cyanosis

Eye disorders: miosis

Gastrointestinal disorders: subileus

General disorders and administration site conditions: application site reaction, influenza-like illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitis

Musculoskeletal and connective tissue disorders: muscle twitching

Nervous system disorders: hypoesthesia

Psychiatric disorders: disorientation, euphoric mood

Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: respiratory depression

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

Pediatrics

The safety of fentanyl transdermal patch was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 2 years of age through 18 years of age. Adverse reactions reported by ≥1% of fentanyl-transdermal-patch-treated pediatric patients are shown in Table 5.

Table 5. Adverse Reactions Reported by ≥1% of Fentanyl-transdermal-patch-treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal Patch

8.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of fentanyl transdermal patch. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Cardiac Disorders: Tachycardia, Bradycardia

Eye Disorders: Vision blurred

Gastrointestinal Disorders: Ileus, Dyspepsia

General Disorders and Administration Site Conditions: Feeling of body temperature change

Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction

Investigations: Weight decreased

Nervous System Disorders: Convulsions (including Clonic convulsions and Grand mal convulsion), Amnesia

Psychiatric Disorders: Agitation

Respiratory, Thoracic, and Mediastinal Disorders: Respiratory distress, Apnea, Bradypnea, Hypoventilation, Dyspnea

Vascular Disorders: Hypotension, Hypertension

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Fentanyl is 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 transdermal patch can be abused and is subject to criminal diversion [see Warnings and Precautions].

9.2 Abuse

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 patch may be diverted for non-medical use, careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.3 Dependence

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 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 concentration 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].

10. OVERDOSAGE

10.1 Clinical Presentation

Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The pharmacokinetic characteristics of fentanyl transdermal patch must also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose have been reported with abuse and misuse of fentanyl transdermal patch.

10.2 Treatment

Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Remove all fentanyl transdermal patch systems.

The pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal is expected to be less than the duration of action of fentanyl, carefully monitor the patient until spontaneous respiration is reliably reestablished. After fentanyl transdermal patch system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Therefore, management of an overdose must be monitored accordingly, at least 72 to 96 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including fentanyl transdermal patch, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

11. DRUG INTERACTIONS

11.1 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 is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce 3A4 activity may reduce the efficacy of fentanyl. The concomitant use of transdermal fentanyl with ritonavir or other potent 3A4 inhibitors such as ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone may result in an increase in fentanyl plasma concentrations (see BOX WARNING, Drug Interactions , WARNINGS, and DOSAGE AND ADMINISTRATION). The concomitant use of other CYP3A4 inhibitors such as diltiazem and erythromycin with transdermal fentanyl may also result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause serious respiratory depression. In this situation, special patient care and observation are appropriate.

11.2 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.

11.3 MAO Inhibitors

Fentanyl 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.

12. PHARMACOKINETICS

Absorption

Fentanyl transdermal patch is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the matrix and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (12.5, 25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.

Following fentanyl transdermal patch 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 patch application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 6). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal patch delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 1). Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12) hours.

A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.

TABLE 6: FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF FENTANYL TRANSDERMAL PATCH

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

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

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours.

____________________________________________________________________

Figure 1. Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal Patch 100 mcg/h

 

TABLE 7: RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS

+ Estimated

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

_________________________________________________________________

Distribution

Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3-8; N=8).

Metabolism

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.

Excretion

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

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.

Hepatic Impairment

Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal patch is limited. The pharmacokinetics of fentanyl transdermal patch delivering 50 μg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), Cmax and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively.

Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal patch, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal patch. Avoid use of fentanyl transdermal patch in patients with severe hepatic impairment [see Dosing and Administration, Warnings and Precautions and Use in Specific Populations].

Renal Impairment

Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal patch is limited. The pharmacokinetics of intravenous injection of 25 μg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found.

Because there is in-vivo evidence of renal contribution to the elimination of fentanyl transdermal patch, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal patch. Avoid the use of fentanyl transdermal patch in patients with severe renal impairment [see Dosing and Administration, Warnings and Precautions and Use in Specific Populations].

Pediatric Use

In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosing and Administration].

Geriatric Use

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, a single fentanyl transdermal patch 100 μg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65 years old (n=21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions and Use in Specific Populations].

13. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: DURAGESIC, by ORTHO MCNEIL JANSSEN.

b) Generic drugs: FENTANYL TRANSDERMAL, by various manufacturers.

2) How Supplied:

Fentanyl transdermal system (by MYLAN PHARM) is supplied in cartons containing 5 individually packaged systems. See chart for information regardingindividual systems.

3) Safety and Handling

Fentanyl transdermal systems are supplied in sealed pouches which pose little risk of exposure to healthcare workers. Do not use a fentanyl transdermal system if the pouch 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 in original unopened pouch. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Apply immediately after removal from individually sealed pouch. Do not use if the pouch seal is broken. For transdermal use only.

A schedule CII narcotic. DEA order form required.

Rx only

Rev 07/12