Label: FENTANYL TRANSDERMAL SYSTEM patch, extended release
Contains inactivated NDC Code(s)
NDC Code(s): 63629-5492-1
- Packager: Bryant Ranch Prepack
- This is a repackaged label.
- Source NDC Code(s): 0406-9050
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CII
- Marketing Status: Abbreviated New Drug Application
Updated February 21, 2018
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FENTANYL TRANSDERMAL SYSTEM safely and effectively. See full prescribing information for FENTANYL TRANSDERMAL SYSTEM.
FENTANYL TRANSDERMAL SYSTEM, for transdermal administration, CII
Initial U.S. Approval: 1968
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION: ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION, and EXPOSURE TO HEAT
See full prescribing information for complete boxed warning.
- Fentanyl transdermal system exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1)
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
- Accidental exposure to fentanyl transdermal system, especially in children, can result in fatal overdose of fentanyl. (5.3)
- Prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.4)
- Initiation of CYP 3A4 inhibitors (or discontinuation of CYP 3A4 inducers) can result in a fatal overdose of fentanyl from fentanyl transdermal system. (5.10)
- Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. Temperature dependent increases in fentanyl release from the system may result in overdose and death. (5.11)
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Fentanyl transdermal system is indicated for the management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (1)
Patients considered opioid-tolerant are those who are taking, for one 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. (1)
Limitations of use:
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve fentanyl transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. (1)
DOSAGE AND ADMINISTRATION
For use in opioid-tolerant patients only.
Initial dose selection: consult conversion instructions. (2.1)
Each transdermal system is intended to be worn for 72 hours. (2.2)
Adhere to instructions concerning administration and disposal of fentanyl transdermal system. (2.4)
Reduce the dose with hepatic, and renal impairment. (2.1)
DOSAGE FORMS AND STRENGTHS
Transdermal system: 12 mcg/hr, 25 mcg/hr, 50 mcg/hr, 75 mcg/hr, 100 mcg/hr. (3)
WARNINGS AND PRECAUTIONS
Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If co-administration is required, consider dose reduction of one or both drugs because of pharmacological effects. (5.5)
Hypotensive effects: Monitor during dose initiation and titration. (5.9)
Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. (5.8)
Bradycardia. Administer with caution to patients with bradyarrhythmias. (5.13)
Most common adverse reactions (≥5%) are nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, anorexia, headache, and diarrhea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Mixed agonist/antagonist and partial agonist opioid analgesics: Avoid use with fentanyl transdermal system because they may reduce analgesic effect of fentanyl transdermal system or precipitate withdrawal symptoms. (5.1, 7.4)
Monoamine oxidase inhibitors (MAOIs): Avoid fentanyl transdermal system in patients taking MAOIs or within 14 days of stopping such treatment. (7.3)
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Breast-feeding is not advised in mothers treated with fentanyl transdermal system. (8.3)
Pediatric Use: Safety and efficacy in pediatric patients below the age of 2 years have not been established. To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl transdermal system. (8.4)
Geriatric Use: Administer fentanyl transdermal system with caution, and in reduced dosages in elderly patients. (8.5)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION: ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and EXPOSURE TO HEAT
- Sections or subsections omitted from the full prescribing information are not listed.
- BOXED WARNING (What is this?)
- 1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Initial Dosing
Daily Dosage (mg/day)
Recommended Fentanyl Transdermal System Dose
3 DOSAGE FORMS AND STRENGTHS
Fentanyl transdermal system is available as:
- Fentanyl Transdermal System 12 mcg/hour* (system size 3.9 cm2) is dark blue in color.
- Fentanyl Transdermal System 25 mcg/hour (system size 7.8 cm2) is red in color.
- Fentanyl Transdermal System 50 mcg/hour (system size 15.6 cm2) is green in color.
- Fentanyl Transdermal System 75 mcg/hour (system size 23.4 cm2) is blue in color.
- Fentanyl Transdermal System 100 mcg/hour (system size 31.2 cm2) is gray in color.
*This lowest dosage is designated as 12 mcg/hour (however, the actual dosage is 12.5 mcg/hour) to distinguish it from a 125 mcg/hr dosage that could be prescribed by multiple patches.
Fentanyl transdermal system is contraindicated in the following patients and situations:
- in patients who are not opioid-tolerant.
- in the management of acute or intermittent 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 patients with significant respiratory compromise, especially if adequate monitoring and resuscitative equipment are not readily available.
- in patients who have acute or severe bronchial asthma.
- in patients who have or are suspected of having paralytic ileus.
- 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 system [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.7 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 pre-existing respiratory depression for respiratory depression, particularly when initiating therapy with fentanyl transdermal system, as in these patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative
non-opioid analgesics in these patients if possible.
5.8 Head Injuries and Increased Intracranial Pressure
Avoid use of fentanyl transdermal system 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 (5.2)]. 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 system, as fentanyl transdermal system may reduce respiratory drive and CO2 retention can further increase intracranial pressure.
5.11 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 system increased fentanyl exposure [see Clinical Pharmacology (12.3)].
Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources [see Dosage and Administration (2.3)].
5.12 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 systems who develop fever closely for opioid side effects and reduce the fentanyl transdermal system dose if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl transdermal system to avoid the risk of potential overdose and death.
5.13 Cardiac Disease
Fentanyl transdermal system may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal system.
5.14 Hepatic Impairment
A clinical pharmacology study with fentanyl transdermal system 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 system and hepatic metabolism of fentanyl, avoid use of fentanyl transdermal system in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system 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 system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosing and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
5.15 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 system, avoid the use of fentanyl transdermal system in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system 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 system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosing and Administration (2.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
5.16 Use in Pancreatic/Biliary Tract Disease
Fentanyl transdermal system may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsened symptoms. Fentanyl transdermal system may cause increases in the serum amylase concentration.
5.18 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 system.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
- Accidental Exposure [see Warnings and Precautions (5.3)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
- Interactions with Central Nervous System Depressants [see Warnings and Precautions (5.5)]
- Hypotensive Effects [see Warnings and Precautions (5.9)]
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.
6.1 Clinical Trial Experience
The safety of fentanyl transdermal system was evaluated in 216 patients who took at least one dose of fentanyl transdermal system in a multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal system. 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 system-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 System-treated Patients and With an Incidence Greater Than Placebo-treated Patients in 1 Double-Blind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal System
Fentanyl Transdermal System
Ear and labyrinth disorders
Abdominal pain upper
General disorders and administration site conditions
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Nervous system disorders
Skin and subcutaneous tissue disorders
Adverse reactions not reported in Table 3 that were reported by ≥1% of fentanyl transdermal system‑treated adult and pediatric patients (N=1854) in 11 controlled and uncontrolled clinical trials of fentanyl transdermal system 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 System-treated Patients in 11 Clinical Trials of Fentanyl Transdermal System
Fentanyl Transdermal System
Immune system disorders
Nervous system disorders
Renal and urinary disorders
Skin and subcutaneous tissue disorders
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
The safety of fentanyl transdermal system 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 system-treated pediatric patients are shown in Table 5.
Table 5. Adverse Reactions Reported by ≥1% of Fentanyl Transdermal System-treated Pediatric Patients in 3 Clinical Trials of Fentanyl Transdermal System
Fentanyl Transdermal System
Abdominal pain upper
General disorders and administration site conditions
Application site reaction
Immune system disorders
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Nervous system disorders
Renal and urinary disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of fentanyl transdermal system. 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: pyrexia
Immune System Disorders: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction
Investigations: weight decreased
Nervous System Disorders: convulsions (including clonic convulsions and grand mal
convulsion), amnesia, depressed level of consciousness, loss of consciousness
Psychiatric Disorders: agitation
Respiratory, Thoracic, and Mediastinal Disorders: respiratory distress, apnea, bradypnea,
Vascular Disorders: hypotension, hypertension
7 DRUG INTERACTIONS
7.1 Central Nervous System Depressants
The concomitant use of fentanyl transdermal system with other CNS depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and fentanyl transdermal system for signs of respiratory depression, sedation and hypotension.
7.2 Drugs Affecting Cytochrome P450 3A4 Isoenzymes
Inhibitors of CYP3A4
Because the CYP3A4 isoenzyme plays a major role in the metabolism of fentanyl, drugs that inhibit CYP3A4 activity may cause decreased clearance of fentanyl which could lead to an increase in fentanyl plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of 3A4 inhibitors. If co-administration with fentanyl transdermal system is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
Inducers of CYP3A4
CYP450 3A4 inducers may induce the metabolism of fentanyl and, therefore, may cause increased clearance of the drug which could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. If co-administration with fentanyl transdermal system is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)].
After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see Clinical Pharmacology (12.3)].
7.3 MAO Inhibitors
Avoid use of fentanyl transdermal system in the patient who would require the concomitant administration of a monoamine oxidase (MAO) inhibitor, or within 14 days of stopping such treatment because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of fentanyl transdermal system or may precipitate withdrawal symptoms. Avoid the use of agonist/antagonist and partial agonist analgesics in patients receiving fentanyl transdermal system.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastrointestinal motility when fentanyl transdermal system is used concurrently with anticholinergic drugs.
8 USE IN SPECIFIC POPULATIONS
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.4)].
Pregnancy C - There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 micro osmotic 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 embryo-toxicity 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).
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.
8.2 Labor and Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. Fentanyl transdermal system is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
8.3 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.
8.4 Pediatric Use
The safety of fentanyl transdermal system 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/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.
The safety and effectiveness of fentanyl transdermal system in children under 2 years of age have not been established.
To guard against excessive exposure to fentanyl transdermal system by young children, advise caregivers to strictly adhere to recommended fentanyl transdermal system application and disposal instructions [see Dosage and Administration (2.4), (2.5) and Warnings and Precautions (5.3)].
8.5 Geriatric Use
Clinical studies of fentanyl transdermal system 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 system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology (12.3)].
Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal system and when given in conjunction with other drugs that depress respiration [see Warnings and Precautions (5.2), (5.6)].
8.6 Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. A clinical pharmacology study with fentanyl transdermal system 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 system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.1), Warnings and Precautions (5.14) and Clinical Pharmacology 12.3)].
8.7 Renal Impairment
The effect of renal impairment on the pharmacokinetics of fentanyl transdermal system 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 system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosing and Administration (2.1), Warnings and Precautions (5.15) and Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance with a high potential for abuse similar to other opioids including morphine, hydromorphone, methadone, oxycodone, and oxymorphone. Fentanyl transdermal system can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to, the following examples: the use of a prescription or over-the-counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“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. Preoccupation with achieving pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. Fentanyl transdermal system, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, 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.
Risks Specific to the Abuse of Fentanyl Transdermal System
Fentanyl transdermal system is intended for transdermal use only. Abuse of fentanyl transdermal system poses a risk of overdose and death. This risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants [see Warnings and Precautions (5.5), and Drug Interactions (7.1)]. Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Fentanyl transdermal system should not be abruptly discontinued [see Dosage and Administration (2.5)]. If fentanyl transdermal system is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.2, 8.3)].
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 system 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 system.
10.2 Treatment of Overdose
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 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 system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20 to 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 system, 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.
Fentanyl transdermal system is a transdermal system containing fentanyl. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:
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 7.8 cm2). The composition per unit area of all system sizes is identical.
Color of Printing on Back of Patch
*Nominal delivery rate per hour
†Nominal delivery rate is 12.5 mcg/hr
Fentanyl transdermal system is a rectangular transparent unit comprising a protective liner and four functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:
1) a backing layer of PET foil;
2) a drug containing layer of fentanyl and dipropylene glycol with hydroxypropyl cellulose;
3) an ethylene vinyl-acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface; and
4) a silicone adhesive. Before use, a protective liner covering the adhesive layer is removed and discarded.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.
Central Nervous System Effects
Fentanyl exerts its principal pharmacologic effects on the central nervous system. Central nervous system effects increase with increasing serum fentanyl concentrations.
In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting directly by stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope.
In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.
Gastrointestinal Tract and Other Smooth Muscle
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.
Fentanyl may cause orthostatic hypotension and fainting. Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with fentanyl transdermal system was less than 1%.
Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg.
Fentanyl transdermal system 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 system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 20 and 72 hours after initial application (see Table 6). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first 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 to 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 to 12) hours.
A clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal 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 System
Mean (SD) Time to
Fentanyl Transdermal System 12 mcg/hr
Fentanyl Transdermal System 25 mcg/hr
Fentanyl Transdermal System 50 mcg/hr
Fentanyl Transdermal System 75 mcg/hr
Fentanyl Transdermal System 100 mcg/hr
*Cmax values dose normalized from 4 x 12.5 mcg/hr: 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 to 27 hours.
Table 7. Range of Pharmacokinetic Parameters of Intravenous Fentanyl in Patients
Volume of Distribution
27 – 75
3 – 8
3 – 12
Hepatically Impaired Patients
3 – 80*
0.8 – 8*
4 – 12*
Renally Impaired Patients
30 – 78
NOTE: Information on volume of distribution and half-life not available for renally impaired patients.
Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8; N=8).
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.
Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.
Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.
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 system 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 system 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 (5.6) and Use in Specific Populations (8.5)].
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 (2.1)].
Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system 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 system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.1), Warnings and Precautions (5.14), and Use in Specific Populations (8.6)].
Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system 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 system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosing and Administration (2.1), Warnings and Precautions (5.15) and Use in Specific Populations (8.7)].
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to 420%) increase in fentanyl AUC0-∞. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor for signs of respiratory depression for an extended period of time and adjust the dosage if warranted [see Boxed Warning and Warnings and Precautions (5.10), and Drug Interactions (7.2)].
Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 μg/kg/day in males or 100 μg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/hr patch based on AUC0-24h comparison).
There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.
Impairment of Fertility
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for
28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.
14 CLINICAL STUDIES
Fentanyl transdermal system as therapy for pain due to cancer has been studied in 153 patients. In this patient population, fentanyl transdermal system has been administered in doses of 25 μg/hr to 600 μg/hr. Individual patients have used fentanyl transdermal system continuously for up to 866 days. At one month after initiation of fentanyl transdermal system therapy, patients generally reported lower pain intensity scores as compared to a prestudy analgesic regimen of oral morphine.
The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year.
In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 289 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.
- 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Addiction, Abuse, and Misuse
Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share fentanyl transdermal system with others and to take steps to protect fentanyl transdermal system from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting fentanyl transdermal system or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients to keep fentanyl transdermal system in a secure place out of the reach of children due to the high risk of respiratory depression or death [see Warnings and Precautions (5.3)].
Fentanyl transdermal system can be accidentally transferred to children. Instruct patients to take special precautions to avoid accidental contact when holding or caring for children.
Instruct patients that, if the patch dislodges and accidentally sticks to the skin of another person, to immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual as accidental exposure may lead to death or other serious medical problems.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4)].
Interactions with Alcohol and Other CNS Depressants
Inform patients that potentially serious additive effects may occur if fentanyl transdermal system is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider.
Important Administration Instructions
Advise patients never to change the dose of fentanyl transdermal system or the number of patches applied to the skin unless instructed to do so by the prescribing healthcare professional.
When no longer needed, advise patients how to safely taper fentanyl transdermal system and not to stop it abruptly to avoid the risk of precipitating withdrawal symptoms.
Warnings About Heat
Warn patients of the potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl. Instruct patients to contact their healthcare provider if they develop a high fever. Instruct patients to:
- avoid strenuous exertion that can increase body temperature while wearing the patch
- avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources including heating pads, electric blankets, sunbathing, heat or tanning lamps, saunas, hot tubs or hot baths, and heated water beds.
Driving or Operating Heavy Machinery
Fentanyl transdermal system may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Instruct patients 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.
Advise women of childbearing potential who become, or are planning to become pregnant, to consult a healthcare provider prior to initiating or continuing therapy with fentanyl transdermal system.
Additive Effects of Alcohol and Other CNS Depressants
Instruct patients not to use alcohol or other CNS depressants (e.g. sleep medications, tranquilizers) while using fentanyl transdermal system because dangerous additive effects may occur, resulting in serious injury or death.
Advise patients of the potential for severe constipation.
Instruct patients to refer to the Instructions for Use for proper disposal of fentanyl transdermal system. To properly dispose of a used patch, instruct patients to remove it, fold so that the adhesive side of the patch adheres to itself, and immediately flush down the toilet. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.
Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed.
Fentanyl Transdermal System, CII
Fentanyl transdermal system is:
- A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, in people who are already regularly using opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
- A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
- Not for use to treat pain that is not around-the-clock.
Important information about fentanyl transdermal system:
- Get emergency help right away if you use too much fentanyl transdermal system (overdose). When you first start taking fentanyl transdermal system, when your dose is changed, or if you take too much (overdose), serious or life threatening breathing problems that can lead to death may occur.
- Never give anyone else your fentanyl transdermal system. They could die from using it. Store fentanyl transdermal system away from children and in a safe place to prevent stealing or abuse. Selling or giving away fentanyl transdermal system is against the law.
- If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems.
- Proper disposal of fentanyl transdermal system after use and for unused patches when no longer needed: Fold the sticky sides of the patch together and flush down the toilet. Do not put patches in a trash can.
Do not use fentanyl transdermal system if you have:
- severe asthma, trouble breathing, or other lung problems.
- a bowel blockage or have narrowing of the stomach or intestines.
Before applying fentanyl transdermal system, tell your healthcare provider if you have a history of:
- head injury, seizures
- problems urinating
- abuse of street or prescription drugs, alcohol addiction, or mental health problems.
- liver, kidney, thyroid problems
- pancreas or gallbladder problems
Tell your healthcare provider if you:
- have a fever
- are pregnant or planning to become pregnant. Prolonged use of fentanyl transdermal system during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
- are breastfeeding. Fentanyl passes into breast milk and may harm your baby.
- are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl transdermal system with certain other medicines can cause serious side effects that could lead to death.
When using fentanyl transdermal system:
- Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider.
- See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system.
- Do not apply more than 1 patch at the same time unless your healthcare provider tells you to.
- You should wear the fentanyl transdermal system continuously for 3 days, unless advised otherwise by your healthcare provider.
- Call your healthcare provider if the dose you are using does not control your pain.
- Do not stop using fentanyl transdermal system without talking to your healthcare provider.
While using fentanyl transdermal system DO NOT:
- Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated waterbeds, or tanning lamps, or engage in exercise that increases your body temperature. These can cause an overdose that can lead to death.
- Drive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you sleepy, dizzy, or lightheaded.
- Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with fentanyl transdermal system may cause you to overdose and die.
The possible side effects of fentanyl transdermal system are:
- constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, itching, redness, or rash where the patch is applied. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions, or you are feeling faint.
These are not all the possible side effects of fentanyl transdermal system. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
This Medication Guide has been approved by the U.S. Food and Drug Administration.
INSTRUCTIONS FOR USE
Instructions for Use
Fentanyl Transdermal System CII
Instructions for Applying a Fentanyl Transdermal System
Be sure that you read, understand, and follow these Instructions for Use before you use fentanyl transdermal system. Talk to your healthcare provider or pharmacist if you have any questions.
Parts of the fentanyl transdermal system:
Before applying fentanyl transdermal system
- Each fentanyl transdermal system is sealed in its own protective pouch. Do not remove a fentanyl transdermal system from the pouch until you are ready to use it.
- Do not use a fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged or changed in any way.
- Fentanyl transdermal systems are available in 4 different doses and patch sizes. Make sure you have the right dose patch or patches that have been prescribed for you.
Applying a fentanyl transdermal system
1. Skin areas where the fentanyl transdermal system may be applied:
- Put the patch on the chest, back, flank (sides of the waist), or upper arm in a place where there is no hair (see Figures 1-4).
For children (and adults with mental impairment):
- Put the patch on the upper back (see Figure 2). This will lower the chances that the child will remove the patch and put it in their mouth.
For adults and children:
- Do not put a fentanyl transdermal system on skin that is very oily, burned, broken out, cut, irritated, or damaged in any way.
- Avoid sensitive areas or those that move around a lot. If there is hair, do not shave (shaving irritates the skin). Instead, clip hair as close to the skin as possible (see Figure 5).
- Talk to your healthcare provider if you have questions about skin application sites.
2. Prepare to apply a fentanyl transdermal system:
- Choose the time of day that is best for you to apply fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider.
- Do not wear more than one fentanyl transdermal system at a time unless your healthcare provider tells you to do so. Before applying a new fentanyl transdermal system, remove the patch you have been wearing.
- Clean the skin area with clear water only. Pat skin completely dry. Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied.
3. Open the pouch: Fold and tear at slit, or cut at slit taking care not to cut the patch. Remove the fentanyl transdermal system. Each fentanyl transdermal system is sealed in its own protective pouch. Do not remove the fentanyl transdermal system from the pouch until you are ready to use it (see Figure 6).
4. Peel: Peel off both parts of the protective liner from the patch. Each fentanyl transdermal system has a clear plastic backing that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this backing off. Throw the clear plastic backing away. Touch the sticky side of the fentanyl transdermal system as little as possible (see Figure 7).
5. Press: Press the patch onto the chosen skin site with the palm of your hand and hold there for at least 30 seconds (see Figure 8). Make sure it sticks well, especially at the edges.
- Fentanyl transdermal system may not stick to all patients. You need to check the patches often to make sure that they are sticking well to the skin.
- If the patch falls off right away after applying, throw it away and put a new one on at a different skin site (see Disposing of a fentanyl transdermal system).
- If you have a problem with the patch not sticking
- Apply first aid tape only to the edges of the patch.
- If you continue to have problems with the patch sticking, you may cover the patch with Bioclusive™ or Tegaderm™. These are special see-through adhesive dressings. Never cover a fentanyl transdermal system with any other bandage or tape. Remove the backing from the Bioclusive™ or Tegaderm™ dressing and place it carefully over the fentanyl transdermal system, smoothing it over the patch and your skin.
- If your patch falls off later, but before 3 days (72 hours) of use, dispose of properly (see Disposing of a fentanyl transdermal system). Apply a new fentanyl transdermal system on at a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider).
6. Wash your hands when you have finished applying a fentanyl transdermal system.
7. Remove a fentanyl transdermal system after wearing it for 3 days (72 hours) (see Disposing of a fentanyl transdermal system). Choose a different skin site to apply a new fentanyl transdermal system. Repeat Steps 2 through 6 above when applying a new fentanyl transdermal system.
Do not apply the new patch to the same place as the last one.
Water and fentanyl transdermal system
- You can bathe, swim or shower while you are wearing a fentanyl transdermal system. If the patch falls off before 3 days (72 hours) after application, dispose of properly (see Disposing of a fentanyl transdermal system). Apply a new fentanyl transdermal system on at a different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until 3 days (72 hours) after you put it on (or as directed by your healthcare provider).
Disposing of a fentanyl transdermal system
- Fold the used fentanyl transdermal system in half so that the sticky side sticks to itself (see Figure 9). Flush the used fentanyl transdermal system down the toilet right away (see Figure 10). A used fentanyl transdermal system can be very dangerous for or lead to death in babies, children, pets, and adults who have not been prescribed fentanyl transdermal system.
- Throw away any fentanyl transdermal systems that are left over from your prescription as soon as they are no longer needed. Remove the leftover patches from their protective pouch and remove the protective liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet. Do not flush the pouch or the protective liner down the toilet. These items can be thrown away in a trashcan.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
Bioclusive is a trademark of Systagenix Wound Management (US), Inc.
Tegaderm is a trademark of 3M Company.
LTS Lohmann Therapy Systems, Corp.
W. Caldwell, NJ 07006
Hazelwood, MO 63042 USA
Printed in USA
- Fentanyl 50mcg/Hr (CII) Patch
INGREDIENTS AND APPEARANCE
FENTANYL TRANSDERMAL SYSTEM
fentanyl transdermal system patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63629-5492(NDC:0406-9050) Route of Administration TRANSDERMAL DEA Schedule CII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENTANYL (UNII: UF599785JZ) (FENTANYL - UNII:UF599785JZ) FENTANYL 50 ug in 1 h Inactive Ingredients Ingredient Name Strength HYDROXYPROPYL CELLULOSE (1200000 MW) (UNII: RFW2ET671P) ETHYLENE-VINYL ACETATE COPOLYMER (19% VINYLACETATE) (UNII: JK6142KK4O) DIPROPYLENE GLYCOL (UNII: E107L85C40) DIMETHICONE (UNII: 92RU3N3Y1O) DIMETHICONE 350 (UNII: 2Y53S6ATLU) HEPTANE (UNII: 456148SDMJ) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-5492-1 5 h in 1 BOTTLE; Type 0: Not a Combination Product 12/08/2014 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077154 06/06/2011 Labeler - Bryant Ranch Prepack (171714327) Establishment Name Address ID/FEI Business Operations Bryant Ranch Prepack 171714327 REPACK(63629-5492) , RELABEL(63629-5492)