Addiction, Abuse, and Misuse Because the use of fentanyl transdermal system exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl transdermal system, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal system are essential [see Warnings and Precautions ( 5.2 )] . Accidental Exposure Accidental exposure of even one dose of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.3 )]. Deaths due to an overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure [see Warnings and Precautions ( 5.3 )] .   Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants C oncomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] .   Neonatal Opioid Withdrawal Syndrome If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be lifethreatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.5 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.6 )] Cytochrome P450 3A4 Interaction The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor or inducer   [see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 )]. Risk of Increased Fentanyl Absorption with Application of External Heat Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources [see Warnings and Precautions ( 5.8 )] .

Fentanyl transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment with a daily opioid analgesic and for which alternative treatment options are inadequate. Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60　mg morphine per day, 25 mcg transdermal fentanyl per hour, 30　mg oral oxycodone per day, 8　mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions ( 5.1 )] , 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. Fentanyl transdermal system is not indicated as an as-needed (prn) analgesic.

Fentanyl transdermal system should be prescribed only by healthcare providers who are knowledgeable about the use of extended-release/long-actingopioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of fentanyl transdermal system for patients in whom lower doses are insuffieciently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with fentanyl transdermal system. Consider the risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose selection: consult conversion instructions. ( 2.3 ) Each transdermal system is intended to be worn for 72 hours. ( 2.3 ) Adhere to instructions concerning administration and disposal of fentanyl transdermal system. ( 2.7, 2.8 ) Mild to moderate hepatic and renal impairment: Initiate treatment with one half the usual starting dose, titrate slowly, and monitor for signs of respiratory and central nervous system depression. ( 2.5, 2.6 ) Do not abruptly discontinue fentanyl transdermal system in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.9 )

Fentanyl transdermal system is supplied in cartons containing 5 individual child-resistant packaged systems. See chart for information regarding individual systems. Fentanyl Transdermal System Dose (mcg/hour) System Size (cm 2 ) Fentanyl Content (mg) NDC Number for Blister Containing Individual System NDC Number for Carton Containing 5 Systems Fentanyl Transdermal System-12* 5.35 1.38 60505-7080-0 60505-7080-2 Fentanyl Transdermal System-25 10.7 2.76 60505-7081-0 60505-7081-2 Fentanyl Transdermal System-37.5 16.05 4.14 60505-7085-0 60505-7085-2 Fentanyl Transdermal System-50 21.4 5.52 60505-7082-0 60505-7082-2 Fentanyl Transdermal System-62.5 26.75 6.90 60505-7086-0 60505-7086-2 Fentanyl Transdermal System-75 32.1 8.28 60505-7083-0 60505-7083-2 Fentanyl Transdermal System-87.5 37.45 9.66 60505-7087-0 60505-7087-2 Fentanyl Transdermal System-100 42.8 11.04 60505-7084-0 60505-7084-2 * This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from 125 mcg/hour strength that could be prescribed by using multiple transdermal systems. Store in original unopened blister. Store up to 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Store fentanyl transdermal system securely and dispose of properly [ see Patient Counseling Information ( 17 ) ]

Fentanyl transdermal system is contraindicated in: patients who are not opioid-tolerant. the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time. the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies). the management of mild pain. patients with significant respiratory depression [see Warnings and Precautions ( 5.12 )] . in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.12 )] . in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.19 )] . in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system [see Adverse Reactions ( 6.2 )] .

Fentanyl transdermal system contains fentanyl, an opioid agonist, for transdermal administration. The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per 10.5 cm 2 ). The composition per unit area of all transdermal system sizes is identical. Strength* (mcg/hour) Size (cm 2 ) Fentanyl Content (mg) 12** 5.35 1.38 25 10.7 2.76 37.5 50 16.05 21.4 4.14 5.52 62.5 75 26.75 32.1 6.90 8.28 87.5 100 37.45 42.8 9.66 11.04 * Nominal delivery rate per hour ** Nominal delivery rate is 12.5 mcg/hour The molecular weight of fentanyl base is 336.5 g/mol, and the empirical formula is C 22 H 28 N 2 O. The n-octanol: water partition coefficient is 860:1. The pKa is 8.4. The chemical name is N-phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is: Fentanyl transdermal system is a rectangular transparent unit comprising a release liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are: 1) a backing layer of polyethylene terephalate film; 2) a drug-in-adhesive layer. Before use, a release liner covering the drug-in-adhesive layer is removed and discarded.

Table 6 includes clinically significant drug interactions with fentanyl transdermal system. Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal System Inhibitors of CYP3A4 Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions ( 5.7 )]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention : If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and evaluate patient at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.11) ] . Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.11 )] or opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Beacuse respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )]. Diuretics Clinical Impact : Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact : The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.1 , 5.3 ), Drug Abuse and Dependence ( 9.2 )] . Inform patients that leaving fentanyl transdermal system unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl transdermal system should be disposed of by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [ see Instructions for Use ]. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share 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 dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.3 )].  Accidental Exposure Inform patients that accidental exposure, especially in children, may result in 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. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if fentanyl transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.   Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage ( 10 )] .   If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone, in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.10 ); Postmarketing Experience ( 6.2 )] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking fentanyl transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl transdermal system [see Drug Interactions ( 7 )]. 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.   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. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber [ see Dosage and Administration ( 2.9 ) ]. Driving or Operating Heavy Machinery Inform patients that fentanyl transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.21 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.12 )] . Hypotension Inform patients that fentanyl transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.14 )]. Anaphylaxis Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4 ), Adverse Reactions ( 6 )]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of 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 ( 5.5 ), Use in Specific Populations ( 8.1 )] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that fentanyl transdermal system can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system [see Use in Specific Populations ( 8.2 )] . Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Manufactured by Manufactured for Aveva Drug Delivery Systems, Inc. Apotex Corp. Miramar, FL 33025 Weston, Florida 33326

Risk Summary 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. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system. Clinical Considerations Monitor infants exposed to fentanyl transdermal system through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.2 ), Nonclinical Toxicology ( 13.1 )].

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/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 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 ( 2.7 ), ( 2.8 ) and Warnings and Precautions ( 5.3 )] .

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, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34　hours [see Clinical Pharmacology ( 12.3 )] . Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl transdermal system slowly in geriatric patients and frequently re-evaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12 )] . Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Carcinogenesis In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33   mcg/kg/day in males or 100   mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100   mcg/h patch based on AUC 0-24h comparison). Mutagenesis There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitro assays. Impairment of Fertility The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 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.

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 ( 5.5 )] Interactions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions ( 5.4 )] Serotonin Syndrome  [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency  [see Warnings and Precautions ( 5.13 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.19 )] Seizures [see Warnings and Precautions ( 5.20 )] Withdrawal [see Warnings and Precautions ( 5.21 )]

Fentanyl transdermal system contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] .  Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.   Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug  use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.   Misuse and abuse of fentanyl transdermal system increases risk of overdosage, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.   All patients treated with opioids require careful and frequent re-evaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl transdermal system abuse include those with a history of prolonged use of products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl transdermal system in combination with other abused drugs.   “Drug seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.   Fentanyl transdermal system, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.   Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of 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 ( 5.4 ) and Drug Interactions ( 7 )] . Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1 )] . Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system.

Clinical Presentation Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Treatment of Overdose Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Once stable, examine the patient and ensure that all fentanyl transdermal systems have been removed.  Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl transdermal system, 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. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

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 mcg/h to 600 mcg/h. 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 pre-study 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.

Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance.

Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with fentanyl transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl transdermal system is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl transdermal system, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 2 times the daily human dose administered by a 100 mcg/h patch on a mg/m 2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03　mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03　mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m 2 basis). There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0,　0.025,　0.1, 0.4　mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4　mg/kg (approximately 3 times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2 basis). The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4　mg/kg/day fentanyl via intravenous infusion from Day 6 of pregnancy through 3　weeks of lactation. Fentanyl treatment (0.4　mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Day　28 which recovered by Day 50). The mid-dose and the high-dose are 0.4 and 1.6　times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2 basis.

Structure

Fentanyl Transdermal System, Cll (fen' ta nil) Fentanyl transdermal system is : A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent that requires an extended treatment period with a daily opioid pain medicine, 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 to be used on an “as needed” basis. Important information about fentanyl transdermal system: Get emergency help or call 911 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. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking fentanyl transdermal system with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) may cause severe drowsiness, decreased awareness, breathing difficulties, with slow or shallow breathing, coma, and death. Never give anyone else your fentanyl transdermal system. They could die from taking it. Selling or giving away fentanyl transdermal system is against the law. Store fentanyl transdermal system, securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems.  Dispose of expired, unwanted, or unused fentanyl transdermal system, by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [ see Instructions for Use ]. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. 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 liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you: have a fever are pregnant or planning to become pregnant. Use of fentanyl transdermal system for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. are breastfeeding. Not recommended during treatment with fentanyl transdermal system. It may harm your baby. are living in a household where there are small children or someone who has abused street or prescription drugs. are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl with certain other medicines can cause serious side effects that could lead to death. Notice your pain getting worse. If your pain gets worse fater you use fentanyl transdermal system, do not use more of fentanyl transdermal system without first talking to your doctor. Talk to your doctor if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after using fentanyl transdermal system. When using fentanyl transdermal system : Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system patch. Do not apply more than 1 patch at the same time unless your healthcare provider tells you to. You should wear the fentanyl transdermal patch continuously for 3 days, unless advised otherwise by your healthcare provider. Do not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die. 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 or call 911 right away 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, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.  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 Manufactured by: Aveva Drug Delivery Systems, Inc., Miramar, FL  33025; Manufactured for: Apotex Corp., Weston, FL  33326, [email protected] or call 1-888-333-6127, 9 A.M. to 5 P.M., Eastern Time, Monday through Friday. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issue: May 2023

Transdermal system: Fentanyl Transdermal System 12 mcg/hour* (system size 5.35 cm 2 ) Fentanyl Transdermal System 25 mcg/hour (system size 10.7 cm 2 ) Fentanyl Transdermal System   37.5　mcg/hour (system size 16.05　cm 2 ) Fentanyl Transdermal System 50 mcg/hour (system size 21.4 cm 2 ) Fentanyl Transdermal System   62.5　mcg/hour (system size 26.75　cm 2 ) Fentanyl Transdermal System 75 mcg/hour (system size 32.1 cm 2 ) Fentanyl Transdermal System   87.5　mcg/hour (system size 37.45　cm 2 ) Fentanyl Transdermal System 100 mcg/hour (system size 42.8 cm 2 ) * This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.

Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

Effects on the Central Nervous System Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8　breaths/minute or a pCO 2 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. Effects on the Gastrointestinal Tract and Other Smooth Muscle Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50　mcg/kg. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 )]. Concentration–Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.3 , 2.4 )].

Absorption 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, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. Following 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 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of Fentanyl Transdermal System   Mean (SD) Time to Maximal Concentration T max (h) Mean (SD) Maximal Concentration C max (ng/mL) Fentanyl Transdermal System 12 mcg/hour 28.8 (13.7) 0.38 (0.13)* Fentanyl Transdermal System 25 mcg/hour 31.7 (16.5) 0.85 (0.26)** Fentanyl Transdermal System 50 mcg/hour 32.8 (15.6) 1.72 (0.53)** Fentanyl Transdermal System 75 mcg/hour 35.8 (14.1) 2.32 (0.86)** Fentanyl Transdermal System 100 mcg/hour 29.9 (13.3) 3.36 (1.28)** * C max values dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers ** C max values: Study C-2002-048 dose proportionality study in healthy volunteers NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20 to 27 hours. Figure 1 Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100   mcg/h Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl In Patients   Clearance (L/h) Range  [70 kg] Volume of Distribution V SS (L/kg) Range Half-Life t 1/2 (h) Range Surgical Patients 27 - 75 3 - 8 3 - 12 Hepatically Impaired Patients 3 - 80+ 0.8 - 8+ 4 - 12+ Renally Impaired Patients 30 - 78 – – +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 to 8; N=8). Elimination Metabolism Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.  Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. Excretion Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%. Specific Populations Age: Geriatric Population Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the 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 system　100　mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65　years old (n=21, mean age 71　years) and worn for 72　hours. The mean C max and AUC ∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45　years old. Inter-subject variability in AUC ∞ was higher in elderly subjects than in healthy adult subjects 18 to 45　years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65　years old than in subjects 18　to 45　years old (34.4　hours versus 23.5　hours) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )] .  Age: Pediatric Population In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration ( 2.3 )]. Hepatic Impairment Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C max and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of 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 ( 2.5 ), Warnings and Precautions ( 5.17 ), and Use in Specific Populations ( 8.6 )] . Renal Impairment Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Because there is in-vivo evidence of renal contribution to the elimination of 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 ( 2.6 ), Warnings and Precautions ( 5.18 ) and Use in Specific Populations ( 8.7 )]. Drug Interaction Studies CYP3A4 Inhibitors Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CYP3A4 inhibitor,   and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3　days. The ritonavir dose was 200　mg　 three times a day on Day　1 and 300　mg three times a day on Day　2 followed by one morning dose of 300　mg on Day　3. On Day　2, fentanyl was given as a single IV dose at 5　mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to 420%) increase in fentanyl AUC 0-∞ . The concomitant use of transdermal fentanyl with all CYP3A4　inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving 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 ( 5.6 ), and Drug Interactions ( 7 )]. CYP3A4 Inducers Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.

Indications and Usage ( 1 ) Dosage and Administration ( 2.1, 2.3 ) Warnings and Precautions ( 5.10 )

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Not recommended. ( 8.2 ) Severe Hepatic and Renal Impairment: Use not recommended. ( 8.6 , 8.7 )

Risk of Increased Fentanyl Absorption with Elevated Body Temperature : Regularly evaluate patients with fever closely for sedation and respiratory depression and reduce the dose if necessary. Warn patients to avoid strenuous exertion that may lead to increased body temperature ( 5.9 ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. ( 5.12 ) Serotonin Syndrome with Concomitant Use of Serotonergic Drugs : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue fentanyl transdermal system immediately if serotonin syndrome is suspected. ( 5.11 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.13 ) Severe Hypotension : Regularly evaluate during dose initiation and titration. Avoid the use of fentanyl transdermal system in patients with circulatory shock. ( 5.14 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness : Regularly evaluate for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma. ( 5.15 )

PRINCIPAL DISPLAY PANEL - 25 mcg/hr Carton Front Panel NDC 60505-7081-2 Five (25 mcg/hr) Systems FENTANYL TRANSDERMAL SYSTEM CII 25 mcg/hr Rx Only In vivo delivery of 25 mcg/hr fentanyl for 72 hours Because it can cause trouble breathing which can be fatal, DO NOT USE FENTANYL TRANSDERMAL SYSTEM: For short term or any post-operative pain, or occasional pain For mild pain or pain that can be treated with non-opioid or as-needed opioid medication Unless you have been using other narcotic opioid medicines (must be opioid tolerant) Each transdermal system contains: 2.76 mg fentanyl DO NOT USE IF SEAL ON POUCH IS BROKEN KEEP OUT OF REACH OF CHILDREN Read enclosed FENTANYL TRANSDERMAL SYSTEM Medication Guide for important safety information. ONLY for pain requiring opioid medicine around-the-clock Apotex Corp. Back Panel Inactive Ingredients: isopropyl myristate, octyldodecanol, polybutene, and polyisobutene adhesive. Dosage: For information for use, see accompanying product literature. Apply immediately upon removal from pouch and after removal of the protective liner. Do not expose area to heat. Store in original unopened pouch. Store up to 25ºC (77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF). See Medication Guide for important safety information. For your convenience in recording narcotic use, INITIAL/DATE 1._______________ 2._______________ 3._______________ 4._______________ 5._______________ For questions regarding this product, please call Apotex Corp. at 1-888-333-6127, 9 A.M. to 5 P.M.Eastern Time, Monday through Friday. If this is a medical emergency, please call 911.. Manufactured by: Aveva Drug Delivery Systems An Apotex Company. Miramar, FL 33 Manufactured for: Apotex Corp. Weston, FL 33326 0000000 Rev.03/2017

Addiction, Abuse, and Misuse Because the use of fentanyl transdermal system exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of fentanyl transdermal system, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal system are essential [see Warnings and Precautions ( 5.2 )] . Accidental Exposure Accidental exposure of even one dose of fentanyl transdermal system, especially in children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.3 )]. Deaths due to an overdose of fentanyl have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure [see Warnings and Precautions ( 5.3 )] .   Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants C oncomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] .   Neonatal Opioid Withdrawal Syndrome If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be lifethreatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.5 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.6 )] Cytochrome P450 3A4 Interaction The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving fentanyl transdermal system and any CYP3A4 inhibitor or inducer   [see Warnings and Precautions ( 5.7 ) and Clinical Pharmacology ( 12.3 )]. Risk of Increased Fentanyl Absorption with Application of External Heat Exposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase fentanyl absorption and has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the application site and surrounding area to direct external heat sources [see Warnings and Precautions ( 5.8 )] .

Fentanyl transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment with a daily opioid analgesic and for which alternative treatment options are inadequate. Patients considered opioid-tolerant are those who are taking, for one week or longer, at least 60　mg morphine per day, 25 mcg transdermal fentanyl per hour, 30　mg oral oxycodone per day, 8　mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions ( 5.1 )] , 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. Fentanyl transdermal system is not indicated as an as-needed (prn) analgesic.

Fentanyl transdermal system should be prescribed only by healthcare providers who are knowledgeable about the use of extended-release/long-actingopioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of fentanyl transdermal system for patients in whom lower doses are insuffieciently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with fentanyl transdermal system. Consider the risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.4 ) Initial dose selection: consult conversion instructions. ( 2.3 ) Each transdermal system is intended to be worn for 72 hours. ( 2.3 ) Adhere to instructions concerning administration and disposal of fentanyl transdermal system. ( 2.7, 2.8 ) Mild to moderate hepatic and renal impairment: Initiate treatment with one half the usual starting dose, titrate slowly, and monitor for signs of respiratory and central nervous system depression. ( 2.5, 2.6 ) Do not abruptly discontinue fentanyl transdermal system in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.9 )

Fentanyl transdermal system is supplied in cartons containing 5 individual child-resistant packaged systems. See chart for information regarding individual systems. Fentanyl Transdermal System Dose (mcg/hour) System Size (cm 2 ) Fentanyl Content (mg) NDC Number for Blister Containing Individual System NDC Number for Carton Containing 5 Systems Fentanyl Transdermal System-12* 5.35 1.38 60505-7080-0 60505-7080-2 Fentanyl Transdermal System-25 10.7 2.76 60505-7081-0 60505-7081-2 Fentanyl Transdermal System-37.5 16.05 4.14 60505-7085-0 60505-7085-2 Fentanyl Transdermal System-50 21.4 5.52 60505-7082-0 60505-7082-2 Fentanyl Transdermal System-62.5 26.75 6.90 60505-7086-0 60505-7086-2 Fentanyl Transdermal System-75 32.1 8.28 60505-7083-0 60505-7083-2 Fentanyl Transdermal System-87.5 37.45 9.66 60505-7087-0 60505-7087-2 Fentanyl Transdermal System-100 42.8 11.04 60505-7084-0 60505-7084-2 * This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from 125 mcg/hour strength that could be prescribed by using multiple transdermal systems. Store in original unopened blister. Store up to 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Store fentanyl transdermal system securely and dispose of properly [ see Patient Counseling Information ( 17 ) ]

Fentanyl transdermal system is contraindicated in: patients who are not opioid-tolerant. the management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time. the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies). the management of mild pain. patients with significant respiratory depression [see Warnings and Precautions ( 5.12 )] . in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.12 )] . in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.19 )] . in patients with hypersensitivity to fentanyl (e.g., anaphylaxis) or any components of the transdermal system [see Adverse Reactions ( 6.2 )] .

Table 6 includes clinically significant drug interactions with fentanyl transdermal system. Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal System Inhibitors of CYP3A4 Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions ( 5.7 )]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention : If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and evaluate patient at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.11) ] . Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.11 )] or opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Beacuse respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )]. Diuretics Clinical Impact : Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact : The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store fentanyl transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.1 , 5.3 ), Drug Abuse and Dependence ( 9.2 )] . Inform patients that leaving fentanyl transdermal system unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused fentanyl transdermal system should be disposed of by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [ see Instructions for Use ]. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of fentanyl transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share 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 dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.3 )].  Accidental Exposure Inform patients that accidental exposure, especially in children, may result in 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. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if fentanyl transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with fentanyl transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.   Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage ( 10 )] .   If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone, in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.10 ); Postmarketing Experience ( 6.2 )] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome, and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking fentanyl transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking fentanyl transdermal system [see Drug Interactions ( 7 )]. 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.   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. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing a tapering plan with the prescriber [ see Dosage and Administration ( 2.9 ) ]. Driving or Operating Heavy Machinery Inform patients that fentanyl transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.21 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.12 )] . Hypotension Inform patients that fentanyl transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.14 )]. Anaphylaxis Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4 ), Adverse Reactions ( 6 )]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of 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 ( 5.5 ), Use in Specific Populations ( 8.1 )] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that fentanyl transdermal system can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system [see Use in Specific Populations ( 8.2 )] . Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )]. Manufactured by Manufactured for Aveva Drug Delivery Systems, Inc. Apotex Corp. Miramar, FL 33025 Weston, Florida 33326

Risk Summary 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. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system. Clinical Considerations Monitor infants exposed to fentanyl transdermal system through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.2 ), Nonclinical Toxicology ( 13.1 )].

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/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 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 ( 2.7 ), ( 2.8 ) and Warnings and Precautions ( 5.3 )] .

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, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34　hours [see Clinical Pharmacology ( 12.3 )] . Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of fentanyl transdermal system slowly in geriatric patients and frequently re-evaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.12 )] . Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Carcinogenesis In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33   mcg/kg/day in males or 100   mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100   mcg/h patch based on AUC 0-24h comparison). Mutagenesis There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitro assays. Impairment of Fertility The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hour patch on a mg/m 2 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.

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 ( 5.5 )] Interactions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions ( 5.4 )] Serotonin Syndrome  [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency  [see Warnings and Precautions ( 5.13 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.19 )] Seizures [see Warnings and Precautions ( 5.20 )] Withdrawal [see Warnings and Precautions ( 5.21 )]

Fentanyl transdermal system contains fentanyl, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] .  Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.   Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug  use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.   Misuse and abuse of fentanyl transdermal system increases risk of overdosage, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of fentanyl transdermal system with alcohol and other central nervous system depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.   All patients treated with opioids require careful and frequent re-evaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of fentanyl transdermal system abuse include those with a history of prolonged use of products containing fentanyl, those with a history of drug or alcohol abuse, or those who use fentanyl transdermal system in combination with other abused drugs.   “Drug seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.   Fentanyl transdermal system, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.   Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to the Abuse of 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 ( 5.4 ) and Drug Interactions ( 7 )] . Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1 )] . Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting or injecting fentanyl extracted from the transdermal system.

Clinical Presentation Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Treatment of Overdose Give primary attention to the reestablishment of a patent airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Once stable, examine the patient and ensure that all fentanyl transdermal systems have been removed.  Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in fentanyl transdermal system, 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. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Fentanyl transdermal system contains fentanyl, an opioid agonist, for transdermal administration. The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/hour per 10.5 cm 2 ). The composition per unit area of all transdermal system sizes is identical. Strength* (mcg/hour) Size (cm 2 ) Fentanyl Content (mg) 12** 5.35 1.38 25 10.7 2.76 37.5 50 16.05 21.4 4.14 5.52 62.5 75 26.75 32.1 6.90 8.28 87.5 100 37.45 42.8 9.66 11.04 * Nominal delivery rate per hour ** Nominal delivery rate is 12.5 mcg/hour The molecular weight of fentanyl base is 336.5 g/mol, and the empirical formula is C 22 H 28 N 2 O. The n-octanol: water partition coefficient is 860:1. The pKa is 8.4. The chemical name is N-phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is: Fentanyl transdermal system is a rectangular transparent unit comprising a release liner and two functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are: 1) a backing layer of polyethylene terephalate film; 2) a drug-in-adhesive layer. Before use, a release liner covering the drug-in-adhesive layer is removed and discarded.

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 mcg/h to 600 mcg/h. 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 pre-study 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.

Fentanyl transdermal system contains fentanyl, a Schedule II controlled substance.

Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with fentanyl transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival and developmental delays at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl transdermal system is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including fentanyl transdermal system, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 2 times the daily human dose administered by a 100 mcg/h patch on a mg/m 2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03　mg/kg) to pregnant rats from Gestation Day 6 to 18 suggested evidence of embryo-toxicity and a slight increase in mean delivery time in the 0.03　mg/kg/day group (0.1 times the human dose administered by a 100 mcg/h patch on a mg/m 2 basis). There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0,　0.025,　0.1, 0.4　mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4　mg/kg (approximately 3 times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2 basis). The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4　mg/kg/day fentanyl via intravenous infusion from Day 6 of pregnancy through 3　weeks of lactation. Fentanyl treatment (0.4　mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Day　28 which recovered by Day 50). The mid-dose and the high-dose are 0.4 and 1.6　times the daily human dose administered by a 100　mcg/hour patch on a mg/m 2 basis.

Structure

Fentanyl Transdermal System, Cll (fen' ta nil) Fentanyl transdermal system is : A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent that requires an extended treatment period with a daily opioid pain medicine, 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 to be used on an “as needed” basis. Important information about fentanyl transdermal system: Get emergency help or call 911 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. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking fentanyl transdermal system with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) may cause severe drowsiness, decreased awareness, breathing difficulties, with slow or shallow breathing, coma, and death. Never give anyone else your fentanyl transdermal system. They could die from taking it. Selling or giving away fentanyl transdermal system is against the law. Store fentanyl transdermal system, securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. If the patch accidentally sticks to a family member while in close contact, take the patch off, wash the area with water, and get emergency help right away because an accidental exposure to fentanyl transdermal system can lead to death or other serious medical problems.  Dispose of expired, unwanted, or unused fentanyl transdermal system, by folding the patch so that the adhesive side of the patch adheres to itself, and immediately flushing down the toilet (if a drug take-back option is not readily available) [ see Instructions for Use ]. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. 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 liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you: have a fever are pregnant or planning to become pregnant. Use of fentanyl transdermal system for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. are breastfeeding. Not recommended during treatment with fentanyl transdermal system. It may harm your baby. are living in a household where there are small children or someone who has abused street or prescription drugs. are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking fentanyl with certain other medicines can cause serious side effects that could lead to death. Notice your pain getting worse. If your pain gets worse fater you use fentanyl transdermal system, do not use more of fentanyl transdermal system without first talking to your doctor. Talk to your doctor if the pain you have increases, if you feel more sensitive to pain, or if you have new pain after using fentanyl transdermal system. When using fentanyl transdermal system : Do not change your dose. Apply fentanyl transdermal system exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. See the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system patch. Do not apply more than 1 patch at the same time unless your healthcare provider tells you to. You should wear the fentanyl transdermal patch continuously for 3 days, unless advised otherwise by your healthcare provider. Do not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die. 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 or call 911 right away 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, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.  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 Manufactured by: Aveva Drug Delivery Systems, Inc., Miramar, FL  33025; Manufactured for: Apotex Corp., Weston, FL  33326, [email protected] or call 1-888-333-6127, 9 A.M. to 5 P.M., Eastern Time, Monday through Friday. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issue: May 2023

Transdermal system: Fentanyl Transdermal System 12 mcg/hour* (system size 5.35 cm 2 ) Fentanyl Transdermal System 25 mcg/hour (system size 10.7 cm 2 ) Fentanyl Transdermal System   37.5　mcg/hour (system size 16.05　cm 2 ) Fentanyl Transdermal System 50 mcg/hour (system size 21.4 cm 2 ) Fentanyl Transdermal System   62.5　mcg/hour (system size 26.75　cm 2 ) Fentanyl Transdermal System 75 mcg/hour (system size 32.1 cm 2 ) Fentanyl Transdermal System   87.5　mcg/hour (system size 37.45　cm 2 ) Fentanyl Transdermal System 100 mcg/hour (system size 42.8 cm 2 ) * This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from a possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.

Fentanyl is an opioid agonist. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are distributed in the human brain, spinal cord, and other tissues.

Effects on the Central Nervous System Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Fentanyl causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. In clinical trials of 357 non-opioid tolerant subjects treated with fentanyl transdermal system, 13 subjects experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8　breaths/minute or a pCO 2 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. Effects on the Gastrointestinal Tract and Other Smooth Muscle Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Fentanyl produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50　mcg/kg. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids. The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 )]. Concentration–Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.3 , 2.4 )].

Absorption 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, 37.5, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. Following 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 7: Fentanyl Pharmacokinetic Parameters Following First 72-Hour Application of Fentanyl Transdermal System   Mean (SD) Time to Maximal Concentration T max (h) Mean (SD) Maximal Concentration C max (ng/mL) Fentanyl Transdermal System 12 mcg/hour 28.8 (13.7) 0.38 (0.13)* Fentanyl Transdermal System 25 mcg/hour 31.7 (16.5) 0.85 (0.26)** Fentanyl Transdermal System 50 mcg/hour 32.8 (15.6) 1.72 (0.53)** Fentanyl Transdermal System 75 mcg/hour 35.8 (14.1) 2.32 (0.86)** Fentanyl Transdermal System 100 mcg/hour 29.9 (13.3) 3.36 (1.28)** * C max values dose normalized from 4 x 12.5 mcg/h: Study 2003-038 in healthy volunteers ** C max values: Study C-2002-048 dose proportionality study in healthy volunteers NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20 to 27 hours. Figure 1 Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100   mcg/h Table 8: Range of Pharmacokinetic Parameters of Intravenous Fentanyl In Patients   Clearance (L/h) Range  [70 kg] Volume of Distribution V SS (L/kg) Range Half-Life t 1/2 (h) Range Surgical Patients 27 - 75 3 - 8 3 - 12 Hepatically Impaired Patients 3 - 80+ 0.8 - 8+ 4 - 12+ Renally Impaired Patients 30 - 78 – – +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 to 8; N=8). Elimination Metabolism Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug.  Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. Excretion Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%. Specific Populations Age: Geriatric Population Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the 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 system　100　mcg/hour patch was applied to a skin site on the upper outer arm in a group of healthy elderly Caucasians ≥65　years old (n=21, mean age 71　years) and worn for 72　hours. The mean C max and AUC ∞ values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45　years old. Inter-subject variability in AUC ∞ was higher in elderly subjects than in healthy adult subjects 18 to 45　years (58% and 37%, respectively). The mean half-life value was longer in subjects ≥65　years old than in subjects 18　to 45　years old (34.4　hours versus 23.5　hours) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )] .  Age: Pediatric Population In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to [see Dosage and Administration ( 2.3 )]. Hepatic Impairment Information on the effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of fentanyl transdermal system delivering 50 mcg/hour of fentanyl for 72 hours was evaluated in patients hospitalized for surgery. Compared to the controlled patients (n=8), C max and AUC in the patients with cirrhosis (n=9) increased 35% and 73%, respectively. Because there is in-vitro and in-vivo evidence of extensive hepatic contribution to the elimination of 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 ( 2.5 ), Warnings and Precautions ( 5.17 ), and Use in Specific Populations ( 8.6 )] . Renal Impairment Information on the effect of renal impairment on the pharmacokinetics of fentanyl transdermal system is limited. The pharmacokinetics of intravenous injection of 25 mcg/kg fentanyl was evaluated in patients (n=8) undergoing kidney transplantation. An inverse relationship between blood urea nitrogen level and fentanyl clearance was found. Because there is in-vivo evidence of renal contribution to the elimination of 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 ( 2.6 ), Warnings and Precautions ( 5.18 ) and Use in Specific Populations ( 8.7 )]. Drug Interaction Studies CYP3A4 Inhibitors Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CYP3A4 inhibitor,   and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3　days. The ritonavir dose was 200　mg　 three times a day on Day　1 and 300　mg three times a day on Day　2 followed by one morning dose of 300　mg on Day　3. On Day　2, fentanyl was given as a single IV dose at 5　mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to 420%) increase in fentanyl AUC 0-∞ . The concomitant use of transdermal fentanyl with all CYP3A4　inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Carefully monitor patients receiving 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 ( 5.6 ), and Drug Interactions ( 7 )]. CYP3A4 Inducers Co-administration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system.

Indications and Usage ( 1 ) Dosage and Administration ( 2.1, 2.3 ) Warnings and Precautions ( 5.10 )

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Not recommended. ( 8.2 ) Severe Hepatic and Renal Impairment: Use not recommended. ( 8.6 , 8.7 )

Risk of Increased Fentanyl Absorption with Elevated Body Temperature : Regularly evaluate patients with fever closely for sedation and respiratory depression and reduce the dose if necessary. Warn patients to avoid strenuous exertion that may lead to increased body temperature ( 5.9 ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. ( 5.12 ) Serotonin Syndrome with Concomitant Use of Serotonergic Drugs : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue fentanyl transdermal system immediately if serotonin syndrome is suspected. ( 5.11 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.13 ) Severe Hypotension : Regularly evaluate during dose initiation and titration. Avoid the use of fentanyl transdermal system in patients with circulatory shock. ( 5.14 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness : Regularly evaluate for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma. ( 5.15 )

PRINCIPAL DISPLAY PANEL - 25 mcg/hr Carton Front Panel NDC 60505-7081-2 Five (25 mcg/hr) Systems FENTANYL TRANSDERMAL SYSTEM CII 25 mcg/hr Rx Only In vivo delivery of 25 mcg/hr fentanyl for 72 hours Because it can cause trouble breathing which can be fatal, DO NOT USE FENTANYL TRANSDERMAL SYSTEM: For short term or any post-operative pain, or occasional pain For mild pain or pain that can be treated with non-opioid or as-needed opioid medication Unless you have been using other narcotic opioid medicines (must be opioid tolerant) Each transdermal system contains: 2.76 mg fentanyl DO NOT USE IF SEAL ON POUCH IS BROKEN KEEP OUT OF REACH OF CHILDREN Read enclosed FENTANYL TRANSDERMAL SYSTEM Medication Guide for important safety information. ONLY for pain requiring opioid medicine around-the-clock Apotex Corp. Back Panel Inactive Ingredients: isopropyl myristate, octyldodecanol, polybutene, and polyisobutene adhesive. Dosage: For information for use, see accompanying product literature. Apply immediately upon removal from pouch and after removal of the protective liner. Do not expose area to heat. Store in original unopened pouch. Store up to 25ºC (77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF). See Medication Guide for important safety information. For your convenience in recording narcotic use, INITIAL/DATE 1._______________ 2._______________ 3._______________ 4._______________ 5._______________ For questions regarding this product, please call Apotex Corp. at 1-888-333-6127, 9 A.M. to 5 P.M.Eastern Time, Monday through Friday. If this is a medical emergency, please call 911.. Manufactured by: Aveva Drug Delivery Systems An Apotex Company. Miramar, FL 33 Manufactured for: Apotex Corp. Weston, FL 33326 0000000 Rev.03/2017