ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling:oAddiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]oLife-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]oAccidental Exposure [see Warnings and Precautions (5.4)]oNeonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]oInteractions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions (5.8)]oSerotonin Syndrome [see Warnings and Precautions (5.11)]oAdrenal Insufficiency [see Warnings and Precautions (5.12)]oSevere Hypotension [see Warnings and Precautions (5.13)]oGastrointestinal Adverse Reactions [see Warnings and Precautions (5.18)]oSeizures [see Warnings and Precautions (5.19)]oWithdrawal [see Warnings and Precautions (5.20)]. oAddiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]. oLife-Threatening Respiratory Depression [see Warnings and Precautions (5.3)]. oAccidental Exposure [see Warnings and Precautions (5.4)]. oNeonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]. oInteractions with Benzodiazepines or Other Central Nervous System Depressants [see Warnings and Precautions (5.8)]. oSerotonin Syndrome [see Warnings and Precautions (5.11)]. oAdrenal Insufficiency [see Warnings and Precautions (5.12)]. oSevere Hypotension [see Warnings and Precautions (5.13)]. oGastrointestinal Adverse Reactions [see Warnings and Precautions (5.18)]. oSeizures [see Warnings and Precautions (5.19)]. oWithdrawal [see Warnings and Precautions (5.20)]. Most common adverse reactions (>= 5%) are nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, anorexia, headache, and diarrhea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety of fentanyl transdermal system was evaluated in 216 patients who took at least one dose of fentanyl transdermal system in multicenter, double-blind, randomized, placebo-controlled clinical trial of fentanyl transdermal system. This trial examined patients over 40 years of age with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement.The most common adverse reactions (>= 5%) in double-blind, randomized, placebo-controlled clinical trial in patients with severe pain were nausea, vomiting, somnolence, dizziness, insomnia, constipation, hyperhidrosis, fatigue, feeling cold, and anorexia. Other common adverse reactions (>= 5%) reported in clinical trials in patients with chronic malignant or nonmalignant pain were headache and diarrhea. Adverse reactions reported for >= 1% of fentanyl transdermal system-treated patients and with an incidence greater than placebo-treated patients are shown in Table 3.The most common adverse reactions that were associated with discontinuation in patients with pain (causing discontinuation in >= 1% of patients) were depression, dizziness, somnolence, headache, nausea, vomiting, constipation, hyperhidrosis, and fatigue.Table 3: Adverse Reactions Reported by >= 1% of Fentanyl Transdermal System-treated Patients and With an Incidence Greater Than Placebo-treated Patients in Double-Blind, Placebo-Controlled Clinical Trial of Fentanyl Transdermal SystemSystem/Organ ClassAdverse ReactionFentanyl Transdermal System%(N 216)Placebo%(N 200)Cardiac disordersPalpitations41Ear and labyrinth disordersVertigo21Gastrointestinal disordersNausea4117Vomiting263Constipation91Abdominal pain upper32Dry mouth20General disorders and administration site conditionsFatigue63Feeling cold62Malaise41Asthenia20Edema peripheral11Metabolism and nutrition disordersAnorexia50Musculoskeletal and connective tissue disordersMuscle spasms42Nervous system disordersSomnolence193Dizziness104Psychiatric disordersInsomnia107Depression10Skin and subcutaneous tissue disordersHyperhidrosis61Pruritus32Rash21Adverse reactions not reported in Table that were reported by >= 1% of fentanyl transdermal system-treated adult and pediatric patients (N 1854) in 11 controlled and uncontrolled clinical trials of fentanyl transdermal system used for the treatment of chronic malignant or nonmalignant pain are shown in Table 4.Table 4: Adverse Reactions Reported by >= 1% of Fentanyl Transdermal System-treated Patients in 11 Clinical Trials of Fentanyl Transdermal SystemSystem/Organ ClassAdverse ReactionFentanyl Transdermal System%(N 1854)Gastrointestinal disordersDiarrhea10Abdominal pain3Immune system disordersHypersensitivity 1Nervous system disordersHeadache12Tremor3Paresthesia2Psychiatric disordersAnxiety3Confusional state2Hallucination1Renal and urinary disordersUrinary retention1Skin and subcutaneous tissue disordersErythema1The following adverse reactions occurred in adult and pediatric patients with an overall frequency of 1% and are listed in descending frequency within each System/Organ Class:Cardiac Disorders: cyanosisEye Disorders: miosisGastrointestinal Disorders: subileusGeneral Disorders and Administration Site Conditions: application site reaction, influenza-like illness, application site hypersensitivity, drug withdrawal syndrome, application site dermatitisMusculoskeletal and Connective Tissue Disorders: muscle twitchingNervous System Disorders: hypoesthesiaPsychiatric Disorders: disorientation, euphoric moodReproductive System and Breast Disorders: erectile dysfunction, sexual dysfunctionRespiratory, Thoracic and Mediastinal Disorders: respiratory depressionSkin and Subcutaneous Tissue Disorders: eczema, dermatitis allergic, dermatitis contactPediatrics: The safety of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, years of age through 18 years of age. Adverse reactions reported by >= 1% of fentanyl transdermal system-treated pediatric patients are shown in Table 5.Table 5: Adverse Reactions Reported by >= 1% of Fentanyl Transdermal System-treated Pediatric Patients in Clinical Trials of Fentanyl Transdermal SystemSystem/Organ ClassAdverse ReactionFentanyl Transdermal System%(N 289)Gastrointestinal disordersVomiting 34Nausea24Constipation 13Diarrhea13Abdominal pain9Abdominal pain upper4Dry mouth2General disorders and administration site conditionsEdema peripheral 5Fatigue2Application site reaction1Asthenia1Immune system disordersHypersensitivity3Metabolism and nutrition disordersAnorexia4Musculoskeletal and connective tissue disordersMuscle spasms 2Nervous system disordersHeadache16Somnolence5Dizziness2Tremor2Hypoesthesia1Psychiatric disordersInsomnia6Anxiety4Depression2Hallucination2Renal and urinary disordersUrinary retention3Respiratory, thoracic and mediastinal disordersRespiratory depression1Skin and subcutaneous tissue disordersPruritus13Rash6Hyperhidrosis3Erythema3. 6.2Post-Marketing Experience The following adverse reactions have been identified during post-approval use of fentanyl transdermal system. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiac Disorders: tachycardia, bradycardiaEye Disorders: vision blurredGastrointestinal Disorders: ileus, dyspepsiaGeneral Disorders and Administration Site Conditions: pyrexia, application site erosion and application site ulcerInvestigations: weight decreasedNervous System Disorders: convulsions (including clonic convulsions and grand mal convulsion), amnesia, depressed level of consciousness, loss of consciousnessPsychiatric Disorders: agitationRespiratory, Thoracic, and Mediastinal Disorders: respiratory distress, apnea, bradypnea, hypoventilation, dyspneaVascular Disorders: hypotension, hypertensionSerotonin Syndrome: Cases of serotonin syndrome, potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.Anaphylaxis: Anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system.Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

BOXED WARNING SECTION.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED FENTANYL ABSORPTION WITH APPLICATION OF EXTERNAL HEAT; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and MisuseFentanyl 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 patients risk prior to prescribing fentanyl transdermal system, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged toocomplete REMS-compliant education program,ocounsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,oemphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and oconsider other tools to improve patient, household, and community safety.Life-threatening Respiratory DepressionSerious, life-threatening, or fatal respiratory depression may occur with use of fentanyl transdermal system. Monitor for respiratory depression, especially during initiation of fentanyl transdermal system or following dose increase. Because of the risk of respiratory depression, fentanyl transdermal system is contraindicated for use as an as-needed analgesic, in non-opioid tolerant patients, in acute pain, and in postoperative pain [see Contraindications (4) and Warnings and Precautions (5.3)].Accidental ExposureAccidental exposure to even one dose of fentanyl transdermal system, especially in children, can result in fatal overdose of fentanyl. 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 (5.4)].Neonatal Opioid Withdrawal SyndromeProlonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for prolonged period in pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.5)].Cytochrome P450 3A4 InteractionThe 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 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 (5.6) and Clinical Pharmacology (12.3)].Risk of Increased Fentanyl Absorption with Application of External HeatExposure 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 (5.7)].Risks from Concomitant Use with Benzodiazepines or Other CNS DepressantsConcomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.8), Drug Interactions (7)].oReserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.oLimit treatment to the minimum effective dosages and durations.oFollow patients for signs and symptoms of respiratory depression and sedation.. ocomplete REMS-compliant education program,. ocounsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,. oemphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and oconsider other tools to improve patient, household, and community safety.. oReserve concomitant prescribing of fentanyl transdermal system and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.. oLimit treatment to the minimum effective dosages and durations.. oFollow patients for signs and symptoms of respiratory depression and sedation.. WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISK OF INCREASED FENTANYL ABSORPTION WITH APPLICATION OF EXTERNAL HEAT; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.oFentanyl transdermal system exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patients risk before prescribing, and monitor regularly for these behaviors or conditions. (5.1)oTo ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. (5.2)oSerious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following dose increase. (5.3)oAccidental exposure to fentanyl transdermal system, especially in children, can result in fatal overdose of fentanyl. (5.4)oProlonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for prolonged period in pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.5)oConcomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of fentanyl. (5.6)oExposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. (5.7)oConcomitant 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.8, 7). oFentanyl transdermal system exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patients risk before prescribing, and monitor regularly for these behaviors or conditions. (5.1). oTo ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. (5.2). oSerious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following dose increase. (5.3). oAccidental exposure to fentanyl transdermal system, especially in children, can result in fatal overdose of fentanyl. (5.4). oProlonged use of fentanyl transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for prolonged period in pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.5). oConcomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in fatal overdose of fentanyl. (5.6). oExposure of the fentanyl transdermal system application site and surrounding area to direct external heat sources has resulted in fatal overdose of fentanyl. Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources. (5.7). oConcomitant 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.8, 7).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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.. 12.2 Pharmacodynamics Effects on the Central Nervous System. Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves 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 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 breaths/minute or pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in subjects weighing less than 63 kg (9 of 13). Although subjects with prior impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive concomitant opioids or other CNS drugs associated with hypoventilation. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.. Effects on the Gastrointestinal Tract and Other Smooth Muscle. Fentanyl causes 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 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.Chronic use of opioids 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 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 potent 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 new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.4) ].. Concentration-Adverse Reaction Relationships. There is 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) ]. 12.3 Pharmacokinetics Absorption. Fentanyl transdermal system is drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at 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 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 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, 62.5, 75, 87.5, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for given patient.Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and 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 7). 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, steady-state serum concentration is reached and is maintained during subsequent applications of patch of the same size (see Figure 1). Patients reach and maintain steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately (range 3-12) 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 SystemNOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours.Mean (SD) Time toMaximal ConcentrationTmax (h)Mean (SD)Maximal ConcentrationCmax (ng/mL)Fentanyl Transdermal System 12 mcg/hour28.8 (13.7)0.38 (0.13)Cmax values dose normalized from x 12.5 mcg/h: Study 2003-038 in healthy volunteers Fentanyl Transdermal System 25 mcg/hour31.7 (16.5)0.85 (0.26)Cmax values: Study C-2002-048 dose proportionality study in healthy volunteers Fentanyl Transdermal System 50 mcg/hour32.8 (15.6)1.72 (0.53) Fentanyl Transdermal System 75 mcg/hour35.8 (14.1)2.32 (0.86) Fentanyl Transdermal System 100 mcg/hour29.9 (13.3)3.36 (1.28) 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 PatientsNOTE: Information on volume of distribution and half-life not available for renally impaired patients.Clearance(L/h)Range[70 kg]Volume of DistributionVSS (L/kg)RangeHalf-Lifet1/2 (h)RangeSurgical Patients27-753-83-12Hepatically Impaired Patients3-80Estimated 0.8-8 4-12 Renally Impaired Patients30-78--. Figure 1: Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/h 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 L/kg (range 3-8; = 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 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 prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, single fentanyl transdermal system 100 mcg/hour patch was applied to skin site on the upper outer arm in group of healthy elderly Caucasians >= 65 years old (n 21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects >= 65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].. Age Pediatric Population. In 1.5 to 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), Cmax and AUC in the patients with cirrhosis (n 9) increased 35% and 73%, respectively. Because there is in vitro and in vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.5) Warnings and Precautions (5.16), 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 (5.17) 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, CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in randomized crossover study. Subjects received oral ritonavir or placebo for days. The ritonavir dose was 200 mg three times day on Day and 300 mg three times day on Day followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as single IV dose at 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 174% (range 52%-420%) increase in fentanyl AUC0-. 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oTo be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. (2.1)oUse the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1).oIndividualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)oDiscuss availability of naloxone with the patient and caregiver and assess each patients need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system. Consider prescribing naloxone based on the patients risk factors for overdose. (2.2, 5.1, 5.3, 5.8)oInitial dose selection: consult conversion instructions. (2.3)oEach transdermal system is intended to be worn for 72 hours. (2.3)oAdhere to instructions concerning administration and disposal of fentanyl transdermal system. (2.7, 2.8)oMild 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)oDo not abruptly discontinue fentanyl transdermal system in physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.9). oTo be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain. (2.1). oUse the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1).. oIndividualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1). oDiscuss availability of naloxone with the patient and caregiver and assess each patients need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system. Consider prescribing naloxone based on the patients risk factors for overdose. (2.2, 5.1, 5.3, 5.8). oInitial dose selection: consult conversion instructions. (2.3). oEach transdermal system is intended to be worn for 72 hours. (2.3). oAdhere to instructions concerning administration and disposal of fentanyl transdermal system. (2.7, 2.8). oMild 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). oDo not abruptly discontinue fentanyl transdermal system in physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.9). 2.1Important Dosage and Administration Instructions Fentanyl transdermal system should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.Due to the risk of respiratory depression, fentanyl transdermal system is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning fentanyl transdermal system therapy. As fentanyl transdermal system is only for use in opioid-tolerant patients, do not begin any patient on fentanyl transdermal system as the first opioid [see Indications and Usage (1)].oUse the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].oInitiate the dosing regimen for each patient individually, taking into account the patients severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].oMonitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with fentanyl transdermal system when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.3)].. oUse the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].. oInitiate the dosing regimen for each patient individually, taking into account the patients severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].. oMonitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with fentanyl transdermal system when serum concentrations from the initial patch will peak [see Warnings and Precautions (5.3)].. 2.2Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with fentanyl transdermal system [see Warnings and Precautions (5.3), Patient Counseling Information (17)]. 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 pharmacist, or as part of community-based program). Consider prescribing naloxone, based on the patients risk factors for overdose, such as concomitant use of CNS depressants, history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.3, 5.8)]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.. 2.3Initial Dosage Do not initiate treatment with fentanyl transdermal system in opioid nontolerant patients [see Contraindications (4)].The recommended starting dose when converting from other opioids to fentanyl transdermal system is intended to minimize the potential for overdosing patients with the first dose.Discontinue all other around-the-clock opioid drugs when fentanyl transdermal system therapy is initiated.While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate patients 24-hour fentanyl requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour fentanyl requirements which could result in adverse reactions. In fentanyl transdermal system clinical trial, patients were converted from their prior opioid to fentanyl transdermal system using Table as guide for the initial fentanyl transdermal system dose.Each fentanyl transdermal system is worn continuously for up to 72 hours [see Dosage and Administration (2.7) ].When converting patients from oral or parenteral opioids to fentanyl transdermal system, use Table (alternatively use Table for adult and pediatric patients taking opioids or doses not listed in Table 1) and consider the following:oThese are not tables of equianalgesic doses.oThe conversion doses in these tables are only for the conversion from one of the listed oral or parenteral opioid analgesics to fentanyl transdermal system.oThe tables cannot be used to convert from fentanyl transdermal system to another opioid because these conversions will result in an overestimation of the dose of the new opioid (these conversions are conservative) and may result in fatal overdosage.Table 1Table should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.9) ].: Dose Conversion from Other Opioids to Fentanyl Transdermal SystemCurrent AnalgesicDaily Dosage (mg/day)Oral morphine60-134135-224225-314315-404Intramuscular or Intravenous morphine10-2223-3738-5253-67Oral oxycodone30-6767.5-112112.5-157157.5-202Oral codeine150-447Oral hydromorphone8-1717.1-2828.1-3939.1-51Intravenous hydromorphone1.5-3.43.5-5.65.7-7.98-10Intramuscular meperidine75-165166-278279-390391-503Oral methadone20-4445-7475-104105-134Recommended Fentanyl Transdermal System Dose25 mcg/hour50 mcg/hour75 mcg/hour100 mcg/hourAlternatively, for adult and pediatric patients taking opioids or doses not listed in Table 1, use the following methodology when converting patients from oral or parenteral opioids to fentanyl transdermal system:1.Calculate the previous 24-hour analgesic requirement.2.Convert this amount to the equianalgesic oral morphine dose using reliable reference.3.Refer to Table for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding recommended initial fentanyl transdermal system dose.4.Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than days after the initial dose and every days thereafter) until analgesic efficacy is attained. 37.5 mcg/hour dose may also be used. For patients that require more than 100 mcg/hour, several transdermal systems may be used.5.Do not use Table to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.Table 2Table should not be used to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative. Use of Table for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.9) ].: Recommended Initial Fentanyl Transdermal System Dose based upon Daily Oral Morphine DoseNOTE: In clinical trials, these ranges of daily oral morphine doses were used as basis for conversion to fentanyl transdermal system.Oral 24-hourMorphine(mg/day)Fentanyl Transdermal SystemDose(mcg/hour)60-13425135-22450225-31475315-404100405-494125495-584150585-674175675-764200765-854225855-944250945-10342751035-1124300For patients that may be more sensitive to the effects of opioids, additional intermediate strengths may be considered during conversion from prior opioids or titrating the dose of the fentanyl transdermal system. For example, rather than converting or titrating to 50 mcg/hr system, 37.5 mcg/hr system is available. Similarly 62.5 mcg/hr system is available for use as an intermediate strength between the 50 mcg/hr and the 75 mcg/hr system, and an 87.5 mcg/hr system is available as an intermediate strength between the 75 mcg/hr system and the 100 mcg/hr system.The additional intermediate strengths, 37.5 mcg/hr, 62.5 mcg/hr and 87.5 mcg/hr, were not used in the clinical studies.For delivery rates in excess of 100 mcg/hour, multiple systems may be used.. oThese are not tables of equianalgesic doses.. oThe conversion doses in these tables are only for the conversion from one of the listed oral or parenteral opioid analgesics to fentanyl transdermal system.. oThe tables cannot be used to convert from fentanyl transdermal system to another opioid because these conversions will result in an overestimation of the dose of the new opioid (these conversions are conservative) and may result in fatal overdosage.. 1.Calculate the previous 24-hour analgesic requirement.. 2.Convert this amount to the equianalgesic oral morphine dose using reliable reference.. 3.Refer to Table for the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding recommended initial fentanyl transdermal system dose.. 4.Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than days after the initial dose and every days thereafter) until analgesic efficacy is attained. 37.5 mcg/hour dose may also be used. For patients that require more than 100 mcg/hour, several transdermal systems may be used.. 5.Do not use Table to convert from fentanyl transdermal system to other therapies because this conversion to fentanyl transdermal system is conservative and will overestimate the dose of the new agent.. 2.4Titration and Maintenance of Therapy Individually titrate fentanyl transdermal system to dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving fentanyl transdermal system to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.Patients who experience breakthrough pain may require dosage adjustment of fentanyl transdermal system, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the fentanyl transdermal system dosage.The dosing interval for fentanyl transdermal system is 72 hours. Do not increase the fentanyl transdermal system dose for the first time until at least days after the initial application. Titrate the dose based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.It may take up to days for fentanyl levels to reach equilibrium on new dose [see Clinical Pharmacology (12.3)]. Therefore, evaluate patients for further titration after no less than two 3-day applications before any further increase in dosage is made.Base dosage increments on the daily dosage of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to 12 mcg/hour increase in fentanyl transdermal system dose.If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.A small proportion of adult patients may not achieve adequate analgesia using 72-hour dosing interval and may require systems to be applied at 48 hours rather than at 72 hours, only if adequate pain control cannot be achieved using 72-hour regimen. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on 72-hour regimen.Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.. 2.5Dosage Modifications in Patients with Hepatic Impairment Avoid the use of fentanyl transdermal system in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions (5.16), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 2.6Dosage Modifications in Patients with Renal Impairment Avoid the use of fentanyl transdermal system in patients with severe renal impairment. In patients with mild to moderate renal impairment, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of respiratory and central nervous system depression, including at each dosage increase [see Warnings and Precautions (5.17), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].. 2.7Administration of Fentanyl Transdermal System FENTANYL TRANSDERMAL SYSTEMS ARE FOR TRANSDERMAL USE ONLY.Proper handling of fentanyl transdermal system is necessary in order to prevent serious adverse outcomes, including death, associated with accidental secondary exposure to fentanyl transdermal system [see Warnings and Precautions (5.4)].. Application and Handling Instructions. oPatients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application.oPatients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged.oThe transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.oEach fentanyl transdermal system may be worn continuously for 72 hours. The next patch is applied to different skin site after removal of the previous transdermal system.oIf problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with transparent adhesive film dressing.oIf the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. new patch may be applied to different skin site.oPatients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system.oContact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of fentanyl transdermal system from an adults body to child while hugging, sharing the same bed as the patient, accidental sitting on patch and possible accidental exposure of caregivers skin to the medication in the patch while applying or removing the patch.oInstruct patients, family members, and caregivers to keep patches in secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed.. oPatients should apply fentanyl transdermal system to intact, non-irritated, and non-irradiated skin on flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site may be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application.. oPatients should apply fentanyl transdermal system immediately upon removal from the sealed package. The patch must not be altered (e.g., cut) in any way prior to application. Fentanyl transdermal system should not be used if the pouch seal is broken or if the patch is cut or damaged.. oThe transdermal system is pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.. oEach fentanyl transdermal system may be worn continuously for 72 hours. The next patch is applied to different skin site after removal of the previous transdermal system.. oIf problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlayed with transparent adhesive film dressing.. oIf the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. new patch may be applied to different skin site.. oPatients (or caregivers who apply fentanyl transdermal system) should wash their hands immediately with soap and water after applying fentanyl transdermal system.. oContact with unwashed or unclothed application sites can result in secondary exposure to fentanyl transdermal system and should be avoided. Examples of accidental exposure include transfer of fentanyl transdermal system from an adults body to child while hugging, sharing the same bed as the patient, accidental sitting on patch and possible accidental exposure of caregivers skin to the medication in the patch while applying or removing the patch.. oInstruct patients, family members, and caregivers to keep patches in secure location out of the reach of children and of others for whom fentanyl transdermal system was not prescribed.. Avoidance of Heat. Instruct patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds, while wearing the system [see Warnings and Precautions (5.7)].. 2.8Disposal Instructions Failure to properly dispose of fentanyl transdermal system has resulted in accidental exposures and deaths, including deaths of children [see Warnings and Precautions (5.4)].Instruct patients to dispose of used patches immediately upon removal by folding the adhesive side of the patch to itself, then flushing down the toilet.Instruct patients to remove unused patches from their pouches, remove the release liners, fold the patches so that the adhesive side of the patch adheres to itself, and to immediately flush the patches down the toilet.Instruct patients to dispose of any patches remaining from prescription as soon as they are no longer needed.. 2.9Safe Reduction or Discontinuation of Fentanyl Transdermal System Do not abruptly discontinue fentanyl transdermal system in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.When decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient using fentanyl transdermal system, there are variety of factors that should be considered, including the dose of fentanyl transdermal system the patient has been using, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to specialist.There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates patient-specific plan to taper the dose of the opioid gradually. For patients on fentanyl transdermal system who are physically opioid-dependent, initiate the taper by small enough increment (e.g., no greater than 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every to weeks. Patients who have been taking opioids for briefer periods of time may tolerate more rapid taper.It may be necessary to provide the patient with lower dosage strength to accomplish successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.When managing patients taking opioid analgesics, particularly those who have been treated for long duration and/or with high doses for chronic pain, ensure that multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.20), Drug Abuse and Dependence (9.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Fentanyl Transdermal System is available as 12 mcg/hour, 25 mcg/hour, 37.5 mcg/hour, 50 mcg/hour, 62.5 mcg/hour, 75 mcg/hour, 87.5 mcg/hour or 100 mcg/hour of fentanyl.oThe 12 mcg/hour (system size 3.13 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 12 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 25 mcg/hour (system size 6.25 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 25 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 37.5 mcg/hour (system size 9.38 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 37.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 50 mcg/hour (system size 12.5 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 50 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 62.5 mcg/hour (system size 15.63 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 62.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 75 mcg/hour (system size 18.75 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 75 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 87.5 mcg/hour (system size 21.88 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 87.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.oThe 100 mcg/hour (system size 25 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 100 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.This lowest strength is designated as 12 mcg/hour (however, the actual strength is 12.5 mcg/hour) to distinguish it from possible 125 mcg/hour dosage that could be prescribed by using multiple transdermal systems.. oThe 12 mcg/hour (system size 3.13 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 12 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 25 mcg/hour (system size 6.25 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 25 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 37.5 mcg/hour (system size 9.38 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 37.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 50 mcg/hour (system size 12.5 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 50 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 62.5 mcg/hour (system size 15.63 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 62.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 75 mcg/hour (system size 18.75 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 75 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 87.5 mcg/hour (system size 21.88 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 87.5 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. oThe 100 mcg/hour (system size 25 cm2) transdermal system consists of translucent rectangular patch with rounded corners, printed with Fentanyl 100 mcg/hr and diagonal stripes in blue ink, on removable release liner. The patch is overlaid and underlaid with additional release liners, and is contained in square pouch. The pouch is labeled with the lot number and expiration date.. Transdermal system: 12 mcg/hour, 25 mcg/hour, 37.5 mcg/hour, 50 mcg/hour, 62.5 mcg/hour, 75 mcg/hour, 87.5 mcg/hour, 100 mcg/hour. (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Fentanyl transdermal system contains fentanyl, Schedule II controlled substance.. 9.2 Abuse Fentanyl transdermal system contains fentanyl, substance with high potential for abuse similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Fentanyl transdermal system can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].The high drug content in long-acting formulations adds to the risk of adverse outcomes from abuse and misuse.All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.Prescription drug abuse is the intentional non-therapeutic use of prescription drug, even once, for its rewarding psychological or physiological effects.Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes physical withdrawal.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 providers. Doctor shopping (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in patient with poor pain control.Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.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 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 (5.8) and Drug Interactions (7)]. Intentional compromise of the transdermal delivery system may result in the uncontrolled delivery of fentanyl and pose 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. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.Physical dependence is physiological state in which the body adapts to the drug after period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or significant dosage reduction of drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to clinically significant degree until after several days to weeks of continued opioid usage.Do not abruptly discontinue fentanyl transdermal system in patient physically dependent on opioids. Rapid tapering of fentanyl transdermal system in patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.When discontinuing fentanyl transdermal system, gradually taper the dosage using patient-specific plan that considers the following: the dose of fentanyl transdermal system the patient has been using, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for long duration at high doses, ensure that multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.9) Warnings and Precautions (5.20)].Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Table includes clinically significant drug interactions with fentanyl transdermal system.Table 6: Clinically Significant Drug Interactions with Fentanyl Transdermal SystemInhibitors of CYP3A4Clinical 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 stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.6)]. After stopping CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or 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. Monitor patients for respiratory depression and sedation at frequent intervals. If CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.Examples:Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juiceCYP3A4 InducersClinical 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 withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.6)]. After stopping 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. Monitor for signs of opioid withdrawal. If CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.Examples:Rifampin, carbamazepine, phenytoinBenzodiazepines and Other Central Nervous System (CNS) DepressantsClinical 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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.8)]. 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, 5.3, 5.8)].Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.Serotonergic DrugsClinical 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, carefully observe 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, linezolidMixed Agonist/Antagonist and Partial Agonist Opioid AnalgesicsClinical Impact:May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.Intervention:Avoid concomitant use.Examples:butorphanol, nalbuphine, pentazocine, buprenorphineMuscle RelaxantsClinical Impact:Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.Intervention:Monitor patients for signs of respiratory depression that may be greater than otherwise expected and 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 (5.3, 5.8)].DiureticsClinical Impact:Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.Intervention:Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.Anticholinergic DrugsClinical Impact:The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.Intervention:Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with fentanyl transdermal system because they may reduce analgesic effect of fentanyl transdermal system or precipitate withdrawal symptoms. (5.20, 7).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION 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 location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.4), Drug Abuse and Dependence (9.2)]. Inform patients that leaving fentanyl transdermal system unsecured can pose 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 systems 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 drug take-back option is not readily available) [see Instructions for Use]. Inform patients that they can visit www.fda.gov/drugdisposal for 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 used 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 known or suspected overdose [see Warnings and Precautions (5.3)]. 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 pharmacist, or as part of 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 naloxones 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: oHow to treat with naloxone, in the event of an opioid overdose oTo tell family and friends about their naloxone and to keep it in place where family and friends can access it in an emergency oTo 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.Accidental Exposure: Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.4)]. 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 healthcare provider [see Warnings and Precautions (5.8), Drug Interactions (7)].Serotonin Syndrome: Inform patients that opioids could cause 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 using fentanyl transdermal system while taking any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while using fentanyl transdermal system [see Drug Interactions (7)].Adrenal Insufficiency: Inform patients that opioids could cause adrenal insufficiency, 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 constellation of these symptoms [see Warnings and Precautions (5.12)].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.Important Discontinuation Instructions: In order to avoid developing withdrawal symptoms, instruct patients not to discontinue fentanyl transdermal system without first discussing tapering plan with the prescriber [see Dosage and Administration (2.9) ].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 high fever. Instruct patients to:oavoid strenuous exertion that can increase body temperature while wearing the patchoavoid 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.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 sitting or lying position) [see Warnings and Precautions (5.13)].Anaphylaxis: Inform patients that anaphylaxis, including anaphylactic shock, has been reported with ingredients contained in fentanyl transdermal system. Advise patients how to recognize such 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 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)].Driving or Operating Heavy Machinery: Inform patients that fentanyl transdermal system may impair the ability to perform potentially hazardous activities such as driving 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)].. oHow to treat with naloxone, in the event of an opioid overdose oTo tell family and friends about their naloxone and to keep it in place where family and friends can access it in an emergency oTo 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.. oavoid strenuous exertion that can increase body temperature while wearing the patch. oavoid 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. Fentanyl transdermal system is drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at 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 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 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, 62.5, 75, 87.5, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for given patient.Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and 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 7). 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, steady-state serum concentration is reached and is maintained during subsequent applications of patch of the same size (see Figure 1). Patients reach and maintain steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 hours. Continued absorption of fentanyl from the skin accounts for slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately (range 3-12) 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 SystemNOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in approximately 20-27 hours.Mean (SD) Time toMaximal ConcentrationTmax (h)Mean (SD)Maximal ConcentrationCmax (ng/mL)Fentanyl Transdermal System 12 mcg/hour28.8 (13.7)0.38 (0.13)Cmax values dose normalized from x 12.5 mcg/h: Study 2003-038 in healthy volunteers Fentanyl Transdermal System 25 mcg/hour31.7 (16.5)0.85 (0.26)Cmax values: Study C-2002-048 dose proportionality study in healthy volunteers Fentanyl Transdermal System 50 mcg/hour32.8 (15.6)1.72 (0.53) Fentanyl Transdermal System 75 mcg/hour35.8 (14.1)2.32 (0.86) Fentanyl Transdermal System 100 mcg/hour29.9 (13.3)3.36 (1.28) 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 PatientsNOTE: Information on volume of distribution and half-life not available for renally impaired patients.Clearance(L/h)Range[70 kg]Volume of DistributionVSS (L/kg)RangeHalf-Lifet1/2 (h)RangeSurgical Patients27-753-83-12Hepatically Impaired Patients3-80Estimated 0.8-8 4-12 Renally Impaired Patients30-78--. Figure 1: Serum Fentanyl Concentrations Following Single and Multiple Applications of Fentanyl Transdermal System 100 mcg/h 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 L/kg (range 3-8; = 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 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 prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. In this study, single fentanyl transdermal system 100 mcg/hour patch was applied to skin site on the upper outer arm in group of healthy elderly Caucasians >= 65 years old (n 21, mean age 71 years) and worn for 72 hours. The mean Cmax and AUC values were approximately 8% lower and 7% higher, respectively, in the elderly subjects as compared with subjects 18 to 45 years old. Inter-subject variability in AUC was higher in elderly subjects than in healthy adult subjects 18 to 45 years (58% and 37%, respectively). The mean half-life value was longer in subjects >= 65 years old than in subjects 18 to 45 years old (34.4 hours versus 23.5 hours) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].. Age Pediatric Population. In 1.5 to 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), Cmax and AUC in the patients with cirrhosis (n 9) increased 35% and 73%, respectively. Because there is in vitro and in vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosing and Administration (2.5) Warnings and Precautions (5.16), 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 (5.17) 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, CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in randomized crossover study. Subjects received oral ritonavir or placebo for days. The ritonavir dose was 200 mg three times day on Day and 300 mg three times day on Day followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as single IV dose at 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 174% (range 52%-420%) increase in fentanyl AUC0-. 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.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Prolonged use of opioid analgesics 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 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 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 Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. 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 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 times the daily human dose administered by 100 mcg/h patch on mg/m2 basis).In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to pregnant rats from Gestation Day to 18 suggested evidence of embryo-toxicity and slight increase in mean delivery time in the 0.03 mg/kg/day group (0.1 times the human dose administered by 100 mcg/h patch on mg/m2 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 to day 18 of pregnancy. Fentanyl produced 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 times the daily human dose administered by 100 mcg/hour patch on mg/m2 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 of pregnancy through 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 100 mcg/hour patch on mg/m2 basis.

SPL MEDGUIDE SECTION.

Medication Guide Fentanyl Transdermal System, CII(fen ta nil)Fentanyl transdermal system is:oA strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, in people who are already regularly using opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.oA long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you use your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.oNot for use to treat pain that is not around-the-clock.Important information about fentanyl transdermal system:oGet emergency help or call 911 right away if you use too many fentanyl transdermal systems (overdose). When you first start using fentanyl transdermal system, when your dose is changed, or if you use too many (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, medicine for the emergency treatment of an opioid overdose.oUsing 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.oNever give anyone else your fentanyl transdermal system. They could die from using it. Selling or giving away fentanyl transdermal system is against the law.oStore fentanyl transdermal system, securely, out of sight and reach of children, and in location not accessible by others, including visitors to the home.oIf the patch accidentally sticks to 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.oDispose 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 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:osevere asthma, trouble breathing, or other lung problems.oa bowel blockage or have narrowing of the stomach or intestines.Before applying fentanyl transdermal system, tell your healthcare provider if you have history of:ohead injury, seizuresoproblems urinatingoliver, kidney, thyroid problemsopancreas or gallbladder problemsoabuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.Tell your healthcare provider if you:ohave feveroare pregnant or planning to become pregnant. Prolonged use of fentanyl transdermal system during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.oare breastfeeding. Not recommended during treatment with fentanyl transdermal system. It may harm your baby.oare living in household where there are small children or someone who has abused street or prescription drugs.oare taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Using fentanyl transdermal system with certain other medicines can cause serious side effects that could lead to death.When using fentanyl transdermal system:oDo 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.oSee the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system.oDo not apply more than patch at the same time unless your healthcare provider tells you to.oYou should wear the fentanyl transdermal system continuously for days, unless advised otherwise by your healthcare provider.oDo not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die.oCall your healthcare provider if the dose you are using does not control your pain.oDo not stop using fentanyl transdermal system without talking to your healthcare provider.While using fentanyl transdermal system DO NOT:oTake 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.oDrive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you sleepy, dizzy, or lightheaded.oDrink 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:oconstipation, 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:otrouble 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 for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration. Instructions for UseFentanyl Transdermal System CII (fen ta nil)Be sure that you read, understand, and follow these Instructions for Use before you apply fentanyl transdermal system (patch). Talk to your healthcare provider or pharmacist if you have any questions.Important information about the fentanyl transdermal system (patch) appearance:oFentanyl transdermal system is rectangular, translucent patch with rounded corners.oFentanyl transdermal system comes in different dosage strengths and sizes:o12 mcg/houro25 mcg/houro37.5 mcg/houro50 mcg/houro62.5 mcg/houro75 mcg/houro87.5 mcg/houro100 mcg/houroThe products active ingredient name, Fentanyl, and dosage strength are randomly printed in blue on each patch.oAll of the patches have blue diagonal stripes. Parts of the fentanyl transdermal system:BEFORE APPLYING FENTANYL TRANSDERMAL SYSTEMoEach fentanyl transdermal system is sealed in its own protective pouch. Do not remove fentanyl transdermal system from the pouch until you are ready to use it.oDo not use fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged or changed in any way.oFentanyl transdermal systems are available in different dosage strengths and patch sizes. Make sure you have the right dose patch or patches that have been prescribed for you.APPLYING FENTANYL TRANSDERMAL SYSTEM1.Skin areas where the fentanyl transdermal system may be applied: For adults:oPut the patch on the chest, back, flank (sides of the waist), or upper arm in place where there is no hair (See Figures A-D). For children (and adults with mental impairment):oPut the patch on the upper back (See Figure B). This will lower the chances that the child will remove the patch and put it in their mouth. For adults and childrenoDo not put fentanyl transdermal system on skin that is very oily, burned, broken out, cut, irritated, or damaged in any way. oAvoid sensitive areas or those that move around lot. If there is hair, do not shave (shaving irritates the skin). Instead, clip hair as close to the skin as possible (See Figure E). oTalk to your healthcare provider if you have questions about skin application sites. 2.Prepare to apply fentanyl transdermal system:oChoose the time of day that is best for you to apply fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider. oDo not wear more than one fentanyl transdermal system at time unless your healthcare provider tells you to do so. Before applying new fentanyl transdermal system, remove the patch you have been wearing. oClean the skin area with clear water only. Pat skin completely dry. Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied. 3.Open the pouch: Tear at notch and remove the fentanyl transdermal system. Each fentanyl transdermal system is packaged with additional pieces of protective film above and below the patch and is sealed in its own protective pouch. Do not remove the fentanyl transdermal system from the pouch until you are ready to use it (See Figure F). The additional pieces of protective film are discarded at time of use (See Figure G).4.Peel: Peel off both parts of the release liner from the patch. Each fentanyl transdermal system has clear plastic release liner that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this release liner off and throw the pieces away. Touch the sticky side of the fentanyl transdermal system as little as possible (See Figure H).5.Press: Press the patch onto the chosen skin site with the palm of your hand and hold there for at least 30 seconds (See Figure I). Make sure it sticks well, especially at the edges.oFentanyl transdermal system may not stick to all people. You need to check the patch often to make sure that it is sticking well to the skin. oIf the patch falls off right away after applying, throw it away and put new one on at different skin site. See the section below called Disposing of fentanyl transdermal system. oIf you have problem with the patch not sticking oApply first aid tape only to the edges of the patch. oIf you continue to have problems with the patch not sticking, you may cover the patch with transparent adhesive film dressing such as BIOCLUSIVE(R) or Askina(R)Derm. These are special see-through adhesive dressings. Never cover fentanyl transdermal system with any other bandage or tape. Remove the liner from the BIOCLUSIVE(R) or Askina(R)Derm dressing and place it carefully over the fentanyl transdermal system, smoothing it over the patch and your skin. oIf your patch falls off before days (72 hours) of use, dispose of (throw away) properly. See the section below Disposing of fentanyl transdermal system. Apply new fentanyl transdermal system on at different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until days (72 hours) after you put it on (or as directed by your healthcare provider).6.Wash your hands when you have finished applying fentanyl transdermal system. 7.Remove fentanyl transdermal system after wearing it for days (72 hours). Dispose of the used patch right away. See the section below Disposing of fentanyl transdermal system. Choose different skin site to apply new fentanyl transdermal system. Repeat Steps through above when applying new fentanyl transdermal system. Do not apply the new patch to the same place as the last one. WATER AND FENTANYL TRANSDERMAL SYSTEMoYou can bathe, swim or shower while you are wearing fentanyl transdermal system. If the patch falls off before days (72 hours) after application, dispose of properly. See the section below Disposing of fentanyl transdermal system. Apply new fentanyl transdermal system on at different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until days (72 hours) after you put it on (or as directed by your healthcare provider). DISPOSING OF FENTANYL TRANSDERMAL SYSTEMoFold the used fentanyl transdermal system in half so that the sticky side sticks to itself (See Figure J). Flush the used fentanyl transdermal system down the toilet right away (See Figure K). used fentanyl transdermal system can be very dangerous for or lead to death in babies, children, pets, and adults who have not been prescribed fentanyl transdermal system.oThrow away any fentanyl transdermal systems that are left over from your prescription as soon as they are no longer needed. Remove the leftover patches from their protective pouch and remove the release liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet. Do not flush the pouch, protective films or the release liner down the toilet. These texts can be thrown away in trash can. This Instructions for Use has been approved by the U.S. Food and Drug Administration. The brands listed are trademarks of their respective owners.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 3/2021FTS:R28/MG:FTS:R13 oA strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, in people who are already regularly using opioid pain medicine, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.. oA long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you use your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.. oNot for use to treat pain that is not around-the-clock.. oGet emergency help or call 911 right away if you use too many fentanyl transdermal systems (overdose). When you first start using fentanyl transdermal system, when your dose is changed, or if you use too many (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, medicine for the emergency treatment of an opioid overdose.. oUsing 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.. oNever give anyone else your fentanyl transdermal system. They could die from using it. Selling or giving away fentanyl transdermal system is against the law.. oStore fentanyl transdermal system, securely, out of sight and reach of children, and in location not accessible by others, including visitors to the home.. oIf the patch accidentally sticks to 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.. oDispose 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 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.. osevere asthma, trouble breathing, or other lung problems.. oa bowel blockage or have narrowing of the stomach or intestines.. ohead injury, seizures. oproblems urinating. oliver, kidney, thyroid problems. opancreas or gallbladder problems. oabuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.. ohave fever. oare pregnant or planning to become pregnant. Prolonged use of fentanyl transdermal system during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.. oare breastfeeding. Not recommended during treatment with fentanyl transdermal system. It may harm your baby.. oare living in household where there are small children or someone who has abused street or prescription drugs.. oare taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Using fentanyl transdermal system with certain other medicines can cause serious side effects that could lead to death.. oDo 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.. oSee the detailed Instructions for Use for information about how to apply and dispose of the fentanyl transdermal system.. oDo not apply more than patch at the same time unless your healthcare provider tells you to.. oYou should wear the fentanyl transdermal system continuously for days, unless advised otherwise by your healthcare provider.. oDo not cut, break, chew, crush, dissolve, snort, or inject fentanyl transdermal system because this may cause you to overdose and die.. oCall your healthcare provider if the dose you are using does not control your pain.. oDo not stop using fentanyl transdermal system without talking to your healthcare provider.. oTake 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.. oDrive or operate heavy machinery, until you know how fentanyl transdermal system affects you. Fentanyl transdermal system can make you sleepy, dizzy, or lightheaded.. oDrink 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.. oconstipation, 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.. otrouble 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.. oFentanyl transdermal system is rectangular, translucent patch with rounded corners.. oFentanyl transdermal system comes in different dosage strengths and sizes:. o12 mcg/hour. o25 mcg/hour. o37.5 mcg/hour. o50 mcg/hour. o62.5 mcg/hour. o75 mcg/hour. o87.5 mcg/hour. o100 mcg/hour. oThe products active ingredient name, Fentanyl, and dosage strength are randomly printed in blue on each patch.. oAll of the patches have blue diagonal stripes. oEach fentanyl transdermal system is sealed in its own protective pouch. Do not remove fentanyl transdermal system from the pouch until you are ready to use it.. oDo not use fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged or changed in any way.. oFentanyl transdermal systems are available in different dosage strengths and patch sizes. Make sure you have the right dose patch or patches that have been prescribed for you.. 1.Skin areas where the fentanyl transdermal system may be applied: For adults:. oPut the patch on the chest, back, flank (sides of the waist), or upper arm in place where there is no hair (See Figures A-D). oPut the patch on the upper back (See Figure B). This will lower the chances that the child will remove the patch and put it in their mouth. oDo not put fentanyl transdermal system on skin that is very oily, burned, broken out, cut, irritated, or damaged in any way. oAvoid sensitive areas or those that move around lot. If there is hair, do not shave (shaving irritates the skin). Instead, clip hair as close to the skin as possible (See Figure E). oTalk to your healthcare provider if you have questions about skin application sites. 2.Prepare to apply fentanyl transdermal system:oChoose the time of day that is best for you to apply fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider. oDo not wear more than one fentanyl transdermal system at time unless your healthcare provider tells you to do so. Before applying new fentanyl transdermal system, remove the patch you have been wearing. oClean the skin area with clear water only. Pat skin completely dry. Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied. oChoose the time of day that is best for you to apply fentanyl transdermal system. Change it at about the same time of day (3 days or 72 hours after you apply the patch) or as directed by your healthcare provider. oDo not wear more than one fentanyl transdermal system at time unless your healthcare provider tells you to do so. Before applying new fentanyl transdermal system, remove the patch you have been wearing. oClean the skin area with clear water only. Pat skin completely dry. Do not use anything on the skin such as soaps, lotions, oils, or alcohol before the patch is applied. 3.Open the pouch: Tear at notch and remove the fentanyl transdermal system. Each fentanyl transdermal system is packaged with additional pieces of protective film above and below the patch and is sealed in its own protective pouch. Do not remove the fentanyl transdermal system from the pouch until you are ready to use it (See Figure F). The additional pieces of protective film are discarded at time of use (See Figure G).. 4.Peel: Peel off both parts of the release liner from the patch. Each fentanyl transdermal system has clear plastic release liner that can be peeled off in two pieces. This covers the sticky side of the patch. Carefully peel this release liner off and throw the pieces away. Touch the sticky side of the fentanyl transdermal system as little as possible (See Figure H).. 5.Press: Press the patch onto the chosen skin site with the palm of your hand and hold there for at least 30 seconds (See Figure I). Make sure it sticks well, especially at the edges.. oFentanyl transdermal system may not stick to all people. You need to check the patch often to make sure that it is sticking well to the skin. oIf the patch falls off right away after applying, throw it away and put new one on at different skin site. See the section below called Disposing of fentanyl transdermal system. oIf you have problem with the patch not sticking oApply first aid tape only to the edges of the patch. oIf you continue to have problems with the patch not sticking, you may cover the patch with transparent adhesive film dressing such as BIOCLUSIVE(R) or Askina(R)Derm. These are special see-through adhesive dressings. Never cover fentanyl transdermal system with any other bandage or tape. Remove the liner from the BIOCLUSIVE(R) or Askina(R)Derm dressing and place it carefully over the fentanyl transdermal system, smoothing it over the patch and your skin. oApply first aid tape only to the edges of the patch. oIf you continue to have problems with the patch not sticking, you may cover the patch with transparent adhesive film dressing such as BIOCLUSIVE(R) or Askina(R)Derm. These are special see-through adhesive dressings. Never cover fentanyl transdermal system with any other bandage or tape. Remove the liner from the BIOCLUSIVE(R) or Askina(R)Derm dressing and place it carefully over the fentanyl transdermal system, smoothing it over the patch and your skin. oIf your patch falls off before days (72 hours) of use, dispose of (throw away) properly. See the section below Disposing of fentanyl transdermal system. Apply new fentanyl transdermal system on at different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until days (72 hours) after you put it on (or as directed by your healthcare provider).. 6.Wash your hands when you have finished applying fentanyl transdermal system. 7.Remove fentanyl transdermal system after wearing it for days (72 hours). Dispose of the used patch right away. See the section below Disposing of fentanyl transdermal system. Choose different skin site to apply new fentanyl transdermal system. Repeat Steps through above when applying new fentanyl transdermal system. Do not apply the new patch to the same place as the last one. oYou can bathe, swim or shower while you are wearing fentanyl transdermal system. If the patch falls off before days (72 hours) after application, dispose of properly. See the section below Disposing of fentanyl transdermal system. Apply new fentanyl transdermal system on at different skin site. Be sure to let your healthcare provider know that this has happened, and do not replace the new patch until days (72 hours) after you put it on (or as directed by your healthcare provider). oFold the used fentanyl transdermal system in half so that the sticky side sticks to itself (See Figure J). Flush the used fentanyl transdermal system down the toilet right away (See Figure K). used fentanyl transdermal system can be very dangerous for or lead to death in babies, children, pets, and adults who have not been prescribed fentanyl transdermal system.. oThrow away any fentanyl transdermal systems that are left over from your prescription as soon as they are no longer needed. Remove the leftover patches from their protective pouch and remove the release liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet. Do not flush the pouch, protective films or the release liner down the toilet. These texts can be thrown away in trash can. Parts of the Fentanyl Transdermal System. Medication Guide Figures - D. Medication Guide Figures E. Medication Guide Figures F. Medication Guide Figures G. Medication Guide Figures H. Medication Guide Figures I. Medication Guide Figures J. Medication Guide Figures K.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: May cause fetal harm. (8.1)oLactation: Not recommended. (8.2)oSevere Hepatic and Renal Impairment: Use not recommended. (8.6, 8.7). oPregnancy: May cause fetal harm. (8.1). oLactation: Not recommended. (8.2). oSevere Hepatic and Renal Impairment: Use not recommended. (8.6, 8.7). 8.1 Pregnancy Risk Summary. Prolonged use of opioid analgesics 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 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 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 Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. 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 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 times the daily human dose administered by 100 mcg/h patch on mg/m2 basis).In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to pregnant rats from Gestation Day to 18 suggested evidence of embryo-toxicity and slight increase in mean delivery time in the 0.03 mg/kg/day group (0.1 times the human dose administered by 100 mcg/h patch on mg/m2 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 to day 18 of pregnancy. Fentanyl produced 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 times the daily human dose administered by 100 mcg/hour patch on mg/m2 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 of pregnancy through 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 100 mcg/hour patch on mg/m2 basis. 8.2 Lactation 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 breastfed infant, advise patients that breastfeeding is not recommended during treatment with fentanyl transdermal system.. Clinical Considerations. Monitor infants exposed to fentanyl 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. 8.3 Females and Males of Reproductive Potential Infertility. Due to effects of androgen deficiency, chronic use of opioids 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)]. 8.4 Pediatric Use The safety of fentanyl transdermal system was evaluated in three open-label trials in 289 pediatric patients with chronic pain, 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 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 (5.4)].. 8.5 Geriatric Use Clinical studies of fentanyl transdermal system did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use caution when selecting 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 prolonged half-life. Moreover, elderly patients may be more sensitive to the active substance than younger patients. study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours [see Clinical Pharmacology (12.3)].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 monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.10)].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.. 8.6Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because there is in vitro and in vivo evidence of extensive hepatic contribution to the elimination of fentanyl transdermal system, hepatic impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid use of fentanyl transdermal system in patients with severe hepatic impairment [see Dosage and Administration (2.5) Warnings and Precautions (5.16) and Clinical Pharmacology (12.3)].. 8.7Renal Impairment The effect of renal impairment on the pharmacokinetics of fentanyl transdermal system has not been fully evaluated. clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because there is in vivo evidence of renal contribution to the elimination of fentanyl transdermal system, renal impairment would be expected to have significant effects on the pharmacokinetics of fentanyl transdermal system. Avoid the use of fentanyl transdermal system in patients with severe renal impairment [see Dosage and Administration (2.6) Warnings and Precautions (5.17) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oRisk of Increased Fentanyl Absorption with Elevated Body Temperature: Monitor 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)oLife-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.10)oSerotonin 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)oAdrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.12)oSevere Hypotension: Monitor during dose initiation and titration. Avoid the use of fentanyl transdermal system in patients with circulatory shock. (5.13)oRisks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma. (5.14). oRisk of Increased Fentanyl Absorption with Elevated Body Temperature: Monitor 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). oLife-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.10). oSerotonin 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). oAdrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.12). oSevere Hypotension: Monitor during dose initiation and titration. Avoid the use of fentanyl transdermal system in patients with circulatory shock. (5.13). oRisks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of fentanyl transdermal system in patients with impaired consciousness or coma. (5.14). 5.1Addiction, Abuse, and Misuse Fentanyl transdermal system contains fentanyl, an opioid agonist and Schedule II controlled substance. As an opioid, fentanyl transdermal system exposes users to the risks of addiction, abuse, and misuse. Because modified-release products such as fentanyl transdermal system deliver the opioid over an extended period of time, there is greater risk for overdose and death due to the larger amount of fentanyl present [see Drug Abuse and Dependence (9)].Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed fentanyl transdermal system. Addiction can occur at recommended doses and if the drug is misused or abused.Assess each patients risk for opioid addiction, abuse, or misuse prior to prescribing fentanyl transdermal system, and monitor all patients receiving fentanyl transdermal system for the development of these behaviors and conditions. Risks are increased in patients with personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as fentanyl transdermal system, but use in such patients necessitates intensive counseling about the risks and proper use of fentanyl transdermal system along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)] .Abuse or misuse of fentanyl transdermal system by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose, and death [see Overdosage (10)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing fentanyl transdermal system. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.. 5.2Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:oComplete REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.oDiscuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.oEmphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.oConsider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.To obtain further information on the opioid analgesic REMS and for list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.. oComplete REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.. oDiscuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.. oEmphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.. oConsider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.. 5.3Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patients clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.Fentanyl transdermal system is indicated only in opioid tolerant patients because of the risk for respiratory depression and death. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of fentanyl transdermal system, the risk is greatest during the initiation of therapy or following dosage increase. Monitor patients closely for respiratory depression within the first 24-72 hours of initiating therapy with and following dosage increases of fentanyl transdermal system.To reduce the risk of respiratory depression, proper dosing and titration of fentanyl transdermal system are essential [see Dosage and Administration (2)]. Overestimating the fentanyl transdermal system dosage when converting patients from another opioid product can result in fatal overdose with the first dose.Accidental exposure to fentanyl transdermal system, especially in children, can result in respiratory depression and death due to an overdose of fentanyl.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 known or suspected overdose [see Patient Counseling Information (17)] .Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9) ].. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose. Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, 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 pharmacist, or as part of community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)]. Consider prescribing naloxone, based on the patients risk factors for overdose, such as concomitant use of CNS depressants, history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.1, 5.8), Patient Counseling Information (17)] . 5.4Accidental Exposure A considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Death and other serious medical problems have occurred when children and adults were accidentally exposed to fentanyl transdermal system. Accidental or deliberate application or ingestion by child or adolescent will cause respiratory depression, and has resulted in deaths. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Improper disposal of fentanyl transdermal system in the trash has resulted in accidental exposures and deaths.Advise patients about strict adherence to the recommended handling and disposal instructions in order to prevent accidental exposure to fentanyl transdermal system [see Dosage and Administration (2.7), (2.8)]. Exposure to fentanyl transdermal systems discarded in the trash by children have been reported and have resulted in deaths.. 5.5Neonatal Opioid Withdrawal Syndrome Prolonged use of fentanyl transdermal system during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].. 5.6Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of fentanyl transdermal system with CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3)], particularly when an inhibitor is added after stable dose of fentanyl transdermal system is achieved. Similarly, discontinuation of CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl transdermal system-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl transdermal system with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl transdermal system-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved [see Dosage and Administration (2.4) Drug Interactions (7)].Concomitant use of fentanyl transdermal system with CYP3A4 inducers or discontinuation of CYP3A4 inhibitor could decrease fentanyl transdermal system plasma concentrations, decrease opioid efficacy or, possibly, lead to withdrawal syndrome in patient who had developed physical dependence to fentanyl. When using fentanyl transdermal system with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].. 5.7Risk of Increased Fentanyl Absorption with Application of External Heat Exposure to heat may increase fentanyl absorption and there have been reports of overdose and death as result of exposure to heat. clinical pharmacology study conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal system increased fentanyl exposure [see Clinical Pharmacology (12.3)].Warn patients to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources [see Dosage and Administration (2.7) ].. 5.8Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of fentanyl transdermal system with benzodiazepines and/or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].If the decision is made to prescribe benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in patient already taking benzodiazepine or other CNS depressant, prescribe lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and 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 (5.3)] .Advise both patients and caregivers about the risks of respiratory depression and sedation when fentanyl transdermal system is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].. 5.9Risk of Increased Fentanyl Absorption with Elevated Body Temperature Based on pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with body temperature of 40C (104F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Monitor patients wearing fentanyl transdermal systems who develop fever closely for sedation and respiratory depression and reduce the fentanyl transdermal system dose, if necessary. Warn patients to avoid strenuous exertion that leads to increased core body temperature while wearing fentanyl transdermal system to avoid the risk of potential overdose and death.. 5.10Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of fentanyl transdermal system in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.. Patients with Chronic Pulmonary Disease. Fentanyl transdermal system-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of fentanyl transdermal system [see Warnings and Precautions (5.3)].. Elderly, Cachectic, or Debilitated Patients. Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].Monitor such patients closely, particularly when initiating and titrating fentanyl transdermal system and when fentanyl transdermal system is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients.. 5.11Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, potentially life-threatening condition, have been reported during concomitant use of fentanyl transdermal system with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to few days of concomitant use, but may occur later than that. Discontinue fentanyl transdermal system immediately if serotonin syndrome is suspected.. 5.12Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.. 5.13Severe Hypotension Fentanyl transdermal system may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of fentanyl transdermal system. In patients with circulatory shock, fentanyl transdermal system may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of fentanyl transdermal system in patients with circulatory shock.. 5.14Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), fentanyl transdermal system may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with fentanyl transdermal system.Opioids may also obscure the clinical course in patient with head injury. Avoid the use of fentanyl transdermal system in patients with impaired consciousness or coma.. 5.15Cardiac Disease Fentanyl transdermal system may produce bradycardia. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with fentanyl transdermal system.. 5.16Hepatic Impairment A clinical pharmacology study with fentanyl transdermal system in patients with cirrhosis has shown that systemic fentanyl exposure increased in these patients. Because of the long half-life of fentanyl when administered as fentanyl transdermal system and hepatic metabolism of fentanyl, avoid use of fentanyl transdermal system in patients with severe hepatic impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired hepatic function. Therefore, to avoid starting patients with mild to moderate hepatic impairment on too high of dose, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration (2.5) Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 5.17Renal Impairment A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Because of the long half-life of fentanyl when administered as fentanyl transdermal system, avoid the use of fentanyl transdermal system in patients with severe renal impairment. Insufficient information exists to make precise dosing recommendations regarding the use of fentanyl transdermal system in patients with impaired renal function. Therefore, to avoid starting patients with mild to moderate renal impairment on too high of dose, start with one half of the usual dosage of fentanyl transdermal system. Closely monitor for signs of sedation and respiratory depression, including at each dosage increase [see Dosage and Administration (2.6) Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. 5.18Risks of Use in Patients with Gastrointestinal Conditions Fentanyl transdermal system is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.The fentanyl in fentanyl transdermal system may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.. 5.19Increased Risk of Seizures in Patients with Seizure Disorders The fentanyl in fentanyl transdermal system may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with history of seizure disorders for worsened seizure control during fentanyl transdermal system therapy.. 5.20Withdrawal Do not abruptly discontinue fentanyl transdermal system in patient physically dependent on opioids. When discontinuing fentanyl transdermal system in physically dependent patient, gradually taper the dosage. Rapid tapering of fentanyl transdermal system in patient physically dependent on opioids may lead to withdrawal syndrome and return of pain [see Dosage and Administration (2.9) Drug Abuse and Dependence (9.3)].Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving full opioid agonist analgesic, including fentanyl transdermal system. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].. 5.21Risks of Driving and Operating Machinery Fentanyl transdermal system may impair the mental or physical abilities required for the performance of potentially dangerous activities, such as driving car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of the fentanyl transdermal system and know how they will react to the medication [see Patient Counseling Information (17)].