FDA label d3245d50-eae4-4b59-b21f-be31a145ab2f

Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion. Fentanyl transdermal system is indicated for management of persistent , moderate to severe chronic pain that: requires continuous, around-the-clock opioid administration for an extended period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/h. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated: in patients who are not opioid-tolerant in the management of acute pain or in patients who require opioid analgesia for a short period of time in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain [e.g., use on an as needed basis (prn)] (See CONTRAINDICATIONS for further information.) Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period. The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and potent any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (See CLINICAL PHARMACOLOGY – Drug Interactions , WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information). The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use .) Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours. Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing fentanyl transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal. Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary.

WARNINGS Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal. The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use ). Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean elimination half-life of fentanyl transdermal system is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal. Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists. All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system application site to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary. Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Misuse, Abuse and Diversion of Opioids Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Fentanyl transdermal system has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION ). Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Hypoventilation (Respiratory Depression) Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose. Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized. The use of concomitant CNS active drugs requires special patient care and observation. Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Chronic Pulmonary Disease Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal system should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure. Head Injuries and Increased Intracranial Pressure Fentanyl transdermal system should not be used in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. Fentanyl transdermal system should be used with caution in patients with brain tumors. Interactions with other CNS Depressants The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced. Interactions with Alcohol and Drugs of Abuse Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Interactions with CYP3A4 Inhibitors The concomitant use of fentanyl transdermal system with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitors should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (see BOX WARNING , CLINICAL PHARMACOLOGY – Drug Interactions , PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information.)

ADVERSE REACTIONS In post-marketing experience, deaths from hypoventilation due to inappropriate use of fentanyl transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS ). Pre-marketing Clinical Trial Experience Although fentanyl transdermal system use in post-operative or acute pain and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was originally evaluated in 357 post-operative adult patients for 1 to 3 days and 153 cancer patients for a total of 510 patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year. Hypoventilation was the most serious adverse reaction observed in 13 (4%) post-operative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naïve patients. Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials. Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1; similar reactions were seen in the 357 post-operative patients. In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months. There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and nausea (24%). Adverse events reported in pediatric patients at a rate of ≥ 1% are presented in Table 1. TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%) Adult (N=380) and Pediatric (N=291) Clinical Trial Experience Body System Adults Pediatrics * Reactions occurring in 3% to 10% of fentanyl transdermal system patients ** Reactions occurring in 10% or more of fentanyl transdermal system patients Body as a Whole Abdominal pain*, headache*, fatigue*,back pain, fever, influenza-like symptoms*, accidental injury, rigors Pain*, headache*, fever, syncope, abdominal pain, allergic reaction, flushing Cardiovascular Arrhythmia, chest pain Hypertension, tachycardia Digestive Nausea**, vomiting**, constipation**, dry mouth**, anorexia*, diarrhea*, dyspepsia*, flatulence Nausea**, vomiting**, constipation*, dry mouth, diarrhea Nervous Somnolence**, insomnia, confusion**, asthenia**, dizziness*, nervousness*, hallucinations*, anxiety*, depression*, euphoria*, tremor, abnormal coordination, speech disorder, abnormal thinking, abnormal gait, abnormal dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction Somnolence*, nervousness**, insomnia*, asthenia*, hallucinations, anxiety, depression, convulsions, dizziness, tremor, speech disorder, agitation, stupor, confusion, paranoid reaction Respiratory Dyspnea*, hypoventilation*, apnea*, hemoptysis, pharyngitis*, hiccups, bronchitis, rhinitis, sinusitis, upper respiratory tract infection* Dyspnea, respiratory depression, rhinitis, coughing Skin and Appendages Sweating**, pruritus*, rash, application site reaction-erythema, papules, itching, edema Pruritus*, application site reaction*, sweating increased, rash, rash erythematous, skin reaction localized Urogenital Urinary retention* Micturition disorder Urinary retention The following adverse effects have been reported in less than 1% of the 510 adult post-operative and cancer patients studied: Cardiovascular: bradycardia Digestive: abdominal distention Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility Respiratory: stertorous breathing, asthma, respiratory disorder Skin and Appendages, General: exfoliative dermatitis, pustules Special Senses: amblyopia Urogenital: bladder pain, oliguria, urinary frequency Post-Marketing Experience - Adults The following adverse reactions have been reported in association with the use of fentanyl transdermal system and not reported in the pre-marketing adverse reactions section above: Body as a Whole: Edema Cardiovascular: tachycardia Metabolic and Nutritional: weight loss Special Senses: blurred vision Urogenital: decreased libido, anorgasmia, ejaculatory difficulty

<table frame="void"> <caption>TABLE 1: ADVERSE EVENTS (at rate of &#x2265; 1%) Adult (N=380) and Pediatric (N=291) Clinical Trial Experience</caption> <col/> <col/> <col/> <thead> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Body System</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Adults</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Pediatrics</td> </tr> </thead> <tfoot> <tr> <td valign="top" colspan="3" styleCode=" Toprule "> * Reactions occurring in 3% to 10% of fentanyl transdermal system patients</td> </tr> <tr> <td valign="top" colspan="3"> ** Reactions occurring in 10% or more of fentanyl transdermal system patients</td> </tr> </tfoot> <tbody> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Body as a Whole</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Abdominal pain*, headache*, fatigue*,back pain, fever, influenza-like symptoms*, accidental injury, rigors</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Pain*, headache*, fever, syncope, abdominal pain, allergic reaction, flushing </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Cardiovascular</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Arrhythmia, chest pain</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Hypertension, tachycardia</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Digestive</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Nausea**, vomiting**, constipation**, dry mouth**, anorexia*, diarrhea*, dyspepsia*, flatulence</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Nausea**, vomiting**, constipation*, dry mouth, diarrhea</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Nervous</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Somnolence**, insomnia, confusion**, asthenia**, dizziness*, nervousness*, hallucinations*, anxiety*, depression*, euphoria*, tremor, abnormal coordination, speech disorder, abnormal thinking, abnormal gait, abnormal dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Somnolence*, nervousness**, insomnia*, asthenia*, hallucinations, anxiety, depression, convulsions, dizziness, tremor, speech disorder, agitation, stupor, confusion, paranoid reaction</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Respiratory</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Dyspnea*, hypoventilation*, apnea*, hemoptysis, pharyngitis*, hiccups, bronchitis, rhinitis, sinusitis, upper respiratory tract infection*</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Dyspnea, respiratory depression, rhinitis, coughing</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Skin and Appendages</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Sweating**, pruritus*, rash, application site reaction-erythema, papules, itching, edema</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Pruritus*, application site reaction*, sweating increased, rash, rash erythematous, skin reaction localized</td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Urogenital</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Urinary retention* Micturition disorder</td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> Urinary retention</td> </tr> </tbody> </table>