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Reassess the benefits, risks, and need for continued opioid therapy at each patient visit

Continue opioid therapy only if there is clinically meaningful improvement that outweighs risks to patient safety1

If benefits do not outweigh harms of continued therapy, optimize other therapies and work with patients to lower the opioid dose or to taper and discontinue the opioid

Please read the Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Intended for healthcare professionals of the United States of America only.

Reference: 1. Dowell D, Haegerich T, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(No.RR‑1):1‑49. https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6501e1.pdf. Accessed January 6, 2017.

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

Accidental Exposure

Accidental exposure to even one dose of Butrans, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Butrans 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 a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant 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 (5.4), Drug Interactions (7)].

  • Reserve concomitant prescribing of BUTRANS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.
INDICATIONS AND USAGE

Butrans® (buprenorphine) transdermal system CIII is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use
  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

  • Butrans is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS
  • Butrans is contraindicated in patients with significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected gastrointestinal obstruction, including paralytic ileus; hypersensitivity (e.g., anaphylaxis) to buprenorphine.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse
  • Butrans contains buprenorphine, a Schedule III controlled substance. Butrans exposes users to the risks of opioid addiction, abuse, and misuse. Because extended-release products such as Butrans deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present.

  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butrans. Addiction can occur at recommended doses and if the drug is misused or abused.

  • Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Butrans, and monitor all patients receiving Butrans for the development of these behaviors and conditions. Risks are increased in patients with a 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 Butrans, but use in such patients necessitates intensive counseling about the risks and proper use of Butrans, along with intensive monitoring for signs of addiction, abuse, or misuse.

  • Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Butrans. 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.

Life‐Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.

  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Butrans, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of Butrans.

  • To reduce the risk of respiratory depression, proper dosing and titration of Butrans are essential. Overestimating the Butrans dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

  • Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome
  • Prolonged use of Butrans 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 using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma and death may result from the concomitant use of Butrans with benzodiazepines 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.

  • If the decision is made to prescribe a 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 a 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 a patient already taking a benzodiazepine or other CNS depressant, prescribe a 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.

  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Butrans 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.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
  • The use of Butrans in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

  • Butrans-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a 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 Butrans.

  • 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.

  • Monitor such patients closely, particularly when initiating and titrating Butrans and when Butrans is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. 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.

QTc Prolongation
  • A positive‐controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval.

  • Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QTc interval.

Severe Hypotension
  • Butrans 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 been compromised by a reduced blood volume or concurrent administration with certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Butrans. In patients with circulatory shock, Butrans may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butrans in patients with circulatory shock.

Risks 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), Butrans 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 Butrans.

  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butrans in patients with impaired consciousness or coma.

Hepatotoxicity
  • Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post‐marketing adverse event reports. For patients at increased risk of hepatotoxicity, obtain baseline liver enzyme levels and monitor periodically and during treatment with Butrans.

Application Site Skin Reactions
  • In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

Anaphylactic/Allergic Reactions
  • Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post‐marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans.

Risks of Use with Application of External Heat
  • Advise patients and their caregivers to avoid exposing the Butrans 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 because an increase in absorption of buprenorphine may occur. Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

Risks of Use in Patients with Fever
  • Monitor patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the Butrans dose if signs of respiratory or central nervous system depression occur.

Risks of Use in Patients with Gastrointestinal Conditions
  • Butrans is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The buprenorphine in Butrans may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders
  • The buprenorphine in Butrans may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Butrans therapy.

Risks of Driving and Operating Machinery
  • Butrans may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butrans and know how they will react to the medication.

Use in Addiction Treatment
  • Butrans has not been studied and is not approved for use in the management of addictive disorders.

ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

Please read the Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Intended for healthcare professionals of the United States of America only.

Reference: 1. Dowell D, Haegerich T, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(No.RR‑1):1‑49. https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6501e1.pdf. Accessed January 6, 2017.

Indications and Usage
INDICATIONS AND USAGE

Butrans® (buprenorphine) transdermal system CIII is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use
  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

  • Butrans is not indicated as an as-needed (prn) analgesic.

Important Safety Information

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

Accidental Exposure

Accidental exposure to even one dose of Butrans, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Butrans 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 a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant 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 (5.4), Drug Interactions (7)].

  • Reserve concomitant prescribing of BUTRANS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.
CONTRAINDICATIONS
  • Butrans is contraindicated in patients with significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected gastrointestinal obstruction, including paralytic ileus; hypersensitivity (e.g., anaphylaxis) to buprenorphine.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse
  • Butrans contains buprenorphine, a Schedule III controlled substance. Butrans exposes users to the risks of opioid addiction, abuse, and misuse. Because extended-release products such as Butrans deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present.

  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butrans. Addiction can occur at recommended doses and if the drug is misused or abused.

  • Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Butrans, and monitor all patients receiving Butrans for the development of these behaviors and conditions. Risks are increased in patients with a 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 Butrans, but use in such patients necessitates intensive counseling about the risks and proper use of Butrans, along with intensive monitoring for signs of addiction, abuse, or misuse.

  • Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Butrans. 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.

Life‐Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.

  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Butrans, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of Butrans.

  • To reduce the risk of respiratory depression, proper dosing and titration of Butrans are essential. Overestimating the Butrans dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

  • Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome
  • Prolonged use of Butrans 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 using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma and death may result from the concomitant use of Butrans with benzodiazepines 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.

  • If the decision is made to prescribe a 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 a 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 a patient already taking a benzodiazepine or other CNS depressant, prescribe a 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.

  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Butrans 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.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
  • The use of Butrans in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

  • Butrans-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a 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 Butrans.

  • 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.

  • Monitor such patients closely, particularly when initiating and titrating Butrans and when Butrans is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. 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.

QTc Prolongation
  • A positive‐controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval.

  • Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QTc interval.

Severe Hypotension
  • Butrans 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 been compromised by a reduced blood volume or concurrent administration with certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Butrans. In patients with circulatory shock, Butrans may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butrans in patients with circulatory shock.

Risks 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), Butrans 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 Butrans.

  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butrans in patients with impaired consciousness or coma.

Hepatotoxicity
  • Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post‐marketing adverse event reports. For patients at increased risk of hepatotoxicity, obtain baseline liver enzyme levels and monitor periodically and during treatment with Butrans.

Application Site Skin Reactions
  • In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

Anaphylactic/Allergic Reactions
  • Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post‐marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans.

Risks of Use with Application of External Heat
  • Advise patients and their caregivers to avoid exposing the Butrans 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 because an increase in absorption of buprenorphine may occur. Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

Risks of Use in Patients with Fever
  • Monitor patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the Butrans dose if signs of respiratory or central nervous system depression occur.

Risks of Use in Patients with Gastrointestinal Conditions
  • Butrans is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The buprenorphine in Butrans may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders
  • The buprenorphine in Butrans may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Butrans therapy.

Risks of Driving and Operating Machinery
  • Butrans may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butrans and know how they will react to the medication.

Use in Addiction Treatment
  • Butrans has not been studied and is not approved for use in the management of addictive disorders.

ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

Please read the Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Intended for healthcare professionals of the United States of America only.

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

Accidental Exposure

Accidental exposure to even one dose of Butrans, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Butrans 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 a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant 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 (5.4), Drug Interactions (7)].

  • Reserve concomitant prescribing of BUTRANS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.
INDICATIONS AND USAGE

Butrans® (buprenorphine) transdermal system CIII is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use
  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

  • Butrans is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS
  • Butrans is contraindicated in patients with significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected gastrointestinal obstruction, including paralytic ileus; hypersensitivity (e.g., anaphylaxis) to buprenorphine.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse
  • Butrans contains buprenorphine, a Schedule III controlled substance. Butrans exposes users to the risks of opioid addiction, abuse, and misuse. Because extended-release products such as Butrans deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present.

  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butrans. Addiction can occur at recommended doses and if the drug is misused or abused.

  • Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Butrans, and monitor all patients receiving Butrans for the development of these behaviors and conditions. Risks are increased in patients with a 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 Butrans, but use in such patients necessitates intensive counseling about the risks and proper use of Butrans, along with intensive monitoring for signs of addiction, abuse, or misuse.

  • Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Butrans. 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.

Life‐Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.

  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Butrans, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of Butrans.

  • To reduce the risk of respiratory depression, proper dosing and titration of Butrans are essential. Overestimating the Butrans dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

  • Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome
  • Prolonged use of Butrans 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 using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma and death may result from the concomitant use of Butrans with benzodiazepines 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.

  • If the decision is made to prescribe a 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 a 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 a patient already taking a benzodiazepine or other CNS depressant, prescribe a 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.

  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Butrans 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.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
  • The use of Butrans in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

  • Butrans-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a 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 Butrans.

  • 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.

  • Monitor such patients closely, particularly when initiating and titrating Butrans and when Butrans is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. 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.

QTc Prolongation
  • A positive‐controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval.

  • Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QTc interval.

Severe Hypotension
  • Butrans 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 been compromised by a reduced blood volume or concurrent administration with certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Butrans. In patients with circulatory shock, Butrans may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butrans in patients with circulatory shock.

Risks 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), Butrans 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 Butrans.

  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butrans in patients with impaired consciousness or coma.

Hepatotoxicity
  • Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post‐marketing adverse event reports. For patients at increased risk of hepatotoxicity, obtain baseline liver enzyme levels and monitor periodically and during treatment with Butrans.

Application Site Skin Reactions
  • In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

Anaphylactic/Allergic Reactions
  • Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post‐marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans.

Risks of Use with Application of External Heat
  • Advise patients and their caregivers to avoid exposing the Butrans 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 because an increase in absorption of buprenorphine may occur. Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

Risks of Use in Patients with Fever
  • Monitor patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the Butrans dose if signs of respiratory or central nervous system depression occur.

Risks of Use in Patients with Gastrointestinal Conditions
  • Butrans is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The buprenorphine in Butrans may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders
  • The buprenorphine in Butrans may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Butrans therapy.

Risks of Driving and Operating Machinery
  • Butrans may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butrans and know how they will react to the medication.

Use in Addiction Treatment
  • Butrans has not been studied and is not approved for use in the management of addictive disorders.

ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

Please read the Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Intended for healthcare professionals of the United States of America only.