Butrans

• Because of the risks of addiction, abuse and misuse with opioids, which can occur at any dosage or duration, and because of the greater risk of overdose and death with extended-release/long-acting opioid formulations
  [see Warnings and Precautions (

  5.1 Addiction, Abuse, and Misuse

  BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  . 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

  [see Drug Abuse and Dependence ]

  .

  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 reassess 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 frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

  )]
  , 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

• BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.
  )
• BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patient's who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid. (
  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.
  )
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (
  2 DOSAGE AND ADMINISTRATION

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patient's who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments.
  • Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with BUTRANS. Consider prescribing naloxone based on the patient's risk factors for overdose.
  • For opioid-naïve patients, initiate treatment with a 5 mcg/hour patch.
  • Instruct patients to wear BUTRANS for 7 days and to wait a minimum of 3 weeks before applying to the same site.
  • Do not abruptly discontinue BUTRANS in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.

  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.

  2.2 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 BUTRANS

  [see Warnings and Precautions ].

  Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient

  [see Warnings and Precautions , Overdosage ].

  Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.

  2.3 Initial Dosage

  Use of BUTRANS as the First Opioid Analgesic

  (opioid-naive patients)
  
  Initiate treatment with BUTRANS with a 5 mcg/hour patch.

  Conversion from Other Opioids to BUTRANS

  
  
  When BUTRANS therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

  There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids.

  Prior Total Daily Dose of Opioid Less than 30 mg of Oral Morphine Equivalents per Day

  : Initiate treatment with BUTRANS 5 mcg/hour at the next dosing interval (see Table 1 below, middle column).

  Prior Total Daily Dose of Opioid Between 30 mg to 80 mg of Oral Morphine Equivalents per Day:

  Taper the patient's current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with BUTRANS. Then initiate treatment with BUTRANS 10 mcg/hour at the next dosing interval (see Table 1 below, right column). Patients may use short-acting analgesics as needed until analgesic efficacy with BUTRANS is attained.

  Prior Total Daily Dose of Opioid Greater than 80 mg of Oral Morphine Equivalents per Day

  : BUTRANS 20 mcg/hour may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents. Consider the use of an alternate analgesic.

  Table 1: Initial BUTRANS Dose

  

  Conversion from Methadone to BUTRANS

  
  
  Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

  

  2.4 Titration and Maintenance of Therapy

  Individually titrate BUTRANS to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving BUTRANS to assess the maintenance of pain control, signs and symptoms of opioid withdrawal and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . Frequent communication is important among the prescriber, other members of healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  The minimum BUTRANS titration interval is 72 hours, based on the pharmacokinetic profile and time to reach steady state levels

  [see Clinical Pharmacology ]

  .

  The maximum BUTRANS dose is 20 mcg/hour. Do not exceed a dose of one 20 mcg/hour BUTRANS system due to the risk of QTc interval prolongation. In a clinical trial, BUTRANS 40 mcg/hour (given as two BUTRANS 20 mcg/hour systems) resulted in prolongation of the QTc interval

  [see Warnings and Precautions , Clinical Pharmacology ].

  Patients who experience breakthrough pain may require dosage adjustment increase of BUTRANS, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the BUTRANS dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase) consider reducing the dosage

  [see Warnings and Precautions ].

  Adjust the dosage to obtain an appropriate balance between the management of pain and opioid-related adverse reactions.

  Because steady-state plasma concentrations are achieved within 72 hours, BUTRANS dosage may be adjusted every 3 days. Dose adjustments may be made in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than two patches of the 5 mcg/hour, or 7.5 mcg/hour, or 10 mcg/hour system(s). The total dose from both patches should not exceed 20 mcg/hour. For the use of two patches, instruct patients to remove their current patch, and apply the two new patches at the same time, adjacent to one another at a different application site

  [see Dosage and Administration ].

  2.5 Safe Reduction or Discontinuation of BUTRANS

  Do not abruptly discontinue BUTRANS 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 a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking BUTRANS, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTRANS) the patient has been taking, 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 a 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 a specialist.

  There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on BUTRANS who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

  It may be necessary to provide the patient with lower dosage strengths to accomplish a 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 a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate 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 an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A 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 , Drug Abuse and Dependence ]

  .

  2.6 Patients with Hepatic Impairment

  BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is only intended for 7-day application, consider use of an alternate analgesic that may permit more flexibility with the dosing in patients with severe hepatic impairment

  [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ].

  2.7 Administration of BUTRANS

  • Instruct patients to apply immediately after removal from the individually sealed pouch. Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way. See the Instructions for Use for step-by-step instructions for applying BUTRANS.
  • Apply BUTRANS to the upper outer arm, upper chest, upper back or the side of the chest. These 4 sites (each present on both sides of the body) provide 8 possible application sites. Rotate BUTRANS among the 8 described skin sites. After BUTRANS removal, wait a minimum of 21 days before reapplying to the same skin site
    [see Clinical Pharmacology ].
  • Apply BUTRANS to a hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Do not apply BUTRANS to irritated skin. If the application site must be cleaned, clean the site with water only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before applying BUTRANS.
  • Incidental exposure of the BUTRANS patch to water, such as while bathing or showering is acceptable based on experience during clinical studies.
  • If problems with adhesion of BUTRANS occur, the edges may be taped with first aid tape. If problems with lack of adhesion continue, the patch may be covered with waterproof or semipermeable adhesive dressings suitable for 7 days of wear.
  • If BUTRANS falls off during the 7-day dosing interval, dispose of the transdermal system properly and place a new BUTRANS patch on at a different skin site.
  • When changing the system, instruct patients to remove BUTRANS and dispose of it properly
    [see Dosage and Administration ].
  • If the buprenorphine-containing adhesive matrix accidentally contacts the skin, instruct patients or caregivers to wash the area with water and not to use soap, alcohol, or other solvents to remove the adhesive because they may enhance the absorption of the drug.

  2.8 Disposal Instructions

  Patients should refer to the Instructions for Use for proper disposal of BUTRANS. Dispose of used and unused patches by following the instructions on the Patch-Disposal Unit that is packaged with the BUTRANS patches.

  Alternatively, patients can dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

  Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.
  ,
  5 WARNINGS AND PRECAUTIONS

  • Opioid-Induced Hyperalgesia and Allodynia
    : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • Life Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
    : Regularly evaluate particularly during initiation and titration.
  • Adrenal Insufficiency
    : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • Severe Hypotension
    : Regularly evaluate during dose initiation and titration. Avoid use of BUTRANS in patients with circulatory shock
  • Risks of Use in Patients with Increased Intracranial Cranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
    : Monitor for sedation and respiratory depression. Avoid use of BUTRANS in patients with impaired consciousness or coma.

  5.1 Addiction, Abuse, and Misuse

  BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  . 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

  [see Drug Abuse and Dependence ]

  .

  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 reassess 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 frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

  5.2 Life-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 patient's clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  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.

  To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential

  [see Dosage and Administration ]

  . 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.

  Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

  Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

  [see Dosage and Administration ].

  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 BUTRANS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). 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.

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. 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 ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

  [see Dosage and Administration , Warnings and Precautions , Overdosage ].

  5.3 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 and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 ]

  .

  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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Drug Interactions , Patient Counseling Information ]

  .

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of BUTRANS for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations ]

  .

  5.5 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 a 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:

  • Complete a
    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.
  • Discuss 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.
  • Emphasize 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.
  • Consider 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 a 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.

  5.6 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

  [see Clinical Pharmacology ]

  . 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.

  5.7 Risks of Use in Patients with Fever

  Regularly evaluate 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.

  5.8 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.

  5.9 Opioid-Induced Hyperalgesia and Allodynia

  Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

  [see Dependence ]

  . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

  Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety)

  [see Dosage and Administration , Warnings and Precautions ].

  5.10 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.

  Patients with Chronic Pulmonary Disease:

  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

  [see Warnings and Precautions ].

  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 ].

  Regularly evaluate patients particularly when initiating and titrating BUTRANS and when BUTRANS is given concomitantly with other drugs that depress respiration

  [see Warnings and Precautions ]

  . Alternatively, consider the use of non-opioid analgesics in these patients.

  5.11 Adrenal 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 a 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.

  5.12 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 already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

  [see Drug Interactions ]

  . Regularly evaluate 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.

  5.13 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 CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BUTRANS may reduce respiratory drive, and the resultant CO₂retention 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.

  5.14 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. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with BUTRANS.

  5.15 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. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

  5.16 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BUTRANS therapy.

  5.17 QTc Prolongation

  Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

  Consider these observations in clinical decisions when prescribing BUTRANS to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

  5.18 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.

  5.19 Withdrawal

  Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids. When discontinuing BUTRANS in a physically dependent patient, gradually taper the dosage. Rapid tapering of buprenorphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

  [see Dosage and Administration , Drug Abuse and Dependence ]

  .

  Additionally, the use of BUTRANS, a partial agonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of BUTRANS with a full opioid agonist analgesic.

  5.20 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.

  5.21 Use in Addiction Treatment

  BUTRANS has not been studied and is not approved for use in the management of addictive disorders.
  )
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (
  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.
  ,
  5.1 Addiction, Abuse, and Misuse

  BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  . 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

  [see Drug Abuse and Dependence ]

  .

  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 reassess 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 frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.
  )
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments. (
  2 DOSAGE AND ADMINISTRATION

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patient's who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments.
  • Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with BUTRANS. Consider prescribing naloxone based on the patient's risk factors for overdose.
  • For opioid-naïve patients, initiate treatment with a 5 mcg/hour patch.
  • Instruct patients to wear BUTRANS for 7 days and to wait a minimum of 3 weeks before applying to the same site.
  • Do not abruptly discontinue BUTRANS in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.

  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.

  2.2 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 BUTRANS

  [see Warnings and Precautions ].

  Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient

  [see Warnings and Precautions , Overdosage ].

  Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.

  2.3 Initial Dosage

  Use of BUTRANS as the First Opioid Analgesic

  (opioid-naive patients)
  
  Initiate treatment with BUTRANS with a 5 mcg/hour patch.

  Conversion from Other Opioids to BUTRANS

  
  
  When BUTRANS therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

  There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids.

  Prior Total Daily Dose of Opioid Less than 30 mg of Oral Morphine Equivalents per Day

  : Initiate treatment with BUTRANS 5 mcg/hour at the next dosing interval (see Table 1 below, middle column).

  Prior Total Daily Dose of Opioid Between 30 mg to 80 mg of Oral Morphine Equivalents per Day:

  Taper the patient's current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with BUTRANS. Then initiate treatment with BUTRANS 10 mcg/hour at the next dosing interval (see Table 1 below, right column). Patients may use short-acting analgesics as needed until analgesic efficacy with BUTRANS is attained.

  Prior Total Daily Dose of Opioid Greater than 80 mg of Oral Morphine Equivalents per Day

  : BUTRANS 20 mcg/hour may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents. Consider the use of an alternate analgesic.

  Table 1: Initial BUTRANS Dose

  

  Conversion from Methadone to BUTRANS

  
  
  Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

  

  2.4 Titration and Maintenance of Therapy

  Individually titrate BUTRANS to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving BUTRANS to assess the maintenance of pain control, signs and symptoms of opioid withdrawal and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . Frequent communication is important among the prescriber, other members of healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  The minimum BUTRANS titration interval is 72 hours, based on the pharmacokinetic profile and time to reach steady state levels

  [see Clinical Pharmacology ]

  .

  The maximum BUTRANS dose is 20 mcg/hour. Do not exceed a dose of one 20 mcg/hour BUTRANS system due to the risk of QTc interval prolongation. In a clinical trial, BUTRANS 40 mcg/hour (given as two BUTRANS 20 mcg/hour systems) resulted in prolongation of the QTc interval

  [see Warnings and Precautions , Clinical Pharmacology ].

  Patients who experience breakthrough pain may require dosage adjustment increase of BUTRANS, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the BUTRANS dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase) consider reducing the dosage

  [see Warnings and Precautions ].

  Adjust the dosage to obtain an appropriate balance between the management of pain and opioid-related adverse reactions.

  Because steady-state plasma concentrations are achieved within 72 hours, BUTRANS dosage may be adjusted every 3 days. Dose adjustments may be made in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than two patches of the 5 mcg/hour, or 7.5 mcg/hour, or 10 mcg/hour system(s). The total dose from both patches should not exceed 20 mcg/hour. For the use of two patches, instruct patients to remove their current patch, and apply the two new patches at the same time, adjacent to one another at a different application site

  [see Dosage and Administration ].

  2.5 Safe Reduction or Discontinuation of BUTRANS

  Do not abruptly discontinue BUTRANS 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 a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking BUTRANS, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTRANS) the patient has been taking, 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 a 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 a specialist.

  There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on BUTRANS who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

  It may be necessary to provide the patient with lower dosage strengths to accomplish a 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 a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate 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 an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A 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 , Drug Abuse and Dependence ]

  .

  2.6 Patients with Hepatic Impairment

  BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is only intended for 7-day application, consider use of an alternate analgesic that may permit more flexibility with the dosing in patients with severe hepatic impairment

  [see Warnings and Precautions , Use in Specific Populations , Clinical Pharmacology ].

  2.7 Administration of BUTRANS

  • Instruct patients to apply immediately after removal from the individually sealed pouch. Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way. See the Instructions for Use for step-by-step instructions for applying BUTRANS.
  • Apply BUTRANS to the upper outer arm, upper chest, upper back or the side of the chest. These 4 sites (each present on both sides of the body) provide 8 possible application sites. Rotate BUTRANS among the 8 described skin sites. After BUTRANS removal, wait a minimum of 21 days before reapplying to the same skin site
    [see Clinical Pharmacology ].
  • Apply BUTRANS to a hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Do not apply BUTRANS to irritated skin. If the application site must be cleaned, clean the site with water only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before applying BUTRANS.
  • Incidental exposure of the BUTRANS patch to water, such as while bathing or showering is acceptable based on experience during clinical studies.
  • If problems with adhesion of BUTRANS occur, the edges may be taped with first aid tape. If problems with lack of adhesion continue, the patch may be covered with waterproof or semipermeable adhesive dressings suitable for 7 days of wear.
  • If BUTRANS falls off during the 7-day dosing interval, dispose of the transdermal system properly and place a new BUTRANS patch on at a different skin site.
  • When changing the system, instruct patients to remove BUTRANS and dispose of it properly
    [see Dosage and Administration ].
  • If the buprenorphine-containing adhesive matrix accidentally contacts the skin, instruct patients or caregivers to wash the area with water and not to use soap, alcohol, or other solvents to remove the adhesive because they may enhance the absorption of the drug.

  2.8 Disposal Instructions

  Patients should refer to the Instructions for Use for proper disposal of BUTRANS. Dispose of used and unused patches by following the instructions on the Patch-Disposal Unit that is packaged with the BUTRANS patches.

  Alternatively, patients can dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

  Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.
  ,
  5 WARNINGS AND PRECAUTIONS

  • Opioid-Induced Hyperalgesia and Allodynia
    : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • Life Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
    : Regularly evaluate particularly during initiation and titration.
  • Adrenal Insufficiency
    : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • Severe Hypotension
    : Regularly evaluate during dose initiation and titration. Avoid use of BUTRANS in patients with circulatory shock
  • Risks of Use in Patients with Increased Intracranial Cranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
    : Monitor for sedation and respiratory depression. Avoid use of BUTRANS in patients with impaired consciousness or coma.

  5.1 Addiction, Abuse, and Misuse

  BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  . 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

  [see Drug Abuse and Dependence ]

  .

  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 reassess 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 frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

  5.2 Life-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 patient's clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  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.

  To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential

  [see Dosage and Administration ]

  . 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.

  Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

  Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

  [see Dosage and Administration ].

  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 BUTRANS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). 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.

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. 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 ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

  [see Dosage and Administration , Warnings and Precautions , Overdosage ].

  5.3 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 and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 ]

  .

  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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Drug Interactions , Patient Counseling Information ]

  .

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of BUTRANS for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations ]

  .

  5.5 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 a 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:

  • Complete a
    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.
  • Discuss 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.
  • Emphasize 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.
  • Consider 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 a 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.

  5.6 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

  [see Clinical Pharmacology ]

  . 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.

  5.7 Risks of Use in Patients with Fever

  Regularly evaluate 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.

  5.8 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.

  5.9 Opioid-Induced Hyperalgesia and Allodynia

  Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

  [see Dependence ]

  . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

  Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety)

  [see Dosage and Administration , Warnings and Precautions ].

  5.10 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.

  Patients with Chronic Pulmonary Disease:

  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

  [see Warnings and Precautions ].

  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 ].

  Regularly evaluate patients particularly when initiating and titrating BUTRANS and when BUTRANS is given concomitantly with other drugs that depress respiration

  [see Warnings and Precautions ]

  . Alternatively, consider the use of non-opioid analgesics in these patients.

  5.11 Adrenal 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 a 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.

  5.12 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 already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

  [see Drug Interactions ]

  . Regularly evaluate 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.

  5.13 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 CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BUTRANS may reduce respiratory drive, and the resultant CO₂retention 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.

  5.14 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. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with BUTRANS.

  5.15 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. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

  5.16 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BUTRANS therapy.

  5.17 QTc Prolongation

  Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

  Consider these observations in clinical decisions when prescribing BUTRANS to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

  5.18 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.

  5.19 Withdrawal

  Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids. When discontinuing BUTRANS in a physically dependent patient, gradually taper the dosage. Rapid tapering of buprenorphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

  [see Dosage and Administration , Drug Abuse and Dependence ]

  .

  Additionally, the use of BUTRANS, a partial agonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of BUTRANS with a full opioid agonist analgesic.

  5.20 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.

  5.21 Use in Addiction Treatment

  BUTRANS has not been studied and is not approved for use in the management of addictive disorders.
  )
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with BUTRANS. Consider prescribing naloxone based on the patient's risk factors for overdose. (
  2.2 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 BUTRANS

  [see Warnings and Precautions ].

  Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient

  [see Warnings and Precautions , Overdosage ].

  Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.
  ,
  5.1 Addiction, Abuse, and Misuse

  BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  . 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

  [see Drug Abuse and Dependence ]

  .

  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 reassess 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 frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.
  ,
  5.2 Life-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 patient's clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  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.

  To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential

  [see Dosage and Administration ]

  . 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.

  Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

  Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

  [see Dosage and Administration ].

  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 BUTRANS. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). 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.

  Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. 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 ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

  [see Dosage and Administration , Warnings and Precautions , Overdosage ].
  ,
  5.3 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 and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 ]

  .

  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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

  If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  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

  [see Drug Interactions , Patient Counseling Information ]

  .
  ,
  10 OVERDOSAGE

  Clinical Presentation

  
  
  Acute overdosage with buprenorphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations

  [see Clinical Pharmacology ]

  .

  Treatment of Overdose

  
  
  In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures.

  Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. However, naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used.

  Remove BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours.

  In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
  )
• For opioid-naïve patients, initiate treatment with a 5 mcg/hour patch. (
  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.
  )
• Instruct patients to wear BUTRANS for 7 days and to wait a minimum of 3 weeks before applying to the same site. (
  2.1 Important Dosage and Administration Information

  • BUTRANS should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals

    [see Warnings and Precautions ]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTRANS for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions ]

    .
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTRANS. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions ]

    .
  • Instruct patients not to use BUTRANS if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut BUTRANS.
  • Instruct patients to avoid exposing BUTRANS to external heat sources, hot water, or prolonged direct sunlight
    [see Warnings and Precautions ]
    .

  BUTRANS is for transdermal use (on intact skin) only. Each BUTRANS patch is intended to be worn for 7 days.
  )
• Do not abruptly discontinue BUTRANS in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.5 Safe Reduction or Discontinuation of BUTRANS

  Do not abruptly discontinue BUTRANS 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 a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking BUTRANS, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTRANS) the patient has been taking, 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 a 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 a specialist.

  There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on BUTRANS who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

  It may be necessary to provide the patient with lower dosage strengths to accomplish a 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 a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate 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 an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A 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 , Drug Abuse and Dependence ]

  .
  )

BUTRANS is a rectangular or square, beige-colored system consisting of a protective liner and functional layers. BUTRANS is available in five strengths:

• BUTRANS 5 mcg/hour Transdermal System (dimensions: 45 mm by 45 mm)
• BUTRANS 7.5 mcg/hour Transdermal System (dimensions: 58 mm by 45 mm)
• BUTRANS 10 mcg/hour Transdermal System (dimensions: 45 mm by 68 mm)
• BUTRANS 15 mcg/hour Transdermal System (dimensions: 59 mm by 72 mm)
• BUTRANS 20 mcg/hour Transdermal System (dimensions: 72 mm by 72 mm)

• Pregnancy
  : May cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome

  [see Warnings and Precautions ].

  Available data with BUTRANS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

  In animal reproduction studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD)

  [see Data].

  Based on animal data, advise pregnant women of the potential risk to a fetus.

  The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  Fetal/neonatal adverse reactions

  
  
  Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

  [see Warnings and Precautions ].

  Labor and Delivery

  
  
  Opioids cross the placenta and may produce respiratory depression in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. BUTRANS is not recommended for use in women immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including BUTRANS, 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.

  Data

  Animal Data

  Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or subcutaneous (SC) administration of buprenorphine during the period of organogenesis. Rats were administered up to one BUTRANS 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6 to 17). Rabbits were administered four BUTRANS 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, 15, 18, and 19) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with BUTRANS application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour.

  In a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as BUTRANS or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant rats were administered 1/4 of one BUTRANS 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from Gestation Day 6 to Lactation Day 21 (weaning). Administration of BUTRANS or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring.
  )
• Lactation
  : Not recommended (
  8.2 Lactation

  Risk Summary

  Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with BUTRANS.

  Clinical Considerations

  Monitor infants exposed to BUTRANS through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.
  ).
• Severe Hepatic Impairment
  : Consider use of an alternate analgesic that may permit more flexibility in dosing. (
  8.6 Hepatic Impairment

  In a study utilizing intravenous buprenorphine, peak plasma levels (C_max) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment

  [see Dosage and Administration and Clinical Pharmacology ].
  )