Drug Safety-related Labeling Changes (SrLC)

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BUTRANS (NDA-021306)

(BUPRENORPHINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2025 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

. . .

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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2).

. . .

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 overdose reversal agents, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

. . .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1, 5.3)].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the- counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

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, gabapentinoids [gabapentin and pregabalin], and other opioids).

Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

. . .

If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

. . .

5.15 Risks of Gastrointestinal Conditions

Subsection title revised

Additions and/or revisions underlined:

. . .

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases.

Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non- cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

5.19 Withdrawal

Additions and/or revisions underlined:

Do not rapidly reduce or 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 (2.5), Drug Abuse and Dependence (9.3)].

. . .

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.15)].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long- acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid- involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code- based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose- related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

7 Drug Interactions

Additions and/or revisions underlined:

. . .

Table 5: Clinically Significant Drug Interactions with BUTRANS

. . .

Additions and/or revisions underlined for Intervention section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)].

Additions and/or revisions underlined for Examples section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.

Additions and/or revisions underlined for Intervention section of Muscle Relaxants of table; please refer to table for complete information:

Because respiratory depression may be greater than otherwise expected, decrease the dosage of BUTRANS and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)].

Newly added Examples section of Muscle Relaxants of table; please refer to table for complete information:

Cyclobenzaprine, metaxalone

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

. . .

Clinical Considerations

. . .

Labor and Delivery

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, 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.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Important information about BUTRANS:

• Get emergency help or call 911 right away if you take too much BUTRANS (overdose). When you first start using BUTRANS, when your dose is changed, or if you use too much (overdose), serious or life- threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.
• Using BUTRANS with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
• Never give anyone else your BUTRANS. They could die from using it. Selling or giving away BUTRANS is against the law.
• Store BUTRANS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

. . .

Tell your healthcare provider if you are:

• noticing your pain getting worse. If your pain gets worse after you use BUTRANS, do not use more of BUTRANS without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after using BUTRANS.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Interaction with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if BUTRANS is used with benzodiazepines or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3)].

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage (10)].

Advise patients and caregivers:

• how to treat with the overdose reversal agent in the event of an opioid overdose.
• to tell family and friends about the opioid overdose reversal agent and to keep it in a place where family and friends can access it in an emergency.
• to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

. . .

12/15/2023 (SUPPL-41)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTRANS

Addiction, Abuse, and Misuse

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

…

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

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.

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

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

…

5.9 Opioid-Induced Hyperalgesia and Allodynia

New subsection added:

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 (9.3)].

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 (2.5), Warnings and Precautions (5.19)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

…

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Tell your healthcare provider if you are:

• noticing your pain getting worse. If your pain gets worse after you take BUTRANS, do not more of BUTRANS without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking BUTRANS.

  …

06/17/2022 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 QTc Prolongation

Newly added subsection

Thorough QT studies with buprenorphine products have demonstrated QT prolongation < or equal to 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.

03/04/2021 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… Patients at increased risk may be prescribed opioids such as BUTRANS, but use in such patients necessitates intensive counseling about the risks and proper use of BUTRANS along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Accidental ingestion of even one dose of BUTRANS, especially by 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 [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in 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 (2.5)].

Newly added information:

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 [see Patient Counseling Information (17)].

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 Warnings and Precautions (5.1, 5.5), Patient Counseling Information (17)].

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

7 Drug Interactions

Table 5: Clinically Significant Drug Interactions with BUTRANS

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.5)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.5)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Important information about BUTRANS:

Additions and/or revisions underlined:

• Get emergency help or call 911 right away if you take too much BUTRANS (overdose). When you first start taking BUTRANS, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.

Before taking BUTRANS, tell your healthcare provider if you have a history of:

• abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

• living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have: …

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with 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) [see Dosage and Administrations (2.2), Warnings and Precautions (5.4)].Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

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.

Additions and/or revisions underlined:

5.14 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.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Table 5: Significant Drug Interactions with BUTRANS

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about BUTRANS:

• Store BUTRANS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

When using BUTRANS:

• Dispose of expired, unwanted, or unused BUTRANS by using the Patch-Disposal Unit. Alternatively, BUTRANS can be disposed of by folding the patch in half and promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store BUTRANS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving BUTRANS unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.

BUTRANS patches can be disposed of by using the Patch- Disposal Unit. Alternatively, expired, unwanted, or unused BUTRANS should be disposed of by folding the patch in half and flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Newly added titled section:

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue BUTRANS without first discussing a tapering plan with the prescriber.

09/18/2018 (SUPPL-34)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: ADDICTION, ABUSE and MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

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 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

• complete a REMS-compliant education program,

• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,

• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and

• consider other tools to improve patient, household, and community safety.

5 Warnings and Precautions

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

(Additions and/or revisions are underlined)

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.

10/13/2017 (SUPPL-27)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

The safety and efficacy of BUTRANS in patients under 18 years of age has not been established. BUTRANS has been evaluated in an open-label clinical trial in pediatric patients. However, definitive conclusions are not possible because of the small sample size.

12/16/2016 (SUPPL-24)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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

Addiction, Abuse, and Misuse

…Assess each patient’s risk prior to prescribing BUTRANS, and monitor all patients regularly for the development of these behaviors and conditions

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

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

4 Contraindications

(Additions and/or revisions are underlined)

BUTRANS is contraindicated in patients with:

• Known or suspected gastrointestinal obstruction, including paralytic ileus

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(Additions and/or revisions are underlined)

…Because extended-release products such as BUTRANS deliver the opioid over an extended period of time…

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BUTRANS, and monitor all patients receiving BUTRANS for the development of these behaviors and conditions…

5.13 Risks of Use with Application of External Heat

(Revised subsection title)

5.14 Risk of Use in Patients with Fever

(Revised subsection title)

5.15 Risks of Use in Patients with Gastrointestinal Conditions

(Revised subsection title; Additions and/or revisions are underlined)

BUTRANS is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus…

5.16 Increased Risk of Seizures in Patients with Seizure Disorders

(Revised subsection title; Additions and/or revisions are underlined)

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…

5.17 Risks of Driving and Operating Machinery

(Revised subsection title)

5.2 Life-Threatening Respiratory Depression

(Additions and/or revisions are underlined)

…Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of BUTRANS.

5.3 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions are underlined)

…Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly…

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Revised subsection title; Additions and/or revisions are underlined)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BUTRANS with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

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.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when BUTRANS is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(Revised subsection title; Additions and/or revisions are underlined)

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.

5.6 Adrenal Insufficiency

(Newly added subsection)

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.

5.7 QTc Prolongation

(Additions and/or revisions are underlined)

…Avoid the use of BUTRANS in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QTc interval.

5.8 Severe Hypotension

(Revised subsection title; Additions and/or revisions are underlined)

…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.

5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness

(Revised subsection title)

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described elsewhere in the labeling:

• Interactions with Benzodiazepines or Other CNS Depressants
• Adrenal Insufficiency
• QTc Prolongation
• Severe Hypotension
• Hepatotoxicity

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in BUTRANS.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

7 Drug Interactions

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Table 5 Includes clinically significant drug interactions with BUTRANS. (Table has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.

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

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

 

Clinical Considerations

Fetal/neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight…Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

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

8.2 Lactation

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

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.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

8.5 Geriatric Use

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…Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of BUTRANS slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Interaction with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if BUTRANS is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider

Interaction with Benzodiazepines

Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician.

Serotonin Syndrome

Inform patients that OPIOIDS could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

MAOI Interaction

Inform patients to avoid taking BUTRANS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking BUTRANS.

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

Important Administration Instructions

Instruct patients how to properly use BUTRANS, including the following:

3.   To avoid exposing the BUTRANS application site to external heat sources, hot water, or prolonged direct sunlight

4.   Do not discontinue BUTRANS without first discussing the need for a tapering regimen with the prescriber

Pregnancy

Embryofetal Toxicity

Inform female patients of reproductive potential that BUTRANS can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise patients that breastfeeding is not recommended during treatment with BUTRANS.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Medication Guide

(Additions and/or revisions are underlined)

Important information about BUTRANS:

• Taking BUTRANS with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

Tell your healthcare provider if you:

• are breastfeeding. Not recommended during treatment with BUTRANS…

When using BUTRANS:

• Do not change your dose. Apply BUTRANS exactly as prescribed by your healthcare provider. Use the lowest effective dose for the shortest time needed.

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.