Drug Safety-related Labeling Changes (SrLC)

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SUBOXONE (NDA-022410)

(BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE)

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

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12/22/2025 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

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) and discuss the importance of having access to an opioid overdose reversal agent.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with SUBOXONE sublingual film. Also consider recommending or prescribing such an agent if the patient has householdmembers (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.2)].

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.

Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of an opioid overdose reversal agent may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage (10)].

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.

5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) increases the risk of adverse reactions including overdose, respiratory depression, and death.

…

If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

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.

7 Drug Interactions

Changes to Table 4. Clinically Significant Drug Interactions; please refer to label for complete information

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

• Inform patients and caregivers that potentially fatal additive effects may occur if SUBOXONE sublingual film is used with benzodiazepines or other CNS depressants (e.g., alcohol, 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 (5.2, 5.3), Drug Interactions (7)].

• 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 (5.2)].

• 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) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to an opioid overdose reversal agent. Also discuss the importance of having access to an opioid overdose reversal agent 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 (some products), or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

There are important differences among the opioid overdose reversal agents. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

…

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. Repeat administration may be necessary, particularly for overdose involving buprenorphine [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is the most important information I should know about SUBOXONE sublingual film?

• SUBOXONE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and lifethreatening breathing problems, especially if you take or use certain other medicines or drugs.

• Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse opioid overdose, including accidental use of SUBOXONE sublingual film by a child. If naloxone or nalmefene is given, you must call 911 or get emergency medical help right away to treat an overdose oraccidental use of an opioid.

…

• Do not take SUBOXONE with certain medicines. Taking SUBOXONE with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous systemdepressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

…

SUBOXONE sublingual film can cause serious side effects, including:

• Trouble breathing. Taking SUBOXONE with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause breathing problems that can lead to coma and death.

…

05/19/2025 (SUPPL-56)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Dose Adjustment during Pregnancy and the Postpartum Period

Dosage adjustments of buprenorphine, such as using higher doses, may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Dosing should be based on individual response, and withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

…

12/15/2023 (SUPPL-52)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

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).

06/17/2022 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Dental Adverse Events

Newly added subsection:

Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss.

Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking SUBOXONE. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after SUBOXONE has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking SUBOXONE before brushing teeth [see Dosing and Administration (2.6), Information for Patients (17), Medication Guide].

5.14 QTc Prolongation

Newly added subsection:

Thorough QT studies with buprenorphine products have demonstrated QT prolongation less than 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 SUBOXONE sublingual film 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.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Local reactions: Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis

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

MEDICATION GUIDE

Additions and/or revisions underlined:

Before taking SUBOXONE, tell your healthcare provider about all your medical conditions, including if you have:

…

• tooth problems, including a history of cavities

How should I take SUBOXONE sublingual film?

…

• After SUBOXONE is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.

• Report any problems with your teeth immediately to your healthcare provider and schedule an appointment with a dentist. Tell your dentist that you have started taking SUBOXONE.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

• Advise patients that, after SUBOXONE has completely dissolved in the oral mucosa, to take a sip of water, swish it gently around their teeth and gums, and swallow. Advise patients to wait for at least one hour after taking SUBOXONE before brushing teeth [see Warnings and Precautions (5.13)].

• Refer patients to dental care services and encourage them to have regular dental checkups while taking SUBOXONE. Instruct patients to inform their dentist that they have started therapy on SUBOXONE [see Warnings and Precautions (5.13)].

…

03/04/2021 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

Use SUBOXONE sublingual film with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre? existing respiratory depression).

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 (2.9)].

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.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBOXONE sublingual film. Also consider

prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.3)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with SUBOXONE sublingual film itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of SUBOXONE sublingual film and its affinity for the mu receptor [see Overdosage (10)].

Inform patients and caregivers of their options for obtaining 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, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

5.3 Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.2)].

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, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.23, Warnings and Precautions (5.2, 5.3)]

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

MEDICATION GUIDE

IMPORTANT:

Additions and/or revisions underlined:

Keep SUBOXONE sublingual film in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally takes SUBOXONE sublingual film, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children.

What is the most important information I should know about SUBOXONE sublingual film?

• SUBOXONE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life?threatening breathing problems, especially if you take or use certain other medicines or drugs. Call your doctor right away or get emergency help if:

  • You feel faint, dizzy, or confused …

• Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of SUBOXONE sublingual film by a child.

PATIENT COUNSELING INFORMATION

Safe Use

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 (5.2)].

• Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

  Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

  Inform patients and caregivers of the options for obtaining 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 the signs and symptoms of an opioid 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. Repeat administration may be necessary, particularly for overdose involving SUBOXONE sublingual film, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.2), 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.

10/30/2019 (SUPPL-34)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

(changes made to Medication Guide to be consistent with the medicaltion Guide for Sublocade, also additions underlined)

…

What is the most important information I should know about SUBOXONE sublingual film?

• Buprenorphine is a medicine in SUBOXONE sublingual film that can cause serious and life-threatening problems, especially if you take or use certain other medicines or drugs. Call your healthcare provider right away or get emergency help if you:

  
  

  
  

  • feel faint or dizzy   o         cannot think well or clearly

  • have mental changes such as confusion     o         have slowed reflexes

  • have slower breathing than you normally have       o         have a high body temperature

  • have severe sleepiness         o         feel agitated

  • have blurred vision o         have stiff muscles

  • have problems with coordination   o         have trouble walking

  • have slurred speech

     

    …

     

• Do not inject (“shoot-up”) or snort SUBOXONE sublingual fim

• Injecting SUBOXONE sublingual film  may cause life-threatening infections and other serious health problems.

• Crushing and/or dissolving SUBOXONE sublingual film  and then injecting it (“shooting up”) could cause serious precipitated withdrawal (sudden, serious, withdrawal symptoms such as pain, cramps, vomiting and diarrhea) in people who are physically dependent on other opioids.

  Snorting SUBOXONE sublingual film could cause precipitated withdrawal. In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBOXONE sublingual film.

10/07/2019 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) 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.

6 Adverse Reactions

Additions and/or revisions underlined:

6.2 Postmarketing Experience

Local reactions: Glossodynia, glossitis …

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions

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

Section has been reformatted; please refer to label for complete information.

Additions and/or revisions underlined in bulleted information:

What is the most important information I should know about SUBOXONE?

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

How should I dispose of unused SUBOXONE?

• SUBOXONE of expired, unwanted, or unused SUBOXONE by 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 SUBOXONE 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 SUBOXONE 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. Expired, unwanted, or unused SUBOXONE should be disposed of by 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.

02/01/2018 (SUPPL-31)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

SUBOXONE sublingual film is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Addiction, Abuse, and Misuse

SUBOXONE sublingual film contains buprenorphine, a Schedule III controlled substance that can be abused in a manner …

5.2 Risk of Respiratory and Central Nervous System (CNS) Depression

Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBOXONE sublingual film.

Use SUBOXONE sublingual film with caution in patients …

5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Newly added information:

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for

prescribed and illicit benzodiazepines.

5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation

Additions and/or revisions underlined:

The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. When discontinuing SUBOXONE sublingual film, gradually taper the dosage.

5.8 Risk of Hepatitis, Hepatic Events

5.9 Hypersensitivity Reactions

5.11 Risk of Overdose in Opioid Naïve Patients

… The doses of buprenorphine and naloxone in this fixed?dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function …

6 Adverse Reactions

Addition of the following:

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

• Addiction, Abuse, and Misuse
• Respiratory and CNS Depression
• Neonatal Opioid Withdrawal Syndrome
• Adrenal Insufficiency
• Opioid Withdrawal
• Hepatitis, Hepatic Events
• Hypersensitivity Reactions
• Orthostatic Hypotension
• Elevation of Cerebrospinal Fluid Pressure
• Elevation of Intracholedochal Pressure

6.1 Clinical Trials Experience

… The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX® (buprenorphine) sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials …

Table 3. Adverse Events (greater than or equal to 5%) by Body System and Treatment Group in a 16 Week Study

6.2 Postmarketing Experience

Newly added information:

Local reactions: Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

… In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risks of major birth defects and miscarriage for the indicated population are 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 …

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data on malformations from trials …

8.2 Lactation

Risk Summary

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and infant urine. Available data …

8.5 Geriatric Use

… Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBOXONE sublingual film should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

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

PATIENT COUNSELING INFORMATION

Safe Use

Additions and/or revisions underlined:

• SUBOXONE sublingual film must be administered whole. 

• Inform patients and caregivers that potentially fatal additive effects may occur if SUBOXONE sublingual film is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by their health care provider.

02/13/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions are underlined)

Advise pregnant women receiving opioid addiction treatment with SUBOXONE sublingual film of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Other adverse event data were derived from larger, controlled studies of SUBOXONE sublingual tablets and SUBUTEX sublingual tablets and of buprenorphine sublingual solution…

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SUBOXONE-sublingual film.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

(Additions and/or revisions are underlined)

The data on use of buprenorphine, one of the active ingredients in SUBOXONE sublingual film, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations. Observational studies have reported on congenital malformations among buprenorphine exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug associated risk.

Clinical Considerations

Dose Adjustment during Pregnancy and the Postpartum Period

Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBOXONE sublingual film.

Labor or Delivery

Opioid dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid?dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine containing products with respect to maternal factors that may lead to poor pregnancy outcomes.

In a multicenter, double blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between buprenorphine treated and methadone treated groups in the number of neonates requiring NOWS treatment or in the peakseverity of NOWS. Buprenorphine exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone?exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1?minute and 5?minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.

Animal Data

The exposure margins listed below are based on body surface area comparisons (mg/m ) to the human sublingual dose of 16 mg buprenorphine via SUBOXONE sublingual tablets.

Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human daily sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco?lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human daily sublingual dose of 16 mg)…

…Fertility, pre, and post natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human daily sublingual dose 16 mg)…

8.2 Lactation

Risk Summary

(Additions and/or revisions are underlined)

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants…

Clinical Considerations

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

Data

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight?adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight?adjusted dose.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

• Inform patients that SUBOXONE sublingual film 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.
• Inform patients that SUBOXONE sublingual film could cause adrenal insufficiency, a potentially life? threatening condition…
• Patients should be advised that if they miss a dose of SUBOXONE sublingual film they should take it as soon as they remember…
• Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

MEDICATION GUIDE SUBOXONE® (Sub?OX?own) (buprenorphine and naloxone) Sublingual Film for Sublingual or Buccal Administration (CIII)

(Additions and/or revisions are underlined)

IMPORTANT:

Keep SUBOXONE sublingual film in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses SUBOXONE sublingual film, get emergency help right away.

Read this Medication Guide that comes with SUBOXONE® (buprenorphine and naloxone) sublingual film before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor. Talk to your doctor or pharmacist if you have questions about SUBOXONE sublingual film.

What is the most important information I should know about SUBOXONE sublingual film?

• SUBOXONE sublingual film can cause serious and life?threatening breathing problems...

• Do not switch from SUBOXONE sublingual film to other medicines that contain buprenorphine without talking with your doctor. The amount of buprenorphine in a dose of SUBOXONE sublingual film is not the same as the amount of buprenorphine in other medicines that contain buprenorphine. Your doctor will prescribe a starting dose of SUBOXONE sublingual film that may be different than other buprenorphine containing medicines you may have been taking.

• SUBOXONE sublingual film contains an opioid that can cause physical dependence.
• Do not stop taking SUBOXONE sublingual film without talking to your doctor. You could become sick with uncomfortable withdrawal signs and symptoms because your body has become used to this medicine.       
• SUBOXONE sublingual film is not for occasional or “as needed” use.
• An overdose and even death can happen if you take benzodiazepines, sedatives, tranquilizers, antidepressants, or alcohol while using SUBOXONE sublingual film.
• Do not inject (“shoot?up”) SUBOXONE sublingual film.
• In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBOXONE sublingual film.

What is SUBOXONE sublingual film?

• SUBOXONE sublingual film is a prescription medicine used to treat adults who are addicted to (dependent on) opioid drugs (either prescription or illegal) as part of a complete treatment program that also includes counseling and behavioral therapy.
• It is not known if SUBOXONE sublingual film is safe or effective in children.

Who should not take SUBOXONE sublingual film?

• Do not take SUBOXONE sublingual film if you are allergic to buprenorphine or naloxone.

What should I tell my doctor before taking SUBOXONE sublingual film?

SUBOXONE sublingual film may not be right for you. Before taking SUBOXONE sublingual film, tell your doctor if you… 

• Are pregnant or plan to become pregnant. If you take SUBOXONE sublingual film while pregnant, your baby may have signs of opioid withdrawal at birth. Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy…

• Are breastfeeding or plan to breastfeed. The active ingredients of SUBOXONE sublingual film can pass into your milk and may harm your baby. Talk to your doctor about the best way to feed your baby if you take SUBOXONE sublingual film…

Tell your doctor about all the medicines you take, including prescription and over?the?counter medicines, vitamins, and herbal supplements. SUBOXONE sublingual film may affect the way other medicines work, and other medicines may affect how SUBOXONE sublingual film works. Some medicines may cause serious or life?threatening medical problems when taken with SUBOXONE sublingual film.

Sometimes the doses of certain medicines and SUBOXONE sublingual film may need to be changed if used together. Do not take any medicine while using SUBOXONE sublingual film until you have talked with your doctor. Your doctor will tell you if it is safe to take other medicines while you are taking SUBOXONE sublingual film.

How should I take SUBOXONE sublingual film?

• Always take SUBOXONE sublingual film exactly as your doctor tells you. Your doctor may change your dose after seeing how it affects you. Do not change your dose unless your doctor tells you to change it.
• Do not take SUBOXONE sublingual film more often than prescribed by your doctor.
• Take SUBOXONE sublingual film 1 time a day.
• After a few days, you can choose whether you will take SUBOXONE sublingual film on the inside of your cheek (buccal administration) or by sublingual administration.
• Your doctor should show you how to take SUBOXONE sublingual film the right way.

 To take SUBOXONE sublingual film on the inside of your cheek (buccal administration):

• If you miss a dose of SUBOXONE sublingual film, take your medicine when you remember…
• Do not stop taking SUBOXONE sublingual film suddenly…To have fewer withdrawal symptoms, ask your doctor how to stop using SUBOXONE sublingual film the right way.
• If you take too much SUBOXONE sublingual film or overdose, call Poison Control or get emergency medical help right away.

 What should I avoid while taking SUBOXONE sublingual film?

• Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how this medication affects you. Buprenorphine can cause drowsiness and slow reaction times. This may happen more often in the first few weeks of treatment when your dose is being changed, but can also happen if you drink alcohol or take other sedative drugs when you take SUBOXONE sublingual film.
• You should not drink alcohol while using SUBOXONE sublingual film, as this can lead to loss of consciousness or even death.

 What are the possible side effects of SUBOXONE sublingual film? SUBOXONE sublingual film can cause serious side effects, including:

• See “What is the most important information I should know about SUBOXONE sublingual film?”
• Respiratory problems. You have a higher risk of death and coma if you take SUBOXONE sublingual film with other medicines, such as benzodiazepines.

• Liver problems. Call your doctor right away if you notice any of these signs of liver problems:...Your doctor should do tests before you start taking and while you take SUBOXONE sublingual film.