Belbuca (Buprenorphine Hydrochloride)

Check Drug InteractionsCheck known drug interactions.

Dosage & administration

* BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (

2.1 Important Dosage and Administration Instructions

* BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
* Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

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

[see Warnings and Precautions (5.1)]

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

[see Warnings and Precautions (5.2)]

.
* BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
* Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.

)
* Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks (

2.1 Important Dosage and Administration Instructions

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)]

5 WARNINGS AND PRECAUTIONS

Opioid-Induced Hyperalgesia and Allodynia

: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. .
*

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

: Regularly evaluate, particularly during initiation and titration.
*

Adrenal Insufficiency

: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
*

Severe Hypotension

: Regularly evaluate during dose initiation and titration. Avoid use of BELBUCA in patients with circulatory shock.
*

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors

Head Injury, or Impaired Consciousness

: Monitor for sedation and respiratory depression. Avoid use of BELBUCA in patients with impaired consciousness or coma.

5.1 Addiction, Abuse, and Misuse

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

[see Drug Abuse and Dependence (9)]

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA. Addiction can occur at recommended dosages 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 BELBUCA and reassess all patients receiving BELBUCA 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 BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, 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)].

Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death

[see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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.

While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.

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

[see Dosage and Administration (2)]

. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.

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

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

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

[see Dosage and Administration (2.5)].

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

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or 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.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

[see Drug Interactions (7)]

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on 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 (5.2), Overdosage (10)]

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

[see Drug Interactions (7)]

5.4 Neonatal Opioid Withdrawal Syndrome

Use of BELBUCA for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

[see Use in Specific Populations (8.1)]

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

* Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
* Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
* Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
* Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.6 Opioid-Induced Hyperalgesia and Allodynia

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

see Dependence (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 (5.17)

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

The use of BELBUCA 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

: BELBUCA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with 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 BELBUCA

[see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients

: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

[see Warnings and Precautions (5.2)]

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

[see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)].

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

5.8 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.9 Severe Hypotension

BELBUCA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

[see Drug Interactions (7)].

Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of BELBUCA. In patients with circulatory shock, BELBUCA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA in patients with circulatory shock.

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

In patients who may be susceptible to the intracranial effects of CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with BELBUCA.

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

5.11 Hepatotoxicity

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in postmarketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and periodically reassess during treatment with BELBUCA.

5.12 Risk of Gastrointestinal Complications

BELBUCA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

BELBUCA may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

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)]

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The buprenorphine in BELBUCA may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BELBUCA therapy.

5.14 Dental Adverse Events

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 BELBUCA. 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 BELBUCA has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking BELBUCA before brushing teeth [

see Dosing and Administration (2.8)

5.15 QTc Prolongation

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

Consider these observations in clinical decisions when prescribing BELBUCA 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

[see Dosage and Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

5.16 Anaphylactic/Allergic Reactions

Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. BELBUCA is contraindicated in patients with a history of hypersensitivity to buprenorphine.

5.17 Withdrawal

Do not rapidly reduce or abruptly discontinue BELBUCA in a patient physically dependent on opioids. When discontinuing BELBUCA 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)]

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

5.18 Risks of Driving and Operating Machinery

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

5.19 Risk of Overdose in Patients with Moderate to Severe Hepatic Impairment

In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be periodically assessed for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine

[see Dosage and Administration (2.6), Use in Specific Populations (8.6)]

5.20 Risks of Use in Cancer Patients with Oral Mucositis

Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid. For patients with known or suspected mucositis, a dose reduction is recommended. Regularly evaluate these patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine

[see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]

)
* Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (

2.1 Important Dosage and Administration Instructions

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)]

5.1 Addiction, Abuse, and Misuse

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

[see Drug Abuse and Dependence (9)]

see Adverse Reactions (6.2)

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death

[see Overdosage (10)].

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

2.1 Important Dosage and Administration Instructions

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)]

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

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

While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.

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

[see Dosage and Administration (2)]

. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.

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

[see Dosage and Administration (2.5)].

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

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).

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)

).
* Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with BELBUCA, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (

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

see Warnings and Precautions (5.1, 5.2, 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) [

see Warnings and Precautions (5.2)

5.1 Addiction, Abuse, and Misuse

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

[see Drug Abuse and Dependence (9)]

see Adverse Reactions (6.2)

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death

[see Overdosage (10)].

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

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

While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.

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

[see Dosage and Administration (2)]

. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.

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

[see Dosage and Administration (2.5)].

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

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).

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

[see Drug Interactions (7)]

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)]

[see Drug Interactions (7)]

)
*

BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours. (

2.1 Important Dosage and Administration Instructions

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)]

)

Patients who are not Opioid Tolerant:

Initiate therapy with 75 mcg BELBUCA once daily or every 12 hours, as tolerated, for at least 4 days before increasing dose to 150 mcg every 12 hours. (

2.3 Initial Dosage

It is safer to underestimate a patient's 24-hour oral buprenorphine dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour buprenorphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to BELBUCA.

Use of BELBUCA in Patients who are not Opioid Tolerant

Initiate treatment in patients who are not opioid tolerant with a 75 mcg film once daily or, if tolerated, every 12 hours (see Table 1) for at least 4 days, then increase dose to 150 mcg every 12 hours. Individual titration to a dose that provides adequate analgesia and minimizes adverse reactions should proceed in increments of 150 mcg every 12 hours, no more frequently than every 4 days. Doses up to 450 mcg every 12 hours were studied in patients who were not opioid tolerant in the clinical trials

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

* There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
* BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
* There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

BELBUCA doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of BELBUCA. Individual titration should proceed in increments of 150 mcg every 12 hours, no more frequently than every 4 days.

Conversion from Methadone to BELBUCA

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

)
*

Conversion from Other Opioid Analgesics to BELBUCA

: Taper current daily opioid dose to 30 mg oral morphine sulfate equivalents (MSE) or less prior to initiating therapy with BELBUCA. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)
* For patients taking less than 30 mg oral MSE, initiate therapy with 75 mcg once daily or every 12 hours. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)
* For patients taking between 30 mg and 89 mg oral MSE, initiate therapy with 150 mcg BELBUCA every 12 hours following analgesic taper. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)
* For patients taking between 90 mg and 160 mg oral MSE, initiate therapy with 300 mcg BELBUCA every 12 hours following analgesic taper. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)
* For patients taking greater than 160 mg oral MSE, consider alternate analgesic. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

* BELBUCA doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of BELBUCA. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

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

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)
*

Patients with Severe Hepatic Impairment

: Reduce the starting and incremental dose by half that of patients with normal liver function. (

2.6 Dosage Modifications in Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment (i.e., Child-Pugh C), reduce the starting dose and reduce the titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg

[see Warnings and Precautions (5.19), Use in Special Populations (8.6), Clinical Pharmacology (12.3)].

5.19 Risk of Overdose in Patients with Moderate to Severe Hepatic Impairment

[see Dosage and Administration (2.6), Use in Specific Populations (8.6)]

8.6 Hepatic Impairment

BELBUCA has not been evaluated in patients with severe hepatic impairment.

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended

[see Dosage and Administration (2.6)]

. Regularly evaluate patients with severe hepatic impairment for signs and symptoms of overdose. A dosage reduction in patients with moderate hepatic impairment (Child-Pugh B) is not needed; however, regularly evaluate these patients for signs and symptoms of toxicity or overdose. A dosage reduction in patients with mild hepatic impairment (Child-Pugh A) is not needed

[see Dosage and Administration (2.6), Warnings and Precautions (5.19), Clinical Pharmacology (12.3)]

)
*

Patients with Oral Mucositis

: Reduce the starting and incremental dose by half that of patients without mucositis. (

2.7 Dosage Modifications in Patients with Oral Mucositis

In patients with known or suspected mucositis, reduce the starting dosage and titration incremental dosage by half compared to patients without mucositis

[see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)].

5.20 Risks of Use in Cancer Patients with Oral Mucositis

[see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]

)
* Periodically reassess patients receiving BELBUCA to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (

2.4 Titration and Maintenance of Therapy

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

[see Warnings and Precautions (5.1, 5.17)]

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

Patients who experience breakthrough pain may require dosage adjustment of BELBUCA or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the BELBUCA dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

[see Warnings and Precautions (5)]

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

The minimum titration interval of BELBUCA is 4 days, based on the pharmacokinetic profile and time to reach steady-state plasma levels

[see Clinical Pharmacology (12.3)].

Individual titration should proceed in increments of no more than 150 mcg every 12 hours.

The maximum BELBUCA dose is 900 mcg every 12 hours.

Do not exceed a dose of BELBUCA 900 mcg every 12 hours due to the potential for QTc interval prolongation

[see Warnings and Precautions (5.15), Adverse Reactions (6.1), Clinical Pharmacology (12.2)]

. If pain is not adequately managed on BELBUCA 900 mcg, consider an alternate analgesic.

)
* Do not rapidly reduce or abruptly discontinue BELBUCA in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (

2.5 Safe Reduction or Discontinuation of BELBUCA

Do not rapidly reduce or abruptly discontinue BELBUCA in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking BELBUCA, there are a variety of factors that should be considered, including the total daily dose of opioid (including BELBUCA) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication-assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

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

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

[see Warnings and Precautions (5.17), Drug Abuse and Dependence (9.3)]

5.17 Withdrawal

[see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)]

)

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Belbuca prescribing information

WARNING: SERIOUS LIFE-THREATENING RISKS FROM USE OF BELBUCA

See full prescribing information for complete boxed warning.

BELBUCA exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (
5.1 Addiction, Abuse, and Misuse
BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA. Addiction can occur at recommended dosages 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 BELBUCA and reassess all patients receiving BELBUCA 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 BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, 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)].
Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk 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.
)
Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential. Instruct patients on proper administration of BELBUCA to reduce the risk. (
2.1 Important Dosage and Administration Instructions
BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)]
.
BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
,
2.8 Administration of BELBUCA
BELBUCA should not be used if the package seal is broken or the film is cut, damaged, or changed in any way.
First, the patient must use the tongue to wet the inside of the cheek or rinse the mouth with water to wet the area for placement of BELBUCA. BELBUCA is then applied immediately after removal from the individually sealed package. The yellow side of the BELBUCA film is placed against the inside of the cheek. The entire BELBUCA film is held in place with clean, dry fingers for 5 seconds and then left in place on the inside of the cheek until fully dissolved.
BELBUCA adheres to the moist buccal mucosa and will completely dissolve after application, usually within 30 minutes. The film should not be manipulated with the tongue or finger(s) and eating food and drinking liquids should be avoided until the film has dissolved.
Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow. Advise patients to wait for at least one hour after taking BELBUCA before brushing teeth [
see Warnings and Precautions (5.14), Adverse Reactions (6.2)
].
A BELBUCA film, if chewed or swallowed, may result in lower peak concentrations and lower bioavailability than when used as directed
.
Demonstrate proper administration technique to the patient
.
,
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.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential
[see Dosage and Administration (2)]
. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.
Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].
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)
].
)
Accidental exposure to BELBUCA, especially in children, can result in fatal overdose of buprenorphine. (
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.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential
[see Dosage and Administration (2)]
. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.
Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].
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)
].
)

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 for use in patients for whom alternative treatment options are inadequate. (

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

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)]

[see Drug Interactions (7)]

7 DRUG INTERACTIONS

Table 5 includes clinically significant drug interactions with BELBUCA.

Table 5: Clinically Significant Drug Interactions
Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Regularly evaluate patients with concurrent use of BELBUCA and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA and warn patients to use benzodiazepines concurrently with BELBUCA only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3)] .
Intervention:	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)] .
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin),, other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of BELBUCA and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BELBUCA is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of BELBUCA until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of BELBUCA and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the BELBUCA dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BELBUCA dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue BELBUCA if serotonin syndrome is suspected.
Examples:	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 inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of BELBUCA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of BELBUCA and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Because respiratory depression may be greater than otherwise expected, decrease the dosage of BELBUCA 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)] .
Examples:	cyclobenzaprine, metaxalone
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Evaluate patients for signs of urinary retention or reduced gastric motility when BELBUCA is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	If prescribing an NNRTI to a patient taking BELBUCA frequently reevaluate for this interaction and adjust dosing as necessary.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Evaluate patients taking BELBUCA and atazanavir with and without ritonavir and reduce the dose of BELBUCA if warranted.
Examples:	atazanavir, ritonavir

Benzodiazepines
: May increase buprenorphine-induced respiratory depression. Regularly evaluate patients on concurrent therapy closely.
CYP3A4 Inhibitors/Inducers
: Initiating CYP3A4 inhibitors or discontinuing CYP3A4 inducers may result in an increase in buprenorphine plasma concentrations. Evaluate patients starting CYP3A4 inhibitors or stopping CYP3A4 inducers at frequent intervals for respiratory depression.
Serotonergic Drugs
: Concomitant use may result in serotonin syndrome. Discontinue BELBUCA if serotonin syndrome is suspected.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
: Avoid use with BELBUCA because they may reduce analgesic effect of BELBUCA or precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs)
: Can potentiate the effects of buprenorphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI.

)

Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (
5.4 Neonatal Opioid Withdrawal Syndrome
Use of BELBUCA for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations (8.1)]
.
)
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
)

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

WARNING: SERIOUS LIFE-THREATENING RISKS FROM USE OF BELBUCA

See full prescribing information for complete boxed warning.

BELBUCA exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions.
Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential. Instruct patients on proper administration of BELBUCA to reduce the risk.
Accidental exposure to BELBUCA, especially in children, can result in fatal overdose of buprenorphine.
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 for use in patients for whom alternative treatment options are inadequate.
Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.

Addiction, Abuse, and Misuse

Because the use of BELBUCA 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)]

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of BELBUCA, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential. Misuse or abuse of BELBUCA by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death

[see Dosage and Administration (2.1, 2.8), Warnings and Precautions (5.2)]

Accidental Exposure

Accidental exposure of even one dose of BELBUCA, especially in children, can result in a fatal overdose of buprenorphine

[see Warnings and Precautions (5.2)]

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 BELBUCA and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate

[see Warnings and Precautions (5.3), Drug Interactions (7)]

Neonatal Opioid Withdrawal Syndrome (NOWS)

Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery

[see Warnings and Precautions (5.4)]

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription

[see Warnings and Precautions (5.5)]

12/2025

Indications and Usage (

1 INDICATIONS AND USAGE

BELBUCA is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

BELBUCA buccal film contains buprenorphine, a partial opioid agonist. BELBUCA is indicated for the management of severe and persistent pain that requires an opioid analgesic that cannot be adequately treated with alternative options, including immediate-release opioids.

Limitations of Use

Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including BELBUCA, for use in patients for whom alternative treatment are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
BELBUCA is not indicated as an as-needed (prn) analgesic.

Limitations of Use

Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy
[see Warnings and Precautions (5.1)]
, reserve opioid analgesics, including BELBUCA, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
BELBUCA is not indicated as an as-needed (prn) analgesic.

)

12/2025

Dosage and Administration (

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

see Warnings and Precautions (5.1, 5.2, 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) [

see Warnings and Precautions (5.2)

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

2.5 Safe Reduction or Discontinuation of BELBUCA

[see Warnings and Precautions (5.17), Drug Abuse and Dependence (9.3)]

)

12/2025

Warnings and Precautions (

5.1 Addiction, Abuse, and Misuse

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

[see Drug Abuse and Dependence (9)]

see Adverse Reactions (6.2)

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death

[see Overdosage (10)].

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

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

While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.

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

[see Dosage and Administration (2)]

. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.

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

[see Dosage and Administration (2.5)].

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

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).

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

[see Drug Interactions (7)]

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)]

[see Drug Interactions (7)]

5.12 Risk of Gastrointestinal Complications

BELBUCA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

[see Clinical Pharmacology (12.2)]

5.17 Withdrawal

[see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)]

)

12/2025

BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
2.1 Important Dosage and Administration Instructions
- BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)].
  Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)]
  .
- BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
- Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
)
Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks (
2.1 Important Dosage and Administration Instructions
- BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)].
  Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)]
  .
- BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
- Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
,
5 WARNINGS AND PRECAUTIONS
Opioid-Induced Hyperalgesia and Allodynia
: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. .
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
: Regularly evaluate, particularly during initiation and titration.
Adrenal Insufficiency
: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
Severe Hypotension
: Regularly evaluate during dose initiation and titration. Avoid use of BELBUCA in patients with circulatory shock.
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors
,
Head Injury, or Impaired Consciousness
: Monitor for sedation and respiratory depression. Avoid use of BELBUCA in patients with impaired consciousness or coma.
5.1 Addiction, Abuse, and Misuse
BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA. Addiction can occur at recommended dosages 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 BELBUCA and reassess all patients receiving BELBUCA 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 BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, 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)].
Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential
[see Dosage and Administration (2)]
. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.
Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].
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
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or 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.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
[see Drug Interactions (7)]
.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on 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 (5.2), Overdosage (10)]
. Advise both patients and caregivers about the risks of respiratory depression and sedation when BELBUCA is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
[see Drug Interactions (7)]
.
5.4 Neonatal Opioid Withdrawal Syndrome
Use of BELBUCA for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations (8.1)]
.
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
5.6 Opioid-Induced Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [
see Dependence (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 (5.17)
].
5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of BELBUCA 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
: BELBUCA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with 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 BELBUCA
[see Warnings and Precautions (5.2)].
Elderly, Cachectic, or Debilitated Patients
: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
[see Warnings and Precautions (5.2)]
.
Regularly evaluate patients, particularly when initiating and titrating BELBUCA and when BELBUCA is given concomitantly with other drugs that depress respiration
[see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)].
Alternatively, consider the use of non-opioid analgesics in these patients.
5.8 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
5.9 Severe Hypotension
BELBUCA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)
[see Drug Interactions (7)].
Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of BELBUCA. In patients with circulatory shock, BELBUCA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA in patients with circulatory shock.
5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with BELBUCA.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BELBUCA in patients with impaired consciousness or coma.
5.11 Hepatotoxicity
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in postmarketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and periodically reassess during treatment with BELBUCA.
5.12 Risk of Gastrointestinal Complications
BELBUCA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
BELBUCA may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
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)]
.
5.13 Increased Risk of Seizures in Patients with Seizure Disorders
The buprenorphine in BELBUCA may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BELBUCA therapy.
5.14 Dental Adverse Events
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 BELBUCA. 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 BELBUCA has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking BELBUCA before brushing teeth [
see Dosing and Administration (2.8)
].
5.15 QTc Prolongation
Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.
Consider these observations in clinical decisions when prescribing BELBUCA 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
[see Dosage and Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.2)].
5.16 Anaphylactic/Allergic Reactions
Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. BELBUCA is contraindicated in patients with a history of hypersensitivity to buprenorphine.
5.17 Withdrawal
Do not rapidly reduce or abruptly discontinue BELBUCA in a patient physically dependent on opioids. When discontinuing BELBUCA 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)]
.
Additionally, the use of BELBUCA, a partial agonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of BELBUCA with a full opioid agonist analgesic.
5.18 Risks of Driving and Operating Machinery
BELBUCA may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to side effects of BELBUCA and know how they will react to the medication.
5.19 Risk of Overdose in Patients with Moderate to Severe Hepatic Impairment
In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be periodically assessed for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine
[see Dosage and Administration (2.6), Use in Specific Populations (8.6)]
.
5.20 Risks of Use in Cancer Patients with Oral Mucositis
Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid. For patients with known or suspected mucositis, a dose reduction is recommended. Regularly evaluate these patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine
[see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]
.
)
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (
2.1 Important Dosage and Administration Instructions
- BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)].
  Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)]
  .
- BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
- Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
,
5.1 Addiction, Abuse, and Misuse
BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA. Addiction can occur at recommended dosages 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 BELBUCA and reassess all patients receiving BELBUCA 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 BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, 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)].
Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
)
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments. (
2.1 Important Dosage and Administration Instructions
- BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)].
  Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)]
  .
- BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
- Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
,
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.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential
[see Dosage and Administration (2)]
. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.
Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].
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)
].
).
Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with BELBUCA, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (
2.2 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). 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, 5.2, 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) [
see Warnings and Precautions (5.2)
].
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.
,
5.1 Addiction, Abuse, and Misuse
BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA. Addiction can occur at recommended dosages 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 BELBUCA and reassess all patients receiving BELBUCA 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 BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, 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)].
Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
,
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid 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.
While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential
[see Dosage and Administration (2)]
. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose.
Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.5)].
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
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or 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.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
[see Drug Interactions (7)]
.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on 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 (5.2), Overdosage (10)]
. Advise both patients and caregivers about the risks of respiratory depression and sedation when BELBUCA is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
[see Drug Interactions (7)]
.
)
BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours. (
2.1 Important Dosage and Administration Instructions
BELBUCA should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BELBUCA for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BELBUCA. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)]
.
BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa once daily or every 12 hours.
Instruct patients not to use BELBUCA if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying BELBUCA to areas of the mouth with any open sores or lesions.
)

Patients who are not Opioid Tolerant:

Initiate therapy with 75 mcg BELBUCA once daily or every 12 hours, as tolerated, for at least 4 days before increasing dose to 150 mcg every 12 hours. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

Conversion from Other Opioid Analgesics to BELBUCA

: Taper current daily opioid dose to 30 mg oral morphine sulfate equivalents (MSE) or less prior to initiating therapy with BELBUCA. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

For patients taking less than 30 mg oral MSE, initiate therapy with 75 mcg once daily or every 12 hours. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

For patients taking between 30 mg and 89 mg oral MSE, initiate therapy with 150 mcg BELBUCA every 12 hours following analgesic taper. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

For patients taking between 90 mg and 160 mg oral MSE, initiate therapy with 300 mcg BELBUCA every 12 hours following analgesic taper. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

For patients taking greater than 160 mg oral MSE, consider alternate analgesic. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

BELBUCA doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of BELBUCA. (

2.3 Initial Dosage

Use of BELBUCA in Patients who are not Opioid Tolerant

[see Clinical Studies (14)]

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Other Opioid Analgesics to BELBUCA

When BELBUCA therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient's daily opioid dose prior to taper, as described in Table 1. Patients may require additional short-acting analgesics during the taper period and during titration.
BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day. Consider the use of an alternate analgesic.
There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of BELBUCA.

In a BELBUCA clinical trial with an open-label titration period, patients were converted from their prior opioid to BELBUCA using Table 1 as a guide for the initial BELBUCA dose.

Table 1: Initial BELBUCA Dose Based on Prior Opioid Expressed as Oral Morphine Sulfate Equivalents
Prior Daily Dose of Opioid Analgesic Before Taper to 30 mg Oral MSE	Initial BELBUCA Dose
Less than 30 mg oral MSE	BELBUCA 75 mcg once daily or every 12 hours
30 mg to 89 mg oral MSE	BELBUCA 150 mcg every 12 hours
90 mg to 160 mg oral MSE	BELBUCA 300 mcg every 12 hours
Greater than 160 mg oral MSE	Consider alternate analgesic

Conversion from Methadone to BELBUCA

)

Patients with Severe Hepatic Impairment
: Reduce the starting and incremental dose by half that of patients with normal liver function. (
2.6 Dosage Modifications in Patients with Severe Hepatic Impairment
In patients with severe hepatic impairment (i.e., Child-Pugh C), reduce the starting dose and reduce the titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg
[see Warnings and Precautions (5.19), Use in Special Populations (8.6), Clinical Pharmacology (12.3)].
,
5.19 Risk of Overdose in Patients with Moderate to Severe Hepatic Impairment
In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be periodically assessed for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine
[see Dosage and Administration (2.6), Use in Specific Populations (8.6)]
.
,
8.6 Hepatic Impairment
BELBUCA has not been evaluated in patients with severe hepatic impairment.
The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.
Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended
[see Dosage and Administration (2.6)]
. Regularly evaluate patients with severe hepatic impairment for signs and symptoms of overdose. A dosage reduction in patients with moderate hepatic impairment (Child-Pugh B) is not needed; however, regularly evaluate these patients for signs and symptoms of toxicity or overdose. A dosage reduction in patients with mild hepatic impairment (Child-Pugh A) is not needed
[see Dosage and Administration (2.6), Warnings and Precautions (5.19), Clinical Pharmacology (12.3)]
.
)
Patients with Oral Mucositis
: Reduce the starting and incremental dose by half that of patients without mucositis. (
2.7 Dosage Modifications in Patients with Oral Mucositis
In patients with known or suspected mucositis, reduce the starting dosage and titration incremental dosage by half compared to patients without mucositis
[see Warnings and Precautions (5.20), Clinical Pharmacology (12.3)].
,
5.20 Risks of Use in Cancer Patients with Oral Mucositis
Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid. For patients with known or suspected mucositis, a dose reduction is recommended. Regularly evaluate these patients for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine
[see Dosage and Administration (2.7), Clinical Pharmacology (12.3)]
.
)
Periodically reassess patients receiving BELBUCA to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (
2.4 Titration and Maintenance of Therapy
Individually titrate BELBUCA to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving BELBUCA to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse
[see Warnings and Precautions (5.1, 5.17)]
. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.
Patients who experience breakthrough pain may require dosage adjustment of BELBUCA or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the BELBUCA dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage
[see Warnings and Precautions (5)]
. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
The minimum titration interval of BELBUCA is 4 days, based on the pharmacokinetic profile and time to reach steady-state plasma levels
[see Clinical Pharmacology (12.3)].
Individual titration should proceed in increments of no more than 150 mcg every 12 hours.
The maximum BELBUCA dose is 900 mcg every 12 hours.
Do not exceed a dose of BELBUCA 900 mcg every 12 hours due to the potential for QTc interval prolongation
[see Warnings and Precautions (5.15), Adverse Reactions (6.1), Clinical Pharmacology (12.2)]
. If pain is not adequately managed on BELBUCA 900 mcg, consider an alternate analgesic.
)
Do not rapidly reduce or abruptly discontinue BELBUCA in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
2.5 Safe Reduction or Discontinuation of BELBUCA
Do not rapidly reduce or abruptly discontinue BELBUCA in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking BELBUCA, there are a variety of factors that should be considered, including the total daily dose of opioid (including BELBUCA) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication-assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on BELBUCA who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic
[see Warnings and Precautions (5.17), Drug Abuse and Dependence (9.3)]
.
,
5.17 Withdrawal
Do not rapidly reduce or abruptly discontinue BELBUCA in a patient physically dependent on opioids. When discontinuing BELBUCA 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)]
.
Additionally, the use of BELBUCA, a partial agonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of BELBUCA with a full opioid agonist analgesic.
)

Dosage strengths of BELBUCA are based on the active moiety, buprenorphine.

The 75 mcg dosage form is a buccal film that contains 75 mcg buprenorphine. The film is white on one side, with E0 printed in black, and yellow on the other side.

The 150 mcg dosage form is a buccal film that contains 150 mcg buprenorphine. The film is white on one side, with E1 printed in black, and yellow on the other side.

The 300 mcg dosage form is a buccal film that contains 300 mcg buprenorphine. The film is white on one side, with E3 printed in black, and yellow on the other side.

The 450 mcg dosage form is a buccal film that contains 450 mcg buprenorphine. The film is white on one side, with E4 printed in black, and yellow on the other side.

The 600 mcg dosage form is a buccal film that contains 600 mcg buprenorphine. The film is white on one side, with E6 printed in black, and yellow on the other side.

The 750 mcg dosage form is a buccal film that contains 750 mcg buprenorphine. The film is white on one side, with E7 printed in black, and yellow on the other side.

The 900 mcg dosage form is a buccal film that contains 900 mcg buprenorphine. The film is white on one side, with E9 printed in black, and yellow on the other side.

Pregnancy
: May cause fetal harm. (
8.1 Pregnancy
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome
[see Warnings and Precautions (5.4)]
. There are no adequate and well-controlled studies of BELBUCA or buprenorphine in pregnant women. Limited published data on use of buprenorphine, the active ingredient in BELBUCA, in pregnancy, have not shown an increased risk of major malformations. Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of BELBUCA. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related
[see Data]
.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
[see Warnings and Precautions (5.4)]
.
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic 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. BELBUCA 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 BELBUCA, can prolong labor through actions which 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 dilation, which tends to shorten labor.
Data
Animal Data
The exposure margins listed below are based on body surface area comparisons (mg/m²) to MRHD of 1.8 mg buprenorphine via BELBUCA.
Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1351 times the MRHD of 1.8 mg). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg).
In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 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 5.4 times the MRHD of 1.8 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 54 times the MRHD of 1.8 mg) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg).
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine during gestation and lactation at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 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 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg).
)
Lactation
: Not recommended. (
8.2 Lactation
Risk Summary
Based on two studies in 13 lactating women being treated for opioid dependence and their breastfed infants, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants
[see Data]
. There are no data on the effects of BELBUCA on milk production. 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 BELBUCA.
Clinical Considerations
Monitor infants exposed to BELBUCA 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 breastfeeding is stopped.
Data
Based on limited data from a study of six lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose. The median concentrations of buprenorphine and norbuprenorphine in infant urine were 1.0 nmol/L and 2.3 nmol/L, respectively.
Based on limited data from a study of seven lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L, respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
No adverse reactions were observed in the infants in these two studies.
)
Moderate or Severe Hepatic Impairment
: Periodically assess for signs and symptoms of toxicity or overdose. (
5.19 Risk of Overdose in Patients with Moderate to Severe Hepatic Impairment
In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be periodically assessed for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine
[see Dosage and Administration (2.6), Use in Specific Populations (8.6)]
.
,
8.6 Hepatic Impairment
BELBUCA has not been evaluated in patients with severe hepatic impairment.
The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.
Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended
[see Dosage and Administration (2.6)]
. Regularly evaluate patients with severe hepatic impairment for signs and symptoms of overdose. A dosage reduction in patients with moderate hepatic impairment (Child-Pugh B) is not needed; however, regularly evaluate these patients for signs and symptoms of toxicity or overdose. A dosage reduction in patients with mild hepatic impairment (Child-Pugh A) is not needed
[see Dosage and Administration (2.6), Warnings and Precautions (5.19), Clinical Pharmacology (12.3)]
.
)

Belbuca (Buprenorphine Hydrochloride)

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