These Highlights Do Not Include All The Information Needed To Use Belbuca Safely And Effectively. See Full Prescribing Information For Belbuca.

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)].

Store at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F). Store BELBUCA securely and dispose of properly.

BELBUCA contains buprenorphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of BELBUCA increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of BELBUCA with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of BELBUCA abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use BELBUCA in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

BELBUCA, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

BELBUCA is a buccal film that provides transmucosal delivery of buprenorphine, a partial opioid agonist. BELBUCA is a rectangular bi-layer, peppermint-flavored, buccal film with rounded corners, consisting of a white to off-white backing layer with strength identifier printed in black ink and a light yellow to yellow active mucoadhesive layer containing buprenorphine hydrochloride. The yellow side of the film is applied to the inside of the cheek where it adheres to the moist buccal mucosa to deliver the drug as the film dissolves.

Buprenorphine hydrochloride USP is the active ingredient in BELBUCA. The chemical name of buprenorphine hydrochloride is 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- α-(1,1-dimethylethyl)-4, 5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-, hydrochloride, [5α, 7α, (S)]. Its structural formula is as follows:

The molecular weight of buprenorphine hydrochloride is 504.10; the empirical formula is C₂₉H₄₁NO₄∙HCl. Buprenorphine hydrochloride occurs as a white or off-white crystalline powder. It is sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane. The pKa is 8.5 for the amine function and 10.0 for the phenol function.

Dosage strengths of BELBUCA are based on the active moiety, buprenorphine. BELBUCA is available as 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg buprenorphine per film. The strength of each film is dependent on the buprenorphine concentration in the formulation and the surface area of the film.

Table 6 lists the dosage strength, equivalent amount of buprenorphine hydrochloride USP (active ingredient), unique identifier and film size for each strength.

Each buccal film also contains carboxymethylcellulose sodium USP, citric acid anhydrous USP, hydroxyethylcellulose NF, hydroxypropylcellulose NF, methylparaben NF, monobasic sodium phosphate anhydrous USP, peppermint oil NF, polycarbophil USP, propylene glycol USP, propylparaben NF, sodium benzoate NF, sodium hydroxide NF, saccharin sodium NF, titanium dioxide USP, vitamin E acetate USP, yellow iron oxide, purified water USP, and TekPrint SW-9008 black ink (shellac NF, black iron oxide NF).

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not rapidly reduce or abruptly discontinue BELBUCA in a patient physically dependent on opioids. Rapid tapering of BELBUCA in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing BELBUCA, gradually taper the dosage using a patient-specific plan that considers the following: the dose of BELBUCA the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.17)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

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.

The safety and efficacy of BELBUCA have not been established in pediatric patients.

Of the total number of patients that were treated with BELBUCA in controlled and open-label chronic pain trials (2,127), 340 patients were 65 years and older. Of those, 49 patients were aged 75 years and older. The incidences of selected BELBUCA-related adverse effects were higher in older subjects.

No notable differences in pharmacokinetics were observed from population pharmacokinetic analysis in subjects aged 65 and older compared to younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of BELBUCA slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].

Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

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.

The efficacy of BELBUCA has been evaluated in three 12-week double-blind, placebo-controlled clinical trials in patients who were not opioid tolerant and opioid-experienced patients with moderate-to-severe chronic low back pain using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain did not show a statistically significant pain reduction for BELBUCA compared to placebo.

BELBUCA is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)]
• Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.16), Adverse Reactions (6)]

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.

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6)]
• Adrenal Insufficiency [see Warnings and Precautions (5.8)]
• Severe Hypotension [see Warnings and Precautions (5.9)]
• Hepatotoxicity [see Warnings and Precautions (5.11)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)]
• Seizures [see Warnings and Precautions (5.13)]
• QTc Prolongation [see Warnings and Precautions (5.15)]
• Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.16)]

Table 5 includes clinically significant drug interactions with BELBUCA.

BELBUCA (bel-BUE-kuh)

(buprenorphine buccal film), CIII

Before you use BELBUCA buccal film, it is important that you read the Medication Guide and these Patient Instructions for Use so that you use BELBUCA the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use BELBUCA.

Important:

• BELBUCA buccal film is sealed in a foil package. Do not open the package until ready to use. After opening, use the entire BELBUCA buccal film right away.
• Do not apply BELBUCA buccal film if the package seal is broken or the film is cut, damaged, or changed in any way.
• BELBUCA buccal film is available in different strengths. Make sure you have the strength that has been prescribed for you.
• Avoid placing BELBUCA buccal film to areas of the mouth with any open sores or lesions.

Open the BELBUCA package:

• Hold the foil package as shown below (see Figure A). Fold along the dotted line at the top of the foil package.
  
  
  Figure A
• Keep folded and tear down or cut with scissors at the notch in the direction of the scissors on the dotted line (see Figure B). Tear all the way to the bottom. Be careful to avoid cutting and damaging the BELBUCA buccal film when using scissors.
  
  
  Figure B
• Remove BELBUCA film from the foil package (see Figure C).
  
  
  Figure C

Use BELBUCA buccal film as follows:

• 1.
  Use your tongue to wet the inside of your cheek or rinse your mouth with water to moisten the area in your mouth before you place BELBUCA.
• 2.
  Hold the BELBUCA buccal film with clean, dry fingers with the yellow side facing up (see Figure D).
  
  
  Figure D
• 3.
  Using a finger, place the yellow side of the BELBUCA buccal film against the inside of your moistened cheek. Press and hold the BELBUCA buccal film in place for 5 seconds and then take your finger away (see Figure E).
  
  
  Figure E
• 4.
  The BELBUCA buccal film will stick to the inside of your cheek (see Figure F).
  
  
  Figure F
• 5.
  Leave the BELBUCA buccal film in place until it has completely dissolved, usually within 30 minutes after you apply it.
  • Avoid eating food or drinking liquids until BELBUCA buccal film has dissolved.
  • Avoid touching or moving BELBUCA buccal film with your tongue or finger after it is in place.
  • Do not chew or swallow BELBUCA.
  • After BELBUCA is completely dissolved, rinse your mouth with water and swallow. Wait at least one hour before brushing your teeth.

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

For more information call Collegium Pharmaceutical, Inc. at 855-331-5615.

Manufactured for:

Collegium Pharmaceutical, Inc., Stoughton, MA 02072

BELBUCA is a trademark of BioDelivery Sciences International, Inc., a wholly owned subsidiary of Collegium Pharmaceutical, Inc.

©2025 BioDelivery Sciences International, Inc. All rights reserved.

BEL-001-MG-XX2025

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)].

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.

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 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.

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

BELBUCA contains buprenorphine hydrochloride, a Schedule III controlled substance.

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.

• 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. (5.6).
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.8)
• Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use of BELBUCA in patients with circulatory shock. (5.9)
• 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. (5.10)

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) ].

• 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)
• 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, 5)
• 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, 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. (2.1, 5.2).
• 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, 5.1, 5.2, 5.3)
• 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)
• 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)
• 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)
  • For patients taking less than 30 mg oral MSE, initiate therapy with 75 mcg once daily or every 12 hours. (2.3)
  • 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)
  • 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)
  • For patients taking greater than 160 mg oral MSE, consider alternate analgesic. (2.3)
• BELBUCA doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of BELBUCA. (2.3)
• Patients with Severe Hepatic Impairment: Reduce the starting and incremental dose by half that of patients with normal liver function. (2.6, 5.19, 8.6)
• Patients with Oral Mucositis: Reduce the starting and incremental dose by half that of patients without mucositis. (2.7, 5.20)
• 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)
• 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, 5.17)

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.

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

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2,127 patients were treated with BELBUCA in controlled and open-label chronic pain trials. There were 504 patients treated for approximately six months and 253 patients treated for approximately one year. The clinical trial population consisted of patients with chronic moderate-to-severe pain.

The most common serious adverse drug reactions (all ≤ 0.2%) occurring during clinical trials with BELBUCA were: cellulitis, pneumonia, ileus, atrial fibrillation, coronary artery disease, cerebrovascular accident, syncope, transient ischemic attack, chest pain, non-cardiac chest pain, ankle fracture, cholecystitis, osteoarthritis, and dehydration.

The most common adverse events (≥ 2%) leading to discontinuation were nausea, vomiting, and liver function test abnormality.

The most common adverse events (≥ 5%) reported by patients who were not opioid tolerant, opioid-experienced patients, and overall patients exposed to BELBUCA in clinical trials and compared against placebo are shown in Table 2, Table 3 and Table 4:

The most common (≥ 5%), common (≥ 1% to < 5%), and least common (< 1%) adverse reactions reported by patients taking BELBUCA in the controlled and open-label clinical studies are presented below:

Most common adverse reactions (≥ 5%): nausea, constipation, headache, vomiting, fatigue, dizziness, and somnolence.

Common (≥ 1% to < 5%) adverse reactions (organized by MedDRA [Medical Dictionary for Regulatory Activities] System Organ Class):

Blood and lymphatic system disorders: anemia

Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth

General disorders and administration site conditions: peripheral edema, pyrexia, drug withdrawal syndrome

Infections and infestations: upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, gastroenteritis

Injury, poisoning, and procedural complications: contusion, fall

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle spasms, back pain

Psychiatric disorders: anxiety, insomnia, depression

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, sinus congestion

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash

Vascular disorders: hot flush, hypertension

Least common (<1%) adverse reactions:

Abdominal discomfort, acute sinusitis, dyspepsia, toothache, asthenia, chills, cellulitis, tooth abscess, excoriation, laceration, aspartate aminotransferase increased, blood pressure increased, blood testosterone decreased, electrocardiogram QT prolonged, liver function test abnormal, musculoskeletal pain, neck pain, hypoesthesia, lethargy, migraine, tremor, cough, dyspnea, nasal congestion, rhinorrhea.

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Not recommended. (8.2)
• Moderate or Severe Hepatic Impairment: Periodically assess for signs and symptoms of toxicity or overdose. (5.19, 8.6)

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

BELBUCA (buprenorphine buccal film) films are supplied in cartons containing 60 individual child-resistant foil packages as follows:

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.

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)].

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.

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)].

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)].

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.

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) ].

NDC 59385-021-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

75 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

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)].

NDC 59385-022-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

150 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-023-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

300 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-024-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

450 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-025-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

600 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-026-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

750 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-027-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

900 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

• 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.

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)].

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)].

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)
• 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, 2.8, 5.2)
• Accidental exposure to BELBUCA, especially in children, can result in fatal overdose of buprenorphine. (5.2)
• 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, 7)
• 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)
• 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)

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.

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)].

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.

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)].

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)].

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.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with 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.

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.

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)].

Store at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F). Store BELBUCA securely and dispose of properly.

BELBUCA contains buprenorphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of BELBUCA increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of BELBUCA with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of BELBUCA abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use BELBUCA in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

BELBUCA, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

BELBUCA is a buccal film that provides transmucosal delivery of buprenorphine, a partial opioid agonist. BELBUCA is a rectangular bi-layer, peppermint-flavored, buccal film with rounded corners, consisting of a white to off-white backing layer with strength identifier printed in black ink and a light yellow to yellow active mucoadhesive layer containing buprenorphine hydrochloride. The yellow side of the film is applied to the inside of the cheek where it adheres to the moist buccal mucosa to deliver the drug as the film dissolves.

Buprenorphine hydrochloride USP is the active ingredient in BELBUCA. The chemical name of buprenorphine hydrochloride is 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- α-(1,1-dimethylethyl)-4, 5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-, hydrochloride, [5α, 7α, (S)]. Its structural formula is as follows:

The molecular weight of buprenorphine hydrochloride is 504.10; the empirical formula is C₂₉H₄₁NO₄∙HCl. Buprenorphine hydrochloride occurs as a white or off-white crystalline powder. It is sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane. The pKa is 8.5 for the amine function and 10.0 for the phenol function.

Dosage strengths of BELBUCA are based on the active moiety, buprenorphine. BELBUCA is available as 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg buprenorphine per film. The strength of each film is dependent on the buprenorphine concentration in the formulation and the surface area of the film.

Table 6 lists the dosage strength, equivalent amount of buprenorphine hydrochloride USP (active ingredient), unique identifier and film size for each strength.

Each buccal film also contains carboxymethylcellulose sodium USP, citric acid anhydrous USP, hydroxyethylcellulose NF, hydroxypropylcellulose NF, methylparaben NF, monobasic sodium phosphate anhydrous USP, peppermint oil NF, polycarbophil USP, propylene glycol USP, propylparaben NF, sodium benzoate NF, sodium hydroxide NF, saccharin sodium NF, titanium dioxide USP, vitamin E acetate USP, yellow iron oxide, purified water USP, and TekPrint SW-9008 black ink (shellac NF, black iron oxide NF).

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not rapidly reduce or abruptly discontinue BELBUCA in a patient physically dependent on opioids. Rapid tapering of BELBUCA in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing BELBUCA, gradually taper the dosage using a patient-specific plan that considers the following: the dose of BELBUCA the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.17)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

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.

The safety and efficacy of BELBUCA have not been established in pediatric patients.

Of the total number of patients that were treated with BELBUCA in controlled and open-label chronic pain trials (2,127), 340 patients were 65 years and older. Of those, 49 patients were aged 75 years and older. The incidences of selected BELBUCA-related adverse effects were higher in older subjects.

No notable differences in pharmacokinetics were observed from population pharmacokinetic analysis in subjects aged 65 and older compared to younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of BELBUCA slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].

Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

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.

The efficacy of BELBUCA has been evaluated in three 12-week double-blind, placebo-controlled clinical trials in patients who were not opioid tolerant and opioid-experienced patients with moderate-to-severe chronic low back pain using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain did not show a statistically significant pain reduction for BELBUCA compared to placebo.

BELBUCA is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)]
• Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.16), Adverse Reactions (6)]

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.

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6)]
• Adrenal Insufficiency [see Warnings and Precautions (5.8)]
• Severe Hypotension [see Warnings and Precautions (5.9)]
• Hepatotoxicity [see Warnings and Precautions (5.11)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)]
• Seizures [see Warnings and Precautions (5.13)]
• QTc Prolongation [see Warnings and Precautions (5.15)]
• Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.16)]

Table 5 includes clinically significant drug interactions with BELBUCA.

BELBUCA (bel-BUE-kuh)

(buprenorphine buccal film), CIII

Before you use BELBUCA buccal film, it is important that you read the Medication Guide and these Patient Instructions for Use so that you use BELBUCA the right way. Ask your healthcare provider or pharmacist if you have any questions about the right way to use BELBUCA.

Important:

• BELBUCA buccal film is sealed in a foil package. Do not open the package until ready to use. After opening, use the entire BELBUCA buccal film right away.
• Do not apply BELBUCA buccal film if the package seal is broken or the film is cut, damaged, or changed in any way.
• BELBUCA buccal film is available in different strengths. Make sure you have the strength that has been prescribed for you.
• Avoid placing BELBUCA buccal film to areas of the mouth with any open sores or lesions.

Open the BELBUCA package:

• Hold the foil package as shown below (see Figure A). Fold along the dotted line at the top of the foil package.
  
  
  Figure A
• Keep folded and tear down or cut with scissors at the notch in the direction of the scissors on the dotted line (see Figure B). Tear all the way to the bottom. Be careful to avoid cutting and damaging the BELBUCA buccal film when using scissors.
  
  
  Figure B
• Remove BELBUCA film from the foil package (see Figure C).
  
  
  Figure C

Use BELBUCA buccal film as follows:

• 1.
  Use your tongue to wet the inside of your cheek or rinse your mouth with water to moisten the area in your mouth before you place BELBUCA.
• 2.
  Hold the BELBUCA buccal film with clean, dry fingers with the yellow side facing up (see Figure D).
  
  
  Figure D
• 3.
  Using a finger, place the yellow side of the BELBUCA buccal film against the inside of your moistened cheek. Press and hold the BELBUCA buccal film in place for 5 seconds and then take your finger away (see Figure E).
  
  
  Figure E
• 4.
  The BELBUCA buccal film will stick to the inside of your cheek (see Figure F).
  
  
  Figure F
• 5.
  Leave the BELBUCA buccal film in place until it has completely dissolved, usually within 30 minutes after you apply it.
  • Avoid eating food or drinking liquids until BELBUCA buccal film has dissolved.
  • Avoid touching or moving BELBUCA buccal film with your tongue or finger after it is in place.
  • Do not chew or swallow BELBUCA.
  • After BELBUCA is completely dissolved, rinse your mouth with water and swallow. Wait at least one hour before brushing your teeth.

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

For more information call Collegium Pharmaceutical, Inc. at 855-331-5615.

Manufactured for:

Collegium Pharmaceutical, Inc., Stoughton, MA 02072

BELBUCA is a trademark of BioDelivery Sciences International, Inc., a wholly owned subsidiary of Collegium Pharmaceutical, Inc.

©2025 BioDelivery Sciences International, Inc. All rights reserved.

BEL-001-MG-XX2025

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)].

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.

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 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.

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

BELBUCA contains buprenorphine hydrochloride, a Schedule III controlled substance.

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.

• 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. (5.6).
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.7)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.8)
• Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use of BELBUCA in patients with circulatory shock. (5.9)
• 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. (5.10)

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) ].

• 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)
• 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, 5)
• 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, 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. (2.1, 5.2).
• 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, 5.1, 5.2, 5.3)
• 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)
• 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)
• 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)
  • For patients taking less than 30 mg oral MSE, initiate therapy with 75 mcg once daily or every 12 hours. (2.3)
  • 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)
  • 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)
  • For patients taking greater than 160 mg oral MSE, consider alternate analgesic. (2.3)
• BELBUCA doses of 600 mcg, 750 mcg, and 900 mcg are only for use following titration from lower doses of BELBUCA. (2.3)
• Patients with Severe Hepatic Impairment: Reduce the starting and incremental dose by half that of patients with normal liver function. (2.6, 5.19, 8.6)
• Patients with Oral Mucositis: Reduce the starting and incremental dose by half that of patients without mucositis. (2.7, 5.20)
• 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)
• 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, 5.17)

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.

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

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2,127 patients were treated with BELBUCA in controlled and open-label chronic pain trials. There were 504 patients treated for approximately six months and 253 patients treated for approximately one year. The clinical trial population consisted of patients with chronic moderate-to-severe pain.

The most common serious adverse drug reactions (all ≤ 0.2%) occurring during clinical trials with BELBUCA were: cellulitis, pneumonia, ileus, atrial fibrillation, coronary artery disease, cerebrovascular accident, syncope, transient ischemic attack, chest pain, non-cardiac chest pain, ankle fracture, cholecystitis, osteoarthritis, and dehydration.

The most common adverse events (≥ 2%) leading to discontinuation were nausea, vomiting, and liver function test abnormality.

The most common adverse events (≥ 5%) reported by patients who were not opioid tolerant, opioid-experienced patients, and overall patients exposed to BELBUCA in clinical trials and compared against placebo are shown in Table 2, Table 3 and Table 4:

The most common (≥ 5%), common (≥ 1% to < 5%), and least common (< 1%) adverse reactions reported by patients taking BELBUCA in the controlled and open-label clinical studies are presented below:

Most common adverse reactions (≥ 5%): nausea, constipation, headache, vomiting, fatigue, dizziness, and somnolence.

Common (≥ 1% to < 5%) adverse reactions (organized by MedDRA [Medical Dictionary for Regulatory Activities] System Organ Class):

Blood and lymphatic system disorders: anemia

Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth

General disorders and administration site conditions: peripheral edema, pyrexia, drug withdrawal syndrome

Infections and infestations: upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, gastroenteritis

Injury, poisoning, and procedural complications: contusion, fall

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle spasms, back pain

Psychiatric disorders: anxiety, insomnia, depression

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, sinus congestion

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash

Vascular disorders: hot flush, hypertension

Least common (<1%) adverse reactions:

Abdominal discomfort, acute sinusitis, dyspepsia, toothache, asthenia, chills, cellulitis, tooth abscess, excoriation, laceration, aspartate aminotransferase increased, blood pressure increased, blood testosterone decreased, electrocardiogram QT prolonged, liver function test abnormal, musculoskeletal pain, neck pain, hypoesthesia, lethargy, migraine, tremor, cough, dyspnea, nasal congestion, rhinorrhea.

• Pregnancy: May cause fetal harm. (8.1)
• Lactation: Not recommended. (8.2)
• Moderate or Severe Hepatic Impairment: Periodically assess for signs and symptoms of toxicity or overdose. (5.19, 8.6)

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

BELBUCA (buprenorphine buccal film) films are supplied in cartons containing 60 individual child-resistant foil packages as follows:

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.

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)].

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.

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)].

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)].

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.

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) ].

NDC 59385-021-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

75 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

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)].

NDC 59385-022-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

150 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-023-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

300 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-024-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

450 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-025-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

600 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-026-60

CIII

Belbuca ^®

(buprenorphine buccal film)

Push To

Open

750 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

NDC 59385-027-60

CIII

Belbuca ^®

(buprenorphine buccal film)

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Open

900 mcg

60 pouches containing 1 buccal film each

Use entire film. Do not cut, tear, chew or swallow film.

Keep Belbuca out of sight and reach of children.

Children who accidentally take Belbuca will

need emergency medical care.

Dispense the enclosed

Medication Guide

to each patient.

Rx only

• 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.

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)].

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)].

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)
• 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, 2.8, 5.2)
• Accidental exposure to BELBUCA, especially in children, can result in fatal overdose of buprenorphine. (5.2)
• 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, 7)
• 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)
• 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)

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.

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)].

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.

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)].

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)].

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.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with 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.

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.