2.1  Important Dosage and Administration Instructions

BELBUCA should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

BELBUCA buccal film is for oral buccal use only and is to be applied to the buccal mucosa 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.

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with BELBUCA and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

2.2 Initial Dosing

Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, response,  prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

Use of BELBUCA as the Initial Opioid Analgesic (Opioid Naïve Patients)

Initiate treatment in opioid naïve patients with a 75 mcg film once daily or, if tolerated, every 12 hours (see Table 1) for at least 4 days, then increase dose to 150 mcg every 12 hours. Individual titration to a dose that provides adequate analgesia and minimizes adverse reactions should proceed in increments of 150 mcg every 12 hours, no more frequently than every 4 days. Doses up to 450 mcg every 12 hours were studied in opioid naïve patients in the clinical trials [see Clinical Studies (14)]. 

Conversion from Other Opioids to BELBUCA

There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids.  To reduce the risk of opioid withdrawal, taper patients to no more than 30 mg oral morphine sulfate equivalents (MSE) daily before beginning BELBUCA. Following analgesic taper, base the starting dose on the patient’s daily opioid dose prior to taper, as described in Table 1.  Patients may require additional short-acting analgesics during the taper period and during titration.

BELBUCA may not provide adequate analgesia for patients requiring greater than 160 mg oral MSE per day.  Consider the use of an alternate analgesic.

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

Conversion from Methadone to BELBUCA

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

2.3 Titration and Maintenance of Therapy

Individually titrate BELBUCA to a dose that provides adequate analgesia and minimizes adverse reactions  Continually reeva luate patients receiving BELBUCA to assess the maintenance of pain control and the relative incidence of adverse reactions and monitor for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. 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 long-term therapy, periodically reassess the continued need for opioid analgesics.

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 (5.7), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].  If pain is not adequately managed on BELBUCA 900 mcg, consider an alternate analgesic.

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 unacceptable opioid-related adverse reactions are observed, adjust the dose to obtain an appropriate balance between the management of pain and opioid-related adverse reactions.

2.4  Discontinuation of BELBUCA

When a patient no longer requires therapy with BELBUCA, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue BELBUCA.

2.5  Dosage Modifications in Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment (i.e., Child-Pugh C), reduce the starting dose and reduce the titration dose by half that of patients with normal liver function, from 150 mcg to 75 mcg. [see Warnings and Precautions (5.11), Use in Special Populations (8.6), Clinical Pharmacology (12.3)].

2.6  Dosage Modifications in Patients with Oral Mucositis

In patients with known or suspected mucositis, reduce the starting dosage and titration incremental dosage by half compared to patients without mucositis.  [see Warnings and Precautions (5.15), Clinical Pharmacology (12.3)].

2.7  Administration of BELBUCA

BELBUCA should not be used if the package seal is broken or the film is cut, damaged, or changed in any way.

First, the patient must use the tongue to wet the inside of the cheek or rinse the mouth with water to wet the area for placement of BELBUCA. BELBUCA is then applied immediately after removal from the individually sealed package. . The yellow side of the BELBUCA film is placed against the inside of the cheek. The entire BELBUCA film is held in place with clean, dry fingers for 5 seconds and then left BELBUCA 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.

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[see Patient Counseling Information (17)].

2.8  Disposal Instructions

Dispose of unused BELBUCA as soon as it is no longer needed.

To dispose of unused BELBUCA film:

1. Remove all BELBUCA films from their foil packages.
2. Drop the BELBUCA films into toilet and flush.
3. Discard foil packaging in trash.

Do not flush BELBUCA down the toilet in the foil packages or cartons [see Patient Counseling Information (17)].

5.1  Addiction, Abuse, and Misuse

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

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BELBUCA and monitor all patients receiving BELBUCA for the development of these behaviors or 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 BELBUCA, but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, along with intensive monitoring for signs of addiction, abuse, or misuse. 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 [see Drug Abuse and Dependence (9)].

Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death [see Overdosage (10)].

Opioid agonists such as buprenorphine are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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 the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2  Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of buprenorphine, even when used as recommended. Respiratory depression, from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death.  Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (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 dose increase.  Closely monitor patients for respiratory depression when initiating therapy with BELBUCA and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential [see Dosage and Administration (2.3)]. 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, might result in respiratory depression and death due to an overdose of buprenorphine.

5.3  Neonatal Opioid Withdrawal Syndrome

Prolonged use of BELBUCA during pregnancy can result in withdrawal signs 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, failure to gain weight; and there have been reports of convulsions, apnea, respiratory depression, and bradycardia. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn [see Use in Specific Populations (8.1)].

5.4  Risks due to Interactions with Central Nervous System Depressants

Hypotension, profound sedation, coma or respiratory depression may result if BELBUCA is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). 

When considering the use of BELBUCA in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, eva luate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin BELBUCA is made, start with a lower dosage of BELBUCA, monitor patients for signs of sedation, respiratory depression, and hypotension, and consider using a lower dosage of the concomitant CNS depressant [see Drug Interactions (7)].

5.5  Risk of Life-Threatening Respiratory Depression in Elderly, Cachectic, and Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating BELBUCA and when BELBUCA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].

5.6  Risk of Apnea in Patients with Chronic Pulmonary Disease

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.

BELBUCA-treated  patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of BELBUCA [see Warnings and Precautions (5.2)]. Therefore, closely monitor these patients, especially when initiating and titrating BELBUCA.  Alternatively, consider the use of alternative non-opioid analgesics in these patients.

5.7  QTc Prolongation

BELBUCA has been observed to prolong the QTc interval in some subjects participating in clinical trials.  Consider these observations in clinical decisions when prescribing BELBUCA to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients.  Avoid the use of BELBUCA in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval. [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].

5.8  Severe Hypotension

BELBUCA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of BELBUCA. In patients with circulatory shock, BELBUCA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA in patients with circulatory shock.

5.9  Risks of Use in Patients with Head Injury or Increased Intracranial Pressure

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.

5.10  Hepatotoxicity

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse events 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 hepatoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically during treatment with BELBUCA.

5.11  Risk of Overdose in Patients With Moderate to Severe Hepatic Impairment

In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. [see Dosage and Administration (2.5), Use in Specific Populations (8.6)].

5.12  Anaphylactic/Allergic Reactions

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

5.13  Risk of Use in Patients with Gastrointestinal Conditions

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.  Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.14  Increased Risk of Seizures in Patients with Seizure Disorders

Buprenorphine 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. Monitor patients with a history of seizure disorders for worsened seizure control during BELBUCA therapy.

5.15  Risks of Use in Cancer Patients with Oral Mucositis

Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid.   For patients with known or suspected mucositis, a dose reduction is recommended.  Monitor these patients carefully for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.  [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

5.16  Risks of Driving and Operating Machinery

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