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 reevaluate 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 [s ee 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 (CO 2) 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, evaluate 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO 2 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.

6.1 Clinical Trial Experience

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 opioid naïve, opioid experienced, and overall patients exposed to BELBUCA in clinical trials and compared against placebo are shown in Tables 2, 3 and 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, somnolence, diarrhea, dry mouth, and upper respiratory tract infection.

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

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

Infections and infestations: 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

8.1  Pregnancy

Risk Summary

There are no adequate and well-controlled studies of BELBUCA or buprenorphine in pregnant women. Limited published data on use of buprenorphine, the active ingredient in BELBUCA, in pregnancy, have not shown an increased risk of major malformations.  In animal reproduction studies, embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis via the oral route of administration at doses approximately 53 to 11 times the maximum recommended human dose (MRHD), respectively. In pre- and post-natal development studies in rats, dystocia was observed after treatment with buprenorphine via the IM route of administration at a dose approximately 27 times the MRHD, and increased neonatal death was observed after treatment via the oral, IM, and SC routes of administration at doses approximately 4, 3, and 0.5 times the MRHD, respectively. No teratogenic effects were observed in rats treated with buprenorphine via the oral, IM, and IV routes of administration during organogenesis at doses approximately 853, 27,  and 4 times the MRHD, respectively, or in rabbits treated with buprenorphine via the oral, SC, and IV routes of administration at doses approximately 267, 53,  and 9 times the MRHD, respectively.  However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related [see Data].  

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical  Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.  Observe newborns for symptoms of neonatal opioid withdrawal syndrome, including poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions ( 5.3)] .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate.  BELBUCA is not recommended for use in women immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate.  Opioid analgesics, including BELBUCA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.  However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Data

Animal Data

Buprenorphine administration during organogenesis was not teratogenic in rats or rabbits after intramuscular (IM) or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 53 times, respectively, the maximum recommended human dose (MRHD) for buccal BELBUCA of 1.8 mg on a mg/m 2 basis), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4 and 9 times, respectively, the MRHD), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 853 times the MRHD) and 25 mg/kg/day in rabbits (estimated exposure was approximately 267 times the MRHD).  Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5 times the MRHD), but were not observed at oral doses up to 160 mg/kg/day (estimated exposure was approximately 853 times the MRHD.  Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 53 times the MRHD) or oral administration of 1 mg/kg/day or greater estimated exposure was approximately 11 times the MRHD) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater (estimated exposure was approximately 11 times the MRHD) and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure was approximately 2 times the MRHD).

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 27 times the MRHD). Fertility, peri- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4 times the MRHD), after IM doses of 0.5 mg/kg/day and up (approximately 3 times the MRHD), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD). Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 427 times the MRHD).

8.2  Lactation

Risk Summary

Based on two studies in 13 lactating women being treated for opioid dependence and their breastfed infants, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants [see Data]. There are no data on the effects of BELBUCA on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with BELBUCA

Clinical Considerations

Infants exposed to BELBUCA through breast milk should ­be monitored for excess sedation and respiratory depression.  Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.

Data

Based on limited data from a study of six lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.  The median concentrations of buprenorphine and norbuprenorphine in infant urine were 1.0 nmol/L and 2.3 nmol/L, respectively.

Based on limited data from a study of seven lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L, respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.

No adverse reactions were observed in the infants in these two studies.

8.4 Pediatric Use

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

8.5 Geriatric Use

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 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 [see Clinical Pharmacology ( 12.3)] .

8.6 Hepatic Impairment

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

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

Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended [ see Dosage and Administration ( 2.5) ].  Monitor 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, monitor 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 ( 2.5), Warnings and Precautions ( 5.11) and Clinical Pharmacology ( 12.3)] .

8.7  Renal Impairment

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent patients and 6 patients with normal renal function following IV administration of 0.3 mg buprenorphine.

9.1 Controlled Substance

BELBUCA contains buprenorphine hydrochloride, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids.  BELBUCA can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions ( 5.1)] .

9.2 Abuse

All patients treated with opioids, including BELBUCA, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction, even under appropriate medical use. 

Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. 

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“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 health care providers(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all persons with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction.

BELBUCA, like other opioids, can be diverted for non-medical 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 re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.

Risks Specific to Abuse of BELBUCA

BELBUCA is intended for buccal use only. Abuse of BELBUCA poses a risk of overdose and death. This risk is increased with concurrent abuse of BELBUCA with alcohol and other substances, including other opioids and benzodiazepines [see Warnings and Precautions ( 5.4), Drug Interactions ( 7)] . Intentional compromise of the buccal film might result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions ( 5.1)]. Abuse may occur by applying the buccal film in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the buccal film.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

BELBUCA should not be abruptly discontinued [see Dosage and Administration ( 2.4)]. If BELBUCA is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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, or diarrhea or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.1)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Effects on the Central Nervous System

The principal action of therapeutic value of buprenorphine is analgesia and is thought to be due to buprenorphine binding with high affinity to opioid receptors on neurons in the brain and spinal cord. Buprenorphine may also cause sedation or somnolence via an action in the brain.

Buprenorphine produces mu opioid receptor-mediated respiratory depression by direct action on brainstem respiratory centers by reducing sensitivity of the brainstem to increases in carbon dioxide tension and to electrical stimulation.

Buprenorphine causes miosis, even in total darkness, and little tolerance develops to this effect.  Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings).  Marked mydriasis rather than miosis may be seen with worsening hypoxia in the setting of buprenorphine overdose.

Unlike other opioids, buprenorphine appears to exhibit a dose-ceiling effect. 

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary, and pancreatic secretions are decreased by buprenorphine.  Buprenorphine causes a reduction in motility associated with an increase in tone in the stomach and duodenum.  Digestion of food in the small intestine is delayed and propulsive contractions are decreased.  Propulsive peristaltic waves in the colon are decreased while tone is increased to the point of spasm.  The end result is constipation.  Buprenorphine may cause an increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Effects on the Cardiovascular System

Buprenorphine may cause a reduction in blood pressure. 

Effects on Cardiac Electrophysiology

QTc prolongation with BELBUCA has been observed. Of the 1590 patients that were treated with BELBUCA in controlled and open-label chronic pain trials at doses up to 900 mcg every 12 hours, 2% demonstrated a prolongation of QTcF to a post-baseline value between 450 - 480 msec during therapy.

Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans.  They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.  Overall, the effects of opioids appear to be modestly immunosuppressive.

12.3 Pharmacokinetics

Absorption

Systemic plasma levels of buprenorphine increased in a linear manner (C max and AUC) over the single dose range of 75 to 1200 mcg as shown in Table 7. The absolute bioavailability of BELBUCA ranged from 46 to 65%.

Following the multiple dose administration (60 to 240 mcg every 12 hours) of BELBUCA, apparent steady-state buprenorphine plasma concentrations were achieved prior to the 6 th dose.  Buprenorphine steady-state C max and AUC increased proportional to dose. 

Systemic exposure to buprenorphine from BELBUCA film was reduced by 23-27% by the ingestion of liquids (cold, hot and room temperature water) during film administration; additionally coadministration with low pH liquid, such as decaffeinated cola, decreased buprenorphine exposure from BELBUCA by approximately 37%.  The consumption of liquids should be avoided until the buccal film has completely dissolved [see Dosage and Administration ( 2.7)] . 

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Elimination

Metabolism

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioid-like activity

Excretion

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine was free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated).

Based on multiple dose studies performed with BELBUCA, the mean plasma elimination half-life of buprenorphine was 27.6±11.2 hours. 

Drug Interactions

CYP3A4 Inhibitors and Inducers: Buprenorphine undergoes N-dealkylation pathway mediated primarily by CYP3A4, so its metabolism can be inhibited by CYP3A4 inhibitors.  The interaction of buprenorphine with all CYP3A4 inducers has not been studied. [see Drug Interactions ( 7)] .

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite,norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns.

Specific Populations

Hepatic Impairment

BELBUCA has not been evaluated in patients with severe hepatic impairment. The pharmacokinetics of buprenorphine following an IV infusion of 0.3 mg of buprenorphine were compared in 8 patients with mild hepatic impairment (Child-Pugh A), 4 patients with moderate impairment (Child-Pugh B), and 12 subjects with normal hepatic function. Buprenorphine and norbuprenorphine plasma levels did not increase in mild or moderately impaired patient cohorts.

In another pharmacokinetic study, the disposition of buprenorphine was determined after administering a 2.0/0.5 mg buprenorphine/naloxone sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function. In subjects with mild hepatic impairment, the changes in mean C max, AUC 0-last, and half-life values of buprenorphine were not clinically significant. No dose adjustment is needed in patients with mild hepatic impairment.

For subjects with moderate and severe hepatic impairment, mean C max , AUC 0-last, and half-life values of buprenorphine were increased. [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.11), and Use in Specific Populations ( 8.6)] .

Oral Mucositis

In an open-label pharmacokinetic study in 6 cancer patients with Grade 3 mucositis, buprenorphine was absorbed more rapidly from BELBUCA resulting in a higher C max (~79%) and AUC (~56%) compared to age- and gender-matched healthy control patients [see Dosage and Administration ( 2.6), Warnings and Precautions ( 5.15) ].

Geriatric Patients

No notable differences in pharmacokinetics were observed from population PK analysis in subjects aged 65 compared to younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 

Pediatric Patients

BELBUCA has not been studied in children and is not recommended for pediatric use.

Sex

No notable sex differences in pharmacokinetics were observed from population PK analysis.

Renal Impairment

No studies in patients with renal impairment have been performed with BELBUCA. In an independent study, the effect of impaired renal function on buprenorphine pharmacokinetics after IV bolus and after continuous IV infusion administration was evaluated; and no notable differences in plasma buprenorphine concentrations were identified in patients with normal renal function compared to impaired renal function or renal failure.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day for 27 months (estimated exposure was approximately 3, 29, and 299 times the maximum recommended human dose (MRHD) of  buccal Belbuca of 1.8 mg on a mg/m 2 basis, respectively). Statistically significant dose-related increases in testicular interstitial (Leydig’s) cell tumors occurred.  In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 267 times the MRHD).

Mutagenesis

Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems.  Results were negative in yeast ( S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay. 

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study.  Results were positive in the Green-Tweets ( E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [ 3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.

Impairment of Fertility

Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg/day (estimated exposure approximately 427 times the MRHD) or up to 5 mg/kg/day IM or SC (estimated exposure was approximately 27 times the MRHD).