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BELBUCA®^ (Buprenorphine buccal film), CIII
INDICATIONS AND USAGE BELBUCA is indicated for the management of pain severe enough to require daily, around-the- clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioid formulations [see Warnings and Precautions (5.1)], reserve BELBUCA for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- BELBUCA is not indicated as an as-needed (prn) analgesic.
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUTION AND MITIGATION STRATEGY
(REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE;
NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
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 BELBUCA and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions and Overdosage.
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions. 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
- complete a REMS-compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of BELBUCA. Monitor for respiratory depression, especially during initiation of BELBUCA or following a dose increase. Misuse or abuse of BELBUCA by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of
buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions. Accidental Exposure
Accidental exposure to even one dose of BELBUCA, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions. Neonatal Opioid Withdrawal Syndrome
Prolonged use of BELBUCA during pregnancy can result in neonatal opioid withdrawal syndrome, which 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 [see Warnings and Precautions.
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions, Drug Interactions.
- Reserve concomitant prescribing of BELBUCA and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
CONTRAINDICATIONS
BELBUCA is contraindicated in patients with:
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
- Known or suspected gastrointestinal obstruction, including paralytic ileus
- Hypersensitivity (e.g., anaphylaxis) to buprenorphine
WARNINGS AND PRECAUTIONS 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.
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.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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 dosage increase. Monitor patients closely for respiratory depression when initiating therapy with BELBUCA and following dosage increases.
To reduce the risk of respiratory depression, proper dosing, and titration of BELBUCA are essential. 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.
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with BELBUCA. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of BELBUCA 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Risks due to Interactions with Benzodiazepines or Other Central Nervous System Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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.
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. Follow patients closely for signs and symptoms of respiratory depression and sedation.
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.
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.
Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of BELBUCA in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
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.
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of 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.
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 hepatotoxicity (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.
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.
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.
Withdrawal
Do not 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.
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.
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.
Increased Risk of Seizures in Patients with Seizure Disorders
The buprenorphine in BELBUCA may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during BELBUCA therapy.
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.
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.
Table 1:Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Naïve Patients
Open-Label Titration Phase
Double-Blind Treatment Phase
MedDRA Preferred Term BELBUCA
(N=749)
BELBUCA
(N=229)
Placebo (N=232)
Nausea 50% 10% 7%
Constipation 13% 4% 3%
Vomiting 8% 4% <1%
Headache 8% 2% 3%
Dizziness 6% 2% <1%
Somnolence 7% 1% <1%
Fatigue 5% 0% 1%
Table 2:Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Experienced Patients
Open-Label Titration Phase
Double-Blind Treatment Phase
MedDRA Preferred Term BELBUCA (N=810)
BELBUCA
(N=254)
Placebo (N=256)
Nausea 17% 7% 7%
Constipation 8% 3% 1%
Vomiting 7% 5% 2%
Headache 7% 2% 3%
Dizziness 5% 2% <1%
Somnolence 5% 1% <1%
Drug Withdrawal Syndrome
Table 3:Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies
Open-Label Titration Phase
Double-Blind Treatment Phase
MedDRA Preferred Term BELBUCA (N=1889)
BELBUCA
(N=600)
Placebo (N=606)
Nausea 33% 9% 8%
Constipation 11% 4% 2%
Vomiting 7% 5% 2%
Headache 8% 4% 3%
Dizziness 6% 2% <1%
Somnolence 6% <1% <1%
Drug Withdrawal Syndrome
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:
