WHEN PATIENTS WITH CHRONIC PAIN NEED TO MOVE BEYOND SHORT-ACTING OPIOIDS, TRANSITION TO LONG-ACTING THERAPY WITH BELBUCA®

OPIOID-EXPERIENCED

Proven efficacy and sustained chronic pain relief1-3

belbuca clinical data weekly average nrs pain intensity

NRS=Numeric Rating Scale, where 0=no pain and 10=worst pain imaginable.

Primary efficacy endpoint achieved:

  • The change in mean pain intensity score from double-blind baseline to Week 12 was statistically significant in favor of the BELBUCA® group compared with the placebo group (-0.98; 95% CI, -1.32 to -0.64; P<0.0001)1-3
  • Significant reduction in mean NRS pain intensity scores in opioid-experienced patients1-3
  • Patients maintained consistent levels of chronic pain relief after titrating to an optimal dose1-3

Opioid-experienced patients reported significant pain relief1,2,4

belbuca clinical data percentage improvement in nrs pain
  • Twice as many patients taking BELBUCA® showed not only a 30% reduction, but also a 50% reduction in pain score at Week 12 versus patients taking placebo1,4
STUDY DESIGN1,2

The efficacy and safety of BELBUCA® was evaluated in a multicenter, double-blind, placebo-controlled study in opioid-experienced patients with moderate to severe chronic low back pain (CLBP). The primary objective of this study was to determine the change in mean average NRS daily pain intensity score from baseline to Week 12 of the double-blind treatment period. A total of 810 patients entered the open-label titration phase of the study. Of those 510 (63%) were able to titrate to an optimal dose by the end of the open-label titration phase, 491 (61%) contined to the randomized double-blind treatment phase, and 342 (42%) completed the 12-week treatment phase. Patients were permitted to take hydrocodone/acetaminophen (HC/APAP) 5/325 mg as analgesic rescue as needed up to a maximum of 4 doses (8 tablets) per day during the open-label dose titration period. During the 12-week treatment phase, patients in both the BELBUCA® and placebo groups were allowed rescue medication up to 2 doses of 5/325 mg or 10/650 mg of HC/APAP per day for the first 2 weeks, and allowed 1 dose of 5/325 mg or 10/650 mg per day thereafter.

LESS USE OF RESCUE MEDICATION2,5

Opioid-experienced patients reported chronic pain relief with less use of rescue medication compared with placebo2,5

belbuca clinical data rescue medication use

A significantly lower percentage of patients in the BELBUCA® group took rescue medication at each week (except Week 2) than those in the placebo group (P<0.0001 to P=0.0226)5

  • Patients were permitted to take HC/APAP 5/325 mg as analgesic rescue as needed up to a maximum of 4 doses per day during the open-label titration phase1
  • For the first 2 weeks of the double-blind treatment phase, patients were allowed up to 2 doses of 5/325 mg or 10/650 mg of HC/APAP per day to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, patients were allowed 1 dose of 5/325 mg or 10/650 mg per day1

For opioid-experienced patients

OPIOID-NAIVE

Many opioid-naive patients taking BELBUCA® were able to titrate to an optimal dose and maintain consistent levels of chronic pain relief without further dose titration1,6

belbuca clinical data weekly average nrs pain intensity

Patients were considered “opioid-naive” if they had been taking a stable daily dose of non-opioid analgesic medication for at least 4 weeks and/or had been taking up to 10 mg morphine sulfate equivalent (MSE) opioid analgesic medication in addition to the stable daily dose of non-opioid analgesic7

The change in mean NRS pain intensity score from double-blind baseline to Week 12 was statistically significant in favor of the BELBUCA® group compared with the placebo group (P=0.0012)7

STUDY DESIGN1,6,7

The efficacy and safety of BELBUCA® was evaluated in a multicenter, double-blind, placebo-controlled study in opioid-naive patients with moderate to severe CLBP. The primary objective of this study was to determine the change in mean average NRS daily pain intensity score from baseline to Week 12 of the double-blind treatment period. A total of 749 patients entered the open-label titration phase of the study. Of those, 456 (61%) were able to titrate to an optimal dose by the end of the open-label titration phase, 420 (56%) continued to the randomized double-blind treatment phase, and 311 (42%) completed the 12-week treatment phase. During the 12-week treatment phase, patients in both the BELBUCA® and placebo groups were allowed rescue medication up to 2 tablets of HC/APAP 5/325 mg per day for the first 2 weeks, and allowed 1 to 2 tablets of acetaminophen 500 mg per day thereafter.

For opioid-naïve patients:

INDICATION

BELBUCA® (buprenorphine) buccal film 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, 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.

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; and hypersensitivity (e.g., anaphylaxis) to buprenorphine.

IMPORTANT SAFETY INFORMATION about BELBUCA®

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; AND 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 patients regularly for the development of these behaviors and conditions.

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.

Accidental Exposure

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

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.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate, limit dosages and durations to the minimum required, and follow patients for signs and symptoms of respiratory depression and sedation.

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® and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
  • 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 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 intensive monitoring for signs of addiction, abuse, or misuse.
  • Abuse or misuse of BELBUCA® by swallowing may cause choking, overdose, and death.
  • Opioids 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.

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.
  • 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.

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.

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. Follow patients closely for signs and symptoms of respiratory depression and sedation.

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.
  • Patients with Chronic Pulmonary Disease: BELBUCA®-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of BELBUCA®.
  • 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 with 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.

Adrenal Insufficiency

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

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.

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). Monitor 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.

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 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.

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. 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 or Severe Hepatic Impairment

  • In a pharmacokinetic study of 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.

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 transiently higher plasma levels of the opioid. A dose reduction is recommended in these patients. Monitor 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.

ADVERSE REACTIONS

  • The most common adverse reactions (≥5%) reported by patients treated with BELBUCA® in the clinical trials were nausea, constipation, headache, vomiting, fatigue, dizziness, somnolence, diarrhea, dry mouth, and upper respiratory tract infection.
Please see full Prescribing Information, including Boxed Warning and Medication Guide, for BELBUCA®.

To report SUSPECTED ADVERSE REACTIONS, contact BioDelivery Sciences International, Inc. at 1-800-469-0261 or the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.

Intended for healthcare professionals of the United States of America only.

REFERENCES: 1. BELBUCA® (Prescribing Information). Raleigh, NC: BioDelivery Sciences International, Inc.; December 2016. 2. Gimbel J, Spierings ELH, Katz N, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-experienced patients with moderate to severe chronic low back pain: results of a phase 3, enriched enrollment, randomized withdrawal study. Pain. 2016;157(11):2517-2526. 3. Data on file, DOF-BL-12. BioDelivery Sciences International, Inc.; 2016. 4. Data on file, DOF-BL-13. BioDelivery Sciences International, Inc.; 2016. 5. Data on file, DOF-BL-08. BioDelivery Sciences International, Inc.; 2016. 6. Data on file, DOF-BL-19. BioDelivery Sciences International, Inc.; 2016. 7. Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-naïve patients with moderate to severe chronic low back pain. Postgrad Med. 2016;128(1):1-11.