tiny Concern Concern Addiction Concern sibility Efficacy use Tolerability Concern Responsibility Abuse Tolerability Efficacy nsibility Abuse

Transcription

1 e rn lerability ratory cacy ndence depression nsibility crutiny ndence onsibility hological dependence buse rability ychological dependence dependence Addiction al dependence tiny dependence rability esponsibility y depression bility III CIII atory se gical pression dependence depression se Respiratory al ility dependence y depression ependence ncern ty ion CIII piratory depression piratory depression sponsibility l ponsibility dependence use cal cerndependence dependence ychological e spiratory depression sponsibility y ndence depression y endence ence piratory CIII Psychological depression dependence ponsibility sychological dependence bility Respiratory gical tiny depression ysical dependence ssion ry depression cern Psychological ependence iratory fficacy esponsibility depression dependence ependence dence rutiny se nsibility nsibility Respiratory depression ession ility chological dependence ssion ern ysical dependence pendence ssion ern pendence atory depression nce tiny sibility When managing chronic pain... RETHINK RELIEF

2 BELBUCA is the first and only Schedule III long-acting opioid that uses novel buccal film technology Respiratory depr to deliver buprenorphine for appropriate patients living with chronic pain 1-3 * 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. IMPORTANT SAFETY INFORMATION about BELBUCA WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS Addiction,, 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 patient s risk prior to prescribing BELBUCA, and monitor patients regularly for these behaviors and conditions. Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to 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. 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 Con 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. Psychological d R Psyc Abu R Physical de Res 2 Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com.

3 ession cern ependence espiratory depression hological dependence When considering LAO therapy... RETHINK... Respiratory Depression Addiction CONSIDER BELBUCA AS YOUR FIRST CHOICE FOR LONG-ACTING OPIOID (LAO) THERAPY se espiratory depression pendence ponsibility (buprenorphine buccal film) A Responsible Choice * Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

4 piratory depression ogical dependence onsibility pression BUPRENORPHINE IS A SCHEDULE III OPIOID WITH UNIQUE PHARMACOLOGY Conc R Psychological de Resp Physical depend Scr Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor 1 Binds tightly to mu-opioid receptors and detaches slowly 1,4 Exhibits a mean plasma elimination half-life of 27.6±11.2 hours 1 Appears to exhibit a dose-ceiling effect on respiratory depression 1,5-7 IMPORTANT SAFETY INFORMATION about BELBUCA 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. WARNINGS AND PRECAUTIONS Addiction,, 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 if the drug is misused or abused. 4 Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com.

5 esponsibility ern pendence iratory depression ence utiny Psychological dependen...and APPEARS TO EXHIBIT A DOSE-CEILING EFFECT ON RESPIRATORY DEPRESSION Buprenorphine displays a nonlinear dose-response curve that plateaus to a ceiling effect on respiratory depression at doses above the recommended total daily dose for chronic pain 5,8,9 CII Opioids* Ceiling effect PCO 2 Buprenorphine Dose Traditional, full mu-opioid receptor agonists exhibit linear- and dose-proportional respiratory depression 5,6,9-11 Buprenorphine displays a nonlinear dose-response curve that plateaus to a ceiling effect on respiratory depression at doses above the recommended daily dose for chronic pain 5,8,9 Adapted from Wiegand TJ, Bettendorf JA. Buprenorphine/naloxone toxicity. Accessed October 22, *Schedule II (CII) opioids: morphine, fentanyl, and methadone. Conceptual representation of partial pressure carbon dioxide (PCO 2 levels) dose-response with buprenorphine. PCO 2 levels are used as a measure of respiratory depression. IMPORTANT SAFETY INFORMATION about BELBUCA 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. (buprenorphine buccal film) A Responsible Choice

6 piratory depression ogical dependence onsibility pression Conc R Psychological de PAIN RELIEF SIGNIFICANTLY GREATER THAN PLACEBO IN MANY OPIOID-EXPERIENCED PATIENTS Resp Physical depend Scr Respo Primary Endpoint: 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) 1,12,13 Significant reduction in mean NRS pain intensity scores in opioid-experienced patients 1,12,13 Cumulative Percentage of Patients With Response 70% 60% 50% 40% 30% 20% 10% 0% Percentage Improvement in NRS Pain Score From Prior to Open-Label Titration to Study Endpoint 1,14 64 % 33% difference P< % 39 % 30% 50% Percentage Improvement in NRS NRS=numeric rating scale, where 0=no pain and 10=worst pain imaginable. 17 % BELBUCA n=243 Placebo n=248 22% difference P< 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 placebo 1,13 6 Study Design 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. 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 were dosed in the open-label titration phase of the study. Of those, 511 (63%) were able to titrate to an optimal dose by the end of the open-label titration phase. Double-blind study medication was given to 511 patients, with 254 randomized to BELBUCA and 257 to placebo. In all, 206 (81%) patients who received BELBUCA and 147 (57%) who received placebo completed the 12 week treatment phase. Patients were permitted to take hydrocodone/acetaminophen (HC/APAP) 5/325 mg (1 tablet) every 6 hours as needed for analgesic rescue, up to a maximum of 4 doses per day during the opioid taper phase. When patients received 30 mg morphine milligram equivalents (MME) for at least 3 days, they were eligible to enter the open-label dose-titration period, where they were permitted to take rescue medication up to 4 doses (1 or 2 tablets) of HC/APAP 5/325 mg/d. During the 12 week treatment phase, patients in both the BELBUCA and placebo groups were allowed rescue medication up to 2 doses (1 or 2 tablets) of 5/325 mg/d of HC/APAP for the first 2 weeks and allowed 1 dose (1 or 2 tablets) of 5/325 mg/d thereafter. 12 Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com.

7 esponsibility ern pendence iratory depression ence utiny nsibility TOLERABILITY COMPARABLE TO PLACEBO Adverse Events Reported in 5% of Patients During the Open-Label and Double-Blind Treatment Phases in Opioid-Experienced Patients 1 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 0% 4% 10% MedDRA=Medical Dictionary for Regulatory Activities. Most common adverse events ( 5% of patients) were nausea, constipation, vomiting, headache, dizziness, and somnolence 1 Discontinuation due to adverse events 1 : Of the 810 patients who began the open-label titration phase, 81 (10%) discontinued due to an adverse event During the double-blind treatment phase, the rate of discontinuation due to adverse events among patients in the placebo group was 5% versus 2% in the BELBUCA group Discontinuation due to nausea in patients taking BELBUCA was 1,15 : 2.6% (21 of 810 patients) during the open-label titration phase 0.4% (1 of 254 patients) during the double-blind treatment phase There were no reports of respiratory depression in the pivotal Phase III clinical studies of BELBUCA, including the long-term safety study 12,16,17 IMPORTANT SAFETY INFORMATION about BELBUCA 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. (buprenorphine buccal film) A Responsible Choice

8 atory depression ical dependence nsibility ssion OPTIMAL DOSE WAS 450 MCG EVERY 12 HOURS IN THE MAJORITY OF PATIENTS Conce R Ef Psychological dep Respir Physical depende Scru Respon Patients Randomized to BELBUCA : Dose Distribution at End of Open-Label Titration Phase % 150 mcg 4% (n=10) 300 mcg 12% (n=30) n= % 900 mcg 36% (n=93) 750 mcg 17% (n=42) 600 mcg 17% (n=43) 450 mcg 14% (n=36) OPEN-LABEL TITRATION PHASE Patients were titrated every 4 to 8 days and reached their optimal dose, on average, within 25 days 12,18,19 * Optimal dose was defined as a dose of medication that 18 Patients found satisfactory for both analgesia and tolerability (preferably without the need for rescue medication) and no more than 1 dose of 5/325 mg/d HC/APAP (1 or 2 tablets per dose) Patients were willing to continue at the same dose for the 12-week, double-blind treatment phase *In the clinical trial, average time to reach optimal dose was 24.5 days in the open-label titration phase. IMPORTANT SAFETY INFORMATION about BELBUCA Addiction,, 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 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. 8 Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com.

9 esponsibility endence rn ficacy atory depression nce tiny sibility DOSING GETTING PATIENTS STARTED Psychological de When transitioning opioid-experienced patients, start by tapering their current opioid dose to no more than 30 mg oral MME daily 1 30 mg oral MME 20, 21 = 200 mg codeine 12.5 mcg/h fentanyl transdermal 30 mg hydrocodone 7.5 mg hydromorphone 20 mg oxycodone 10 mg oxymorphone There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. 1 There are no established conversion ratios defined by clinical trials for conversion from other opioids to BELBUCA. Determine the appropriate BELBUCA STARTING DOSE based on the patient s total daily opioid dose prior to taper 1 After tapering their current opioid down to 30 mg/d oral MME or less 1... Previous Daily Dose of Opioid Analgesic (prior to taper) BELBUCA STARTING DOSE TITRATION: INCREASE DOSE AS NEEDED* <30 mg oral MME 75 mcg once daily or q12h 150 mcg 300 mcg 450 mcg 600 mcg 750 mcg 900 mcg mg oral MME 150 mcg q12h 300 mcg 450 mcg 600 mcg 750 mcg 900 mcg mg oral MME 300 mcg q12h 450 mcg 600 mcg 750 mcg 900 mcg For patients previously taking oral MME >160 mg, consider an alternate analgesic. 1 *All patients should be titrated no more frequently than every 4 days, and dosed in q12h intervals. 1 Opioid-naive and opioid-intolerant patients: Begin at 75 mcg QD or q12h for at least 4 days; increase to 150 mcg q12h before continuing to titrate in increments of 150 mcg q12h. 1 NOTE: Only doses up to 450 mcg q12h were studied in opioid-naive patients. 1 Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with BELBUCA, and adjust the dosage accordingly. 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. 1 (buprenorphine buccal film) A Responsible Choice

10 atory depression ical dependence nsibility ssion HOW TO ADMINISTER Just peel, place, and press Conce R Ef Psychological dep Respir Physical depende Scru Before prescribing BELBUCA, please review the Medication Guide with patients, as well as the Instructions for Use to educate them on the proper application technique. Tell your patients to just follow these 3 simple steps 1 : Peel Place Press PEEL Tear open the individually sealed foil package by folding on the dotted line and tearing down at the perforation, or use scissors to cut open Carefully remove the film from the package using clean, dry hands and fingers PLACE Ensure the inside of the cheek where the film will be placed is wet by using the tongue or rinsing the mouth with water Hold film with clean, dry fingers and place on the fingertip with the yellow side facing up PRESS Press the yellow side against the inside of the cheek Hold the film in place for 5 seconds to allow it to adhere to the buccal mucosa Leave BELBUCA on the inside of the cheek until it fully dissolves (typically within 30 minutes) Patients can speak and swallow normally while the film is in place. Please share this important information with your patients Remember to apply at the same time(s) each day Never use BELBUCA if the pouch seal is broken or the buccal film is damaged or changed in any way You may need to use 2 fingers to hold the film securely before placing it in your mouth It may help to press another finger to the outside of your cheek to position the film correctly Avoid applying the film to areas of the mouth with any open sores or lesions Do not chew or swallow the film, as it may cause choking, overdose, or death Chewing or swallowing BELBUCA may yield lower peak concentrations and lower bioavailability than when used as directed Avoid touching or moving the film with tongue or finger after it is in place Do not eat or drink until the film has completely dissolved BELBUCA has a mild peppermint flavor As BELBUCA dissolves, it is normal for the texture of the film to change 10 IMPORTANT SAFETY INFORMATION about BELBUCA Addiction,, and Misuse 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. Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com.

11 esponsibility endence rn ficacy atory depression nce tiny Individualize treatment and titrate to the optimal dose 12-HOUR DOSING FOR CONSISTENT RELIEF* Efficac Psychological depend Broad range of 7 dosage strengths Individualize treatment and titrate up to the lowest dose that provides adequate analgesia and minimizes adverse reactions 1 Patients in both the BELBUCA and placebo groups of the clinical trials were allowed to receive rescue medications to minimize opioid withdrawal symptoms and/or breakthrough pain 1 Films are actual size. Maximum dose is 900 mcg every 12 hours. 1 How to prescribe Titration example script BELBUCA 150 mcg Apply 1 film buccally every 12 hours Days supply: 15 Qty: 30 Refills: 0 Maintenance example script BELBUCA is Schedule III and can be refilled up to 5 times over 6 months before patients would require a new prescription, depending on state or local regulations. If you prefer to follow up with patients more frequently, consider prescribing a lower number of refills. 1,22 BELBUCA 600 mcg Apply 1 film buccally every 12 hours Days supply: 30 Qty: 60 Refills: 5 Remember to monitor and periodically reassess patients as they begin and throughout treatment with BELBUCA. Examples only. Please refer to the full Prescribing Information to determine appropriate dosing. BELBUCA Copay Card Eligible patients pay as little as $0 copay now and only $25 copay later * Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. In the 1st month, eligible patients pay as little as $0 up front and save up to $100 off their copay per prescription, for up to 3 prescriptions. In the 2nd month, patients pay as little as $25 up front and save up to $75 off their remaining copay per prescription, for up to 3 prescriptions. In the 3rd-12th months, patients pay as little as $25 up front and save up to $75 off their remaining copay per prescription, for only 1 prescription per month. Restrictions apply. Please see eligibility criteria on the back of the card. NOTE: Since each individual BELBUCA Copay Card contains a unique number, please do not photocopy or print multiple copies. BioDelivery Sciences is committed to helping patients access and use the medication they need. (buprenorphine buccal film) A Responsible Choice

12 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. IMPORTANT SAFETY INFORMATION about BELBUCA WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS Addiction,, 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 patient s risk prior to prescribing BELBUCA, and monitor patients regularly for these behaviors and conditions. Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to 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. 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. 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. 12

13 WARNINGS AND PRECAUTIONS Addiction,, 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. 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. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addition, abuse, and misuse, the FDA has required a REMS for these products. Under the REMS requirements, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. To obtain further information on the REMS and for a list of accredited REMS CME/CE, call , or log on to Healthcare providers are strongly encouraged to complete a REMS-compliant education program; to discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients or caregivers; to emphasize to patients and caregivers the importance of reading the Medication Guide; and to consider using other tools to improve patient, household, and community safety, such as patientprescriber agreements that reinforce patient-prescriber responsibilities. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended., 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. (buprenorphine buccal film) A Responsible Choice

14 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 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. 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. 14

15 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 or FDA at FDA-1088 or Intended for healthcare professionals of the United States of America only. REFERENCES: 1. BELBUCA [Prescribing Information]. Raleigh, NC: BioDelivery Sciences International, Inc.; December Data on file. DOF-BL-04. BioDelivery Sciences International, Inc.; Center for Drug Evaluation and Research (U.S.). Orange book: approved drug products with therapeutic equivalence evaluations. Rockville, MD: U.S. Dept. of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, Accessed October Davis MP. Twelve reasons for considering buprenorphine as a frontline analgesic in the management of pain. J Support Oncol. 2012; Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006;96(5): Wiegand TJ, Bettendorf JA. Buprenorphine/naloxone toxicity. Medscape website. com/article/ overview#showall. Updated December 29, Accessed October 22, Yassen A, Olofsen E, van Dorp E, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the reversal of buprenorphine-induced respiratory depression by naloxone: a study in healthy volunteers. Clin Pharmacokinet. 2007;46(11): Walsh SL, Preston KL, Bigelow GE, Stitzer ML. Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther. 1995;274(1): Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55(5): Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth. 2005;94(6): Dahan A, Romberg R, Teppema L, Sarton E, Bijl H, Olofsen E. Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion. Anesthesiology. 2004;101(5): Data on file. DOF-BL-13. BioDelivery Sciences International, Inc.; Gimbel J, Spierings ELH, Katz N, Xiang Q, Tzanis E, Finn A. 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): Data on file. DOF-BL-12. BioDelivery Sciences International, Inc.; Data on file. DOF-BL-09. BioDelivery Sciences International, Inc.; Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. and tolerability of buccal buprenorphine in opioid-naïve patients with moderate to severe chronic low back pain. Postgrad Med. 2016;128(1): Hale M, Urdaneta V, Kirby MT, Xiang Q, Rauck R. Long-term safety and analgesic efficacy of buprenorphine buccal film in patients with moderate-to-severe chronic pain requiring around-the-clock opioids. J Pain Res. 2017;10: Data on file. DOF-BL-01. BioDelivery Sciences International, Inc.; Data on file. DOF-BL-11. BioDelivery Sciences International, Inc.; Therapeutic Research Center. Equianalgesic dosing of opioids for pain management. New Hampshire Medical Society website. Chart-Prescriber-Letter-2012.pdf. Published Accessed October McPherson ML. Transdermal and parenteral fentanyl dosage calculations and conversions. In: McPherson ML, ed. Demystifying opioid conversion calculations: a guide to effective dosing. 1st ed. Bethesda, MD: AHSP; 2009: Drug Enforcement Administration. Questions & Answers Prescriptions. US Department of Justice website. Accessed (buprenorphine buccal film) May 9, Drug Enforcement Administration. Controlled substances by CSA schedule. gov/21cfr/21usc/812.htm. Accessed October 22, A Responsible Choice

16 al dependence A RESPONSIBLE CHOICE Conce Psychological depende The first and only Schedule III long-acting opioid with buccal delivery for chronic pain* Schedule III drug class 23 May have a potential for abuse less than substances in Schedules I or II, and abuse may lead to moderate or low physical dependence or high psychological dependence Proven efficacy for chronic pain 1,12 The majority of patients previously taking 160 mg/d oral morphine milligram equivalents (MME) achieved consistent chronic pain relief 12-hour dosing 1 May deliver around-the-clock analgesia Novel buccal film technology 2 Bypasses the first-pass metabolism, enhancing the bioavailability of buprenorphine Dose-ceiling effect on respiratory depression 5,6,9-11 Unlike other opioids, buprenorphine appears to exhibit a dose-ceiling effect on respiratory depression Established tolerability in opioid-experienced patients 1 Rates of side effects were comparable to placebo Individualized titration 1 Range of 7 film strengths enables titration up to the lowest effective and tolerable dose Please visit us at BELBUCA.com Please visit the Opioid Analgesic REMS website at Opioid Analgesic REMS=Opioid Analgesic Risk Evaluation and Mitigation Strategy. *Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Controlled Substances Act, 21 U.S.C. 812(b)(3). IMPORTANT SAFETY INFORMATION about BELBUCA 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. Please see additional Important Safety Information, including Boxed Warning, on pages Please see full Prescribing Information at BELBUCA.com. Rx Only BELBUCA is a registered trademark of BioDelivery Sciences International, Inc BioDelivery Sciences International, Inc. All rights reserved. Printed in USA. BEL December 2018 BELBUCA.com (buprenorphine buccal film) A Responsible Choice