Buprenorphine

1 INDICATIONS AND USAGE Buprenorphine sublingual tablet is indicated for the treatment of opioid dependence and is preferred for induction. Buprenorphine sublingual tablet should be used as part of a complete treatment plan to include counseling and psychosocial support. Buprenorphine sublingual tablet, contains buprenorphine, a partial opioid agonist, and is indicated for the treatment of opioid dependence and is preferred for induction. (1) Buprenorphine sublingual tablet should be used as part of a complete treatment plan that includes counseling and psychosocial support. (1)

12.1 Mechanism of Action Buprenorphine sublingual tablet contains buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

2 DOSAGE AND ADMINISTRATION Administer buprenorphine sublingual tablet sublingually as a single daily dose. (2.1) Strongly consider prescribing naloxone at the time buprenorphine sublingual tablet is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. (2.2) To avoid precipitating withdrawal, induction with buprenorphine sublingual tablet should be undertaken when objective and clear signs of withdrawal are evident. (2.3) Buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is generally initiated after two days of buprenorphine sublingual tablet titration. (2.4) Administer buprenorphine sublingual tablets as directed in the Full Prescribing Information. (2.3, 2.4, 2.5) Buprenorphine sublingual tablet must be administered whole. Do not cut, chew, or swallow buprenorphine sublingual tablets. (2.5) When discontinuing treatment, gradually taper to avoid signs and symptoms of withdrawal. (2.9) 2.1 Important Dosage and Administration Instructions Buprenorphine sublingual tablet is administered sublingually as a single daily dose. Buprenorphine sublingual tablet does not contain naloxone and is preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of buprenorphine sublingual tablet for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablet; for example, those patients who have been shown to be hypersensitive to naloxone. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. 2.2 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. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine sublingual tablet. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.2)]. Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine sublingual tablet itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine sublingual tablet and its affinity for the mu-opioid receptor [see Overdosage (10)]. Inform patients and caregivers of their options for obtaining 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) [see Patient Counseling Information (17)]. 2.3 Induction Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-acting opioid products), the time since last opioid use, and the degree or level of opioid dependence. Patients dependent on heroin or other short-acting opioid products: At treatment initiation, the first dose of buprenorphine sublingual tablet should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioid. It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapid

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Respiratory and CNS Depression [see Warnings and Precautions (5.2, 5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)] • Adrenal Insufficiency [see Warnings and Precautions (5.6)] • Opioid Withdrawal [see Warnings and Precautions (5.7, 5.10)] • Hepatitis, Hepatic Events [see Warnings and Precautions (5.8)] • Hypersensitivity Reactions [see Warnings and Precautions (5.9)] • Orthostatic Hypotension [see Warnings and Precautions (5.16)] • Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.17)] • Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.18)] Adverse events commonly observed with administration of buprenorphine are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. ( 6 )To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch. 6.1 Clinical Trials 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. The safety of buprenorphine sublingual tablet was supported by clinical trials using buprenorphine sublingual tablet, buprenorphine and naloxone sublingual tablet and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction. Few differences in adverse event profile were noted between buprenorphine sublingual tablet or buprenorphine administered as a sublingual solution. The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 1). Table 1. Adverse Events ≥ 5% by Body System and Treatment Group in a 4-week study N(%) N(%) Body System / Adverse Event (COSTART Terminology) Buprenorphine Sublingual Tablets 16 mg/day N = 103 Placebo N = 107 Body as a Whole Asthenia 5 (4.9%) 7 (6.5%) Chills 8 (7.8%) 8 (7.5%) Headache 30 (29.1%) 24 (22.4%) Infection 12 (11.7%) 7 (6.5%) Pain 19 (18.4%) 20 (18.7%) Pain Abdomen 12 (11.7%) 7 (6.5%) Pain Back 8 (7.8%) 12 (11.2%) Withdrawal Syndrome 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 4 (3.9%) 7 (6.5%) Digestive System Constipation 8 (7.8%) 3 (2.8%) Diarrhea 5 (4.9%) 16 (15.0%) Nausea 14 (13.6%) 12 (11.2%) Vomiting 8 (7.8%) 5 (4.7%) Nervous System Insomnia 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 10 (9.7%) 14 (13.1%) Skin and Appendages Sweating 13 (12.6%) 11 (10.3%) The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study. Table 2. Adverse Events (≥ 5%) by Body System and Treatment Group in a 16-week Study Body System /Adverse Event (COSTART Terminology) Buprenorphine Dose* Very Low* (N=184) Low* (N=180) Moderate* (N=186) High* (N=181) Total* (N=731) N (%) N (%) N (%) N (%) N (%) Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu Syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury Accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain Back 18 (10%) 29 (16%) 28

5 WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: Buprenorphine can be abused in a similar manner to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. (5.1) Respiratory Depression: Life-threatening respiratory depression and death have occurred in association with buprenorphine use. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets. (5.2, 5.3) Unintentional Pediatric Exposure : Store buprenorphine sublingual tablet safely out of the sight and reach of children. Buprenorphine can cause severe, possibly fatal, respiratory depression in children. (5.4) Neonatal Opioid Withdrawal Syndrome : Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. (5.5) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.6) Risk of Opioid Withdrawal with Abrupt Discontinuation : If treatment is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. (5.7) Risk of Hepatitis, Hepatic Events : Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events. (5.8) Precipitation of Opioid Withdrawal Signs and Symptoms : An opioid withdrawal syndrome is likely to occur with parenteral misuse of buprenorphine sublingual tablet by individuals physically dependent on full opioid agonists, or by sublingual administration before the agonist effects of other opioids have subsided. (5.10) Risk of Overdose in Opioid-Naïve Patients: Buprenorphine sublingual tablet is NOT appropriate as an analgesic. There have been reported deaths of opioid naïve individuals who received a 2 mg sublingual dose of buprenorphine. (5.11) 5.1 Addiction, Abuse, and Misuse Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)]. 5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets [see Warnings and Precautions (5.3), Drug Interactions (7)]. Use buprenorphine sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression). 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 [see Patient Counseling Information (17)]. 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,

4 CONTRAINDICATIONS Buprenorphine sublingual tablet is contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions (5.9)]. Hypersensitivity to buprenorphine. ( 4 )

10 OVERDOSAGE Clinical Presentation The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death. Treatment of Overdose In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated. In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of buprenorphine sublingual tablet should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.