BRIXADI

WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; BRIXADI RISK EVALUATION AND MITIGATION STRATEGY Serious harm or death could result if administered intravenously. BRIXADI forms a liquid crystalline gel upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo‐embolic events, including life-threatening pulmonary emboli, if administered intravenously. (5.1) Because of the risk of serious harm or death that could result from intravenous self‐administration, BRIXADI is only available through a restricted program called the BRIXADI REMS. Healthcare settings and pharmacies that order and dispense BRIXADI must be certified in this program and comply with the REMS requirements. (5.2) WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; BRIXADI RISK EVALUATION AND MITIGATION STRATEGY See full prescribing information for complete boxed warning. Serious harm or death could result if administered intravenously. ( 5.1 ) BRIXADI is only available through a restricted program called the BRIXADI REMS. Healthcare settings and pharmacies that order and dispense BRIXADI must be certified in this program and comply with the REMS requirements. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: Buprenorphine can be abused in a manner similar to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. ( 5.3 ) Respiratory Depression: Life-threatening respiratory depression and death have occurred in association with buprenorphine. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BRIXADI. ( 5.4 , 5.5 ) Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.6 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.7 ) Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment with BRIXADI is discontinued, monitor patients for withdrawal and treat appropriately. ( 5.8 ) Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to and during treatment. ( 5.9 ) Latex Allergy: The packaging of this product contains natural rubber latex which may cause allergic reactions. ( 5.10 ) Risk of Withdrawal in Patients Dependent on Full Agonist Opioids: Administer a test dose of transmucosal buprenorphine and monitor for precipitated withdrawal before injecting BRIXADI. ( 5.11 ) Treatment of Emergent Acute Pain: Treat pain with a non-opioid analgesic whenever possible. If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect. ( 5.12 ) 5.1 Risk of Serious Harm or Death with Intravenous Administration Intravenous injection presents significant risk of serious harm or death as BRIXADI forms a liquid crystalline gel upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, could result if administered intravenously [see Warnings and Precautions (5.2) , Drug Abuse and Dependence (9.2) ] . Do not administer intravenously, intramuscularly, or intradermally. 5.2 BRIXADI Risk Evaluation and Mitigation Strategy (REMS) BRIXADI is available only through a restricted program called the BRIXADI REMS because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense BRIXADI directly to a healthcare provider for administration by a healthcare provider. Notable requirements of the BRIXADI REMS include the following: Healthcare Settings and Pharmacies that order and dispense BRIXADI must be certified in the BRIXADI REMS. Certified Healthcare Settings and Pharmacies must establish processes and procedures to verify BRIXADI is provided directly to a healthcare provider for administration by a healthcare provider, and the drug is not dispensed to the patient. Certified Healthcare Settings and Pharmacies must not distribute, transfer, loan, or sell BRIXADI. Further information is available at www.BRIXADIREMS.com or by calling 1-833-274-9234. 5.3 Addiction, Abuse, and Misuse BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid use disorder and addictive behaviors [see Drug Abuse and Dependence (9.2) ] . 5.4 Life-Threatening Respiratory and Central Nervous System (CNS) Depression Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant drugs including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BRIXADI [see Drug Interactions (7) , Warnings and Precautions (5.5) , Patient Counseling Information (17) ] . Use BRIXADI with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression) . Due to its extended-release characteristics, if BRIXADI is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). 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, monitor patient during treatment and consider dose reduction using best practices for opioid taper. [see Clinical Supervision (2.5) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing or recommending an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with BRIXADI. Also consider prescribing or recommending such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.2) ]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the- counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Advise patients and caregivers that an opioid overdose reversal agent, such as naloxone or nalmefene, may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of an opioid overdose reversal agent may be necessary due to the long duration of action of buprenorphine and its affinity for the mu receptor [see Overdosage (10) ]. Educate patients and caregivers on how to recognize respiratory depression and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered. 5.5 Managing Risks From Concomitant Use of Benzodiazepines or Other CNS Depressants Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) increases the risk of adverse reactions including overdose, respiratory depression, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone. As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines sedatives, opioid analgesics, and alcohol. Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate. Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use with buprenorphine. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patients' buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use. If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder [see Dosage and Administration (2.2) , Warnings and Precautions (5.4) , Overdosage (10) ]. In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [ see Drug Interactions (7) ]. 5.6 Neonatal Opioid Withdrawal Syndrome Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare providers should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations (8.1) ] . Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) ] . This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy. 5.7 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. 5.8 Risk of Opioid Withdrawal with Abrupt Discontinuation of BRIXADI Treatment Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence (9.2 , 9.3) ] . Patients who elect to discontinue BRIXADI treatment should be monitored for withdrawal signs and symptoms with consideration given to the product's extended-release characteristics [See Clinical Pharmacology (12.3) ]. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing BRIXADI. 5.9 Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine for the treatment of opioid use disorder, both in clinical trials and through postmarketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, 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. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests are recommended prior to initiation of treatment to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Monitor patients with declining hepatic function for side effects resulting from increased exposure to buprenorphine. 5.10 Hypersensitivity Reactions Cases of hypersensitivity to buprenorphine containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or other components is a contraindication to the use of BRIXADI [see Contraindications (4) ]. Latex Allergies : The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals. 5.11 Precipitation of Opioid Withdrawal Signs and Symptoms Because of the partial agonist properties of buprenorphine, BRIXADI injection may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. In patients who are new entrants to treatment, administer a test dose of transmucosal buprenorphine and monitor for precipitated withdrawal and treat appropriately [see Dosage and Administration (2.3) ]. 5.12 Risks Associated with Treatment of Emergent Acute Pain While on BRIXADI, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving BRIXADI with non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare provider, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation. Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with BRIXADI [see Patient Counseling Information (17) ] . Please refer to Section 2.5 for further details on duration of exposure following discontinuation for both weekly and monthly BRIXADI formulations. [see Clinical Supervision (2.5) ] . 5.13 Use in Opioid Naïve Patients There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. BRIXADI is not appropriate for use in opioid naïve patients. 5.14 Use in Patients With Impaired Hepatic Function In a pharmacokinetic study with transmucosal buprenorphine, 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. The effect of hepatic impairment on the pharmacokinetics of BRIXADI, has not been studied. Because of the long-acting nature of the product, adjustments to dosages of BRIXADI are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI. Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine and patients may require a dose adjustment [see Use in Specific Populations (8.6) ]. 5.15 QTc Prolongation Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT- prolonging agents is not known. Consider these observations in clinical decisions when prescribing BRIXADI to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia. [see Clinical Pharmacology (12.2) ]. 5.16 Impairment of Ability to Drive and Operate Machinery BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially for the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the BRIXADI (weekly) or BRIXADI (monthly) injections, which achieves steady-state at the fourth weekly or monthly injection. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BRIXADI does not adversely affect their ability to engage in such activities. [see Clinical Pharmacology (12.3) ]. 5.17 Orthostatic Hypotension Buprenorphine may produce orthostatic hypotension in ambulatory patients. 5.18 Elevation of Cerebrospinal Fluid Pressure Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances where cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. 5.19 Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. 5.20 Effects in Acute Abdominal Conditions Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. 5.21 Unintentional Pediatric Exposure Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.3) ] Respiratory and CNS Depression [see Warnings and Precautions (5.4) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.6) ] Adrenal Insufficiency [see Warnings and Precautions (5.7) ] Opioid Withdrawal [see Warnings and Precautions (5.8 , 5.11) ] Hepatitis, Hepatic Events [see Warnings and Precautions (5.9) ] Hypersensitivity Reactions [see Warnings and Precautions (5.10) ] Orthostatic Hypotension [see Warnings and Precautions (5.17) ] Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (5.18) ] Elevation of Intracholedochal Pressure [see Warnings and Precautions (5.19) ] Adverse reactions commonly associated with BRIXADI administration (in ≥5% of patients) were injection site pain, headache, constipation, nausea, injection site erythema, injection site pruritus, insomnia, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Braeburn at 1-833-274-9234 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 BRIXADI was evaluated in 440 opioid-dependent patients across two, Phase 3 clinical studies: one double-blind, active-control (n=213) and one open-label (n=227). In these studies, a total of 305 patients were exposed to BRIXADI for at least 24 weeks and 132 patients were exposed for at least 48 weeks. In the first 12-week phase of the double-blind, double-dummy, active-controlled study, patients received BRIXADI (weekly) (16, 24, 32 mg) or matching placebo injections after a one-week titration. In the second 12-week phase of the study, patients remaining in the study received BRIXADI (monthly) (64, 96, 128, or 160 mg) or matching placebo injections. The 160 mg monthly dose is not an approved dose. Those randomized to receiving placebo injections were the active control groups and received sublingual buprenorphine/naloxone tablets at corresponding doses to BRIXADI. Patients receiving active BRIXADI injections also received placebo sublingual tablets. Adverse reactions led to premature discontinuation in 10 (4.7%) patients in the group receiving BRIXADI compared to 5 (2.3%) patients in the sublingual buprenorphine/naloxone group, during the double-blind study. Adverse reactions commonly reported after BRIXADI administration (≥5%, regardless of dose and regimen) in the double-blind study, were injection site pain (9.9%), headache (7.5%), constipation (7.5%), nausea (7.0%), injection site erythema (6.6%), injection site pruritus (6.1%), Insomnia (5.6%), and urinary tract infection (5.2%). Table 5 shows the adverse reactions for BRIXADI compared with the active-control group (SL BPN/NX) in the double-blind study. Table 5: Adverse Reactions in the Phase 3 Double-Blind Study: ≥ 2% of Patients Receiving BRIXADI (Excluding Injection Site Reactions). System Organ Class (SOC) BRIXADI Total = This group includes all subjects exposed to varying doses of both the BRIXADI (weekly) and BRIXADI (monthly) formulations. SL BPN/NX = SL BPN/NX denotes the active comparator: patients assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a 'booster' injection of BRIXADI (weekly), 8mg, per protocol. All patients in Study 421 received a single test dose of 4mg SL BPN/NX before randomization into either arm. Preferred Term (PT) = report of adverse reactions that occurred in ≥ 2% of the patients randomized to BRIXADI in Study HS-11-421. Patients are represented once per PT (N=213) n(%) (N=215) n(%) Cardiac disorders 6 (2.8%) 9 (4.2%) Tachycardia 5 (2.3) 5 (2.3) Gastrointestinal disorders 43 (20.2%) 45 (20.9%) Constipation 16 (7.5) 16 (7.4) Diarrhea 6 (2.8) 7 (3.3) Nausea 15 (7.0) 17 (7.9) Vomiting 9 (4.2) 8 (3.7) Infections and infestations 42 (19.7%) 50 (23.3%) Urinary tract infection 11 (5.2) 10 (4.7) Upper respiratory tract infection 9 (4.2) 9 (4.2) Musculoskeletal and connective tissue disorders 20 (9.4%) 22 (10.2%) Arthralgia 7 (3.3) 3 (1.4) Nervous system disorders 27 (12.7%) 27 (12.6%) Headache 16 (7.5) 17 (7.9) Psychiatric disorders 20 (9.4%) 20 (9.3%) Anxiety 6 (2.8) 7 (3.3) Insomnia 12 (5.6) 6 (2.8) Injection site reactions in the double-blind study are presented in Table 6 below. The majority of injection site-related adverse events were mild or moderate in severity. No injection site reactions were reported as severe intensity. Table 6: Injection site reactions in the Double-Blind Phase 3 Study: ≥ 2% of Patients Receiving BRIXADI Preferred Term (PT) = Injection site reactions (ISR) that occurred in ≥2% of patients receiving BRIXADI, in the controlled trial, HS-11-421. Patients are represented once per PT. BRIXADI Total = This group includes patients exposed to varying doses of both the BRIXADI weekly and monthly formulations. (N=213) n(%) SL BPN/NX = SL BPN/NX denotes the active comparator: subjects assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a supplemental 'booster' injection of BRIXADI (weekly), 8mg, per protocol. (N=215) n(%) Administration site reactions = The ISRs that occurred in ≥2% of the patients randomized to BRIXADI were reported under the HGLT of Administration site reactions. However, ISRs were also identified under the Bacterial infectious disorders HGLT (of which, there were three injection site related cellulitis reactions in the BRIXADI group and one in the SL BPN/NX group, respectively) but those numbers did not rise to level of reporting. Tabulation included all events coded as treatment emergent and injection site reactions, regardless of treatment emergent flags. 44 (20.7%) 49 (22.8%) Injection site pain 21 (9.9%) 17 (7.9%) Injection site erythema 14 (6.6%) 12 (5.6%) Injection site pruritus 13 (6.1%) 13 (6.0%) Injection site swelling 10 (4.7%) 7 (3.3%) Injection site reaction 9 (4.2%) 7 (3.3%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported postmarketing adverse event observed with buprenorphine sublingual tablets, excluding drug exposure during pregnancy, was drug misuse or abuse. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with buprenorphine [see Contraindications (4) ]. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] . The following adverse reactions have been identified during post-approval use of an identical buprenorphine extended-release injection for subcutaneous use outside of the United States and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Injection site mass, abscess, ulceration, and necrosis : Cases of injection site abscess, ulceration and necrosis have been reported after treatment initiation. Some cases have required debridement and antibiotic treatment. The likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration. Insufficient dosing : Cases of drug withdrawal reactions consistent with insufficient drug dosing have been reported, often occurring at or after two weeks of treatment initiation and resolving upon dose increase. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opiods. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.

<table width="85%" ID="t5"><caption>Table 5: Adverse Reactions in the Phase 3 Double-Blind Study: &#x2265; 2% of Patients Receiving BRIXADI (Excluding Injection Site Reactions).</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">System Organ Class (SOC)</th><th styleCode="Rrule">BRIXADI Total<footnote> = This group includes all subjects exposed to varying doses of both the BRIXADI (weekly) and BRIXADI (monthly) formulations. </footnote></th><th styleCode="Rrule">SL BPN/NX<footnote> = SL BPN/NX denotes the active comparator: patients assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a &apos;booster&apos; injection of BRIXADI (weekly), 8mg, per protocol. All patients in Study 421 received a single test dose of 4mg SL BPN/NX before randomization into either arm.</footnote></th></tr><tr><th styleCode="Lrule Rrule"> Preferred Term (PT)<footnote> = report of adverse reactions that occurred in &#x2265; 2% of the patients randomized to BRIXADI in Study HS-11-421. Patients are represented once per PT</footnote></th><th styleCode="Rrule">(N=213) n(%)</th><th styleCode="Rrule">(N=215) n(%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Cardiac disorders</content></td><td styleCode="Rrule"><content styleCode="bold">6 (2.8%)</content></td><td styleCode="Rrule"><content styleCode="bold">9 (4.2%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tachycardia</td><td styleCode="Rrule">5 (2.3)</td><td styleCode="Rrule">5 (2.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"><content styleCode="bold">43 (20.2%)</content></td><td styleCode="Rrule"><content styleCode="bold">45 (20.9%)</content></td></tr><tr><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">16 (7.5)</td><td styleCode="Rrule">16 (7.4)</td></tr><tr><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">6 (2.8)</td><td styleCode="Rrule">7 (3.3)</td></tr><tr><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">15 (7.0)</td><td styleCode="Rrule">17 (7.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">9 (4.2)</td><td styleCode="Rrule">8 (3.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule"><content styleCode="bold">42 (19.7%)</content></td><td styleCode="Rrule"><content styleCode="bold">50 (23.3%)</content></td></tr><tr><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">11 (5.2)</td><td styleCode="Rrule">10 (4.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Upper respiratory tract infection</td><td styleCode="Rrule">9 (4.2)</td><td styleCode="Rrule">9 (4.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"><content styleCode="bold">20 (9.4%)</content></td><td styleCode="Rrule"><content styleCode="bold">22 (10.2%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Arthralgia</td><td styleCode="Rrule">7 (3.3)</td><td styleCode="Rrule">3 (1.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule"><content styleCode="bold">27 (12.7%)</content></td><td styleCode="Rrule"><content styleCode="bold">27 (12.6%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">16 (7.5)</td><td styleCode="Rrule">17 (7.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td><td styleCode="Rrule"><content styleCode="bold">20 (9.4%)</content></td><td styleCode="Rrule"><content styleCode="bold">20 (9.3%)</content></td></tr><tr><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">6 (2.8)</td><td styleCode="Rrule">7 (3.3)</td></tr><tr><td styleCode="Lrule Rrule"> Insomnia</td><td styleCode="Rrule">12 (5.6)</td><td styleCode="Rrule">6 (2.8)</td></tr></tbody></table>

<table width="85%" ID="t6"><caption>Table 6: Injection site reactions in the Double-Blind Phase 3 Study: &#x2265; 2% of Patients Receiving BRIXADI</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th valign="middle" align="center" styleCode="Lrule Rrule">Preferred Term (PT)<footnote> = Injection site reactions (ISR) that occurred in &#x2265;2% of patients receiving BRIXADI, in the controlled trial, HS-11-421. Patients are represented once per PT.</footnote></th><th styleCode="Rrule">BRIXADI Total<footnote> = This group includes patients exposed to varying doses of both the BRIXADI weekly and monthly formulations. </footnote> (N=213) n(%)</th><th styleCode="Rrule">SL BPN/NX<footnote> = SL BPN/NX denotes the active comparator: subjects assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a supplemental &apos;booster&apos; injection of BRIXADI (weekly), 8mg, per protocol.</footnote> (N=215) n(%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Administration site reactions<footnote> = The ISRs that occurred in &#x2265;2% of the patients randomized to BRIXADI were reported under the HGLT of Administration site reactions. However, ISRs were also identified under the Bacterial infectious disorders HGLT (of which, there were three injection site related cellulitis reactions in the BRIXADI group and one in the SL BPN/NX group, respectively) but those numbers did not rise to level of reporting. Tabulation included all events coded as treatment emergent <content styleCode="italics">and </content>injection site reactions, regardless of treatment emergent flags.</footnote></content></td><td styleCode="Rrule"><content styleCode="bold">44 (20.7%)</content></td><td styleCode="Rrule"><content styleCode="bold">49 (22.8%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Injection site pain</td><td styleCode="Rrule">21 (9.9%)</td><td styleCode="Rrule">17 (7.9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Injection site erythema</td><td styleCode="Rrule">14 (6.6%)</td><td styleCode="Rrule">12 (5.6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Injection site pruritus</td><td styleCode="Rrule">13 (6.1%)</td><td styleCode="Rrule">13 (6.0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Injection site swelling</td><td styleCode="Rrule">10 (4.7%)</td><td styleCode="Rrule">7 (3.3%)</td></tr><tr><td styleCode="Lrule Rrule"> Injection site reaction</td><td styleCode="Rrule">9 (4.2%)</td><td styleCode="Rrule">7 (3.3%)</td></tr></tbody></table>