BRIXADI

1 INDICATIONS AND USAGE BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support. BRIXADI contains buprenorphine, a partial opioid agonist. BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. ( 1 ) BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support. ( 1 )

2 DOSAGE AND ADMINISTRATION Only healthcare providers should prepare and administer BRIXADI. ( 2.1 ) BRIXADI (weekly) and BRIXADI (monthly) are different formulations. Doses of BRIXADI (weekly) cannot be combined to yield an equivalent BRIXADI (monthly) dose. ( 2.1 ) BRIXADI should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm ( 2.1 ) Strongly consider recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) at the time BRIXADI 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 ) Injection sites for BRIXADI (weekly) should be alternated/rotated for each injection. ( 2.7 ) See Full Prescribing Information for administration instructions. ( 2.7 ) 2.1 Important Dosage and Administration Instructions FOR SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER BRIXADI INTRAVENOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY [see Warnings and Precautions (5.1) , Instructions for Use (2.6) ]. BRIXADI exists in two formulations. Doses of BRIXADI (weekly) cannot be combined to yield a monthly dose. Only healthcare providers should prepare and administer BRIXADI. Administer BRIXADI as a single injection. Do not divide. BRIXADI should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm. In patients who are not currently receiving buprenorphine treatment, for BRIXADI (weekly), the upper arm site should only be used after steady-state has been achieved (4 consecutive doses) [see Instructions for Use (2.6) ]. Injection in the arm site was associated with approximately 10% lower plasma levels than other sites. Injection sites should be alternated/rotated between injections for BRIXADI (weekly) [see Instructions for Use (2.6) ]. For all patients, the dose of BRIXADI must be individualized based on patient tolerability and/or efficacy. BRIXADI (weekly) should be administered in 7-day intervals. BRIXADI (monthly) should be administered in 28-day intervals. For patients not currently receiving buprenorphine treatment, begin with a test dose of 4 mg transmucosal buprenorphine to establish that buprenorphine is tolerated without precipitated withdrawal, and then transition to BRIXADI (weekly). Initiating treatment with BRIXADI as the first buprenorphine product has not been studied. Initiating treatment with BRIXADI (monthly) in new entrants to treatment has not been studied [see Dosage and Administration (2.3) ] . Patients who are currently being treated with other buprenorphine-containing products can start treatment with either BRIXADI (weekly) or BRIXADI (monthly) [see Dosage and Administration (2.3) ] . Administer each injection using only the syringe and safety needle included with the product [see Instructions for Use (2.6) ] . Caution: The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals [see Warnings and Precautions (5.10) ] . To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point, and the monthly dose may be administered up to 1 week before or after the monthly time point. If a dose is missed, the next dose should be administered as soon as practically possible. 2.2 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 overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. Also consider prescribing or recommending such a…

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…

4 CONTRAINDICATIONS BRIXADI is contraindicated in patients with hypersensitivity (e.g., anaphylactic shock) to buprenorphine, or any other ingredients in the solution for injection [see Warnings and Precautions (5.10) ]. Hypersensitivity to buprenorphine or any other ingredients in BRIXADI. ( 4 )

7 DRUG INTERACTIONS Table 7: Clinically Significant Drug Interactions Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatment [see Warnings and Precautions (5.5) ] . 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 Warnings and Precautions (5.4) ]. Examples: Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids. Inhibitors of CYP3A4 Clinical Impact: The effects on buprenorphine exposure in patients treated with BRIXADI have not been studied, and the effects may be dependent on the route of administration. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity [see Clinical Pharmacology (12.3) ]. The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BRIXADI is achieved. Intervention: Patients Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inhibitors: Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate. Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inhibitor : Monitor for signs and symptoms of over-medication. If signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, reduce the dose of BRIXADI. If available doses do not permit achievement of the desired dose, it may be necessary to discontinue treatment with BRIXADI and treat the patient with a formulation of buprenorphine that permits more precise dose adjustments. Patients Stabilized on BRIXADI in the Setting of Concomitant Medication That is a CYP3A4 Inhibitor, and the Concomitant Medication is Discontinued : Monitor for withdrawal and consider a dosage adjustment of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level in the absence of the concomitant medication, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments. Examples: azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), and protease inhibitors (e.g., ritonavir, indinavir, and saquinavir) CYP3A4 Inducers Clinical Impact: The effects of co-administered CYP3A4 inducers on buprenorphine exposure in patients treated with BRIXADI have not been studied. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity [see Clinical Pharmacology (12.3) ] . CYP3A4 inducers may induce metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a de…

8.1 Pregnancy Risk Summary The data on use of buprenorphine, the active ingredient in BRIXADI in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on sublingual buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data ]. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses 21 times and equal to, respectively, the mean daily dose of 4.6 mg buprenorphine delivered by either 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly). Pre- and post-natal development studies in rats demonstrated increased neonatal deaths at doses approximately equal to and above and dystocia at 11 times the mean daily dose of 4.6 mg buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 4 times and greater than the mean daily dose of 4.6 mg of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses 2 and 21 times the mean daily dose of 4.6 mg of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. BRIXADI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus Clinical Considerations Disease-associated maternal and embryo-fetal risk Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Dose Adjustment during Pregnancy and the Postpartum Period Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely, and the dose adjusted as necessary. Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with BRIXADI. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.6) ]. Labor or Delivery Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate. Data Human Data Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of in…

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%) Tachycard…