SUBLOCADE

SUBLOCADE (buprenorphine extended-release) injection is a clear, viscous, colorless to yellow to amber, sterile solution for subcutaneous injection only . It is designed to deliver buprenorphine at a controlled rate over a one month period. The active ingredient in SUBLOCADE is buprenorphine free base, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist. Buprenorphine is dissolved in the ATRIGEL ® delivery system at 18% by weight. The ATRIGEL ® delivery system is a biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent, N -methyl-2-pyrrolidone (NMP). SUBLOCADE is provided in dosage strengths of 100 mg and 300 mg. Table 6 presents the delivered amounts of the raw materials and the approximate delivered volume for the two dosage strengths. Table 6 Amounts of Raw Materials and Delivered Volume for the Dosage Strengths Raw Materials in SUBLOCADE 100 mg Dosage 300 mg Dosage Buprenorphine 100 mg 300 mg Poly(DL-lactide-co-glycolide) 178 mg 533 mg N -methyl-2-pyrrolidone 278 mg 833 mg Approximate Delivered Volume 0.5 mL 1.5 mL The molecular weight of buprenorphine free base is 467.6, and its molecular formula is C 29 H 41 NO 4 . Chemically, buprenorphine is (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol. The structural formula is: Structural Formula

SUBLOCADE 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. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. SUBLOCADE contains buprenorphine, a partial opioid agonist, and 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 ) SUBLOCADE should be used as part of a complete treatment program that includes counseling and psychosocial support. ( 1 )

SUBLOCADE is for healthcare provider preparation and administration only. ( 2.1 ) SUBLOCADE is administered only by subcutaneous injection in the abdomen, thigh, buttock, or back of the upper arm. ( 2.1 ) Strongly consider prescribing naloxone at the time SUBLOCADE 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 ) Patients not currently taking buprenorphine should receive an initial dose (e.g. 4 mg) of transmucosal buprenorphine before administering the first injection of SUBLOCADE. Monitor patients in a healthcare setting after injection with SUBLOCADE to assess for symptoms of worsening withdrawal or sedation. Patients' symptoms should be stable or improving prior to release from the healthcare setting. ( 2.3 ) The second injection of SUBLOCADE may be administered as early as one week after the first injection. ( 2.3 ) Injection sites should be rotated between doses. ( 2.3 ) The recommended dose of SUBLOCADE is two initial doses of 300 mg followed by 100 mg monthly maintenance doses. ( 2.3 ) Increasing the maintenance dose to 300 mg monthly may be considered for patients in which the benefits outweigh the risks. ( 2.3 ) Examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot. ( 2.4 ) See Full Prescribing Information for administration instructions. ( 2.5 ) 2.1 Important Dosing and Administration Information FOR SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER SUBLOCADE INTRAVENOUSLY, INTRAMUSCULARLY OR INTRADERMALLY [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 , 5.6 )] . SUBLOCADE is for healthcare provider preparation and administration only. SUBLOCADE must be injected into the subcutaneous tissue of the abdomen, thigh, buttock, or back of the upper arm. Patients not currently taking buprenorphine should receive an initial dose (e.g. 4 mg) of transmucosal buprenorphine before administering the first injection of SUBLOCADE. Monitor patients in a healthcare setting after injection with SUBLOCADE to assess for symptoms of worsening withdrawal or sedation. Patients' symptoms should be stable or improving prior to release from the healthcare setting. The second injection of SUBLOCADE may be administered as early as one week after the first injection. Injection sites should be rotated between doses. Administer maintenance injections at least 26 days apart. A patient who misses a maintenance dose should receive the next dose as soon as possible. Administer each injection only using the syringe and safety needle included with the product [see Dosage and Administration ( 2.5 )] . 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 SUBLOCADE. 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 ( 5.4 )] . Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine 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 Recommended Dosage Induction in patients not already receiving buprenorphine Treatment with buprenorphine should be initiated when objective and clear signs of opioid withdrawal are evident in order to minimize the risk of precipitating withdrawal [see Warnings and Precautions ( 5.12 )] . Patients should receive an initial dose (e.g. 4 mg) of transmucosal buprenorphine and be observed for one hour to confirm tolerability before administering the first injection of SUBLOCADE. The recommended starting dose of SUBLOCADE is 300 mg. Monitor patients in a healthcare setting after injection with SUBLOCADE to assess for symptoms of worsening withdrawal or sedation. Patients' symptoms should be stable or improving prior to release from the healthcare setting. On induction day, up to an additional 8 mg of transmucosal buprenorphine could be administered to manage withdrawal symptoms. The recommended dose for the second injection is 300 mg. The second injection may be administered as early as 1 week and up to 1 month after the initial injection, based on patient need [ see Table 1 ]. Transition of patients already receiving transmucosal buprenorphine Patients who have been on 8 mg to 24 mg daily of transmucosal buprenorphine may be transitioned directly to the recommended starting dose of 300 mg of SUBLOCADE. The recommended dose for the second injection is 300 mg. The second injection may be administered as early as 1 week and up to 1 month after the initial injection, based on patient need [ see Table 1 ]. Patients established on long-term treatment and whose symptoms are controlled with 8 mg to 18 mg daily of transmucosal buprenorphine may receive 100 mg of SUBLOCADE as their second dose if symptoms remain controlled following the initial dose of 300 mg [ see Table 1 ]. Maintenance dosage After the first two injections, the recommended maintenance dosage of SUBLOCADE is 100 mg monthly. A monthly maintenance dosage of 300 mg may be considered in patients who tolerate 100 mg of SUBLOCADE monthly, but do not demonstrate a satisfactory clinical response. Maintenance doses should be administered with at least 26 days between injections. Table 1 Recommended Dosing Schedule TM BUP, transmucosal buprenorphine; NA, not applicable a The second injection may be administered as early as 1 week and up to 1 month after the initial injection based on patient need. b A monthly maintenance dosage of 300 mg may be considered in patients who tolerate SUBLOCADE, but do not demonstrate a satisfactory clinical response. c On induction day, additional transmucosal buprenorphine may be administered as needed to manage withdrawal symptoms. Monitor patients for 1 hour to confirm tolerability before administering the first injection of SUBLOCADE. d Patients established on long-term treatment and whose symptoms are controlled with 8 mg to 18 mg daily of transmucosal buprenorphine may receive 100 mg of SUBLOCADE as their second dose if symptoms remain controlled following the initial dose of 300 mg. Previous Dose of TM BUP TM BUP SUBLOCADE Initial Dose Injection #1 Injection #2 a Maintenance Dose b Initiation in patients not already receiving buprenorphine NA 4 mg c 300 mg 300 mg 100 mg Transition of patients already receiving transmucosal buprenorphine 8 – 24 mg/day NA 300 mg 300 mg d 100 mg Missed doses A patient who misses a maintenance dose should receive the next dose as soon as possible, with the following dose given at least 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect. For patients in established treatment of 100 mg monthly, there may be instances when allowance for a two-month dosing interval may be appropriate (e.g., extended travel); in those instances, a single 300 mg dose may be given to cover a two-month period. Thereafter, the 100 mg monthly regimen would resume. Patients should be cautioned that the peak plasma level after injection of a 300 mg dose will be higher than their usual monthly dose and that they may experience sedation or other buprenorphine- related effects. 2.4 Clinical Supervision Periodic assessment is necessary to determine effectiveness of the treatment plan and overall patient progress. When evaluating the patient, examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot. Due to the chronic nature of opioid use disorder, the need for continuing medication-assisted treatment should be re-evaluated periodically. There is no maximum recommended duration of maintenance treatment. For some patients, treatment may continue indefinitely. If considering stopping treatment, the clinical status of the patient should be considered. If SUBLOCADE is discontinued, its extended-release characteristics should be considered and the patient should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. After steady-state has been achieved (4-6 months), patients discontinuing SUBLOCADE may have detectable plasma and urine levels of buprenorphine for twelve months or longer [see Clinical Pharmacology ( 12.3 )] . 2.5 Instructions for Use IMPORTANT INFORMATION: For subcutaneous injection only . Do not inject intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.1 , 5.6 )] . To be prepared and administered by a healthcare provider only. Read the instructions carefully before handling the product. As a universal precaution, always wear gloves. SUBLOCADE must be injected into the subcutaneous tissue of the abdomen, thigh, buttock, or back of the upper arm. Remove SUBLOCADE from the refrigerator prior to administration. The product requires at least 15 minutes to reach room temperature. Do not open the foil pouch until the patient has arrived for his or her injection. Discard SUBLOCADE if left at room temperature for longer than 12 weeks. Do not attach the needle until time of administration. STEP 1: GETTING READY Remove the foil pouch and safety needle from the carton. Open the pouch and remove the syringe. Discard the oxygen absorber pack. It is not needed. Figure 1 STEP 2: CHECK THE LIQUID CLARITY Check that the medication does not contain contaminants or particles. SUBLOCADE ranges from colorless to yellow to amber. Variations of color within this range do not affect the potency of the product. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Figure 2 STEP 3: ATTACH THE SAFETY NEEDLE Remove the cap from the syringe and the safety needle supplied in the carton from its sterile package. Gently twist the needle clockwise until it is tight and firmly attached. Do not remove the plastic cover from the needle. Figure 3 STEP 4: PREPARE THE INJECTION SITE Choose one of the following body regions for subcutaneous injection (see Figure 4 ): Abdomen between the transpyloric and transtubercular planes Back of the upper arm Buttock Thigh Ensure that the selected injection site has adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment). Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way. To avoid irritation, rotate injection sites. Clean the injection site well with an alcohol swab. Figure 4 STEP 5: REMOVE EXCESS AIR FROM SYRINGE Hold the syringe upright for several seconds to allow air bubbles to rise. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution. Remove needle cover and slowly depress the plunger to push out the excess air from the syringe. Small bubbles may remain in the medication. Large air gaps, however, can be minimized by pulling back on the plunger rod to pop air bubbles prior to expelling the air very slowly. Air should be expelled very carefully to avoid loss of medication. If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage. Figure 5 STEP 6: PINCH THE INJECTION SITE Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection. Figure 6 STEP 7: INJECT THE MEDICATION SUBLOCADE is for subcutaneous injection only. Do not inject intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.1 , 5.6 )] . Insert needle fully into the subcutaneous tissue. Actual angle of injection will depend on the amount of subcutaneous tissue. Use a slow, steady push to inject the medication. Continue pushing until all of the medication is given. Figure 7 STEP 8: WITHDRAW THE NEEDLE Withdraw the needle at the same angle used for insertion and release the pinched skin. Do not rub the injection area after the injection. There may be a small amount of blood or fluid at the injection site; wipe with a cotton ball or gauze before applying a gauze pad or bandage using minimal pressure. Figure 8 STEP 9: LOCK THE NEEDLE GUARD AND DISCARD THE SYRINGE Lock the needle guard into place by pushing it against a hard surface such as a table ( Figure 9 ). Dispose of all syringe components in a secure sharps disposal container. Figure 9 STEP 10: INSTRUCT THE PATIENT Advise the patient that they may have a lump for several weeks that will decrease in size over time. Instruct the patient not to rub or massage the injection site and to be aware of the placement of any restrictive clothing, such as belts, waistbands, or sleeves. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 2.6 Limits on Distribution SUBLOCADE is subject to a risk evaluation and mitigation strategy (REMS) program that includes, among other elements, a restricted distribution system. The purpose of the restricted distribution system is to ensure that SUBLOCADE is only administered by a health care provider [see Warnings and Precautions ( 5.2 )] . 2.7 Removal of the Depot In the event the depot must be removed, it can be surgically excised under local anesthesia within 14 days of injection. Only the most recently-injected depot can be removed. The removed depot should be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product and pharmaceutical biohazardous waste, and per applicable federal, state, and local regulations. The residual plasma concentrations from previous injections will decrease gradually over subsequent months [see Clinical Pharmacology ( 12.3 )] . Patients who have the depot removed should be monitored for signs and symptoms of withdrawal and treated appropriately [see Warnings and Precautions ( 5.9 )] .

SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of the ATRIGEL ® delivery system [see Warnings and Precautions ( 5.11 )] . Hypersensitivity to buprenorphine or any other ingredients in SUBLOCADE. ( 4 )

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 ( 5.7 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.8 )] Opioid Withdrawal [see Warnings and Precautions ( 5.9 , 5.12 )] Hepatitis, Hepatic Events [see Warnings and Precautions ( 5.10 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.11 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.18 )] Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions ( 5.19 )] Elevation of Intracholedochal Pressure [see Warnings and Precautions ( 5.20 )] Adverse reactions commonly associated with SUBLOCADE (in ≥ 5% of subjects) were constipation, headache, nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 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 SUBLOCADE was evaluated in 848 opioid-dependent subjects (see Table 2 ). In these studies, there was a total of 557 subjects who received at least 6 monthly SC injections of SUBLOCADE and 138 subjects who received 12 monthly SC injections. Adverse events led to premature discontinuation in 4% of the group receiving SUBLOCADE compared with 2% in the placebo group (13-0001, NCT02357901). In the Phase 3 open-label study (13-0003, NCT02510014), adverse events leading to drug dose reductions were reported in 7.3% of subjects receiving SUBLOCADE. Table 2 Total Subjects Exposed to SUBLOCADE *Not included in total subjects exposed to SUBLOCADE † FLEX = 300 mg initial dose with an option to receive either 100 mg or 300 mg for subsequent dosing per clinician's discretion ‡ = Not included in total unique subjects exposed to SUBLOCADE, already accounted for in Study 13-0001 section of table Study 13-0001 (NCT02357901) Up to 6 Injections Study 13-0003 (NCT02510014) Total Subjects Exposed To SUBLOCADE Roll-Over Up to 6 Injections De-Novo Up to 12 Injections SUBLOCADE 300/100 mg SUBLOCADE 300/300 mg Placebo From SUBLOCADE 300/100 mg To SUBLOCADE 300/Flex† From SUBLOCADE 300/300 mg To SUBLOCADE 300/Flex† From Placebo To SUBLOCADE 300/Flex† SUBLOCADE 300/Flex N = 203 N = 201 N = 100* N = 112‡ N = 113‡ N = 32 N = 412 N = 848 Table 3 shows the non-injection site-related adverse reactions (ADRs) for the groups receiving SUBLOCADE 300/300 mg (6 doses of 300 mg SC injections) 300/100 mg (300 mg SC injections for the first two doses followed by 4 doses of 100 mg SC injections) and placebo (volume-matched ATRIGEL ® delivery system subcutaneous injections) reported following administration in the 6 month, double-blind, placebo-controlled study. The systemic safety profile for SUBLOCADE, given by a healthcare provider in clinical trials, was consistent with the known safety profile of transmucosal buprenorphine. Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation and somnolence. Dose dependent hepatic effects observed in the Phase 3, double-blind study (13-0001, NCT02357901) included the incidence of ALT more than 3 times the upper limit of normal (> 3 × ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300-mg, SUBLOCADE 300/100-mg, and placebo groups, respectively. The incidence of AST > 3 × ULN was 11.4%, 7.9%, and 1.0%, respectively. Adverse drug reactions [by MedDRA Preferred Terms (PT)] reported in at least 2% of subjects receiving SUBLOCADE are grouped by System Organ Class (SOC). Table 3 Adverse Reactions for Phase 3 Double-Blind Study: ≥ 2% of Subjects Receiving SUBLOCADE System Organ Class Preferred Term PLACEBO SUBLOCADE 300/100 mg SUBLOCADE 300/300 mg Count (%) Count (%) Count (%) *There were no cases of serious liver injury attributed to study drug. Total N = 100 N = 203 N = 201 Gastrointestinal disorders 12 (12%) 51 (25.1%) 45 (22.4%) Constipation 0 19 (9.4) 16 (8) Nausea 5 (5) 18 (8.9) 16 (8) Vomiting 4 (4) 19 (9.4) 11 (5.5) General disorders and administration site conditions 17 (17%) 40 (19.7%) 49 (24.4%) Fatigue 3 (3) 8 (3.9) 12 (6) Investigations* 2 (2%) 21 (10.3%) 19 (9.5%) Alanine aminotransferase increased (ALT) 0 2 (1) 10 (5) Aspartate aminotransferase increased (AST) 0 7 (3.4) 9 (4.5) Blood creatine phosphokinase increased (CPK) 1 (1) 11 (5.4) 5 (2.5) Gamma-glutamyl transferase increased (GGT) 1 (1) 6 (3) 8 (4) Nervous system disorders 7 (7%) 35 (17.2%) 25 (12.4%) Headache 6 (6) 19 (9.4) 17 (8.5) Sedation 0 7 (3.4) 3 (1.5) Dizziness 2 (2) 5 (2.5) 3 (1.5) Somnolence 0 10 (4.9) 4 (2) Table 4 shows the injection site-related adverse events reported by ≥ 2 subjects in the Phase 3 studies. Most injection site adverse drug reactions (ADRs) were of mild to moderate severity, with one report of severe injection site pruritus. None of the injection site reactions were serious. One reaction, an injection site ulcer, led to study treatment discontinuation. Table 4 Injection Site Adverse Drug Reactions Reported by ≥ 2 Subjects in the Phase 3 Studies *Patients received SUBOXONE film for a run-in period before they switched to SUBLOCADE injection. Preferred term, n (%) 13-0001 (Ph3DB) 13-0003 (Ph3OL) All Phase 3* Roll–over De-novo SUBLOCADE 300/300 (N = 201) SUBLOCADE 300/100 (N = 203) Placebo (N = 100) SUBLOCADE 300 → SUBLOCADE 300/Flex (N = 113) SUBLOCADE 100 → SUBLOCADE 300/Flex (N = 112) Placebo → SUBLOCADE 300/Flex (N = 32) SUBLOCADE 300/Flex (N = 412) Total SUBLOCADE (N = 848) Subjects with any injection site reactions 38 (18.9%) 28 (13.8%) 9 (9.0%) 6 (5.3%) 13 (11.6%) 2 (6.3%) 61 (14.8%) 140 (16.5%) Injection site pain 12 (6.0%) 10 (4.9%) 3 (3.0%) 4 (3.5%) 2 (1.8%) 2 (6.3%) 33 (8.0%) 61 (7.2%) Injection site pruritus 19 (9.5%) 13 (6.4%) 4 (4.0%) 2 (1.8%) 6 (5.4%) 1 (3.1%) 17 (4.1%) 56 (6.6%) Injection site erythema 6 (3.0%) 9 (4.4%) 0 1 (0.9%) 4 (3.6%) 0 21 (5.1%) 40 (4.7%) Injection site induration 2 (1.0%) 2 (1.0%) 0 0 1 (0.9%) 0 7 (1.7%) 12 (1.4%) Injection site bruising 2 (1.0%) 2 (1.0%) 0 0 0 0 2 (0.5%) 6 (0.7%) Injection site swelling 1 (0.5%) 2 (1.0%) 0 1 (0.9%) 1 (0.9%) 0 1 (0.2%) 6 (0.7%) Injection site discomfort 1 (0.5%) 1 (0.5%) 0 0 0 0 3 (0.7%) 5 (0.6%) Injection site reaction 1 (0.5%) 0 0 0 3 (2.7%) 0 1 (0.2%) 5 (0.6%) Injection site cellulitis 0 1 (0.5%) 0 0 0 0 2 (0.5%) 3 (0.4%) Injection site infection 1 (0.5%) 0 1 (1.0%) 0 0 0 2 (0.5%) 3 (0.4%) Longer-term experience In an interim analysis of the ongoing open-label long-term safety study (13-0003), safety was evaluated for up to 12 injections over the course of a year (see Table 2 ). Adverse events were reported for 432 of 669 subjects during the treatment period. The overall adverse event profile was similar to the double-blind trial described above. Rapid Induction study The proportion of patients who experienced an adverse event associated with opioid withdrawal was 31.4% in patients who received SUBLOCADE injection after an initial dose of transmucosal buprenorphine (rapid induction) and 25.1% in those who first received transmucosal buprenorphine for at least 7 days (standard induction). Three fentanyl positive patients in the rapid induction arm had serious adverse events associated with opioid withdrawal, and none in the standard induction arm. 6.2 Postmarketing Experience The most frequently reported systemic postmarketing adverse event observed with buprenorphine sublingual tablets was drug misuse or abuse. The most frequently reported systemic postmarketing adverse event with buprenorphine/naloxone sublingual tablets and film was peripheral edema. 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. 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 ingredients contained in SUBLOCADE. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 5 includes clinically significant drug interactions with SUBLOCADE. Table 5 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 of a prescribed benzodiazepine or other 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 treatments [see Warnings and Precautions ( 5.4 , 5.5 )] . If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions ( 5.4 )]. Examples: Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. Inhibitors of CYP3A4 Clinical Impact: The effects of co-administered CYP3A4 inhibitors on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. The concomitant use of sublingual buprenorphine and CYP3A4 inhibitors (e.g., ketoconazole) can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects. Intervention: Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors [e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)] should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inhibitors, the patients should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, it may be necessary to remove the depot and treat the patient with a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inhibitor, and the concomitant medication is discontinued, the patient should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The effects of co-administered CYP3A4 inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. CYP3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome. Intervention: Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inducers, the patients should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inducer, and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if the dose provided by SUBLOCADE is excessive in the absence of the concomitant inducer, it may be necessary to remove the SUBLOCADE and treat the patient with a formulation of buprenorphine that permits dose adjustments [see Clinical Pharmacology ( 12.3 )] . Examples: Rifampin, carbamazepine, phenytoin, phenobarbital Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and sublingual buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Intervention: Patients who are on chronic treatment with SUBLOCADE should be monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen. Examples: Efavirenz, nevirapine, etravirine, delavirdine Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on sublingual buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine after sublingual administration, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with SUBLOCADE, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to remove the depot and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments. Examples: Atazanavir, ritonavir Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Intervention: None Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully monitor the patient for signs and symptoms of serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Intervention: The use of SUBLOCADE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: Phenelzine, tranylcypromine, linezolid Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients receiving muscle relaxants and SUBLOCADE for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.4 , 5.5 )] . Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when SUBLOCADE is used concomitantly with anticholinergic drugs. CYP3A4 Inhibitors and Inducers : Monitor patients starting or ending CYP3A4 inhibitors or inducers for potential over- or under-dosing. ( 7 ) Serotonergic Drugs : If concomitant use is warranted, monitor for serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. ( 7 )

Storage and Handling Store refrigerated at 2°C to 8°C (35.6°F to 46.4°F). Once outside the refrigerator this product may be stored in its original packaging at room temperature, 15°C to 30°C (59°F to 86°F), for up to 12 weeks prior to administration. Discard SUBLOCADE if left at room temperature for longer than 12 weeks. SUBLOCADE is a Schedule III drug product. Handle with adequate security and accountability. After administration, syringes should be properly disposed, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations. Rx Only.