SUBLOCADE

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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 recommending or prescribing an opioid overdose reversal agent (e.g., naloxone, nalmefene) 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 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 recommending or prescribing an overdose reversal agent for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBLOCADE. Also consider recommending or prescribing such an agent 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 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warning and Precautions ( 5.4 )] . 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…

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 SUBLOCADE. ( 5.4 , 5.5 ) Risk of Serious Injection Site Reactions : Likelihood may be increased with inadvertent intramuscular or intradermal administration. Evaluate and treat as appropriate. ( 5.6 ). Neonatal Opioid Withdrawal Syndrome : Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. ( 5.7 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.8 ) Risk of Opioid Withdrawal With Abrupt Discontinuation : If treatment with SUBLOCADE is discontinued, monitor patients for several months for withdrawal and treat appropriately. ( 5.9 ) Risk of Hepatitis, Hepatic Events : Monitor liver function tests prior to and during treatment. ( 5.10 ) Risk of Withdrawal in Patients Dependent on Full Agonist Opioids : Verify that patients have tolerated transmucosal buprenorphine before injecting SUBLOCADE. ( 5.12 ) 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. ( 5.13 ) 5.1 Risk of Serious Harm or Death With Intravenous Administration Intravenous injection presents significant risk of serious harm or death as SUBLOCADE forms a solid mass 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 [see Warnings and Precautions ( 5.6 )] . 5.2 SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS) Program SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program 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 SUBLOCADE directly to a healthcare provider for administration by a healthcare provider. Notable requirements of the SUBLOCADE REMS Program include the following: Healthcare Settings and Pharmacies that order and dispense SUBLOCADE must be certified in the SUBLOCADE REMS Program. Certified Healthcare Settings and Pharmacies must establish processes and procedures to verify SUBLOCADE 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 SUBLOCADE. Further information is available at www.SublocadeREMS.com or call 1-866-258-3905. 5.3 Addiction, Abuse, and Misuse SUBLOCADE 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 Risk of 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 com…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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 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, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), 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 g…

8.1 Pregnancy Risk Summary The data on use of buprenorphine, the active ingredient in SUBLOCADE, 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 buprenorphine that were not designed appropriately to assess the risk of major malformations [see Human Data ] . Observational studies have reported congenital malformations among buprenorphine‐exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Human Data ] . In animal reproduction studies with SUBLOCADE, SUBLOCADE administered subcutaneously to pregnant rats and rabbits during the period of organogenesis at a buprenorphine dose equivalent to 38 and 15 times, respectively, the maximum recommended human dose (MRHD) of 300 mg caused embryolethality, which appeared to be attributable primarily to the SUBLOCADE vehicle (ATRIGEL ® delivery system). In addition, reduced fetal body weights, increased visceral malformations and skeletal malformations were observed in rats and rabbits at buprenorphine doses equivalent to 38 and 15 times, respectively, the MRHD. These effects were also observed with the ATRIGEL ® delivery system alone, but the skeletal and visceral malformations in rat appear at least partially attributable to buprenorphine [see Animal 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 is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. SUBLOCADE 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. Fetal/neonatal adverse reactions Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBLOCADE. 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 ( 5.7 )] . 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 overdose reversal agent, 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 on malformations 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. Pregnancy in an opioid dependent woman poses challenges to treating physicians and potential hazards for the fetus including control of illicit drug, nicotine and alcohol use, infections, prematur…

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 ( 5.7 )] 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 rec…