SUBLOCADE
Generic: BUPRENORPHINE
Basic Information
Manufacturer
Indivior Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
SUBCUTANEOUS
FDA Set ID
6189fb21-9432-45f8-8481-0bfaf3ccde95
Indications & Usage
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 )
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 )
Adverse Reactions
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 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).
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.
( 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).
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.