Buprenorphine and Naloxone
Generic: BUPRENORPHINE AND NALOXONE
Basic Information
Manufacturer
Dr.Reddys Laboratories Inc
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
BUCCAL
SUBLINGUAL
FDA Set ID
718756d7-0131-b173-6c45-5ee039b311b0
Indications & Usage
1 INDICATIONS AND USAGE Buprenorphine and naloxone sublingual film is indicated for treatment of opioid dependence.
Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
Buprenorphine and naloxone sublingual film contains buprenorphine, a partial-opioid agonist and naloxone, an opioid antagonist, and is indicated for treatment of opioid dependence.
( 1 ) Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
( 1 )
Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
Buprenorphine and naloxone sublingual film contains buprenorphine, a partial-opioid agonist and naloxone, an opioid antagonist, and is indicated for treatment of opioid dependence.
( 1 ) Buprenorphine and naloxone sublingual film should be used as part of a complete treatment plan that includes counseling and psychosocial support.
( 1 )
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Respiratory and CNS Depression [see Warnings and Precautions ( 5.2 ), ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.5 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.6 )] Opioid Withdrawal [see Warnings and Precautions ( 5.7 , 5.10 )] Hepatitis, Hepatic Events [see Warnings and Precautions ( 5.8 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )] Orthostatic Hypotension [see Warnings and Precautions ( 5.16 )] Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions ( 5.17 ) ] Elevation of Intracholedochal Pressure [see Warnings and Precautions ( 5.18 ) Adverse events commonly observed with the sublingual/buccal administration of the buprenorphine and naloxone sublingual film are oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc.
at 1-888-375-3784 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 buprenorphine and naloxone sublingual film is supported by clinical trials using buprenorphine sublingual tablets and buprenorphine and naloxone sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with buprenorphine and naloxone sublingual film administered sublingually and 188 patients treated with the film administered buccally.
In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid dependence.
Few differences in the adverse event profile were noted with regard to sublingually and bucally administered buprenorphine and naloxone sublingual film, buprenorphine and naloxone sublingual tablets, buprenorphine sublingual tablets and a buprenorphine ethanolic sublingual solution.
The most common adverse event (>1%) associated with the sublingual administration of the buprenorphine and naloxone sublingual film was oral hypoesthesia.
Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis, and blurred vision.
The most common adverse events associated with the buccal administration were similar to those observed with sublingual administration of the film.
Other adverse event data were derived from larger, controlled studies of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets and of buprenorphine sublingual solution.
In a comparative study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg buprenorphine and naloxone sublingual tablets or 16 mg buprenorphine sublingual tablets.
The following adverse events were reported to occur by at least 5% of patients in a 4 week study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets.
Table 2.
Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study Body System/Adverse Event (COSTART Terminology) Buprenorphine and naloxone sublingual tablets 16 mg/4 mg/day N = 107 n (%) Buprenorphine sublingual tablets 16 mg/day N = 103 n (%) Placebo N = 107 n (%) Body as a Whole Asthenia 7 (6.5%) 5 (4.9%) 7 (6.5%) Chills 8 (7.5%) 8 (7.8%) 8 (7.5%) Headache 39 (36.4%) 30 (29.1%) 24 (22.4%) Infection 6 (5.6%) 12 (11.7%) 7 (6.5%) Pain 24 (22.4%) 19 (18.4%) 20 (18.7%) Pain abdomen 12 (11.2%) 12 (11.7%) 7 (6.5%) Pain back 4 (3.7%) 8 (7.8%) 12 (11.2%) Withdrawal syndrome 27 (25.2%) 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 10 (9.3%) 4 (3.9%) 7 (6.5%) Digestive System Constipation 13 (12.1%) 8 (7.8%) 3 (2.8%) Diarrhea 4 (3.7%) 5 (4.9%) 16 (15.0%) Nausea 16 (15.0%) 14 (13.6%) 12 (11.2%) Vomiting 8 (7.5%) 8 (7.8%) 5 (4.7%) Nervous System Insomnia 15 (14.0%) 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 5 (4.7%) 10 (9.7%) 14 (13.1%) Skin And Appendages Sweating 15 (14.0%) 13 (12.6%) 11 (10.3%) Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a buprenorphine ethanolic solution, over a range of doses in four months of treatment.
Table 3 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial.
Table 3.
Adverse Events (≥ 5%) by Body System and Treatment Group in a 16 Week Study Body System/Adverse Event (COSTART Terminology) Buprenorphine Dose Very Low* N = 184 n (%) Low* N = 180 n (%) Moderate* N = 186 n (%) High* N = 181 n (%) Total* N = 731 n (%) Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%) Withdrawal syndrome 45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%) Digestive System Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%) Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%) Nervous System Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%) Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%) Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%) Respiratory System Cough increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%) Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%) Skin and Appendages Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%) Special Senses Runny eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 5%) * Sublingual solution.
Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderarte” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose The safety of buprenorphine and naloxone sublingual film during treatment induction is supported by a clinical trial using 16 patients treated with buprenorphine and naloxone sublingual film and 18 treated with a buprenorphine-only sublingual film.
Few differences in the adverse event profiles were noted between buprenorphine and naloxone sublingual film and the buprenorphine-only sublingual film.
The most common adverse event occurring during treatment induction and the 3 days following induction using buprenorphine and naloxone sublingual film was restlessness.
Other adverse events were anxiety, piloerection, stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased.
Four subjects left the study early on the first day of sublingual film administration.
However, there was no evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to the administration of buprenorphine or buprenorphine/naloxone sublingual films.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual film.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, glossitis, and blistering and ulceration of the mouth or tongue.
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 buprenorphine and naloxone sublingual film.
Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology ( 12.2 )].
Local reactions :Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.
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 Dr. Reddy’s Laboratories, Inc.
at 1-888-375-3784 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 buprenorphine and naloxone sublingual film is supported by clinical trials using buprenorphine sublingual tablets and buprenorphine and naloxone sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with buprenorphine and naloxone sublingual film administered sublingually and 188 patients treated with the film administered buccally.
In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid dependence.
Few differences in the adverse event profile were noted with regard to sublingually and bucally administered buprenorphine and naloxone sublingual film, buprenorphine and naloxone sublingual tablets, buprenorphine sublingual tablets and a buprenorphine ethanolic sublingual solution.
The most common adverse event (>1%) associated with the sublingual administration of the buprenorphine and naloxone sublingual film was oral hypoesthesia.
Other adverse events were constipation, glossodynia, oral mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal syndrome, hyperhidrosis, and blurred vision.
The most common adverse events associated with the buccal administration were similar to those observed with sublingual administration of the film.
Other adverse event data were derived from larger, controlled studies of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets and of buprenorphine sublingual solution.
In a comparative study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg buprenorphine and naloxone sublingual tablets or 16 mg buprenorphine sublingual tablets.
The following adverse events were reported to occur by at least 5% of patients in a 4 week study of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets.
Table 2.
Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study Body System/Adverse Event (COSTART Terminology) Buprenorphine and naloxone sublingual tablets 16 mg/4 mg/day N = 107 n (%) Buprenorphine sublingual tablets 16 mg/day N = 103 n (%) Placebo N = 107 n (%) Body as a Whole Asthenia 7 (6.5%) 5 (4.9%) 7 (6.5%) Chills 8 (7.5%) 8 (7.8%) 8 (7.5%) Headache 39 (36.4%) 30 (29.1%) 24 (22.4%) Infection 6 (5.6%) 12 (11.7%) 7 (6.5%) Pain 24 (22.4%) 19 (18.4%) 20 (18.7%) Pain abdomen 12 (11.2%) 12 (11.7%) 7 (6.5%) Pain back 4 (3.7%) 8 (7.8%) 12 (11.2%) Withdrawal syndrome 27 (25.2%) 19 (18.4%) 40 (37.4%) Cardiovascular System Vasodilation 10 (9.3%) 4 (3.9%) 7 (6.5%) Digestive System Constipation 13 (12.1%) 8 (7.8%) 3 (2.8%) Diarrhea 4 (3.7%) 5 (4.9%) 16 (15.0%) Nausea 16 (15.0%) 14 (13.6%) 12 (11.2%) Vomiting 8 (7.5%) 8 (7.8%) 5 (4.7%) Nervous System Insomnia 15 (14.0%) 22 (21.4%) 17 (15.9%) Respiratory System Rhinitis 5 (4.7%) 10 (9.7%) 14 (13.1%) Skin And Appendages Sweating 15 (14.0%) 13 (12.6%) 11 (10.3%) Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a buprenorphine ethanolic solution, over a range of doses in four months of treatment.
Table 3 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial.
Table 3.
Adverse Events (≥ 5%) by Body System and Treatment Group in a 16 Week Study Body System/Adverse Event (COSTART Terminology) Buprenorphine Dose Very Low* N = 184 n (%) Low* N = 180 n (%) Moderate* N = 186 n (%) High* N = 181 n (%) Total* N = 731 n (%) Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%) Withdrawal syndrome 45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%) Digestive System Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%) Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%) Nervous System Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%) Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%) Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%) Respiratory System Cough increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%) Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%) Skin and Appendages Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%) Special Senses Runny eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 5%) * Sublingual solution.
Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: “Very low” dose (1 mg solution) would be less than a tablet dose of 2 mg “Low” dose (4 mg solution) approximates a 6 mg tablet dose “Moderarte” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose The safety of buprenorphine and naloxone sublingual film during treatment induction is supported by a clinical trial using 16 patients treated with buprenorphine and naloxone sublingual film and 18 treated with a buprenorphine-only sublingual film.
Few differences in the adverse event profiles were noted between buprenorphine and naloxone sublingual film and the buprenorphine-only sublingual film.
The most common adverse event occurring during treatment induction and the 3 days following induction using buprenorphine and naloxone sublingual film was restlessness.
Other adverse events were anxiety, piloerection, stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased.
Four subjects left the study early on the first day of sublingual film administration.
However, there was no evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to the administration of buprenorphine or buprenorphine/naloxone sublingual films.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual film.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, glossitis, and blistering and ulceration of the mouth or tongue.
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 buprenorphine and naloxone sublingual film.
Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology ( 12.2 )].
Local reactions :Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.
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.