Buprenorphine and Naloxone (Page 4 of 12)

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 tablets was evaluated in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine and naloxone sublingual tablets were supported by clinical trials using buprenorphine sublingual tablets and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.

Few differences in adverse event profile were noted between buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets or buprenorphine administered as a sublingual solution.

The following adverse events were reported to occur by at least 5% of patients in a 4-week study ( Table 1).

Table 1. Adverse Events (≥ 5%) by Body System and Treatment Group in a 4-week Study
Body System / Adverse Event (COSTART Terminology) N (%) Buprenorphine and Naloxone Sublingual Tablets 16 mg/day N=107 N (%) Placebo N=107
Body as a Whole
Asthenia 7 (6.5%) 7 (6.5%)
Chills 8 (7.5%) 8 (7.5%)
Headache 39 (36.4%) 24 (22.4%)
Infection 6 (5.6%) 7 (6.5%)
Pain 24 (22.4%) 20 (18.7%)
Pain Abdomen 12 (11.2%) 7 (6.5%)
Pain Back 4 (3.7%) 12 (11.2%)
Withdrawal Syndrome 27 (25.2%) 40 (37.4%)
Cardiovascular System
Vasodilation 10 (9.3%) 7 (6.5%)
Digestive System
Constipation 13 (12.1%) 3 (2.8%)
Diarrhea 4 (3.7%) 16 (15.0%)
Nausea 16 (15.0%) 12 (11.2%)
Vomiting 8 (7.5%) 5 (4.7%)
Nervous System
Insomnia 15 (14.0%) 17 (15.9%)
Respiratory System
Rhinitis 5 (4.7%) 14 (13.1%)
Skin And Appendages
Sweating 15 (14.0%) 11 (10.3%)

The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.

*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 “Moderate” dose (8 mg solution) approximates a 12 mg tablet dose “High” dose (16 mg solution) approximates a 24 mg tablet dose
Table 2. 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) Low* (N=180) Moderate* (N=186) High* (N=181) Total* (N=731)
N (%) N (%) N (%) N (%) 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%) 34 (5%)

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