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.
Adverse Events In Clinical Trials - SUBOXONE Sublingual Tablets
The safety of SUBOXONE was evaluated in 497 opioid-dependent subjects. The prospective evaluation of SUBOXONE was supported by clinical trials using SUBUTEX (buprenorphine tablets without naloxone) 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 SUBOXONE and SUBUTEX 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 (%) | N (%) |
| SUBOXONE 16 mg/day N=107 |
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.
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 (%) | |
| *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 |
|||||
| 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%) |
| *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 |
|||||
Adverse Events – Post-marketing Experience With SUBOXONE Sublingual Tablets
The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.