ADVERSE REACTIONS
The safety of SUBOXONE has been 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 are 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.
In a comparative study, adverse event profiles were similar for subjects treated with 16 mg SUBOXONE or 16mg SUBUTEX. The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 3).
Table 3. Adverse Events (>/=5%) by Body System and Treatment Group in a 4-week Study
|
|
N (%) |
N (%) |
N (%) |
| Body System/Adverse Event (COSTART Terminology) |
SUBOXONE
16 mg/day N = 107 |
SUBUTEX
16 mg/day N = 103 |
Placebo
N = 107 |
|
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%) |
|
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 4 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.
Table 4. 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%) |
*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 (4mg solution) approximates a 6 mg tablet dose
"Moderate" dose (8mg solution) approximates a 12 mg tablet dose
"High" dose (16mg solution) approximates a 24 mg tablet dose
|
|
DRUG ABUSE AND DEPENDENCE
SUBOXONE and SUBUTEX are controlled as Schedule III narcotics under the Controlled Substances Act.
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces dependence of the opioid type, characterized by moderate withdrawal upon abrupt discontinuation or rapid taper. The withdrawal syndrome is milder than seen with full agonists, and may be delayed in onset (SEE WARNINGS)
Neonatal withdrawal has been reported in the infants of women treated with SUBUTEX during pregnancy (See PRECAUTIONS)
SUBOXONE contains naloxone and if misused parenterally, is highly likely to produce marked and intense withdrawal symptoms in subjects dependent on other opioid agonists.
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