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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

The safety of BUNAVAIL buccal film is supported by clinical trials using buprenorphine and naloxone sublingual tablets, and other trials using buprenorphine tablets and buprenorphine sublingual solutions, as well as an open-label study in 249 patients treated with BUNAVAIL buccal film. 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 addiction. Few differences in the adverse event profile were noted among buprenorphine and naloxone sublingual tablets, buprenorphine sublingual tablets and a buprenorphine ethanolic sublingual solution.

The safety and tolerability of BUNAVAIL was evaluated in a 12-week clinical study of BUNAVAIL in 249 opioid-dependent subjects stabilized on buprenorphine and naloxone sublingual tablet or film dosages of 8-32 mg/day.

The following adverse reactions were reported to occur by at least 5% of patients in a 12-week study with BUNAVAIL: drug withdrawal syndrome, lethargy and headache.

The adverse reactions listed below represent those that were reported by > 1%, but less than 5% of patients from the 12-week clinical trial while receiving BUNAVAIL. Events are classified by system organ class.

  • General disorders and administration site conditions: fatigue and chills
  • Nervous system disorders: somnolence
  • Psychiatric disorders: drug dependence and insomnia
  • Gastrointestinal disorders: constipation and oral mucosal erythema
  • Respiratory, thoracic and mediastinal disorders: rhinorrhea
  • Skin and subcutaneous tissue disorders: hyperhidrosis

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

Table 1 : Adverse Events ( > 5%) by Body System and Treatment Group in a 4-week Study

Body System/ Adverse Event (COSTART) Terminology Buprenorphine/naloxone sublingual tablets 16/4 mg/day
N=107
n(%)
Placebo
N=107
n (%)
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
Rhinitisnai 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 solutions, 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)
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%) 34(5%)
*Sublingual solution. Doses in this table cannot necessarily be delivered in film 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.