Buprenorphine and Naloxone (Page 5 of 15)

5.16 Orthostatic Hypotension

Like other opioids, buprenorphine and naloxone sublingual film may produce orthostatic hypotension in ambulatory patients.

5.17 Elevation of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

5.18 Elevation of Intracholedochal Pressure

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

5.19 Effects in Acute Abdominal Conditions

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

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 buccally 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
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.

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%)

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
*
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 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%)

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 and naloxone sublingual films.

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