Buprenorphine HCl and Naloxone HCl (Page 3 of 11)

5.9 Hypersensitivity Reactions

Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of Buprenorphine and Naloxone Sublingual Tablets.

5.10 Precipitation of Opioid Withdrawal Signs and Symptoms

Because it contains naloxone, Buprenorphine and Naloxone Sublingual Tablets are highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, Buprenorphine and Naloxone Sublingual Tablets may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.

5.11 Risk of Overdose in Opioid Naïve Patients

There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and Naloxone Sublingual Tablets are not appropriate as an analgesic.

5.12 Use in Patients with Impaired Hepatic Function

Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy [see Use in Specific Populations (8.6)] .

5.13 Impairment of Ability to Drive or Operate Machinery

Buprenorphine and Naloxone Sublingual Tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Caution patients about driving or operating hazardous machinery until they are reasonably certain that Buprenorphine and Naloxone Sublingual Tablets therapy does not adversely affect his or her ability to engage in such activities.

5.14 Orthostatic Hypotension

Like other opioids, Buprenorphine and Naloxone Sublingual Tablets may produce orthostatic hypotension in ambulatory patients.

5.15 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.

5.16 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.

5.17 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 Tablets was evaluated in 497 opioid-dependent subjects. The prospective evaluation of Buprenorphine and Naloxone Sublingual Tablets 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 Buprenorphine and Naloxone Sublingual Tablets and Buprenorphine Sublingal 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

N (%)

N (%)

Body System / Adverse Event (COSTART Terminology)

Buprenorphine and Naloxone Sublingual Tablets

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%)

Nausea

16 (15%)

12 (11.2%)

Vomiting

8 (7.5%)

5 (4.7%)

Nervous System

Insomnia

15 (14%)

17 (15.9%)

Respiratory System

Rhinitis

5 (4.7%)

14 (13.1%)

Skin and Appendages

Sweating

15 (14%)

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 (%)

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

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