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ZUBSOLV SIDE EFFECTS

  • Generic Name: buprenorphine and naloxone sublingual tablets
  • Brand Name: Zubsolv
  • Drug Class: Opioid Antagonists
Last updated on MDtodate: 10/11/2022

SIDE EFFECTS

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

  • Addiction, Abuse, and Misuse
  • Respiratory and CNS Depression
  • Neonatal Opioid Withdrawal Syndrome
  • Adrenal Insufficiency
  • Opioid Withdrawal
  • Hepatitis, Hepatic Events
  • Hypersensitivity Reactions
  • Orthostatic Hypotension
  • Elevation of Cerebrospinal Fluid Pressure
  • Elevation of Intracholedochal Pressure

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.

ZUBSOLV for use as initial treatment was evaluated in two clinical trials that had identical, blinded, two-day induction phases, comparing ZUBSOLV to generic buprenorphine. On the first day, subjects received an initial dose of ZUBSOLV 1.4 mg/0.36 mg or generic buprenorphine 2 mg, followed by ZUBSOLV 4.2 mg/1.08 mg or generic buprenorphine 6 mg 1.5 hours later. In total, safety data were available for 538 opioid-dependent subjects exposed to ZUBSOLV (buprenorphine/naloxone) sublingual tablets when used for initial treatment.

Table 1: Adverse Reactions in ≥ 5% of Patients During the Induction Phase by System Organ Class and Preferred Term (Safety Population)

System Organ Class Preferred Term ZUBSOLV
(N=538)
Generic BUP
(N=530)
Overall
(N=1068)
N (%)
Patients with any Adverse Reactions 139 (26%) 136 (26%) 275 (26%)
Gastrointestinal Disorders 64 (12%) 60 (11%) 124 (12%)
Nausea 29 (5%) 36 (7%) 65 (6%)
Vomiting 25 (5%) 26 (5%) 51 (5%)
Nervous System Disorders 48 (9%) 44 (8%) 92 (9%)
Headache 36 (7%) 35 (7%) 71 (7%)
BUP = buprenorphine
ZUBSOLV = buprenorphine/naloxone

 

The safety of buprenorphine/naloxone for longer-term use (up to 16 weeks of treatment) was evaluated in previous studies in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone was supported by clinical trials using 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. See Table 2.

Table 2: Adverse Events > 5% by Body System and Treatment Group in a 4-week Study

Body System / Adverse Event (COSTART Terminology) N (%) N (%)
Buprenorphine/ naloxone 16/4 mg/day
N=107
Placebo
N=107
Body as a Whole
Asthenia 7 (7%) 7 (7%)
Chills 8 (8%) 8 (8%)
Headache 39 (37%) 24 (22%)
Infection 6 (6%) 7 (7%)
Pain 24 (22%) 20 (19%)
Pain Abdomen 12 (11%) 7 (7%)
Pain Back 4 (4%) 12 (11%)
Withdrawal Syndrome 27 (25%) 40 (37%)
Cardiovascular System
Vasodilation 10 (9%) 7 (7%)
Digestive System
Constipation 13 (12%) 3 (3%)
Diarrhea 4 (4%) 16 (15%)
Nausea 16 (15%) 12 (11%)
Vomiting 8 (8%) 5 (5%)
Nervous System
Insomnia 15 (14%) 17 (16%)
Respiratory System
Rhinitis 5 (5%) 14 (13%)
Skin and Appendages
Sweating 15 (14%) 11 (10%)

 

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 3 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.

Table 3: 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 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

 

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of buprenorphine and naloxone sublingual tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure. The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.

Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis

Anaphylaxis has been reported with ingredients contained in ZUBSOLV.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids.

Local Reactions

Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

 

SRC: NLM .

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