Adverse reactions : תופעות לוואי

8       ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling: •   Addiction, Abuse, and Misuse [see Warnings and Precautions (7.1)] •   Respiratory and CNS Depression [see Warnings and Precautions (7.2), (7.3)] •   Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (7.5)] •   Adrenal Insufficiency [see Warnings and Precautions (7.6)]
•   Opioid Withdrawal [see Warnings and Precautions (7.7, 7.10)]
•   Hepatitis, Hepatic Events [see Warnings and Precautions (7.8)]
•   Hypersensitivity Reactions [see Warnings and Precautions (7.9)] •   Orthostatic Hypotension [see Warnings and Precautions (7.16)]
•   Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (7.17)] •   Elevation of Intracholedochal Pressure [see Warnings and Precautions (7.18) 8.1     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 SUBOXONE film is supported by clinical trials using SUBUTEX (buprenorphine) sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with SUBOXONE 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 bucally administered SUBOXONE film, SUBOXONE sublingual tablets, SUBUTEX sublingual tablets and a buprenorphine ethanolic sublingual solution.
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 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 SUBOXONE sublingual tablets and SUBUTEX sublingual tablets and of buprenorphine sublingual solution. In a comparative study of SUBOXONE sublingual tablets and SUBUTEX sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE sublingual tablets or 16 mg SUBUTEX sublingual tablets. The following adverse events were reported to occur by at least 5% of patients in a 4 week study of SUBOXONE sublingual tablets and SUBUTEX sublingual tablets.



Table 2. Adverse Events (5%) by Body System and Treatment Group in a 4 Week Study 
SUBOXONE sublingual      SUBUTEX sublingual tablets                  tablets                 Placebo
Body System/ Adverse Event
16 mg/4 mg/day           16 mg/day               N=107
(COSTART Terminology)
N=107                    N=103                   n (%) n (%)                    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%) 
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.

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 
Buprenorphine Dose
Body System/
Adverse Event
Very Low*      Low*              Moderate*    High*          Total*
(COSTART
N=184          N=180             N=186        N=181          N=731
Terminology) 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
The safety of SUBOXONE film during treatment induction is supported by a clinical trial using 16 patients treated with SUBOXONE film and 18 treated with a buprenorphine-only sublingual film. Few differences in the adverse event profiles were noted between SUBOXONE film and the buprenorphine-only sublingual film.
The most common adverse event occurring during treatment induction and the 3 days following induction using SUBOXONE 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/naloxone sublingual films.



8.2       Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SUBOXONE film. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, glossitis, and blistering and ulceration of the mouth or tongue.
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 SUBOXONE film.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (14.2)].
Local reactions: Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (i.e., diabetes).
Report of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: /https://sideeffects.health.gov.il