Adverse reactions : תופעות לוואי

8       ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling: •   Addiction, Abuse, and Misuse [see Warnings and Precautions (7.2)] •   Respiratory and CNS Depression [see Warnings and Precautions (7.3)] •   Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (7.6)] •   Adrenal Insufficiency [see Warnings and Precautions (7.7)]
•   Opioid Withdrawal [see Warnings and Precautions (7.8, 7.11)]
•   Hepatitis, Hepatic Events [see Warnings and Precautions (7.9)]
•     Hypersensitivity Reactions [see Warnings and Precautions (7.10)] •     Orthostatic Hypotension [see Warnings and Precautions (7.17)] •     Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (7.18)] •     Elevation of Intracholedochal Pressure [see Warnings and Precautions (7.19)] 
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 SUBLOCADE was evaluated in 848 opioid-dependent subjects (see Table 1). In these studies, there was a total of 557 subjects who received at least 6 monthly SC injections of SUBLOCADE and 138 subjects who received 12 monthly SC injections. Adverse events led to premature discontinuation in 4% of the group receiving SUBLOCADE compared with 2% in the placebo group (13- 0001, NCT02357901).
In the Phase 3 open-label study (13-0003, NCT02510014), adverse events leading to drug dose reductions were reported in 7.3% of subjects receiving SUBLOCADE.
Table 1. Total Subjects Exposed to SUBLOCADE
Study 13-0001 (NCT02357901)                        Study 13-0003 (NCT02510014)                           Total Up to 6 Injections                              Roll-Over                         De-Novo        Subjects Up to 6 Injections                    Up to 12      Exposed To
Injections     SUBLOCADE
SUBLOCADE         SUBLOCADE      Placebo         From           From             From         SUBLOCADE 300/100 mg        300/300 mg                  SUBLOCADE      SUBLOCADE          Placebo         300/Flex 300/100 mg     300/300 mg            To
To             To         SUBLOCADE
SUBLOCADE      SUBLOCADE        300/Flex†
300/Flex†      300/Flex†
N = 203          N = 201      N = 100*       N = 112‡       N = 113‡          N= 32         N = 412           N = 848 *Not included in total subjects exposed to SUBLOCADE
† FLEX = 300 mg ini al dose with an op on to receive either 100 mg or 300 mg for subsequent dosing per clinician’s discretion ‡ = Not included in total unique subjects exposed to SUBLOCADE, already accounted for in Study 13-0001 section of table 
Table 2 shows the non-injection site-related adverse reactions (ADRs) for the groups receiving SUBLOCADE 300/300 mg (6 doses of 300 mg SC injections) 300/100 mg (300 mg SC injections for the first two doses followed by 4 doses of 100 mg SC injections) and placebo (volume-matched ATRIGEL® delivery system subcutaneous injections) reported following administration in the 6 month, double- blind, placebo-controlled study. The systemic safety profile for SUBLOCADE, given by a healthcare provider in clinical trials, was consistent with the known safety profile of transmucosal buprenorphine.
Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation and somnolence. Dose dependent hepatic effects observed in the Phase 3, double-blind study (13-0001, NCT02357901) included the incidence of ALT more than 3 times the upper limit of normal (> 3 × ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300-mg, SUBLOCADE 300/100-mg, and placebo groups, respectively. The incidence of AST > 3 × ULN was 11.4%, 7.9%, and 1.0%, respectively. Adverse drug reactions [by MedDRA Preferred Terms (PT)] reported in at least 2% of subjects receiving SUBLOCADE are grouped by System Organ Class (SOC).


Table 2. Adverse Reactions for Phase 3 Double-Blind Study: ≥2% of Subjects Receiving SUBLOCADE 
System Organ Class                                    SUBLOCADE SUBLOCADE Preferred Term                              PLACEBO 300/100 mg 300/300 mg Count (%)   Count (%)    Count (%)
Total                                                                     N = 100     N = 203      N = 201 Gastrointestinal disorders                                               12 (12%)    51 (25.1%)   45 (22.4%) Constipation                                                              0         19 (9.4)      16 (8) Nausea                                                                   5 (5)      18 (8.9)      16 (8) Vomiting                                                                 4 (4)      19 (9.4)     11 (5.5) General disorders and administration site conditions                     17 (17%)    40 (19.7%)   49 (24.4%) Fatigue                                                                  3 (3)      8 (3.9)       12 (6) Investigations*                                                           2 (2%)     21 (10.3%)   19 (9.5%) Alanine aminotransferase increased (ALT)                                  0          2 (1)        10 (5) Aspartate aminotransferase increased (AST)                                0         7 (3.4)      9 (4.5) Blood creatine phosphokinase increased (CPK)                             1 (1)      11 (5.4)     5 (2.5) Gamma-glutamyl transferase increased (GGT)                               1 (1)       6 (3)        8 (4) Nervous system disorders                                                  7 (7%)     35 (17.2%)   25 (12.4%) Headache                                                                 6 (6)      19 (9.4)     17 (8.5) Sedation                                                                  0         7 (3.4)      3 (1.5) Dizziness                                                                2 (2)      5 (2.5)      3 (1.5) Somnolence                                                                0         10 (4.9)      4 (2) *There were no cases of serious liver injury attributed to study drug.

Table 3 shows the injection site-related adverse events reported by ≥2 subjects in the Phase 3 studies.
Most injection site adverse drug reactions (ADRs) were of mild to moderate severity, with one report of severe injection site pruritus. None of the injection site reactions were serious. One reaction, an injection site ulcer, led to study treatment discontinuation.



Table 3. Injection Site Adverse Drug Reactions Reported by ≥2 Subjects in the Phase 3 Studies 13-0003 (Ph3OL)                      All
13-0001 (Ph3DB)                                                                   Phase 3* Roll–over                 De-novo


SUBLOCADE    SUBLOCADE
300 →        100 →
SUBLOCADE                                                            Placebo → SUBLOCADE                   SUBLOCADE    SUBLOCADE
300/300        300/100        Placebo                               SUBLOCADE   SUBLOCADE       Total Preferred term,                                               300/Flex     300/Flex     300/Flex    300/Flex n (%)              (N = 201)       (N = 203)     (N = 100)                                                      SUBLOCADE (N = 113)    (N = 112)    (N = 32)    (N = 412)    (N = 848)
Subjects with any injection     38 (18.9%)      28 (13.8%)     9 (9.0%)     6 (5.3%)    13 (11.6%)    2 (6.3%)   61 (14.8%)   140 (16.5%) site reactions
Injection site
12 (6.0%)       10 (4.9%)     3 (3.0%)     4 (3.5%)     2 (1.8%)     2 (6.3%)    33 (8.0%)    61 (7.2%) pain
Injection site
19 (9.5%)       13 (6.4%)     4 (4.0%)     2 (1.8%)     6 (5.4%)     1 (3.1%)    17 (4.1%)    56 (6.6%) pruritus
Injection site
6 (3.0%)        9 (4.4%)         0         1 (0.9%)     4 (3.6%)        0        21 (5.1%)    40 (4.7%) erythema
Injection site
2 (1.0%)        2 (1.0%)         0            0         1 (0.9%)        0        7 (1.7%)     12 (1.4%) induration
Injection site
2 (1.0%)        2 (1.0%)         0            0            0            0        2 (0.5%)     6 (0.7%) bruising
Injection site
1 (0.5%)        2 (1.0%)         0         1 (0.9%)     1 (0.9%)        0        1 (0.2%)     6 (0.7%) swelling
Injection site
1 (0.5%)        1 (0.5%)         0            0            0            0        3 (0.7%)     5 (0.6%) discomfort
Injection site
1 (0.5%)           0             0            0         3 (2.7%)        0        1 (0.2%)     5 (0.6%) reaction
Injection site
0            1 (0.5%)         0            0            0            0        2 (0.5%)     3 (0.4%) cellulitis
Injection site
1 (0.5%)           0          1 (1.0%)        0            0            0        2 (0.5%)     3 (0.4%) infection
*Patients received SUBOXONE film for a run-in period before they switched to SUBLOCADE injection.

Longer-term experience
In an interim analysis of the ongoing open-label long-term safety study (13-0003), safety was evaluated for up to 12 injections over the course of a year (see Table 1). Adverse events were reported for 432 of 669 subjects during the treatment period. The overall adverse event profile was similar to the double- blind trial described above.
8.2       Postmarketing Experience

The most frequently reported systemic postmarketing adverse event observed with buprenorphine sublingual tablets was drug misuse or abuse. The most frequently reported systemic postmarketing adverse event with buprenorphine/naloxone sublingual tablets and film was peripheral edema.
The following adverse reactions have been identified during post-approval use of buprenorphine.
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.
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 SUBLOCADE.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (14.2)].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., 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