Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:
•        All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1)]
•        Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2)]
•        Anaphylaxis [Warning and Precautions (5.3)]
•        Hepatic Adverse Effects [Warnings and Precautions (5.4)]
•        Pancreatitis [Warnings and Precautions (5.5)] 
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.

In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies
Body System                                         TYGACIL             Comparatorsa Adverse Reactions                                  (N=2514)            (N=2307) Body as a Whole
Abdominal pain                                     6                   4 Abscess                                            2                   2 Asthenia                                           3                   2 Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies
Body System                                               TYGACIL                Comparatorsa Adverse Reactions                                       (N=2514)               (N=2307) Headache                                                6                      7 Infection                                               7                      5 Cardiovascular System
Phlebitis                                               3                      4 Digestive System
Diarrhea                                                12                     11 Dyspepsia                                               2                      2 Nausea                                                  26                     13 Vomiting                                                18                     9 Hemic and Lymphatic System
Anemia                                                  5                      6 Metabolic and Nutritional
Alkaline Phosphatase                                    3                      3 Increased
Amylase Increased                                       3                      2 Bilirubinemia                                           2                      1 BUN Increased                                           3                      1 Healing Abnormal                                        3                      2 Hyponatremia                                            2                      1 Hypoproteinemia                                         5                      3 SGOT Increasedb                                         4                      5 b
SGPT Increased                                          5                      5 Respiratory System
Pneumonia                                               2                      2 Nervous System
Dizziness                                               3                      3 Skin and Appendages
Rash                                                    3                      4 a
Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
b
LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients (see Table 2).
The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.


Table 2. Patients with Outcome of Death by Infection Type
TYGACIL                 Comparator            Risk Difference*
Infection Type     n/N             %       n/N          %        % (95% CI) cSSSI              12/834          1.4     6/813        0.7      0.7 (-0.3, 1.7) cIAI               42/1382         3.0     31/1393      2.2      0.8 (-0.4, 2.0) CAP                12/424          2.8     11/422       2.6     0.2 (-2.0, 2.4) HAP                66/467          14.1    57/467       12.2 1.9 (-2.4, 6.3) Non-VAPa         41/336          12.2    42/345       12.2 0.0 (-4.9, 4.9) a
VAP              25/131          19.1    15/122       12.3 6.8 (-2.1, 15.7) RP                 11/128          8.6     2/43         4.7      3.9 (-4.0, 11.9) DFI                7/553           1.3     3/508        0.6      0.7 (-0.5, 1.8) Overall Adjusted 150/3788          4.0     110/3646     3.0      0.6 (0.1, 1.2)** CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.
* The difference between the percentage of patients who died in TYGACIL and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.
** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.
a
These are subgroups of the HAP population.
Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions (5.10)].

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from TYGACIL was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving TYGACIL in clinical studies: 
Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis 
Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools
Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia Special Senses: taste perversion

Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia 
Skin and Appendages: pruritus
Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
•       anaphylactic reactions
•       acute pancreatitis
•       hepatic cholestasis, and jaundice
•       severe skin reactions, including Stevens-Johnson Syndrome
•       symptomatic hypoglycemia in patients with and without diabetes mellitus
•       hypofibrinogenemia [see Warnings and Precautions (5.6)] 
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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/