Because clinical studies are conducted under varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Phase 3 clinical studies enrolled 2514 Tygacil-treated patients. Tygacil was discontinued due to treatment-emergent adverse events in 5% of patients compared to 4.7% for all comparators. Table 8 shows the incidence of treatment-emergent adverse events reported in ≥2% of patients in these studies.
Click on icon to see table/diagram/image
In all phase 3 and 4 studies that includes a comparator, death occurred in 4% (150/3788) of patients receiving Tygacil and 3% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all cause mortality was 0.9% (95% CI 0.1, 1.8) between tigecycline and comparator treated patients. 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 tigecycline and comparator-treated patients. No significant differences were observed between treatments by tygecycline and comparators by infection type (see Table 9). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbidities.
Click on icon to see table/diagram/image
The most common treatment-emergent 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 26.4% (16.9% mild, 8.1% moderate, 1.3% severe) and vomiting incidence was 18.1% (11% mild, 6.1% moderate, 1% severe).
In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for Tygacil and 8.9% for vancomycin/aztreonam; vomiting incidence was 20% for Tygacil and 4.2% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25.3% for Tygacil and 20.5% for imipenem/cilastatin; vomiting incidence was 19.5% for Tygacil and 15.3% for imipenem/cilastatin.
Discontinuation from tigecycline was most frequently associated with nausea (1.1%) and vomiting (1.1%). For comparators, discontinuations were most frequently associated with nausea (0.5%).
The following treatment-emergent adverse events were reported infrequently (<2%) in patients receiving Tygacil in phase 3 clinical studies: Body as a Whole: Injection site inflammation, pain, reactions, edema and phlebitis.
Cardiovascular System: Thrombophlebitis.
Digestive System: Anorexia, jaundice.
Metabolic/Nutritional System: Bilirubinemia.
Hemic and Lymphatic System: Prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT); increased international normalized ratio (INR).
Skin and Appendages: Pruritus.
For patients who received tigecycline, the following adverse reactions were reported: Blood and Lymphatic System: Prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT); increased international normalized ratio (INR), thrombocytopenia.
Immune System: Anaphylaxis/anaphylactoid reactions.
Metabolism and Nutrition: Bilirubinemia, increased blood urea nitrogen (BUN), hypoproteinemia, hypoglycemia.
Nervous System: Dizziness.
Cardiac: Phlebitis, thrombophlebitis.
Gastrointestinal: Nausea, vomiting, diarrhea, anorexia, abdominal pain, dyspepsia, acute pancreatitis.
Hepatobiliary: Elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), jaundice, hepatic cholestasis.
Skin and Subcutaneous Tissue: Pruritus, rash, severe skin reactions, including Stevens-Johnson syndrome.
General Disorders and Administration Site Conditions: Headache, abnormal healing, injection site inflammation, pain, reactions, edema and phlebitis.
Investigations: Elevated serum amylase.