Adverse Reactions

TYGACIL had a low overall discontinuation rate due to adverse events¹:

• In phase 3 clinical studies with 2,514 patients treated with TYGACIL, the most commonly reported adverse events were nausea (26%) and vomiting (18%)¹
  • Nausea and vomiting generally occurred early (days 1 to 2)^1,25
  • Only 1.3% of patients discontinued TYGACIL due to nausea and 1.0% due to vomiting¹
  • Among patients who experienced nausea and vomiting, approximately 94% of the cases were mild to moderate¹

Treatment-emergent adverse events reported at incidences 2% in patients receiving TYGACIL in Phase 3 clinical trials¹

* Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
† 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.

The discontinuation rate for TYGACIL was comparable to vancomycin + aztreonam and imipenem/cilastatin¹ (see chart below)

Comparable overall discontinuation rates (%)¹

Serious Adverse Events

In Phase 3 double-blind studies that included a comparator and employed a 1:1 randomization, death occurred in 4.7% (107/2274) of patients receiving TYGACIL and 3.8% (85/2264) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all-cause mortality was 1.0% (95% CI -0.3, 2.2) between TYGACIL and comparator treated patients. No significant differences were observed between treatments by infection type (see Table 2). Generally, deaths represented complications of the underlying disease or progression of disease. A causal relationship to TYGACIL has not been established.

Patients with Adverse Events with Outcome of Death by Infection Type

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections;
cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia;
VAP = Ventilator-associated pneumonia.

* The difference between the percentage of patients who died in TYGACIL and comparator treatment groups.
† These are subgroups of the HAP population.
Note: The Phase 3 Studies include 300 and 305 (cSSSI), 301 and 306 (cIAI), 308 and 313 (CAP), and 311 (HAP).

In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events 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.]¹

Laboratory Abnormalities

Increases in PT and activated partial thromboplastin time (aPTT) have been associated with tigecycline, but no clinically significant bleeding episodes occurred. Monitoring of PT and aPTT is advisable in all subjects at risk of abnormal coagulation status.²⁵ In the cSSSI studies, 20 subjects in the tigecycline group and 7 subjects in the vancomycin + aztreonam group had a PT or aPTT greater than 2 times the upper limit of normal. The aPTT for the study group populations had a prolongation of 6.13 seconds, raising the mean value from 33.64 to 39.87 seconds for the final on-therapy value.²⁵ The reported incidences of the various bleeding treatment-emergent adverse effects were no more frequent in the tigecycline-treated subjects.²⁵

Increases in blood urea nitrogen levels (without concomitant rise in creatinine or nephrotoxicity), hypoproteinemia, and abnormal wound healing have also been reported with tigecycline. An antianabolic effect of tigecycline is possible.²⁵

In some patients, hyperbilirubinemia did occur. In the cIAI studies, bilirubinemia occurred in 22 tigecycline-treated subjects (2.7%) versus 10 imipenem/cilastatin-treated subjects (1.2%). Approximately half of the subjects with these treatment-emergent adverse events had elevated bilirubin values at baseline (about half of these were ≥3 times the upper limit of normal range). Mean total serum bilirubin values decreased statistically significantly in both treatment arms from baseline to the final on-therapy value.²⁵

The table below shows the incidence of treatment-emergent adverse events through test of cure reported in ≥2% of patients treated with tigecycline in phase 3 clinical trials regardless of causality.¹

Incidence (%) of Treatment-Emergent Laboratory Abnormalities Through Test of Cure Reported in ≥2% of Patients Treated With Tigecycline in Phase 3 Clinical Studies¹

*100 mg initially, followed by 50 mg every 12 hours.
†Vancomycin + aztreonam, imipenem/cilastatin, linezolid.
‡Liver function test abnormalities in tigecycline-treated patients were reported more frequently in the post-therapy period than those in comparator-treated patients, which occurred more often on therapy.
BUN = blood urea nitrogen; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase.

Drug-Related Adverse Events Reported Infrequently (≥0.2% but <2%) in Patients Treated With Tigecycline in Phase 3 Clinical Studies¹

Drug-Related Laboratory Abnormalities Reported Infrequently (≥0.2% but <2%) in Patients Treated With Tigecycline in Phase 3 Clinical Studies¹

Indications

TYGACIL^® (tigecycline) is indicated for the treatment of adults with:

• Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis
• Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus,
  S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros
• Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila

Important Safety Information

• TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline
• Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics
• Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function. Adverse events may occur after the drug has been discontinued
• The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established
• An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL-treated patients versus comparator-treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options
• TYGACIL may cause fetal harm when administered to a pregnant woman
• The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated
• Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis
• Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis
• Monotherapy should be used with caution in patients with clinically apparent intestinal perforation
• TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi
• The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT
• Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin
• Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective
• The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established

Please see full Prescribing Information.