Adverse Events in Clinical Studies

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

• In phase 3 clinical studies with 1,415 patients treated with TYGACIL, the most commonly reported adverse events were nausea (29.5%) and vomiting (19.7%)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 ≥3% in patients receiving TYGACIL in phase 3 clinical trials (%)¹

	TYGACIL (N=1,415)	Comparator* (N=1,382)
Digestive System
Nausea	29.5%	15.8%
Vomiting	19.7%	10.8%
Diarrhea	12.7%	10.8%
Body as a Whole
Infection	8.3%	5.4%
Fever	7.1%	9.8%
Abdominal pain	6.8%	5.7%
Headache	5.9%	6.5%
Pain	3.7%	2.9%
Abscess	3.2%	2.6%
Cardiovascular System
Hypertension	4.9%	5.6%
Hemic and Lymphatic System
Thrombocythemia	6.1%	6.2%
Anemia	4.2%	4.8%
Leukocytosis	3.7%	2.5%
Metabolic and Nutritional
SGPT increased†	5.6%	4.7%
Hypoproteinemia	4.5%	3.0%
SGOT increased†	4.3%	4.4%
Lactic dehydrogenase increased	4.0%	3.5%
Alkaline phosphatase increased	3.5%	2.6%
Healing abnormal	3.5%	2.6%
Peripheral edema	3.3%	3.3%
Amylase increased	3.1%	1.4%
Nervous System
Dizziness	3.5%	2.7%
Respiratory System
Cough increased	3.7%	3.8%
Other
Local reaction to procedure	9.0%	9.1%

*Vancomycin + aztreonam, imipenem/cilastatin, linezolid.
†These events were more frequently reported on therapy for comparators and post therapy for TYGACIL.

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

Comparable overall discontinuation rates (%)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

Body System	Tigecycline* (N=1,415)	Comparators† (N=1,382)
Metabolic and nutritional system
Alkaline phosphatase increased	3.5	2.6
Amylase increased	3.1	1.4
Bilirubinemia	2.3	0.9
BUN increased	2.1	0.2
Hyperglycemia	1.8	2.9
Hypokalemia	2.1	2.9
Hypoproteinemia	4.5	3.0
Lactic dehydrogenase increased	4.0	3.5
SGOT increased‡	4.3	4.4
SGPT increased‡	5.6	4.7
Hemic and lymphatic system
Anemia	4.2	4.8
Leukocytosis	3.7	2.5
Thrombocythemia	6.1	6.2

*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

Body System	Adverse Event
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, bradycardia, tachycardia, vasodilatation
Digestive system	Anorexia, dry mouth, jaundice, abnormal stools
Metabolic and nutritional system	Increased creatinine, hypocalcemia, hypoglycemia, hyponatremia
Nervous system	Somnolence
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
Urogenital system	Vaginal moniliasis, vaginitis, leukorrhea

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

Body System	Adverse Event
Hemic and lymphatic system	Prolonged activated partial thromboplastin time, prolonged prothrombin time, eosinophilia, increased international normalized ratio, thrombocytopenia
Metabolic and nutritional system	Increased creatinine, hypocalcemia, hypoglycemia, hyponatremia

 

Serious Adverse Events

In phase 3 cSSSI and cIAI studies, death occurred in 2.3% of patients (32/1383) receiving tigecycline and 1.6% of patients (22/1375) receiving comparator drugs; this difference is not statistically significant, and relationship to treatment cannot be established. In all treatment groups, mortality was associated with higher baseline comorbidity and/or greater severity of baseline infections.¹

In phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (6.7%) versus comparators (4.6%). Significant differences in sepsis/septic shock with tigecycline (1.5%) versus comparators (0.5%) were observed. Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established. Other events included nonsignificant differences in abscess (1.8% vs 1.6%) and infections, including wound infections (1.7% vs 1.1%) for tigecycline versus comparators, respectively.¹

Indications and Important Safety Information

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 only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, and Bacteroides fragilis
• Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros

Important Safety Information

• 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
• Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening
• TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline
• TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics
• Glycylcycline class antibiotics are 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
• The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established
• In clinical trials, the most common treatment-emergent adverse events in patients treated with TYGACIL were nausea (29.5%) and vomiting (19.7%)
• TYGACIL may cause fetal harm when administered to a pregnant woman
• The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established
• 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
• Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective
• 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
• Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin
• Monotherapy should be used with caution in patients with clinically apparent intestinal perforation
• In patients with severe hepatic impairment (Child Pugh C), the initial dose of TYGACIL should be 100 mg followed by 25 mg every 12 hours. Patients should be treated with caution and monitored for treatment response
• The following drugs should not be administered simultaneously through the same Y‑site as TYGACIL: amphotericin B and diazepam

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