CONTRAINDICATIONS

TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline.¹

WARNINGS

Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening.¹

Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.¹

TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline. (See PRECAUTIONS, Pregnancy.)¹

The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.¹

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. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.¹

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of
C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.¹

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.¹

PRECAUTIONS

General

Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In Phase 3 cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.¹

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.¹

As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.¹

Prescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.¹

Information for Patients

Patients should be counseled that antibacterial drugs including TYGACIL should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TYGACIL is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may
(1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TYGACIL or other antibacterial drugs in the future.¹

Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.¹

Drug Interactions

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.¹

Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.¹

Drug/Laboratory Test Interactions

There are no reported drug-laboratory test interactions.¹

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.¹

Pregnancy

Teratogenic Effects—Pregnancy Category D
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, ¹⁴C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively. An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.¹

There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)¹

Labor and Delivery

TYGACIL has not been studied for use during labor and delivery.¹

Nursing Mothers

Results from animal studies using ¹⁴C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.¹

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL is administered to a nursing woman. (See WARNINGS.)¹

Use in Patients with Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.¹ (See Dosing and Administration.)

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established. (See WARNINGS.) Therefore, use in patients under 18 years of age is not recommended.¹

Geriatric Use

Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=1415), 278 were 65 and over, while 110 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.¹

OVERDOSAGE

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose IV toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD₅₀) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD₅₀ was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.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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