TYGACIL^®
(TIGECYCLINE)
FOR INJECTION

TYGACIL (tigecycline) is a glycylcycline antibacterial for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. The empirical formula is C₂₉H₃₉N₅O₈ and the molecular weight is 585.65.

The following represents the chemical structure of tigecycline:

TYGACIL is an orange lyophilized powder or cake. Each TYGACIL vial contains 50 mg tigecycline lyophilized powder for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 1. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

TYGACIL (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the C_max of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in C_max did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when TYGACIL is administered with digoxin.

Concomitant administration of TYGACIL (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in C_max by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, TYGACIL is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. Tigecycline is not affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. Tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerase). In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterial drugs. In general, tigecycline is considered bacteriostatic.

Tigecycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

TYGACIL is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions uled below for patients 18 years of age and older:

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 grp. (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 grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. TYGACIL may be initiated as empiric monotherapy before results of these tests are known.

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 that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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

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

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.

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.)

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.

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.

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.

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.

Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. (See ADVERSE REACTIONS.) 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) vs 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.

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 a study of patients with hospital acquired pneumonia, patients were randomized to receive Tygacil (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received Tygacil had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator.

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.

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.

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.

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.

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.)

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

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.

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

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.

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.)

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. (See CLINICAL PHARMACOLOGY, Special Populations, Use in Patients with Hepatic Impairment and DOSAGE AND ADMINISTRATION.)

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.

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.

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. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Phase 3 clinical studies enrolled 1415 patients treated with TYGACIL. TYGACIL was discontinued due to treatment-emergent adverse events in 5.0% of patients compared to 4.7% for all comparators (5.3% for vancomycin/aztreonam and 4.4% for imipenem/cilastatin). Table 4 shows the incidence of treatment-emergent adverse events through test of cure reported in ≥2% of patients in these studies regardless of causality.

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

In Phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (6.7%) vs comparators (4.6%). Significant differences in sepsis/septic shock with TYGACIL (1.5%) vs 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. (See PRECAUTIONS.) Other events included nonsignificant differences in abscess (1.8% vs 1.6%) and infections, including wound infections (1.7% vs 1.1%) for TYGACIL vs comparators, respectively.

The most common treatment-emergent adverse events, 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 29.5% (19.6% mild, 8.5% moderate, 1.4% severe) and vomiting incidence was 19.7% (12.3% mild, 6.3% moderate, 1.1% severe). In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35.0% for TYGACIL and 8.9% for vancomycin/aztreonam; vomiting incidence was 20.0% 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 (1.3%) and vomiting (1.0%). For comparators, discontinuations were most frequently associated with rash (1.1%, vancomycin/aztreonam) and nausea (1.0%, imipenem/cilastatin).

The following drug-related adverse events were reported infrequently (≥0.2% and <2%) in patients receiving TYGACIL in Phase 3 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, bradycardia, tachycardia, vasodilatation
Digestive System: anorexia, dry mouth, jaundice, abnormal stools
Metabolic/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

Worldwide post-marketing adverse events not previously uled in the product label include: anaphylaxis/anaphylactoid reactions, acute pancreatitis.

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.

The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with TYGACIL for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.

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 TYGACIL 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. (See CLINICAL PHARMACOLOGY, Special Populations, Use in Patients with Hepatic Impairment and PRECAUTIONS, Use in Patients with Hepatic Impairment.)

No dosage adjustment of TYGACIL is necessary in patients with renal impairment or in patients undergoing hemodialysis. (See CLINICAL PHARMACOLOGY, Special Populations, Use in Patients with Renal Impairment.)

No dosage adjustment of TYGACIL is necessary based on age, gender, or race. (See CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS, Geriatric Use.)

Each vial of TYGACIL should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL IV bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the IV bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Once reconstituted, TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the IV bag). Alternatively, TYGACIL may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 45 hours following immediate transfer of the reconstituted solution into the IV bag.

TYGACIL may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of TYGACIL with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line. (See DOSAGE AND ADMINISTRATION, Preparation and Handling, Compatibilities/Incompatibilities.)

TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass vial containing 50 mg tigecycline lyophilized powder for reconstitution.

Supplied 10 vials/box. NDC: 0008-4990-02

Prior to reconstitution, TYGACIL should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Once reconstituted, TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the IV bag). Alternatively, TYGACIL may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 45 hours following immediate transfer of the reconstituted solution into the IV bag. Reconstituted solution must be transferred and further diluted for I.V. infusion.

In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.

No evidence of photosensitivity was observed in rats following administration of tigecycline.

TYGACIL was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared TYGACIL (100 mg IV initial dose followed by 50 mg every 12 hours) with vancomycin (1 g IV every 12 hours)/aztreonam (2 g IV every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co‑primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c‑mITT) patients. See Table 5. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 6.

TYGACIL was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared TYGACIL (100 mg IV initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg IV every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable(ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 7. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 8.

• Clinical and Laboratory Standards Institute (CLSI) [formerly National Committee for Clinical Laboratory Standards (NCCLS)]. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – 6^th ed. Approved Standard, CLSI document M7-A6, Vol. 23. CLSI, Wayne, PA. January 2003.
• Clinical and Laboratory Standards Institute (CLSI) [formerly National Committee for Clinical Laboratory Standards (NCCLS)]. Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests – 8^th ed. Approved Standard, CLSI document M2-A8, Vol. 23. CLSI, Wayne, PA. January 2003.
• Clinical and Laboratory Standards Institute (CLSI) [formerly National Committee for Clinical Laboratory Standards (NCCLS)]. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – 6^th ed. Approved Standard, CLSI document M11-A6, Vol. 24. CLSI, Wayne, PA. January 2004.
• Clinical and Laboratory Standards Institute (CLSI) [formerly National Committee for Clinical Laboratory Standards (NCCLS)]. Performance Standards for Antimicrobial Susceptibility Testing – 15^th Informational Supplement. Approved Standard, CLSI document M100-S15, Vol. 25. CLSI, Wayne, PA. January 2005.

U.S. Patent Number: 5,494,903

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Wyeth^®

Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101

W10521C002
ET01
Rev 06/07