ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1)] Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2)] Anaphylaxis [Warning and Precautions (5.3)] Hepatic Adverse Effects [Warnings and Precautions (5.4)] Pancreatitis [Warnings and Precautions (5.5)] All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1)] Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions (5.2)] Anaphylaxis [Warning and Precautions (5.3)] Hepatic Adverse Effects [Warnings and Precautions (5.4)] Pancreatitis [Warnings and Precautions (5.5)] The most common adverse reactions (incidence 5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 2,514 patients were treated with tigecycline. Tigecycline was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table shows the incidence of adverse reactions through test of cure reported in >= 2% of patients in these trials. Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in >= 2% of Patients Treated in Clinical Studies Body System Adverse Reactions Tigecycline (N=2,514)Comparatorsa (N=2,307) Body as Whole Abdominal pain 4 Abscess 2 Asthenia 2 Headache 7 Infection 5 Cardiovascular System Phlebitis 4 Digestive System Diarrhea 12 11 Dyspepsia 2 Nausea 26 13 Vomiting 18 Hemic and Lymphatic System Anemia 6 Metabolic and Nutritional Alkaline Phosphatase Increased 3 Amylase Increased 2 Bilirubinemia 1 BUN Increased 1 Healing Abnormal 2 Hyponatremia 1 Hypoproteinemia 3 SGOT Increasedb 5 SGPT Increasedb 5 Respiratory System Pneumonia 2 Nervous System Dizziness 3 Skin and Appendages Rash 4 Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.b LFT 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.In all 13 Phase and trials that included comparator, death occurred in 4.0% (150/3,788) of patients receiving tigecycline and 3.0% (110/3,646) of patients receiving comparator drugs. In pooled analysis of these trials, based on 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 (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.Table 2. Patients with Outcome of Death by Infection Type Tigecycline ComparatorRisk DifferenceInfection Typen/N%n/N%% (95% CI)cSSSI 12/834 1.4 6/813 0.7 0.7 (-0.3, 1.7) cIAI 42/1,382 3.0 31/1,393 2.2 0.8 (-0.4, 2.0) CAP 12/424 2.8 11/422 2.6 0.2 (-2.0, 2.4) HAP 66/467 14.1 57/467 12.2 1.9 (-2.4, 6.3) Non-VAPa41/336 12.2 42/345 12.2 0.0 (-4.9, 4.9) VAPa 25/131 19.1 15/122 12.3 6.8 (-2.1, 15.7) RP 11/128 8.6 2/43 4.7 3.9 (-4.0, 11.9) DFI 7/553 1.3 3/508 0.6 0.7 (-0.5, 1.8) Overall Adjusted 150/3,788 4.0 110/3,646 3.0 0.6 (0.1, 1.2) CAP Community-acquired pneumonia; cIAI Complicated intra-abdominal infections; cSSSI Complicated skin and skin structure infections; HAP Hospital-acquired pneumonia; VAP Ventilator-associated pneumonia; RP Resistant pathogens; DFI Diabetic foot infections. The difference between the percentage of patients who died in tigecycline and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction. Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI. These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).An analysis of mortality in all trials conducted for approved indications cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) showed an adjusted mortality rate of 2.5% (66/2,640) for tigecycline and 1.8% (48/2,628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with tigecycline (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with tigecycline (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 (5.9)]. The most common adverse reactions were nausea and vomiting which generally occurred during the first to days of therapy. The majority of cases of nausea and vomiting associated with tigecycline and comparators were either mild or moderate in severity. In patients treated with tigecycline, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for tigecycline and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline and 8% for levofloxacin; vomiting incidence was 16% for tigecycline and 6% for levofloxacin. Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (< 1%).The following adverse reactions were reported (< 2%) in patients receiving tigecycline in clinical studies: Body as Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemiaSpecial Senses: taste perversion Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of tigecycline. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.anaphylactic reactionsacute pancreatitishepatic cholestasis, and jaundicesevere skin reactions, including Stevens-Johnson Syndromesymptomatic hypoglycemia in patients with and without diabetes mellitus. anaphylactic reactions. acute pancreatitis. hepatic cholestasis, and jaundice. severe skin reactions, including Stevens-Johnson Syndrome. symptomatic hypoglycemia in patients with and without diabetes mellitus.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tigecycline is tetracycline class antibacterial [see Microbiology (12.4)]. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyNo significant effect of single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.. 12.3 Pharmacokinetics. The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes. Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline Single Dose100 mg(N=224)Multiple Dosea 50 mg every 12h(N=103)Cmax (mcg/mL)b 1.45 (22%) 0.87 (27%) Cmax (mcg/mL)c 0.90 (30%) 0.63 (15%) AUC (mcgoh/mL) 5.19 (36%) - AUC0-24h (mcgoh/mL) - 4.7 (36%) Cmin (mcg/mL) - 0.13 (59%) 1/2 (h) 27.1 (53%) 42.4 (83%) CL (L/h) 21.8 (40%) 23.8 (33%) CLr (mL/min) 38.0 (82%) 51.0 (58%) Vss (L) 568 (43%) 639 (48%) 100 mg initially, followed by 50 mg every 12 hours 30-minute infusion 60-minute infusion. DistributionThe in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 (7 to L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues. Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcgoh/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcgoh/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcgoh/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects. In single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied. EliminationMetabolism Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but glucuronide, an N-acetyl metabolite, and tigecycline epimer (each at no more than 10% of the administered dose) were also present. Tigecycline is substrate of P-glycoprotein (P-gp) based on an in vitro study using cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.Excretion The recovery of total radioactivity in feces and urine following administration of 14C -tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes. Specific PopulationsHepatic Impairment In study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations (8.6) and Dosage and Administration (2.2)]. Renal Impairment single dose study compared subjects with severe renal impairment (creatinine clearance 30 mL/min), end stage renal disease (ESRD) patients receiving tigecycline hours before hemodialysis, ESRD patients receiving tigecycline hour after hemodialysis, and healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis.Geriatric Patients No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65 to 75; n=13, age 75) and younger subjects (n=18) receiving single 100 mg dose of tigecycline. Therefore, no dosage adjustment is necessary based on age [see Use in Specific Populations (8.5)]. Pediatric Patients single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged to 16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or mg/kg. The study showed that for children aged 12 to 16 years (n 16) dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults with the approved dosing regimen. Large variability observed in children aged to 11 years of age (n 8) required additional study to determine the appropriate dosage.A subsequent tigecycline dose-finding study was conducted in to 11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n 17), mg/kg (n 21), and 1.25 mg/kg (n=20). This study showed that for children aged to 11 years, 1.2 mg/kg dose would likely result in exposures comparable to those observed in adults resulting with the approved dosing regimen [see Dosage and Administration (2.3)].GenderIn pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (+- SD) tigecycline clearance between women (20.7 +- 6.5 L/h) and men (22.8 +- 8.7 L/h). Therefore, no dosage adjustment is necessary based on gender. Race In pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and subjects classified as other participating in clinical pharmacology studies, there was no significant difference in the mean (+- SD) tigecycline clearance among the Asian subjects (28.8 +- 8.8 L/h), Black subjects (23 +- 7.8 L/h), Hispanic subjects (24.3 +- 6.5 L/h), White subjects (22.1 +- 8.9 L/h), and other subjects (25 +- 4.8 L/h). Therefore, no dosage adjustment is necessary based on race. Drug Interaction StudiesDigoxinTigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were co-administered to healthy subjects in drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax 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 tigecycline is administered with digoxin. WarfarinConcomitant administration of tigecycline (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax 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 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, tigecycline 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.. In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described above.Tigecycline is substrate of P-gp based on an in vitro study using cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Coadministration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.. 12.4 Microbiology. Mechanism of ActionTigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. In general, tigecycline is considered bacteriostatic; however, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila. ResistanceTo date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is less affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux. Additionally, 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/topoisomerases). However, some ESBL-producing isolates may confer resistance to tigecycline via other resistance mechanisms. Tigecycline resistance in some bacteria (e.g. Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.Interaction with Other AntimicrobialsIn vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials. Antimicrobial ActivityTigecycline has been shown to be active against most of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Gram-positive bacteria Enterococcus faecalis (vancomycin-susceptible isolates) Staphylococcus aureus (methicillin-susceptible and -resistant isolates) Streptococcus agalactiae Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus) Streptococcus pneumoniae (penicillin-susceptible isolates) Streptococcus pyogenes Gram-negative bacteria Citrobacter freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Klebsiella oxytoca Klebsiella pneumoniae Legionella pneumophila Anaerobic bacteria Bacteroides fragilis Bacteroides thetaiotaomicron Bacteroides uniformis Bacteroides vulgatus Clostridium perfringens Peptostreptococcus micros The following in vitro data are available, but their clinical significance is unknown. At least90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for tigecycline against isolates of similar genus or organism group. However, the efficacy of tigecycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Gram-positive bacteria Enterococcus avium Enterococcus casseliflavus Enterococcus faecalis (vancomycin-resistant isolates) Enterococcus faecium (vancomycin-susceptible and -resistant isolates) Enterococcus gallinarum Listeria monocytogenesStaphylococcus epidermidis (methicillin-susceptible and -resistant isolates) Staphylococcus haemolyticusGram-negative bacteria Acinetobacter baumannii Aeromonas hydrophila Citrobacter koseri Enterobacter aerogenes Haemophilus influenzae (ampicillin-resistant) Haemophilus parainfluenzae Pasteurella multocida Serratia marcescens Stenotrophomonas maltophiliaAnaerobic bacteria Bacteroides distasonis Bacteroides ovatus Peptostreptococcus spp. Porphyromonas spp. Prevotella spp. Other bacteria Mycobacterium abscessusMycobacterium fortuitumThere have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Complicated Skin and Skin Structure Infections. Tigecycline 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 tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 intravenous every 12 hours)/aztreonam (2 intravenous every 12 hours) for 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 4. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 5. Table 4. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after to 14 Days of Therapy Tigecyclinea n/N (%) Vancomycin/Aztreonamb n/N (%) Study 300 CE 165/199 (82.9) 163/198 (82.3) c-mITT 209/277 (75.5) 200/260 (76.9) Study 305 CE 200/223 (89.7) 201/213 (94.4) c-mITT 220/261 (84.3) 225/259 (86.9) 100 mg initially, followed by 50 mg every 12 hoursb Vancomycin (1 every 12 hours)/Aztreonam (2 every 12 hours) Table 5. Clinical Cure Rates by Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infectionsa Pathogen Tigecycline n/N (%) Vancomycin/Aztreonam n/N (%) Escherichia coli 29/36 (80.6) 26/30 (86.7) Enterobacter cloacae 10/12 (83.3) 15/15 (100) Enterococcus faecalis (vancomycin-susceptible only) 15/21 (71.4) 19/24 (79.2) Klebsiella pneumoniae 12/14 (85.7) 15/16 (93.8) Methicillin-susceptible Staphylococcus aureus (MSSA) 124/137 (90.5) 113/120 (94.2) Methicillin-resistant Staphylococcus aureus (MRSA) 79/95 (83.2) 46/57 (80.7) Streptococcus agalactiae 8/8 (100) 11/14 (78.6) Streptococcus anginosus grpb 17/21 (81.0) 9/10 (90.0) Streptococcus pyogenes 31/32 (96.9) 24/27 (88.9) Bacteroides fragilis 7/9 (77.8) 4/5 (80.0) Two cSSSI pivotal studies and two Resistant Pathogen studiesb Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus 14.2 Complicated Intra-abdominal Infections. Tigecycline 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 tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every hours) for 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 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7. Table 6. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after to 14 Days of Therapy Tigecyclinea n/N (%) Imipenem/Cilastatin n/N (%) Study 301 ME 199/247 (80.6) 210/255 (82.4) m-mITT 227/309 (73.5) 244/312 (78.2) Study 306 ME 242/265 (91.3) 232/258 (89.9) m-mITT 279/322 (86.6) 270/319 (84.6) 100 mg initially, followed by 50 mg every 12 hoursb Imipenem/Cilastatin (500 mg every hours) Table 7. Clinical Cure Rates by Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infectionsa Pathogen Tigecycline n/N (%) Imipenem/Cilastatin n/N (%) Citrobacter freundii 12/16 (75.0) 3/4 (75.0) Enterobacter cloacae 15/17 (88.2) 16/17 (94.1) Escherichia coli 284/336 (84.5) 297/342 (86.8) Klebsiella oxytoca 19/20 (95.0) 17/19 (89.5) Klebsiella pneumoniae 42/47 (89.4) 46/53 (86.8) Enterococcus faecalis 29/38 (76.3) 35/47 (74.5) Methicillin-susceptible Staphylococcus aureus (MSSA) 26/28 (92.9) 22/24 (91.7) Methicillin-resistant Staphylococcus aureus (MRSA) 16/18 (88.9) 1/3 (33.3) Streptococcus anginosus grpb 101/119 (84.9) 60/79 (75.9) Bacteroides fragilis 68/88 (77.3) 59/73 (80.8) Bacteroides thetaiotaomicron 36/41 (87.8) 31/36 (86.1) Bacteroides uniformis 12/17 (70.6) 14/16 (87.5) Bacteroides vulgatus 14/16 (87.5) 4/6 (66.7) Clostridium perfringens 18/19 (94.7) 20/22 (90.9) Peptostreptococcus micros 13/17 (76.5) 8/11 (72.7) Two cIAI pivotal studies and two Resistant Pathogen studiesb Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus 14.3 Community-Acquired Bacterial Pneumonia. Tigecycline was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies and ). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 1), after at least days of intravenous therapy, switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy 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 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9. Table 8. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after to 14 Days of Total Therapy Tigecyclinea n/N (%) Levofloxacinb n/N (%) 95% CIc Study 1d CE 125/138 (90.6) 136/156 (87.2) (-4.4, 11.2) c-mITT 149/191 (78) 158/203 (77.8) (-8.5, 8.9) Study CE 128/144 (88.9) 116/136 (85.3) (-5, 12.2) c-mITT 170/203 (83.7) 163/200 (81.5) (-5.6, 10.1) 100 mg initially, followed by 50 mg every 12 hoursb Levofloxacin (500 mg intravenous every 12 or 24 hours)c 95% confidence interval for the treatment difference After at least days of intravenous therapy, switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1. Table 9. Clinical Cure Rates by Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumoniaa Pathogen Tigecycline n/N (%) Levofloxacin n/N (%) Haemophilus influenzae 14/17 (82.4) 13/16 (81.3) Legionella pneumophila 10/10 (100.0) 6/6 (100.0) Streptococcus pneumoniae (penicillin-susceptible only)b 44/46 (95.7) 39/44 (88.6) Two CABP studies Includes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for tigecycline and levofloxacin respectively]To further evaluate the treatment effect of tigecycline, post-hoc analysis was conducted in CABP patients with higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors: Age >= 50 yearsPSI score >= 3Streptococcus pneumoniae bacteremiaThe results of this analysis are shown in Table 10. Age >= 50 was the most common risk factor in the higher-risk group. Table 10. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortalitya Tigecycline n/N (%) Levofloxacin n/N (%) 95% CIb Study 1c CE Higher risk Yes 93/103 (90.3) 84/102 (82.4) (-2.3, 18.2) No 32/35 (91.4) 52/54 (96.3) (-20.8, 7.1) c-mITT Higher risk Yes 111/142 (78.2) 100/134 (74.6) (-6.9, 14) No 38/49 (77.6) 58/69 (84.1) (-22.8, 8.7) Study CE Higher risk Yes 95/107 (88.8) 68/85 (80) (-2.2, 20.3) No 33/37 (89.2) 48/51 (94.1) (-21.1, 8.6) c-mITT Higher risk Yes 112/134 (83.6) 93/120 (77.5) (-4.2, 16.4) No 58/69 (84.1) 70/80 (87.5) (-16.2, 8.8) Patients at higher risk of death include patients with any one of the following: >= 50 years of age; PSI score >= 3; or bacteremia due to Streptococcus pneumoniae 95% confidence interval for the treatment difference After at least days of intravenous therapy, switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1.. Age >= 50 years. PSI score >= 3. Streptococcus pneumoniae bacteremia.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Initial dose of 100 mg, followed by 50 mg every 12 hours administered intravenously over approximately 30 to 60 minutes. (2.1)Severe hepatic impairment (Child Pugh C): Initial dose of 100 mg followed by 25 mg every 12 hours. (2.2) Initial dose of 100 mg, followed by 50 mg every 12 hours administered intravenously over approximately 30 to 60 minutes. (2.1). Severe hepatic impairment (Child Pugh C): Initial dose of 100 mg followed by 25 mg every 12 hours. (2.2) 2.1 Recommended Adult Dosage. The recommended dosage regimen for tigecycline for injection is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of tigecycline for injection should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with tigecycline for injection for complicated skin and skin structure infections or for complicated intra-abdominal infections is to 14 days. The recommended duration of treatment with tigecycline for injection for community-acquired bacterial pneumonia is to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patients clinical and bacteriological progress.. 2.2 Dosage in Patients with Hepatic Impairment. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline for injection should be 100 mg followed by 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 (12.3) and Use in Specific Populations (8.6)].. 2.3 Dosage in Pediatric Patients. The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline in adult patients. Avoid use of tigecycline in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested: Pediatric patients aged to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to maximum dose of 50 mg of tigecycline every 12 hours.Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours. The proposed pediatric doses of tigecycline were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].There are no data to provide dosing recommendations in pediatric patients with hepatic impairment.. Pediatric patients aged to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to maximum dose of 50 mg of tigecycline every 12 hours.. Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours. 2.4 Preparation and Administration. Each vial of tigecycline for injection should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringers Injection, USP to achieve concentration of 10 mg/mL of tigecycline. (Note: Each vial contains 6% overage. Thus, mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Reconstituted solution must be transferred and further diluted for intravenous infusion. Withdraw mL of the reconstituted solution from the vial and add to 100 mL intravenous bag for infusion (for 100 mg dose, reconstitute two vials; for 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 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, tigecycline for injection may be stored at room temperature (not to exceed 25C/77F) for up to 24 hours (up to hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25C (77F) after reconstitution, tigecycline should be used immediately. Alternatively, tigecycline for injection mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at to 8C (36 to 46F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag. Tigecycline for injection may be administered intravenously through dedicated line or through 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 tigecycline for injection with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringers Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line.. 2.5 Drug Compatibilities. Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringers Injection, USP. When administered through Y-site, tigecycline for injection is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, Lactated Ringers, lidocaine HCl, metoclopramide, morphine, norepinephrine, potassium chloride, propofol (tested with 5% Dextrose Injection, USP only), ranitidine HCl, theophylline, and tobramycin.. 2.6 Drug Incompatibilities. The following drugs should not be administered simultaneously through the same Y-site as tigecycline for injection: amphotericin B, amphotericin lipid complex, diazepam, esomeprazole, haloperidol and omeprazole.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Tigecycline for injection is tetracycline class antibacterial indicated in patients 18 years of age and older for: Complicated skin and skin structure infections (1.1)Complicated intra-abdominal infections (1.2)Community-acquired bacterial pneumonia (1.3)Limitations of Use: Tigecycline for injection is not indicated for treatment of diabetic foot infection or hospital-acquired pneumonia, including ventilator-associated pneumonia. (1.4)To reduce the development of drug-resistant bacteria and maintain the effectiveness of tigecycline for injection and other antibacterial drugs, tigecycline for injection should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1.5). Complicated skin and skin structure infections (1.1). Complicated intra-abdominal infections (1.2). Community-acquired bacterial pneumonia (1.3). 1.1 Complicated Skin and Skin Structure Infections. Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of 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. 1.2 Complicated Intra-abdominal Infections. Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates of 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. 1.3 Community-Acquired Bacterial Pneumonia. Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae, and Legionella pneumophila.. 1.4 Limitations of Use. Tigecycline for injection is not indicated for the treatment of diabetic foot infections. clinical trial failed to demonstrate non-inferiority of tigecycline for injection for treatment of diabetic foot infections.Tigecycline for injection is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia. In comparative clinical trial, greater mortality and decreased efficacy were reported in tigecycline-treated patients [see Warnings and Precautions (5.2)]. 1.5 Usage. To reduce the development of drug-resistant bacteria and maintain the effectiveness of tigecycline and other antibacterial drugs, tigecycline for injection 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. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tigecycline for injection may be initiated as empiric monotherapy before results of these tests are known.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes. Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline Single Dose100 mg(N=224)Multiple Dosea 50 mg every 12h(N=103)Cmax (mcg/mL)b 1.45 (22%) 0.87 (27%) Cmax (mcg/mL)c 0.90 (30%) 0.63 (15%) AUC (mcgoh/mL) 5.19 (36%) - AUC0-24h (mcgoh/mL) - 4.7 (36%) Cmin (mcg/mL) - 0.13 (59%) 1/2 (h) 27.1 (53%) 42.4 (83%) CL (L/h) 21.8 (40%) 23.8 (33%) CLr (mL/min) 38.0 (82%) 51.0 (58%) Vss (L) 568 (43%) 639 (48%) 100 mg initially, followed by 50 mg every 12 hours 30-minute infusion 60-minute infusion. DistributionThe in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 (7 to L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues. Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcgoh/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcgoh/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcgoh/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects. In single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied. EliminationMetabolism Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but glucuronide, an N-acetyl metabolite, and tigecycline epimer (each at no more than 10% of the administered dose) were also present. Tigecycline is substrate of P-glycoprotein (P-gp) based on an in vitro study using cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.Excretion The recovery of total radioactivity in feces and urine following administration of 14C -tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes. Specific PopulationsHepatic Impairment In study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations (8.6) and Dosage and Administration (2.2)]. Renal Impairment single dose study compared subjects with severe renal impairment (creatinine clearance 30 mL/min), end stage renal disease (ESRD) patients receiving tigecycline hours before hemodialysis, ESRD patients receiving tigecycline hour after hemodialysis, and healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis.Geriatric Patients No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65 to 75; n=13, age 75) and younger subjects (n=18) receiving single 100 mg dose of tigecycline. Therefore, no dosage adjustment is necessary based on age [see Use in Specific Populations (8.5)]. Pediatric Patients single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged to 16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or mg/kg. The study showed that for children aged 12 to 16 years (n 16) dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults with the approved dosing regimen. Large variability observed in children aged to 11 years of age (n 8) required additional study to determine the appropriate dosage.A subsequent tigecycline dose-finding study was conducted in to 11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n 17), mg/kg (n 21), and 1.25 mg/kg (n=20). This study showed that for children aged to 11 years, 1.2 mg/kg dose would likely result in exposures comparable to those observed in adults resulting with the approved dosing regimen [see Dosage and Administration (2.3)].GenderIn pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (+- SD) tigecycline clearance between women (20.7 +- 6.5 L/h) and men (22.8 +- 8.7 L/h). Therefore, no dosage adjustment is necessary based on gender. Race In pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and subjects classified as other participating in clinical pharmacology studies, there was no significant difference in the mean (+- SD) tigecycline clearance among the Asian subjects (28.8 +- 8.8 L/h), Black subjects (23 +- 7.8 L/h), Hispanic subjects (24.3 +- 6.5 L/h), White subjects (22.1 +- 8.9 L/h), and other subjects (25 +- 4.8 L/h). Therefore, no dosage adjustment is necessary based on race. Drug Interaction StudiesDigoxinTigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were co-administered to healthy subjects in drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax 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 tigecycline is administered with digoxin. WarfarinConcomitant administration of tigecycline (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax 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 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, tigecycline 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.. In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described above.Tigecycline is substrate of P-gp based on an in vitro study using cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Coadministration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatrics: Use in patients under 18 years of age is not recommended. Pediatric trials were not conducted because of the higher risk of mortality seen in adult trials. (8.4). 8.1 Pregnancy. Teratogenic Effects--Pregnancy Category [see Warnings and Precautions (5.6)] 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 reductions in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of times and times the human daily dose based on AUC in rats and rabbits, respectively (28 mcgohr/mL and mcgohr/mL at 12 and mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.There are no adequate and well-controlled studies of tigecycline in pregnant women. Tigecycline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. 8.3 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 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 tigecycline is administered to nursing woman [see Warnings and Precautions (5.7)].. 8.4 Pediatric Use. Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in tigecycline-treated adult patients in clinical trials, pediatric trials of tigecycline to evaluate the safety and efficacy of tigecycline were not conducted.In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients to 17 years of age based on data from pediatric pharmacokinetic studies [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Because of effects on tooth development, use in patients under years of age is not recommended [see Warnings and Precautions (5.7)]. 8.5 Geriatric Use. Of the total number of subjects who received tigecycline in Phase clinical studies (n=2,514), 664 were 65 and over, while 288 were 75 and over. No 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.No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following single 100 mg dose of tigecycline [see Clinical Pharmacology (12.3) ]. 8.6 Hepatic Impairment. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by 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 Phar macology (12.3) and Dosage and Administration (2.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. All-Cause Mortality: meta-analysis of Phase and clinical trials demonstrated an increase in all-cause mortality in tigecycline-treated patients compared to controls with risk difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase has not been established. An increase was also seen in meta-analysis limited to the approved indications [0.6% (95% CI 0, 1.2)]. The greatest difference in mortality was seen in tigecycline-treated patients with ventilator-associated pneumonia. (5.1, 5.2)Anaphylactic Reactions: have been reported with tigecycline, and may be life-threatening. Avoid use in patients with known hypersensitivity to tetracyclines. (5.3) Hepatic Adverse Effects: have been reported with tigecycline. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. (5.4) Pancreatitis: including fatalities, has been reported with tigecycline. If pancreatitis is suspected, then consider stopping tigecycline. (5.5) Fetal Harm: Tigecycline may cause fetal harm when administered to pregnant woman. (5.6) Tooth Discoloration: The use of tigecycline during tooth development may cause permanent discoloration of the teeth. (5.7) Clostridium difficile-Associated Diarrhea (CDAD): evaluate if diarrhea occurs. (5.8) All-Cause Mortality: meta-analysis of Phase and clinical trials demonstrated an increase in all-cause mortality in tigecycline-treated patients compared to controls with risk difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase has not been established. An increase was also seen in meta-analysis limited to the approved indications [0.6% (95% CI 0, 1.2)]. The greatest difference in mortality was seen in tigecycline-treated patients with ventilator-associated pneumonia. (5.1, 5.2). Anaphylactic Reactions: have been reported with tigecycline, and may be life-threatening. Avoid use in patients with known hypersensitivity to tetracyclines. (5.3) Hepatic Adverse Effects: have been reported with tigecycline. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. (5.4) Pancreatitis: including fatalities, has been reported with tigecycline. If pancreatitis is suspected, then consider stopping tigecycline. (5.5) Fetal Harm: Tigecycline may cause fetal harm when administered to pregnant woman. (5.6) Tooth Discoloration: The use of tigecycline during tooth development may cause permanent discoloration of the teeth. (5.7) Clostridium difficile-Associated Diarrhea (CDAD): evaluate if diarrhea occurs. (5.8) 5.1 All-Cause Mortality. An increase in all-cause mortality has been observed in meta-analysis of Phase and clinical trials in tigecycline-treated patients versus comparator-treated patients. In all 13 Phase and trials that included comparator, death occurred in 4.0% (150/3,788) of patients receiving tigecycline and 3.0% (110/3,646) of patients receiving comparator drugs. In pooled analysis of these trials, based on random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2,640) for tigecycline and 1.8% (48/2,628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2). The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Tigecycline should be reserved for use in situations when alternative treatments are not suitable [see Boxed Warning, Indications and Usage (1.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia. trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of tigecycline. In this trial, patients were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population). In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received tigecycline (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1)]. Particularly high mortality was seen among tigecycline-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients). 5.3 Anaphylactic Reactions. Anaphylactic reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. Tigecycline is structurally similar to tetracycline-class antibiotics and should be avoided in patients with known hypersensitivity to tetracycline-class antibiotics.. 5.4 Hepatic Adverse Effects. Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. 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 and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued.. 5.5 Pancreatitis. Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions (6.2)].. 5.6 Fetal Harm. Tigecycline may cause fetal harm when administered to 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 Use in Specific Populations (8.1)].. 5.7 Tooth Discoloration. The use of tigecycline during tooth development (last half of pregnancy, infancy, and childhood to the age of years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with tigecycline have shown bone discoloration. Tigecycline should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.. 5.8 Clostridium difficile -Associated Diarrhea. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline, 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 and 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.. 5.9 Sepsis/Septic Shock in Patients with Intestinal Perforation. Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1,642), patients treated with tigecycline and patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The patients treated with tigecycline had higher APACHE II scores (median 13) versus the 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.. 5.10 Tetracycline-Class Adverse Effects. Tigecycline is structurally similar to tetracycline-class antibacterial drugs 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). 5.11 Development of Drug-Resistant Bacteria. Prescribing tigecycline for injection in the absence of 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.