Tygacil

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• nausea
• vomiting

Tigecycline is an antibiotic that fights bacteria in the body.

Tigecycline is used to treat many different bacterial infections of the skin or the digestive system, as well as pneumonia.

Tigecycline should be used only for infections that cannot be treated with other medicines.

Tigecycline may also be used for purposes not listed in this medication guide.

Death has occurred more often in people using tigecycline when compared with people using other antibiotics. Deaths were usually caused by complications from the infection or by other medical conditions. It is not known whether tigecycline treatment causes death.

You should not use this medicine if you are allergic to tigecycline.

To make sure tigecycline is safe for you, tell your doctor if you have:

• liver disease;
• if you are using a blood thinner (warfarin, Coumadin, Jantoven); or
• if you are allergic to a tetracycline antibiotic (demeclocycline, doxycycline, minocycline, tetracycline).

Death has occurred more often in people using tigecycline when compared with people using other antibiotics. Many deaths were caused by complications from the infection being treated. Some deaths were caused by the patients' other medical conditions. It is not known whether tigecycline treatment causes death. Talk to your doctor about the risks and benefits of using tigecycline.

FDA pregnancy category D. Do not use tigecycline if you are pregnant. It could harm the unborn baby or cause permanent tooth discoloration later in life. Use effective birth control, and tell your doctor right away if you become pregnant during treatment.

Tigecycline can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking tigecycline.

It is not known whether tigecycline passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Children should not use tigecycline. Tigecycline can cause permanent yellowing or graying of the teeth in children younger than 8 years old.

Mechanism Of Action

Tigecycline is a tetracycline class antibacterial [see Microbiology (12.4)].

Pharmacodynamics

No significant effect of a single intravenous dose of TYGACIL 50 mg or 200 mg on QTc interval was detected in a randomized, placebo-and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.

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

The 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 L (7 to 9 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 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC012h(1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 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.

Metabolism

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 a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Tigecycline is a substrate of P-glycoprotein (P-gp) based on an in vitro study using a 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 Populations

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 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 and DOSAGE AND ADMINISTRATION].

A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 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 TYGACIL is necessary in patients with renal impairment or in patients undergoing hemodialysis.

No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age >75) and younger subjects (n=18) receiving a single 100-mg dose of TYGACIL. Therefore, no dosage adjustment is necessary based on age [see Use In Specific Populations].

A single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged 8-16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or 2 mg/kg. The study showed that for children aged 12-16 years (n = 16) a 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 8 to 11 years of age (n = 8) required additional study to determine the appropriate dosage.

A subsequent tigecycline dose-finding study was conducted in 8-11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n = 17), 1 mg/kg (n = 21), and 1.25 mg/kg (n=20). This study showed that for children aged 8-11 years, a 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].

In a 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.

In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 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 (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interaction Studies

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 co-administered to healthy subjects in a 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 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 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 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.

In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a 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 a substrate of P-gp based on an in vitro study using a cell line overexpressing Pgp. 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.

Microbiology

Tigecycline 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. In general, tigecycline is considered bacteriostatic; however, TYGACIL has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.

To 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.

In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.

Tigecycline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].

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 least 90 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 due to 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 monocytogenes
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)
Staphylococcus haemolyticus

Gram-negative Bacteria

Acinetobacter baumannii*
Aeromonas hydrophila
Citrobacter koseri
Enterobacter aerogenes
Haemophilus influenzae (ampicillin-resistant)
Haemophilus parainfluenzae
Pasteurella multocida
Serratia marcescens
Stenotrophomonas maltophilia

Anaerobic Bacteria

Bacteroides distasonis
Bacteroides ovatus
Peptostreptococcus spp.
Porphyromonas spp.
Prevotella spp.

Other Bacteria

Mycobacterium abscessus
Mycobacterium fortuitum

*There 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 Test Methods

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 an antibacterial drug for treatment.

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth, and/or agar, or microdilution).1,3,4 For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh (<12h old). The MIC values should be interpreted according to the criteria provided in Table 4.

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,4 This procedure uses paper disks impregnated with 15 mcg tigecycline to test the susceptibility of bacteria to tigecycline. The disc diffusion breakpoints are noted in Table 4.

Anaerobic susceptibility testing with tigecycline should be done by the agar dilution method3,4 since quality control parameters for broth-dilution are not established.

Table 4. Susceptibility Test Result Interpretive Criteria for Tigecycline

A report of "Susceptible" (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" (R) indicates that the antimicrobial drug is not likely to inhibit the growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3,4 Standard tigecycline powder should provide the following range of MIC values noted in Table 5. For the diffusion technique using the 15 mcg tigecycline disk, the criteria provided in Table 5 should be achieved.

Table 5. Acceptable Quality Control Ranges for Tigecycline

Animal Toxicology And/Or Pharmacology

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, (AUC of approximately 50 and 60 mcg·hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.

Clinical Studies

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 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous 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 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 Skin and Skin Structure Infections after 5 to 14 Days of Therapy

Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infectionsa

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 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous 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 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 Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy

Table 9. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infectionsa

TYGACIL was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In Study 1, after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 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 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.

Table 10. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial

Table 11. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumoniaa

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a 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 years
• PSI score ≥3
• Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 12. Age ≥50 was the most common risk factor in the higher-risk group.

Table 12. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortalitya

Tygacil is a prescription medication used to treat serious skin and stomach infections and certain types of pneumonia (lung infection). Tygacil belongs to a group of drugs called glycycline antibiotics, which work by binding to bacteria and killing them.

This medication comes in an injectable form to be given directly into the vein (IV) by a healthcare provider.

Common side effects of Tygacil include nausea, vomiting, and stomach pain. Tygacil  can cause dizziness. Do not drive or operate heavy machinery until you know how Tygacil affects you.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Tygacil, there are no specific foods that you must exclude from your diet when receiving this medication.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Tygacil crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Tygacil.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Avoid exposure to sunlight or tanning beds. Tigecycline can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Antibacterial; glycylcycline antibiotic.1 2

• Glycylcycline antibiotic; synthetic derivative of minocycline.1 2

• Inhibits protein synthesis in susceptible organisms mainly by reversibly binding to 30S ribosomal subunits, thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes.1

• Broad spectrum of antibacterial activity; usually bacteriostatic.1 2

• Spectrum of activity includes various gram-positive aerobic and facultatively aerobic bacteria, including Staphylococcus aureus (including methicillin-resistant [oxacillin-resistant] strains), Streptococcus agalactiae (group B streptococci), S. anginosusgroup (S. anginosus, S. intermedius, S. constellatus), S. pneumoniae (penicillin-susceptible strains), S. pyogenes (group A β–hemolytic streptococci), and Enterococcus faecalis (vancomycin-susceptible strains only).1

• Also active against various gram-negative aerobic and facultatively aerobic bacteria, including Citrobacter freundii, Enterobacter cloacae, Escherichia coli, H. influenzae (β-lactamase-negative strains), Klebsiella oxytoca, and K. pneumoniae, L. pneumophila, and some anaerobic bacteria, including Bacteroides fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, Clostridium perfringens, and Peptostreptococcus micros.1

• May be active against some bacteria resistant to conventional tetracyclines since tigecycline susceptibility not affected by the 2 major tetracycline resistance mechanisms (i.e., ribosomal protection, efflux).1 2 Susceptibility to tigecycline also not affected by many other common resistance mechanisms, including β-lactamases (e.g., extended-spectrum β-lactamases [ESBLs]), target site modifications, macrolide efflux pumps, or enzyme target (e.g., gyrase, topoisomerase) changes.1

• Resistance to tigecycline in some bacteria (e.g., Acinetobacter calcoaceticus-baumannii complex) is attributed to multidrug-resistant (MDR) efflux pumps.1

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Mechanism of Action

Tigecycline is a tetracycline class antibacterial [see Microbiology (12.4)].

Pharmacodynamics

Cardiac Electrophysiology

No significant effect of a single intravenous dose of Tygacil 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.

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.

Distribution

The 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 L (7 to 9 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 mcg∙h/mL) in alveolar cells was approximately 78-fold higher than the AUC0–12h in the serum, and the AUC0–12h (2.28 mcg∙h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0–12h in serum. The AUC0–12h (1.61 mcg∙h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0–12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 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.

Elimination

Metabolism

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 a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Tigecycline is a substrate of P-glycoprotein (P-gp) based on an in vitro study using a 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 Populations

Hepatic Impairment

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 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

A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 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 Tygacil 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 65–75; n=13, age >75) and younger subjects (n=18) receiving a single 100-mg dose of Tygacil. Therefore, no dosage adjustment is necessary based on age [see Use in Specific Populations (8.5)].

Pediatric Patients

A single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged 8–16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or 2 mg/kg. The study showed that for children aged 12–16 years (n = 16) a 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 8 to 11 years of age (n = 8) required additional study to determine the appropriate dosage.

A subsequent tigecycline dose-finding study was conducted in 8–11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n = 17), 1 mg/kg (n = 21), and 1.25 mg/kg (n=20). This study showed that for children aged 8–11 years, a 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)].

Gender

In a 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 a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 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 (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interaction Studies

Digoxin

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 co-administered to healthy subjects in a 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 Tygacil is administered with digoxin.

Warfarin

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 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 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.

In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a 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 a substrate of P-gp based on an in vitro study using a 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.

Microbiology

Mechanism of Action

Tigecycline 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. In general, tigecycline is considered bacteriostatic; however, Tygacil has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.

Resistance

To 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 Antimicrobials

In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.

Antimicrobial Activity

Tigecycline has been shown to be active against most of the following bacteria, 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 least 90 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 due to 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 monocytogenes
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)
Staphylococcus haemolyticus

Gram-negative Bacteria

Acinetobacter baumannii1
Aeromonas hydrophila
Citrobacter koseri
Enterobacter aerogenes
Haemophilus influenzae (ampicillin-resistant)
Haemophilus parainfluenzae
Pasteurella multocida
Serratia marcescens
Stenotrophomonas maltophilia

Anaerobic Bacteria

Bacteroides distasonis
Bacteroides ovatus
Peptostreptococcus spp.
Porphyromonas spp.
Prevotella spp.

Other Bacteria

Mycobacterium abscessus
Mycobacterium fortuitum

Susceptibility Test Methods

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 an antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth, and/or agar, or microdilution).1,3,4 For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh (<12h old). The MIC values should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,4 This procedure uses paper disks impregnated with 15 mcg tigecycline to test the susceptibility of bacteria to tigecycline. The disc diffusion breakpoints are noted in Table 4.

Anaerobic Techniques

Anaerobic susceptibility testing with tigecycline should be done by the agar dilution method3,4 since quality control parameters for broth-dilution are not established.

A report of "Susceptible" (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" (R) indicates that the antimicrobial drug is not likely to inhibit the growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3,4 Standard tigecycline powder should provide the following range of MIC values noted in Table 5. For the diffusion technique using the 15 mcg tigecycline disk, the criteria provided in Table 5 should be achieved.

Complicated Skin and Skin Structure Infections

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 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous 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 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

Complicated Intra-abdominal Infections

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 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous 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 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

Community-Acquired Bacterial Pneumonia

Tygacil was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared Tygacil (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In Study 1, after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 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 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a 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 years
• PSI score ≥3
• Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 12. Age ≥50 was the most common risk factor in the higher-risk group.

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

• Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact his or her healthcare provider [see Warnings and Precautions (5.8)].
• 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.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

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LAB-0794-1.0

Tygacil (tigecycline) is an antibiotic that fights bacteria in the body.

Tygacil is used to treat many different bacterial infections of the skin or the digestive system, as well as pneumonia.

Tygacil should be used only for infections that cannot be treated with other medicines.