Tygacil

Tygacil

tigecycline

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Tigecycline.
Description
Tigecycline is a glycylcycline antibacterial for IV infusion. It is (4S, 4aS, 5aR, 12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. Its empirical formula is C29H39N5O8 and molecular weight is 585.65.
Tygacil is an orange lyophilized powder or cake.
Action
Antibacterial.
Microbiology: Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline, and imparts certain microbiologic properties that transcend any known tetracycline derivative in vitro or in vivo activity. In addition, tigecycline is able to overcome the 2 major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad-spectrum of bacterial pathogens. There has been no cross-resistance observed between tigecycline and other antibiotics. In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotics. In general, tigecycline is considered bacteriostatic.
Tigecycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:
Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecalis (vancomycin-susceptible isolates only); Staphylococcus aureus (methicillin-susceptible and -resistant isolates); Streptococcus agalactiae; Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus); Streptococcus pneumoniae (penicillin-susceptible isolates); Streptococcus pyogenes.
Aerobic and Facultative Gram-Negative Microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli (include ESBL, producing isolates), Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis.
Anaerobic Microorganisms: Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, Peptostreptococcus micros.
Other Microorganism: Chlamydia pneumoniae, Mycoplasma pneumoniae.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of these microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for tigecycline. However, the safety and effectiveness of tigecycline in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:
Aerobic Gram-Positive Microorganisms: 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, Streptococcus pneumonia (penicillin-resistant isolates).
Aerobic Gram-Negative Microorganisms: Acinetobacter calcoaceticus/baumannii complex, Aeromonas hydrophila, Citrobacter koseri, Enterobacter aerogenes, Haemophilus parainfluenzae, Neisseria meningitidis, Pasteurella multocida, Serratia marcescens, Stenotrophomonas maltophilia.
Anaerobic Microorganisms: Bacteroides distasonis, Bacteroides ovatus, Peptostreptococcus, Porphyromonas and Prevotella spp.
Other Microorganisms: Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum.
Susceptibility Testing: When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
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 procedure based on dilution methods (broth, agar or microdilution) or equivalent using standardized inoculum and concentrations of tigecycline. For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh (<12 hrs old). The MIC values should be interpreted according to the criteria provided in Table 1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with tigecycline 15 mcg to test the susceptibility of microorganisms to tigecycline. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tigecycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-mcg tigecycline disk should be interpreted according to the criteria in Table 1.


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A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "Intermediate" 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 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" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Quality Control: As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standard tigecycline powder should provide the MIC values provided in Table 2. For the diffusion technique using the 15-mcg tigecycline disk, the criteria provided in Table 2 should be used to test quality control strains.


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Pharmacokinetics: The mean pharmacokinetic parameters of tigecycline after single and multiple IV doses are summarized in Table 3. IV infusions of tigecycline were administered over approximately 30-60 min (see Table 3).


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Distribution: The in vitro plasma protein-binding of tigecycline ranges from approximately 71-89% at concentrations observed in clinical studies (0.1-1 mcg/mL). In humans, the steady-state volume of distribution of tigecycline averaged 500-700 L (7-9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the human tissues.
Two studies examined the steady-state pharmacokinetic profile of tigecycline in specific tissues or fluids of healthy subjects receiving tigecycline 100 mg followed by 50 mg every 12 hrs. In a bronchoalveolar lavage study, the tigecycline AUC0-12 hrs (134 mcg·hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC0-12 hrs in the serum of these subjects, and the AUC0-12hrs (2.28 mcg·hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12hrs in serum. In a skin blister study, the AUC0-12hrs (1.61 mcg·hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12hrs in the serum of these subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Tissue concentrations at 4 hrs after tigecycline administration were measured in the following tissue and fluid samples: Gallbladder, lung, colon, synovial, fluid, and bone. Tigecycline attained higher concentrations in tissues versus serum in gallbladder (38-fold, n=6), lung (3.7-fold, n=5) and colon (2.3-fold, n=5). 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.
Elimination: 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. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
Special Populations: Use in Patients with 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). In addition, 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).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child-Pugh A and Child-Pugh B). However, in patients with severe hepatic impairment (Child-Pugh C), the dose of Tygacil should be reduced to 100 mg followed by 25 mg every 12 hrs. Patients with severe hepatic impairment (Child-Pugh C) should be treated with caution and monitored for treatment response. (See Precautions and Dosage & Administration.)
Use in Patients with 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 hrs before hemodialysis, 4 ESRD patients receiving tigecycline 1 hr after hemodialysis and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not 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. (See Dosage & Administration.)
Pediatric Use: The pharmacokinetics of tigecycline in patients <18 years have not been established. (See Use in children under Precautions.)
Geriatric Use: No overall 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 the elderly under Precautions.)
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/hr) and men (22.8±8.7 L/hr). 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/hr), Black subjects (23±7.8 L/hr), Hispanic subjects (24.3±6.5 L/hr), White subjects (22.1±8.9 L/hr) and "other" subjects (25±4.8 L/hr). Therefore, no dosage adjustment is necessary based on race.
Drug-Drug Interactions: Tygacil (100 mg followed by 50 mg every 12 hrs) and digoxin (0.5 mg followed by 0.25 mg orally every 24 hrs) 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 is necessary when Tygacil is administered with digoxin.
Concomitant administration of Tygacil (100 mg followed by 50 mg every 12 hrs) 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 increased international normalized ratio (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 P-450 (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.
Toxicology: Animal Toxicology: Decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8.1 and 9.8 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after 2 weeks of dosing.
Bolus IV administration of tigecycline has been associated with a histamine response in preclinical studies. These effects were observed at exposures of 14.3 and 2.8 times the human daily dose based on AUC in rats and dogs, respectively.
No evidence of photosensitivity was observed in rats following administration of tigecycline.
Clinical Studies: Complicated Skin and Skin Structure Infections: Tygacil was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in 2 randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared Tygacil (100 mg IV initial dose followed by 50 mg every 12 hrs) with vancomycin (1 g IV every 12 hrs)/aztreonam (2 g IV every 12 hrs) for 5-14 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 clinically modified intent-to-treat (c-mITT) patients (see Table 4).


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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients with complicated skin and skin structure infections are presented in Table 5. (See Table 5.)


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Complicated Intra-Abdominal Infections: Tygacil was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in 2 randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hrs) with imipenem/cilastatin (500 mg IV every 6 hrs) for 5-14 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).


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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.


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Indications/Uses
Treatment of the following infections caused by susceptible strains of the designated microorganisms: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), including cases with concurrent bacteremia, Streptococcus agalactiae, Streptococcus anginosus group. (includes S. anginosus, S. intermedius and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae and Bacteroides fragilis.
Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli (includes ESBL producing isolates), Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates only), including cases with concurrent bacteremia, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens and Peptostreptococcus micros.
Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tygacil may be initiated as empiric monotherapy before results of these tests are known.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tygacil and other antibacterial drugs, Tygacil should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptible 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.
Dosage/Direction for Use
The recommended dosage regimen for Tygacil is an initial dose of 100 mg, followed by 50 mg every 12 hrs. IV infusions of Tygacil should be administered over approximately 30-60 min every 12 hrs.
The recommended duration of treatment with Tygacil for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5-14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.
Hepatic Impairment: No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child-Pugh A and Child-Pugh B). In patients with severe hepatic impairment (Child-Pugh C), the dose of Tygacil should be reduced to 100 mg followed by 25 mg every 12 hrs. Patients with severe hepatic impairment (Child-Pugh C) should be treated with caution and monitored for treatment response. (See Pharmacokinetics: Special Populations under Actions and Use in Patients with Hepatic Impairment under Precautions.)
Renal Impairment: No dosage adjustment of Tygacil is necessary in patients with renal impairment or in patients undergoing hemodialysis. (See Pharmacokinetics: Special Populations and Use in Patients with Renal Impairment under Actions.)
Children: Safety and effectiveness in patients <18 years have not been established. Therefore, use in patients <18 years is not recommended. (See Warnings.)
No dosage adjustment of Tygacil is necessary based on age, gender or race. (See Pharmacokinetics: Special Populations under Actions and Use in the elderly under Precautions.)
Overdosage
No specific information is available on the treatment of overdosage with tigecycline. IV administration of Tygacil at a single dose of 300 mg over 60 min in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose IV toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.
Contraindications
Known hypersensitivity to tigecycline.
Warnings
An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in Tygacil-treated patients versus comparator. In a pooled analysis of all 13 phase 3 and 4 trials that included a comparator, death occurred in 4% (150/3788) of patients receiving tigecycline and 3% (110/3646) of patients receiving comparator drugs resulting in an unadjusted risk difference of 0.9% (95% CI 0.1, 1.8). In a pooled analysis of these trials, based on a 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. The cause of this increase has not been established. This increase should be considered when selecting among treatment options.
Anaphylaxis/anaphylactoid reactions have been reported in nearly all antibacterial agents, including tigecycline, and may be life-threatening.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Therefore, Tygacil should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics. Due to the structural similarities of glycylcycline class antibiotics to tetracycline class antibiotics, similar adverse effects may include: Photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia).
Tygacil may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline. (See Use in pregnancy under Precautions.)
The use of Tygacil during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with Tygacil have shown bone discoloration. Tygacil should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.
Treatment with antibacterial agents alters the flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the primary cause of "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
Special Precautions
General: Caution should be exercised when considering Tygacil monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In Phase 3 cIAI studies (n=1642), 6 patients treated with tigecycline and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline had higher APACHE II scores (median=13) vs the 2 patients treated with imipenem/cilastatin (APACHE II scores: 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment can not be established.
Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline.
Acute pancreatitis, which can be fatal, has occurred (frequency: uncommon) in association with tigecycline treatment (see Adverse Reactions). 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.
The safety and efficacy of tigecycline in patients with hospital-acquired pneumonia have not been established. In a study of patients with hospital-acquired pneumonia, patients were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hrs) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The subgroup of patients with ventilator-associated pneumonia who received tigecycline had lower cure rates (47.9% vs 70.1% for the clinically evaluable population) and greater mortality [25/131 (19.1%) vs 14/122 (11.5%)] than the comparator. Of those patients with ventilator-associated pneumonia and bacteremia at baseline, those who received tigecycline had greater mortality [9/18 (50%) vs 1/13 (7.7%)] than the comparator.
As with other antibiotic preparations, use of Tygacil may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
Prescribing Tygacil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Information for Patients: Patients should be counseled that antibacterial drugs including Tygacil should only be used to treat bacterial infections. They do not treat viral infections (eg, 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, Tygacil should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by Tygacil or other antibacterial drugs in the future.
Use in Patients with Hepatic Impairment: No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child-Pugh A and Child-Pugh B). In patients with severe hepatic impairment (Child-Pugh C), the dose of tigecycline should be reduced to 100 mg followed by 25 mg every 12 hrs. Patients with severe hepatic impairment (Child-Pugh C) should be treated with caution and monitored for treatment response. (See Pharmacokinetics: Special Populations under Actions and Dosage & Administration.)
Effects on the Ability to Drive or Operate Machinery: Tigecycline can cause dizziness (see Adverse Reactions), which may impair the ability to drive and/or operate machinery.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 4.7 times the human daily dose based on AUC.
Use in pregnancy: Pregnancy Category C: Tigecycline may cause fetal harm when administered to a pregnant woman. 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.
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 4.7 and 1.1 times the human daily dose based on AUC in rats and rabbits, respectively. An increased incidence of fetal loss was observed at exposures of 1.1 times the human daily dose based on AUC in rabbits, at dosages producing minimal maternal toxicity.
There are no adequate and well-controlled studies of tigecycline in pregnant women. Tygacil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Warnings).
Labor and Delivery: Tygacil has not been studied for use during labor and delivery.
Use in lactation: Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.
It is not known whether Tygacil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tygacil is administered to a nursing woman. (See Warnings.)
Use in children: Safety and effectiveness in pediatric patients <18 years have not been established (see Warnings). Therefore, use in patients <18 years is not recommended.
Use in the elderly: Of the total number of subjects who received Tygacil in phase 3 clinical studies (n=2514), 664 were ≥65, while 288 were ≥75. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category C: Tigecycline may cause fetal harm when administered to a pregnant woman. 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.
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 4.7 and 1.1 times the human daily dose based on AUC in rats and rabbits, respectively. An increased incidence of fetal loss was observed at exposures of 1.1 times the human daily dose based on AUC in rabbits, at dosages producing minimal maternal toxicity.
There are no adequate and well-controlled studies of tigecycline in pregnant women. Tygacil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Warnings).
Labor and Delivery: Tygacil has not been studied for use during labor and delivery.
Use in lactation: Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.
It is not known whether Tygacil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tygacil is administered to a nursing woman. (See Warnings.)
Adverse Reactions
Because clinical studies are conducted under varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Phase 3 clinical studies enrolled 2514 Tygacil-treated patients. Tygacil was discontinued due to treatment-emergent adverse events in 5% of patients compared to 4.7% for all comparators. Table 8 shows the incidence of treatment-emergent adverse events reported in ≥2% of patients in these studies.


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In all phase 3 and 4 studies that includes a comparator, death occurred in 4% (150/3788) of patients receiving Tygacil and 3% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all cause mortality was 0.9% (95% CI 0.1, 1.8) between tigecycline and comparator treated patients. In a pooled analysis of these trials, based on a 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. No significant differences were observed between treatments by tygecycline and comparators by infection type (see Table 9). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbidities.


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The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1-2 days of therapy. The majority of cases of nausea and vomiting associated with Tygacil and comparators were either mild or moderate in severity.
In patients treated with Tygacil, nausea incidence was 26.4% (16.9% mild, 8.1% moderate, 1.3% severe) and vomiting incidence was 18.1% (11% mild, 6.1% moderate, 1% severe).
In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for Tygacil and 8.9% for vancomycin/aztreonam; vomiting incidence was 20% for Tygacil and 4.2% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25.3% for Tygacil and 20.5% for imipenem/cilastatin; vomiting incidence was 19.5% for Tygacil and 15.3% for imipenem/cilastatin.
Discontinuation from tigecycline was most frequently associated with nausea (1.1%) and vomiting (1.1%). For comparators, discontinuations were most frequently associated with nausea (0.5%).
The following treatment-emergent adverse events were reported infrequently (<2%) in patients receiving Tygacil in phase 3 clinical studies: Body as a Whole: Injection site inflammation, pain, reactions, edema and phlebitis.
Cardiovascular System: Thrombophlebitis.
Digestive System: Anorexia, jaundice.
Metabolic/Nutritional System: Bilirubinemia.
Hemic and Lymphatic System: Prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT); increased international normalized ratio (INR).
Skin and Appendages: Pruritus.
For patients who received tigecycline, the following adverse reactions were reported: Blood and Lymphatic System: Prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT); increased international normalized ratio (INR), thrombocytopenia.
Immune System: Anaphylaxis/anaphylactoid reactions.
Metabolism and Nutrition: Bilirubinemia, increased blood urea nitrogen (BUN), hypoproteinemia, hypoglycemia.
Nervous System: Dizziness.
Cardiac: Phlebitis, thrombophlebitis.
Gastrointestinal: Nausea, vomiting, diarrhea, anorexia, abdominal pain, dyspepsia, acute pancreatitis.
Hepatobiliary: Elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), jaundice, hepatic cholestasis.
Skin and Subcutaneous Tissue: Pruritus, rash, severe skin reactions, including Stevens-Johnson syndrome.
General Disorders and Administration Site Conditions: Headache, abnormal healing, injection site inflammation, pain, reactions, edema and phlebitis.
Investigations: Elevated serum amylase.
Drug Interactions
Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin (see Pharmacokinetics: Drug-Drug Interactions under Actions).
Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.
Drug/Laboratory Test Interactions: There are no reported drug-laboratory test interactions.
Compatibilities/Incompatibilities: Compatible IV solutions include 0.9% sodium chloride injection, USP and 5% dextrose injection, USP and Lactated Ringer's injection, USP. When administered through a Y-site, Tygacil is compatible with the following drugs or diluents when used with either 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP and administered simultaneously through the same line: Amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, metoclopropramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl and tobramycin.
The following drugs should not be administered simultaneously through the same Y-site as Tygacil: Amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.
Caution For Usage
Preparation and Handling: The lyophilized powder should be reconstituted with 5.3 mL of 0.9% sodium chloride injection, USP or 5% dextrose injection, USP, or Lactated Ringer's injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100-mL IV bag for infusion. For a 100-mg dose, reconstitute using 2 vials into a 100-mL IV bag.
(Note: The vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of Tygacil). The reconstituted solution should be yellow to orange in colour; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discolouration (eg, green or black) prior to administration whenever solution and container permit. Once reconstituted, tigecycline may be stored at room temperature for up to 24 hrs (up to 6 hrs in the vial and the remaining time in the IV bag). Alternatively, tigecycline mixed with 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP may be stored at 2-8°C (36-46°F) for up to 48 hrs following immediate transfer of the reconstituted solution into the IV bag.
Tygacil may be administered IV through a dedicated line or through a Y-site. If the same IV line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Tygacil with either 0.9% sodium chloride injection, USP or 5% dextrose injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line (see Compatibilities/Incompatibilities under Interactions).
Storage
Prior to reconstitution, do not store Tygacil above 25°C. Reconstituted solution must be immediately transferred and further diluted for IV infusion. Once reconstituted, tigecycline may be stored at room temperature for up to 24 hrs (up to 6 hrs in the vial and the remaining time in the IV bag). Alternatively, Tygacil mixed with 0.9% sodium chloride injection, USP, or 5% dextrose injection, USP may be stored at 2°-8°C (36°-46°F) for up to 48 hrs following immediate transfer of the reconstituted solution into the IV bag.
Shelf-Life: 24 months.
ATC Classification
J01AA12 - tigecycline ; Belongs to the class of tetracyclines. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj (vial) 50 mg (lyophilized powd for IV infusion) x 10's/box.
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