Tygacil

Tigecycline.

Each 5 mL tigecycline vial contains 50 mg of tigecycline lyophilized powder for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. After reconstitution, 1 mL contains 10 mg of tigecycline.
Excipients/Inactive Ingredients: Lactose monohydrate, hydrochloric acid, sodium hydroxide and nitrogen.

Anti-infective, Glycylcycline antibacterial. ATC code: J01C XXX.
Pharmacology: Pharmacodynamics: Mechanism of action: Tigecycline, a glycylcycline antibiotic, 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 two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotics. In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration (MIC), a 2-log reduction in colony counts was observed with tigecycline against Enterococcus spp., Staphylococcus aureus, and Escherichia coli. However, tigecycline has shown some bactericidal activity, and a 3-log reduction was observed against Neisseria gonorrhoeae. Tigecycline has also demonstrated bactericidal activity against common respiratory strains of Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila.
Susceptibility Test Methods: Dilution Techniques: Quantitative methods are used to determine antimicrobial 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 using testing medium that is fresh (<12 hours 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 15 μg tigecycline 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 μg tigecycline disk should be interpreted according to the criteria in Table 1. (See 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 μg tigecycline disk, laboratories should use the criteria provided in Table 2 to test quality control strains. (See Table 2.)

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The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. The information as follows provides only approximate guidance on the probability as to whether the microorganism will be susceptible to tigecycline or not.
Susceptible: Gram-positive aerobes: Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis (vancomycin-resistant strains), Enterococcus faecalis^* (includes vancomycin-susceptible strains), Enterococcus faecium (vancomycin-susceptible and -resistant isolates), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus^* (includes methicillin-susceptible and -resistant strains), Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates), Staphylococcus haemolyticus, Streptococcus agalactiae^*, Streptococcus anginosus^* (includes S. anginosus, S. intermedius, S. constellatus), Streptococcus pneumoniae^* (penicillin-susceptible isolates), Streptococcus pyogenes^*, Viridans group streptococci.
Gram-negative aerobes: Acinetobacter baumannii^ǂ, Aeromonas hydrophila, Citrobacter freundii^*, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae^*, Escherichia coli^* (including extended spectrum beta lactamase-producing strains), Haemophilus influenzae (ampicillin-resistant), Haemophilus parainfluenzae, Klebsiella oxytoca^*, Klebsiella pneumoniae^* (including extended spectrum beta lactamase-producing strains), Legionella pneumophila*, Pasteurella multocida, Serratia marcescens, Stenotrophomonas maltophilia.
Anaerobic bacteria: Bacteroides fragilis^*, Bacteroides distasonis, Bacteroides thetaiotaomicron^*, Bacteroides uniformis^*, Bacteroides vulgatus^*, Clostridium perfringens^*, Peptostreptococcus spp., Peptostreptococcus micros^*, Porphyromonas spp., Prevotella spp.
Atypical bacteria: Mycobacterium abscessus, Mycobacterium fortuitum.
^* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.
^ǂ 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.
Resistant: Gram-negative aerobes: Pseudomonas aeruginosa.
Anaerobic bacteria: No naturally-occurring species have been found to be inherently resistant to tigecycline.
Resistance: To date there has been no cross-resistance observed between tigecycline and other antibacterial drugs. 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 in vitro studies, no antagonism has been observed between tigecycline and any other commonly used antibiotic class.
Clinical trial data on Efficacy: Complicated Skin and Skin Structure Infections (cSSSI): Tigecycline was evaluated in adults for the treatment of (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with vancomycin (1 g IV every 12 hours)/aztreonam (2 g IV every 12 hours) for 5 to 14 days. Subjects 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) subjects. (See Table 3.)

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Clinical cure rates at TOC by pathogen in the microbiologically evaluable (ME) subjects with cSSSI are presented in the Table 4. (See Table 4.)

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Complicated Intra-abdominal Infections (cIAI): Tigecycline was evaluated in adults for the treatment of cIAI in two randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg IV every 6 hours) for 5 to 14 days. Subjects with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of the 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 ME and the microbiologic modified intent-to-treat (m-mITT) subjects. (See Table 5.)

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Clinical cure rates at TOC by pathogen in the ME subjects with cIAI are presented in Table 6. (See Table 6.)

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Methicillin-Resistant Staphylococcus aureus (MRSA): Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, and other infections) due to MRSA in Study 307.
Study 307 was a randomized, double-blind, active-controlled, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) and vancomycin (1 g IV every 12 hours) for the treatment of infections due to MRSA. Subjects with cIAI, cSSSI, and other infections were enrolled in this study. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the m-mITT subjects. For clinical cure rates see Table 7 for MRSA. (See Table 7.)

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Cardiac Electrophysiology: No significant effect of a single intravenous dose of tigecycline 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 for the recommended dosage regimen after single and multiple intravenous doses are summarized in Table 8.
Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes. (See Table 8.)

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Absorption: Tigecycline is administered intravenously, and therefore has 100% bioavailability.
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 μg/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of ¹⁴C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, thyroid gland, kidney, spleen, and salivary gland. In humans, 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 of humans.
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 hours. In a bronchoalveolar lavage study, the tigecycline AUC_0-12h (134 μg·h/mL) in alveolar cells was approximately 77.5-fold higher than the AUC_0-12h in the serum of these subjects, and the AUC_0-12h (2.28 μg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in serum. In a skin blister study, the AUC_0-12h (1.61 μg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h 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 hours 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=6). 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. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
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.
Special Populations: Hepatic insufficiency: In a study comparing 10 subjects with mild hepatic impairment (Child Pugh A), 10 subjects with moderate hepatic impairment (Child Pugh B), and 5 subjects 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 subjects with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in subjects 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 subjects with severe hepatic impairment (Child Pugh C).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in subjects with mild to moderate hepatic impairment (Child Plug A and Child Pugh B). However, in subjects with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced to 100 mg followed by 25 mg every 12 hours. Subjects with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Dosage & Administration).
Renal insufficiency: A single-dose study compared 6 subjects with severe renal impairment (creatinine clearance Cl_Cr ≤30 mL/min), 4 end stage renal disease subjects receiving tigecycline 2 hours before hemodialysis, 4 end stage renal disease subjects receiving tigecycline after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally-impaired subject groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in subjects with renal impairment or in subjects undergoing hemodialysis (see Dosage & Administration).
Elderly: 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 tigecycline. Therefore, no dosage adjustment is necessary based on age.
Children: The pharmacokinetics of tigecycline in patients less than 18 years of age have not been established.
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.
Toxicology: Preclinical safety data: Carcinogenicity: Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline.
Mutagenicity: No mutagenic or clastogenic potential was found in a battery of tests, including an 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.
Reproduction toxicity: 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 estrus cycles at exposures up to 4.7 times the human daily dose based on AUC.
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 times and 1.1 times the human daily dose based on AUC in rats and rabbits, respectively.
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 the nursing pups as a result of exposure via the maternal milk.
Other: Decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8.1 times and 9.8 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.
Bolus intravenous 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 the AUC in rats and dogs, respectively.
No evidence of photosensitivity was observed in rats following administration of tigecycline.

Tigecycline is indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms in the conditions listed as follows for patients 18 years of age and older: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.
Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, E. coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates only), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tigecycline 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 tigecycline and other antibacterial drugs, tigecycline 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.

The recommended dosage regimen for tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
The recommended duration of treatment with tigecycline for complicated skin and skin structure infections (cSSSI) or for complicated intra-abdominal infections (cIAI) is 5 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.
Use in patients with renal impairment: No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis (see Pharmacology: Pharmacokinetics under Actions).
Use in patients with hepatic impairment: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh A and Child Pugh B). Based on the pharmacokinetic profile of tigecycline in patients with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be altered to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Pharmacology: Pharmacokinetics under Actions).
Use in children: Clinical trials to establish the safety and effectiveness of tigecycline in patients under 18 years of age have not been conducted. Therefore, use in patients under 18 years of age is not recommended (see Precautions).
Use in elderly: In a pooled analysis of 3900 subjects who received tigecycline in Phase 3 and 4 clinical studies, 1026 were 65 years and over. Of these, 419 were 75 years and over. No unexpected overall differences in safety were observed between these subjects and younger subjects. No dosage adjustment is necessary in elderly patients.
Race and gender: No dosage adjustment is necessary based on race or gender. (See Pharmacology: Pharmacokinetics under Actions).
Mode of administration: Intravenous infusion.

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

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

An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in tigecycline-treated subjects versus comparator-treated subjects. In a pooled analysis of all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of subjects receiving tigecycline and 3.0% (110/3646) of subjects 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 subjects. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options (see Adverse Reactions).
Anaphylactic reaction/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Therefore, tigecycline should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.
Results of studies in rats with tigecycline have shown bone discoloration. Tigecycline may be associated with permanent tooth discoloration in humans during tooth development.
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 diarrhoea subsequent to the administration of any antibacterial agent.
Caution should be exercised when considering tigecycline monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In Phase 3 and 4 cIAI studies (n=2775), 140/1382 tigecycline-treated subjects and 142/1393 comparator-treated subjects presented with intestinal perforations. Of these subjects, 8/140 subjects treated with tigecycline and 8/142 subjects treated with comparator developed sepsis/septic shock. The relationship of this outcome to treatment cannot be established.
Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, pancreatitis and anti-anabolic action (which has led to increased BUN, azotemia, acidosis and hyperphosphatemia).
Pancreatitis acute, which can be fatal, has occurred (frequency: uncommon) in association with tigecycline treatment (see Adverse Reactions). The diagnosis of pancreatitis acute should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of pancreatitis acute. 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 patients suspected of having developed pancreatitis.
Monitoring of blood coagulation parameters, including blood fibrinogen, is recommended prior to treatment initiation with tigecycline and regularly while on treatment. (See Adverse Reactions).
The safety and efficacy of tigecycline in patients with hospital acquired pneumonia (HAP) have not been established. In a study of subjects with HAP, subjects were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, subjects were allowed to receive specified adjunctive therapies. The sub-group of subjects with ventilator-associated pneumonia (VAP) who received tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator. Of those subjects with VAP and bacteremia at baseline, those who received tigecycline had greater mortality (9/18 [50.0%] versus 1/13 [7.7%]) than the comparator.
As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If super infection occurs, appropriate measures should be taken.
Abuse and Dependence: Drug abuse and dependence have not been demonstrated and are unlikely.
Effects on ability to drive and use machines: Tigecycline can cause dizziness (see Adverse Reactions), which may impair the ability to drive and/or operate machinery.

Pregnancy: 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) have been observed with tigecycline.
Tigecycline was not teratogenic in the rat or rabbit (see Pharmacology: Toxicology: Preclinical safety data under Actions).
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.
Tigecycline has not been studied for use during labor and delivery.
Lactation: It is not known whether this drug is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of tigecycline/metabolites in milk (see Pharmacology: Toxicology: Preclinical safety data under Actions). Because many drugs are excreted in human milk, caution should be exercised when tigecycline is administered to a nursing woman (see Precautions).
Fertility: The effects of tigecycline on fertility in humans have not been studied. Nonclinical studies conducted with tigecycline in rats do not indicate harmful effects with respect to fertility or reproductive performance. (See Pharmacology: Toxicology: Preclinical safety data under Actions).

Expected frequency of adverse reactions is presented in CIOMS frequency categories: Very common ≥10%; Common ≥1% and <10%; Uncommon ≥0.1% and <1%; Rare ≥0.01% and <0.1%; Very rare <0.01%; Frequency not known cannot be estimated from the available data.
For patients who received tigecycline, the following adverse reactions were reported: (See Table 9.)

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In a pooled analysis of all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of subjects receiving tigecycline and 3.0% (110/3646) of subjects receiving comparator drugs. In a pooled analysis of these trials, the risk difference of all-cause mortality was 0.9% (95% CI 0.1, 1.8) between tigecycline and comparator-treated subjects. 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-treated and comparator-treated subjects. No significant differences were observed between tigecycline and comparators within each infection type (see Table 10). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbidities. (See Table 10.)

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The most common treatment-emergent adverse reactions in subjects treated with tigecycline were nausea 29.9% (19.3% mild; 9.2% moderate; 1.4% severe) and vomiting 19.9% (12.1% mild; 6.8% moderate; 1.1% severe). In general, nausea or vomiting occurred early (Days 1-2).
Discontinuation from tigecycline was most frequently associated with nausea (1.6%) and vomiting (1.3%).

Tigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg every 24 hours) were co-administered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the C_max of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in C_max did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when tigecycline is administered with digoxin.
Concomitant administration of tigecycline (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%, 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 tests 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 CYP450 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 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 previously.
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. Co-administration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.
Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.
Concomitant use of tigecycline and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Therefore, serum concentrations of the calcineurin inhibitor should be monitored during treatment with tigecycline to avoid drug toxicity.
Interference with laboratory and other diagnostic tests: There are no reported drug-laboratory test interactions.

Incompatibilities: Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.
Tigecycline 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, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.
The following drugs should not be administered simultaneously through the same line as tigecycline: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.
Special precautions for disposal and other handling: The lyophilized powder should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL IV bag for infusion. For a 100 mg dose, reconstitute two vials 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 the drug). 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 discoloration (e.g., green or black) prior to administration whenever solution and container permit. Once reconstituted, tigecycline should be used immediately.
Tigecycline may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline 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) administrated via this common line (see Incompatibilities previously mentioned).

Store below 30°C.
Once reconstituted, tigecycline should be used immediately.
Reconstituted solution must be transferred and further diluted for IV infusion.

Tetracyclines

J01AA12 - tigecycline ; Belongs to the class of tetracyclines. Used in the systemic treatment of infections.

B