Tygacil

Tygacil also contains the following excipients: Lactose monohydrate 100 mg, hydrochloric acid or sodium hydroxide for pH adjustment. It does not contain preservatives.

Mode 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 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. 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 S. pneumoniae, H. influenzae and L. pneumophila.
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 in testing medium that is fresh (<12 hrs old). The MIC values should be interpreted according to the criteria provided in Table 1. (See 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. (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-mcg 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 following information 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* (includes vancomycin-susceptible strains), Enterococcus faecalis (includes vancomycin-resistant strains), Enterococcus faecium (includes vancomycin-susceptible and -resistant strains), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus* [includes methicillin-susceptible and methicillin-resistant strains, including isolates that bear molecular and virulence markers commonly associated with community-acquired methicillin-resistant Staphylococcus aureus (MRSA) including the SCCmec type IV element and the pvl gene], Staphylococcus epidermidis (includes methicillin-susceptible and -resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae*, Streptococcus anginosus* (includes S. anginosus, S. intermedius, S. constellatus), Streptococcus pyogenes*, Streptococcus pneumoniae* (penicillin-susceptible isolates), Streptococcus pneumoniae (penicillin-resistant isolates), Viridans group streptococci.
Gram-Negative Aerobes: Acinetobacter calcoaceticus/baumannii complex, Aeromonas hydrophila, Citrobacter freundii*, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae*, Escherichia coli* [including extended-spectrum β-lactamase (ESBL)-producing strains], Haemophilus influenzae*, Haemophilus parainfluenzae, Klebsiella oxytoca*, Klebsiella pneumoniae* (including ESBL-producing strains), Klebsiella pneumoniae (including AmpC-producing strains), Legionella pneumophila*, Moraxella catarrhalis*, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida; Salmonella enterica ser. Enteritidis, Paratyphi, Typhi and Typhimurium; Shigella boydii, Shigella dysenteriae, Shigella flexneri, Serratia marcescens, Shigella sonnei, Stenotrophomonas maltophilia.
Anaerobic Bacteria: Bacteroides fragilis*, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron*, Bacteroides uniformis*, Bacteroides vulgatus*, Clostridium difficile, Clostridium perfringens*, Peptostreptococcus spp, Peptostreptococcus micros*, Porphyromonas spp and Prevotella spp.
Atypical Bacteria: Chlamydia pneumoniae*, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycoplasma pneumoniae*.
*Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.
Resistant: Gram-Negative Aerobes: Pseudomonas aeruginosa.
Anaerobic Bacteria: No naturally occurring species has been found to be inherently resistant to tigecycline.
Resistance: There have been no cross-resistance observed between tigecycline and other antibiotics.
Tigecycline is able to overcome the 2 major tetracycline resistance mechanisms, ribosomal protection and efflux.
In in vitro studies, no antagonism has been observed between tigecycline and any other commonly used antibiotic class.
Pharmacodynamics: Clinical Efficacy: Complicated Skin and Skin Structure Infections: Tigecycline 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 tigecycline (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 clinical modified intent-to-treat (c-mITT) patients (see Table 3).
Clinical cure rates at TOC by pathogen in microbiologically evaluable patients with complicated skin and skin structure infections are presented in Table 4. (See Tables 3 and 4.)

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Complicated Intra-Abdominal Infections: Tigecycline 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 and the microbiologic modified intent-to-treat (m-mITT) patients. (See Table 5.)

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Clinical cure rates at TOC by pathogen in microbiologically evaluable patients with cIAI are presented in Table 6. (See Table 6.)

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Community-Acquired Pneumonia (CAP): Tigecycline was evaluated in adults for the treatment of CAP in 2 randomized, double-blind, active-controlled, multinational, multicenter studies (studies 308 and 313). These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hrs) with levofloxacin (500 mg IV every 12 or 24 hrs). In 1 study (study 308), after at least 3 days of IV therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7-14 days. Patients with CAP who required hospitalization and IV therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit in the co-primary populations of the CE and c-mITT patients (see Table 7). Clinical cure rates at TOC by pathogen in microbiologically evaluable patients are presented in Table 8. (See Table 8.)

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Vancomycin-Resistant Enterococcus (VRE) spp and MRSA: Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI and other infections) due to VRE and 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 hrs) and vancomycin (1 g IV every 12 hrs) for the treatment of infections due to MRSA and evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hrs) and linezolid (600 mg IV every 12 hrs) for the treatment of infections due to VRE for 7-28 days. Patients 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 microbiologically evaluable and m-mITT patients. (See Table 9 for MRSA and Table 10 for VRE.)

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Resistant Gram-Negative Pathogens: Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, CAP and other infections) due to resistant gram-negative pathogens in study 309.
Study 309 was an open-label, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hrs) for the treatment of infections due to resistant gram-negative pathogens for 7-28 days. Patients with cIAI, cSSSI, CAP 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 microbiologically evaluable and m-mITT patients. (See Table 11.)

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Rapidly Growing Mycobacterial Infections: In uncontrolled clinical studies and compassionate-use experience from 8 countries, 52 patients with rapidly growing mycobacterial infections (most frequently M. abscessus lung disease) were treated with tigecycline, along with other antibiotics. The mean and median durations of treatment were approximately 5½ and 3 months, respectively (range: 3 days to approximately 3½ years). Approximately half of the patients achieved clinical improvement (ie, improvement in signs and symptoms of lung disease, or healing of wound, skin lesions or nodules in disseminated disease). Approximately half of the patients required dose reductions or discontinued treatment due to nausea, vomiting or anorexia.
Pharmacokinetics: The mean pharmacokinetic parameters of tigecycline for this dosage regimen after single and multiple IV doses are summarized in Table 12.
IV infusions of tigecycline should be administered over approximately 30-60 min. (See Table 12.)

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Absorption: Tigecycline is administered IV and therefore has 100% bioavailability.
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). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving a single or multiple doses of ¹⁴C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, salivary glands, thyroid gland, spleen and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500-700 L (7-9 L/kg), indicating that 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 hrs. In a bronchoalveolar lavage study, the tigecycline AUC_{0-12 hrs} (134 mcg·hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC_{0-12 hrs} in the serum of these subjects and the AUC_{0-12 hrs} (2.28 mcg·hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC_{0-12 hrs} in serum. In a skin blister study, the AUC_{0-12 hrs} (1.61 mcg·hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_{0-12 hrs} 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=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 following the administration of ¹⁴C-tigecycline, tigecycline was the primary ¹⁴C-labeled material recovered in urine and faeces, 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 the total radioactivity in faeces and urine following administration of ¹⁴C-tigecycline indicates that 59% of the dose is eliminated by biliary/faecal 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.
Special Populations: Hepatic Insufficiency: 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 B). However, in patients with severe hepatic impairment (Child-Pugh C), the dose of Tygacil should be altered 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 Hepatic Insufficiency under Dosage & Administration).
Renal Insufficiency: A single-dose study compared 6 subjects with severe renal impairment (creatinine clearance ≤30 mL/min), 4 end-stage renal dialysis patients receiving tigecycline 2 hrs before haemodialysis, 4 end-stage renal dialysis patients receiving tigecycline after haemodialysis 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 haemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing haemodialysis (see Renal Insufficiency under Dosage & Administration).
Elderly Patients: No overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects. Therefore, no dosage adjustment is necessary based on age.
Paediatric Patients: The pharmacokinetics of tigecycline in patients <18 years has not been established.
Gender: There were no differences in the clearance of tigecycline between men and women. Therefore, no dosage adjustment is necessary based on gender.
Race: There were no differences in the clearance of tigecycline based on race.

Treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed as follows for patients ≥18 years: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus), Streptococcus pyogenes and Bacteroides fragilis.
Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens and Peptostreptococcus micros.
Community-acquired pneumonia caused by Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pneumoniae (penicillin-susceptible isolates only), including cases with concurrent bacteremia, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila.
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 only be used 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.

Initial Dose: 100 mg followed by 50 mg every 12 hrs by IV route.
Tygacil is administered by IV infusion. The infusion time should be approximately 30-60 min (see Instructions for Use and Handling as follows).
The recommended duration of treatment with tigecycline for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5-14 days. The recommended duration of treatment with tigecycline for community-acquired pneumonia is 7-14 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 Insufficiency: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh A and 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 hrs. Patients with severe hepatic impairment (Child-Pugh C) should be treated with caution and monitored for treatment response (see Pharmacokinetics under Actions).
Renal Insufficiency: No dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis (see Pharmacokinetics under Actions).
Elderly: No dosage adjustment is necessary in elderly patients (see Pharmacokinetics under Actions).
Gender and Race: No dosage adjustment is necessary based on gender and race (see Pharmacokinetics under Actions).
Administration: Instructions for Use and Handling: The lyophilized powder should be reconstituted with 5.3 mL of 0.9% sodium chloride injection or 5% dextrose injection or Lactated Ringer's injection 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 the drug.) The reconstituted solution should be yellow to orange in colour; if not, the solution should be discarded. 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 or 5% dextrose injection. Injection should be made with an infusion solution compatible with tigecycline and any other medicinal product(s) via this common line (see Incompatibilities under Interactions).
Reconstituted solution must be transferred and further diluted for IV infusion.

No specific information is available on the treatment of overdosage with tigecycline. IV administration of tigecycline 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 haemodialysis.

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 patients versus comparator-treated patients. 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 in all-cause mortality should be considered when selecting among treatment options. (See Precautions and Adverse Reactions.)
Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. 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 teeth 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 diarrhea subsequent to the administration of any antibacterial agent.

Caution should be exercised when considering tigecycline monotherapy in patients with 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) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores=4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.
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).
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 15/122 (12.3%)] 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.
Abuse and Dependence: Drug abuse and dependence have not been demonstrated and are unlikely.
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.
Use in 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.
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.
Use in Lactation: It is not known whether Tygacil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tigecycline is administered to a nursing woman.
Use in Children: Safety and effectiveness in patients <18 years have not been established. Therefore, use in patients <18 years is not recommended.
Use in the Elderly: Of the total number of subjects who received tigecycline in phase 3 clinical studies (n=2514), 664 were ≥65 years, while 228 were ≥75 years. 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: 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.
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.
Use in Lactation: It is not known whether Tygacil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tigecycline is administered to a nursing woman.

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%) and very rare (<0.01%).
For patients who received tigecycline, the following adverse reactions were reported: Blood and Lymphatic System Disorders: Common: Prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT). Uncommon: Increased international normalized ratio (INR).
Immune System Disorders: Undetermined Frequency: Anaphylaxis/anaphylactoid reactions.
Metabolism and Nutrition Disorders: Common: Bilirubinemia, increased blood urea nitrogen (BUN), hypoproteinemia, hypoglycemia.
Nervous System Disorders: Common: Dizziness.
Cardiac Disorders: Common: Phlebitis. Uncommon: Thrombophlebitis.
Respiratory, Thoracic and Mediastinal Disorders: Common: Pneumonia.
Gastrointestinal Disorders: Very Common: Nausea, vomiting, diarrhea. Common: Anorexia, abdominal pain, dyspepsia. Uncommon: Acute pancreatitis.
Hepatobiliary Disorders: Common: Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum (AST and ALT abnormalities in tigecycline-treated patients were reported more frequently in the post-therapy period than in those in comparator-treated patients, which occurred more often on therapy). Uncommon: Jaundice. Undetermined Frequency: Hepatic cholestasis.
Skin and Subcutaneous Tissue Disorders: Common: Pruritus, rash. Undetermined Frequency: Severe skin reactions including Stevens-Johnson syndrome.
General Disorders and Administration Site Conditions: Common: Headache, abnormal healing. Uncommon: Injection site inflammation, pain, reaction, edema and phlebitis.
Investigations: Common: Elevated serum amylase.
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. 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 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 tigecycline and comparators within each infection type (see Table 13). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, or complications of infection or underlying co-morbidities.

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The most common treatment-emergent adverse reactions in patients treated with tigecycline were nausea 26.4% (16.9% mild; 8.1% moderate; 1.3% severe) and vomiting 18.1% (11% mild; 6.1% moderate; 1% severe). In general, nausea or vomiting occurred early (days 1-2).
Discontinuation from tigecycline was most frequently associated with nausea (1.1%) and vomiting (1.1%).

Tetracyclines

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

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