TYGACIL (tigecycline) is a tetracycline derivative (a glycylcycline) for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7­bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2­naphthacenecarboxamide. The empirical formula is C₂₉H₃₉N₅O₈ and the molecular weight is 585.65.

The following represents the chemical structure of tigecycline:

TYGACIL is an orange lyophilized powder or cake. Each TYGACIL vial contains 50 mg tigecycline lyophilized powder for reconstitution for intravenous infusion and 100 mg of lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.

Last updated on RxList: 4/16/2009

TYGACIL is a tetracycline-class antibacterial indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions listed below for patients 18 years of age and older:

Complicated Skin and Skin Structure Infections

Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

Complicated Intra-abdominal Infections

Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Community-Acquired Bacterial Pneumonia

Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta­lactamase negative isolates), and Legionella pneumophila.

Usage

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 or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. TYGACIL may be initiated as empiric monotherapy before results of these tests are known.

General Dosage and Administration

The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with TYGACIL for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with TYGACIL for community-acquired bacterial pneumonia is 7 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.

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 initial dose of TYGACIL should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY  and Use in Specific Populations].

Preparation and Handling

Each vial of TYGACIL should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) 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 intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Once reconstituted, TYGACIL mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). Alternatively, TYGACIL may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

TYGACIL 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 TYGACIL with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer's Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line.

Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 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: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as TYGACIL: amphotericin B and diazepam.

Dosage Forms and Strengths

Each single-dose 5 mL glass vial contains 50 mg of tigecycline as an orange lyophilized powder for reconstitution.

Storage and Handling

TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass vial containing 50 mg tigecycline lyophilized powder for reconstitution.

Supplied 10 vials/box. NDC: 0008-4990-02

Prior to reconstitution, TYGACIL should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Once reconstituted, TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). Alternatively, TYGACIL mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag. Reconstituted solution must be transferred and further diluted for intravenous infusion.

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Wyeth Pharmaceuticals Inc. Philadelphia, PA 19101.

Last updated on RxList: 4/16/2009

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in ≥ 2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies

Body System Adverse Reactions	TYGACIL (N=2514)	Comparatorsa (N=2307)
Body as a Whole
Abdominal pain	6	4
Abscess	3	3
Asthenia	3	2
Headache	6	7
Infection	8	5
Cardiovascular System
Phlebitis	3	4
Digestive System
Diarrhea	12	11
Dyspepsia	2	2
Nausea	26	13
Vomiting	18	9
Hemic and Lymphatic System
Anemia	4	5
Metabolic and Nutritional
Alkaline Phosphatase Increased	4	3
Amylase Increased	3	2
Bilirubinemia	2	1
BUN Increased	3	1
Healing Abnormal	4	3
Hypoproteinemia	5	3
SGOT Increasedb	4	5
SGPT Increasedb	5	5
Nervous System
Dizziness	3	3
Skin and Appendages
Rash	3	4
a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid. b LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

In cSSSI and cIAI studies, death occurred in 2.3% (32/1383) of patients receiving TYGACIL and 1.6% (22/1375) of patients receiving comparator drugs; this difference is not statistically significant and relationship to treatment cannot be established. In all treatment groups, mortality was associated with higher baseline comorbidity and/or greater severity of baseline infections.

In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS].

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% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea ( < 1%).

The following adverse reactions were reported infrequently ( < 2%) in patients receiving TYGACIL in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia, hyponatremia

Special Senses: taste perversion

Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

• anaphylaxis/anaphylactoid reactions
• acute pancreatitis
• hepatic cholestasis, and jaundice

Warfarin

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY].

Oral Contraceptives

Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

Last updated on RxList: 4/16/2009

Included as part of the PRECAUTIONS section.

Anaphylaxis/Anaphylactoid Reactions

Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.

Hepatic Effects

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.

Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia

A study of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL. In this study, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL 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.

Use During Pregnancy

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 Specific Populations].

Tooth Development

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 (yellow­gray-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.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Patients With Intestinal Perforation

Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL 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.

Tetracycline-Class Effects

TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL.

Superinfection

As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

Development of Drug-Resistant Bacteria

Prescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg·hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.

Use in Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

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 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg•hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.

There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL is administered to a nursing woman [see WARNINGS AND PRECAUTIONS].

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see WARNINGS AND PRECAUTIONS].

Geriatric Use

Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. 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.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY].

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 initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY  and DOSAGE AND ADMINISTRATION].

Last updated on RxList: 4/16/2009

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL 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 intravenous 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.

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

Last updated on RxList: 4/16/2009

Mechanism of Action

Tigecycline is an antibacterial drug.

Pharmacokinetics

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 2. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 2. Mean (CV%) Pharmacokinetic Parameters of Tigecycline

	Single Dose 100 mg (N=224)	Multiple Dosea 50 mg every 12h (N=103)
Cmax (mcg/mL)b	1.45 (22%)	0.87 (27%)
Cmax (mcg/mL)c	0.90 (30%)	0.63 (15%)
AUC (mcg•h/mL)	5.19 (36%)	-
AUC0-24h (mcg•h/mL)	-	4.70 (36%)
Cmin (mcg/mL)	-	0.13 (59%)
t½ (h)	27.1 (53%)	42.4 (83%)
CL (L/h)	21.8 (40%)	23.8 (33%)
CLτ (mL/min) (mL/min)	38.0 (82%)	51.0 (58%)
Vss (L)	568 (43%)	639 (48%)
a 100 mg initially, followed by 50 mg every 12 hours b 30-minute infusion c 60-minute infusion

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.

Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC_0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC_0-12h in the serum, and the AUC_0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in serum. The AUC_0-12h (1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.

Metabolism

Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

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 and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Specific Populations

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). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

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 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of TYGACIL is necessary in patients with renal impairment or in patients undergoing hemodialysis.

Geriatric Patients

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

Gender

In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.

Race

In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as “other” participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and “other” subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

Drug Interactions

TYGACIL (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when TYGACIL is administered with digoxin.

Concomitant administration of TYGACIL (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, TYGACIL is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

Microbiology

Mechanism of Action

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

Mechanism(s) of Resistance

To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is not 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). Tigecycline resistance in some bacteria (e.g. Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.

Interaction with Other Antimicrobials

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

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

Facultative Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates)
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus agalactiae
Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus pneumoniae (penicillin-susceptible isolates)
Streptococcus pyogenes

Facultative Gram-negative bacteria

Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae (beta-lactamase negative isolates)
Klebsiella oxytoca
Klebsiella pneumoniae
Legionella pneumophila

Anaerobic bacteria

Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Clostridium perfringens
Peptostreptococcus micros

At least 90% of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) that are at concentrations that are achievable using the prescribed dosing regimens. However, the clinical significance of this is unknown because the safety and effectiveness of tigecycline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive bacteria

Enterococcus avium
Enterococcus casseliflavus
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible and -resistant isolates)
Enterococcus gallinarum
Listeria monocytogenes
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)
Staphylococcus haemolyticus

Facultative Gram-negative bacteria

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

Anaerobic bacteria

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

Other bacteria

Mycobacterium abscessus
Mycobacterium fortuitum

*There have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting 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)^1,3,4 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 ( < 12h old). The MIC values should be interpreted according to the criteria provided in Table 3.

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^2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg tigecycline to test the susceptibility of bacteria 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 3.

Anaerobic Techniques

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

Table 3. Susceptibility Test Result Interpretive Criteria for Tigecycline

Pathogen	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion (zone diameters in mm)
	S	I	R	S	I	R
Staphylococcus aureus (including methicillin-resistant isolates)	≤ 0.5a	-	-	≥ 19	-	-
Streptococcus spp. other than S. pneumoniae	≤ 0.25a	-	-	≥ 19	-	-
Streptococcus pneumoniae	≤ 0.06a	-	-	≥ 19	-	-
Enterococcus faecalis (vancomycinsusceptible isolates)	≤ 0.25a	-	-	≥ 19	-	-
Enterobacteriaceaeb	≤ 2	4	≥ 8	≥ 19	15-18	≤ 14
Haemophilus influenzae	≤ 0.25a	-	-	≥ 19	-	-
Anaerobesc	≤ 4	8	≥ 16	n/a	n/a	n/a
a The current absence of resistant isolates precludes defining any results other than “Susceptible.” Isolates yielding MIC results suggestive of “Nonsusceptible” category should be submitted to reference laboratory for further testing. b Tigecycline has decreased in vitro activity against Morganella spp., Proteus spp. and Providencia spp. c Agar dilution

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.^1,2,3,4 Standard tigecycline powder should provide the MIC values provided in Table 4. For the diffusion technique using the 15 mcg tigecycline disk the criteria provided in Table 4 should be achieved.

Table 4. Acceptable Quality Control Ranges for Susceptibility Testing

QC organism	Minimum Inhibitory Concentrations (mcg/mL)	Disk Diffusion (zone diameters in mm)
Staphylococcus aureus ATCC 25923	Not Applicable	20-25
Staphylococcus aureus ATCC 29213	0.03-0.25	Not Applicable
Escherichia coli ATCC 25922	0.03-0.25	20-27
Enterococcus faecalis ATCC 29212	0.03-0.12	Not Applicable
Streptococcus pneumoniae ATCC 49619	0.016-0.12	23-29
Haemophilus influenzae ATCC 49247	0.06-0.5	23-31
Bacteroides fragilisa ATCC 25285	0.12-1	Not Applicable
Bacteroides thetaiotaomicrona ATCC 29741	0.5-2	Not Applicable
Eubacterium lentuma ATCC 43055	0.06-0.5	Not Applicable
Clostridium difficilea ATCC 70057	0.12-1	Not Applicable
ATCC = American Type Culture Collection a Agar dilution

Animal Toxicology and/or Pharmacology

In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg•hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.

Clinical Studies

Complicated Skin and Skin Structure Infections

TYGACIL was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis ( ≥ 10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 5. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 6.

Table 5. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy

	TYGACILa n/N (%)	Vancomycin/Aztreonamb n/N (%)
Study 300
CE	165/199 (82.9)	163/198 (82.3)
c-mITT	209/277 (75.5)	200/260 (76.9)
Study 305
CE	200/223 (89.7)	201/213 (94.4)
c-mITT	220/261 (84.3)	225/259 (86.9)
a 100 mg initially, followed by 50 mg every 12 hours bVancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)

Table 6. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infections^a

Pathogen	TYGACIL n/N (%)	Vancomycin/Aztreonam n/N (%)
Escherichia coli	29/36 (80.6)	26/30 (86.7)
Enterobacter cloacae	10/12 (83.3)	15/15 (100)
Enterococcus faecalis (vancomycin-susceptible only)	15/21 (71.4)	19/24 (79.2)
Klebsiella pneumoniae	12/14 (85.7)	15/16 (93.8)
Methicillin-susceptible Staphylococcus aureus (MSSA)	124/137 (90.5)	113/120 (94.2)
Methicillin-resistant Staphylococcus aureus (MRSA)	79/95 (83.2)	46/57 (80.7)
Streptococcus agalactiae	8/8 (100)	11/14 (78.6)
Streptococcus anginosus grp.b	17/21 (81.0)	9/10 (90.0)
Streptococcus pyogenes	31/32 (96.9)	24/27 (88.9)
Bacteroides fragilis	7/9 (77.8)	4/5 (80.0)
a Two cSSSI pivotal studies and two Resistant Pathogen studies b Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Complicated Intra-abdominal Infections

TYGACIL was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 7. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 8.

Table 7. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy

	TYGACILa n/N (%)	Imipenem/Cilastatinb n/N (%)
Study 301
ME	199/247 (80.6)	210/255 (82.4)
m-mITT	227/309 (73.5)	244/312 (78.2)
Study 306
ME	242/265 (91.3)	232/258 (89.9)
m-mITT	279/322 (86.6)	270/319 (84.6)
a 100 mg initially, followed by 50 mg every 12 hours bImipenem/Cilastatin (500 mg every 6 hours)

Table 8. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infections^a

Pathogen	TYGACIL n/N (%)	Imipenem/Cilastatin n/N (%)
Citrobacter freundii	12/16 (75.0)	3/4 (75.0)
Enterobacter cloacae	15/17 (88.2)	16/17 (94.1)
Escherichia coli	284/336 (84.5)	297/342 (86.8)
Klebsiella oxytoca	19/20 (95.0)	17/19 (89.5)
Klebsiella pneumoniae	42/47 (89.4)	46/53 (86.8)
Enterococcus faecalis	29/38 (76.3)	35/47 (74.5)
Methicillin-susceptible Staphylococcus aureus (MSSA)	26/28 (92.9)	22/24 (91.7)
Methicillin-resistant Staphylococcus aureus (MRSA)	16/18 (88.9)	1/3 (33.3)
Streptococcus anginosus grp.b	101/119 (84.9)	60/79 (75.9)
Bacteroides fragilis	68/88 (77.3)	59/73 (80.8)
Bacteroides thetaiotaomicron	36/41 (87.8)	31/36 (86.1)
Bacteroides uniformis	12/17 (70.6)	14/16 (87.5)
Bacteroides vulgatus	14/16 (87.5)	4/6 (66.7)
Clostridium perfringens	18/19 (94.7)	20/22 (90.9)
Peptostreptococcus micros	13/17 (76.5)	8/11 (72.7)
a Two cIAI pivotal studies and two Resistant Pathogen studies b Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Community-Acquired Bacterial Pneumonia

TYGACIL was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 308), after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 9. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 10.

Table 9. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy

	TYGACILa n/N (%)	Levofloxacinb n/N (%)	95% CIc
Study 308d
CE	125/138 (90.6)	136/156 (87.2)	(-4.4, 11.2)
c-mITT	149/191 (78)	158/203 (77.8)	(-8.5, 8.9)
Study 313
CE	128/144 (88.9)	116/136 (85.3)	(-5.0, 12.2)
c-mITT	170/203 (83.7)	163/200 (81.5)	(-5.6, 10.1)
a 100 mg initially, followed by 50 mg every 12 hours bLevofloxacin (500 mg intravenous every 12 or 24 hours) c 95% confidence interval for the treatment difference d After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

Table 10. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumonia^a

Pathogen	TYGACIL n/N (%)	Levofloxacin n/N (%)
Haemophilus influenzae	14/17 (82.4)	13/16 (81.3)
Legionella pneumophila	10/10 (100.0)	6/6 (100.0)
Streptococcus pneumoniae (penicillin-susceptible only)b	44/46 (95.7)	39/44 (88.6)
a Two CABP studies b Includes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for TYGACIL and levofloxacin respectively]

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:

• Age ≥ 50 years
• PSI score ≥ 3
• Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 11. Age ≥ 50 was the most common risk factor in the higher-risk group.

Table 11. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortality^a

	TYGACIL n/N (%)	Levofloxacin n/N (%)	95% CIb
Study 308c
CE
Higher risk
Yes	93/103 (90.3)	84/102 (82.4)	(-2.3, 18.2)
No	32/35 (91.4)	52/54 (96.3)	(-20.8, 7.1)
c-mITT
Higher risk
Yes	111/142 (78.2)	100/134 (74.6)	(-6.9, 14)
No	38/49 (77.6)	58/69 (84.1)	(-22.8, 8.7)
Study 313
CE
Higher risk
Yes	95/107 (88.8)	68/85 (80)	(-2.2, 20.3)
No	33/37 (89.2)	48/51 (94.1)	(-21.1, 8.6)
c-mITT
Higher risk
Yes	112/134 (83.6)	93/120 (77.5)	(-4.2, 16.4)
No	58/69 (84.1)	70/80 (87.5)	(-16.2, 8.8)
a Patients at higher risk of death include patients with any one of the following: ≥ 50 year of age; PSI score ≥ 3; or bacteremia due to Streptococcus pneumoniae b 95% confidence interval for the treatment difference c After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

 

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – 8th ed. Approved Standard, CLSI document M07-A8, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests – 10^th ed. Approved Standard, CLSI document M02-A10, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – 7^th ed. Approved Standard, CLSI document M11-A7, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2007.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing – 19th Informational Supplement. Approved Standard, CLSI document M100-S19, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.

Last updated on RxList: 4/16/2009

• Patients should be counseled that antibacterial drugs including TYGACIL should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TYGACIL is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by TYGACIL or other antibacterial drugs in the future.
• Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Last updated on RxList: 4/16/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TIGECYCLINE - INJECTION

(tye-geh-SYE-kleen)

COMMON BRAND NAME(S): Tygacil

USES: This medication is used to treat certain serious bacterial infections which may be resistant to other antibiotics. This medication is known as a glycylcycline antibiotic. It works by stopping the growth of bacteria.

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

HOW TO USE: This medication is given by injection into a vein (intravenously-IV) over 30-60 minutes by a healthcare professional. Doses are usually repeated every 12 hours or as directed by your doctor. The dose and length of treatment depend on your condition and response to therapy.

If you are receiving this medication at home, learn how to properly inject this medication. Follow all instructions for proper mixing and dilution with the correct IV fluids. If you have questions regarding the use of this medication, consult your pharmacist.

This medication is normally yellow to orange in color. Before using, check this product visually for particles or discoloration (e.g., green or black). If either is present, do not use the liquid.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals.

Continue to take this medication until the full-prescribed amount is finished even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition worsens or has not improved within 14 days.

SIDE EFFECTS: Nausea, vomiting, headache, dizziness, or pain/swelling at the injection site may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: sunburn (sun sensitivity), change in the amount of urine, unusual fatigue.

Tell your doctor immediately if any of these rare but very serious side effects occur: severe stomach/abdominal pain, hearing changes (e.g., ringing in the ears, decreased hearing), persistent or severe headache, vision changes (e.g., blurred vision, double vision), irregular heartbeat, easy bleeding/bruising, yellowing of the eyes or skin, dark urine.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a resistant bacteria. This condition may occur weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, or blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge or other new symptoms.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using tigecycline, tell your doctor or pharmacist if you are allergic to it; or to tetracyclines (such as doxycycline, minocycline, tetracycline); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: severe liver disease.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Before having surgery, tell your doctor or dentist that you are using this medication.

This medication should not be used in children younger than 8 years of age because it may cause permanent tooth discoloration and other problems. Tooth discoloration may also occur in older children and young adults. Consult your doctor for more information.

This medication is not recommended for use during pregnancy because of possible harm to an unborn baby. Women of child-bearing age should use effective birth control while using this medication. Consult your doctor for more details.

It is not known whether this drug passes into breast milk. Because of possible harm to a nursing infant, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: "blood thinners" (e.g., warfarin), live bacterial vaccines.

This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

Laboratory and/or medical tests (e.g., liver function tests, blood counts, cultures) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed vials at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Once mixed with the correct IV fluids, this medication should be given within 6 hours, or the mixed drug may be stored in the refrigerator between 36-46 degrees F (2-8 degrees C) for up to 24 hours. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.