TYGACIL
-
tigecycline injection, powder, lyophilized, for solution
Wyeth Pharmaceuticals Company
----------
|
|||||||||||||||||||||||||||||||||
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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:
1.1 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.
1.2 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.
1.3 Community-Acquired Bacterial Pneumonia
Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.
1.4 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.
2 DOSAGE AND ADMINISTRATION
2.1 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.
2.2 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 (12.3) and Use in Specific Populations (8.6)].
2.3 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 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.
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.
3 DOSAGE FORMS AND STRENGTHS
Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution.
4 CONTRAINDICATIONS
TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline.
5 WARNINGS AND PRECAUTIONS
5.1 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.
5.2 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.
5.3 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 14/122 [11.5%]) than the comparator.
5.4 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 (8.1)].
5.5 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 (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
5.6 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.
5.7 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.
5.8 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.
5.9 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.
5.10 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.
6 ADVERSE REACTIONS
6.1 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.
In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. In a pooled analysis of these studies, the risk difference of all-cause mortality was 1.0% (95% CI 0.2, 1.8) between TYGACIL and comparator treated patients. No significant differences were observed between treatments by infection type (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening or complications of infection or underlying co-morbities.
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 (5.7)].
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
Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
6.2 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
7 DRUG INTERACTIONS
7.1 Warfarin
Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see Clinical Pharmacology (12.3)].
7.2 Oral Contraceptives
Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects—Pregnancy Category D [see Warnings and Precautions (5.4)]
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.
8.3 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 (5.5)].
8.4 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 (5.5)].
8.5 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 (12.3)].
8.6 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 (12.3) and Dosage and Administration (2.2)].
10 OVERDOSAGE
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.
11 DESCRIPTION
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]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tigecycline is an antibacterial drug [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.
| Single Dose | Multiple Dosea | |
|---|---|---|
| 100 mg | 50 mg every 12h | |
| (N=224) | (N=103) | |
| a 100 mg initially, followed by 50 mg every 12 hours | ||
| 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%) |
| CLr (mL/min) | 38.0 (82%) | 51.0 (58%) |
| Vss (L) | 568 (43%) | 639 (48%) |
Distribution
The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.
Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.
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 (8.6) and Dosage and Administration (2.2)].
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 (8.5)].
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.
12.4 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 (1)].
Facultative Gram-positive bacteria
Enterococcus faecalis (vancomycin-susceptible isolates)
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus pneumoniae (penicillin-susceptible isolates)
Facultative Gram-negative bacteria
Haemophilus influenzae (beta-lactamase negative isolates)
Anaerobic bacteria
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 faecalis (vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible and -resistant isolates)
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)
Facultative Gram-negative bacteria
Acinetobacter baumannii*
Haemophilus influenzae (ampicillin-resistant)
Anaerobic bacteria
Other bacteria
*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 4.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure2,4 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 4.
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.
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 5. For the diffusion technique using the 15 mcg tigecycline disk the criteria provided in Table 5 should be achieved.
| QC organism | Minimum Inhibitory Concentrations (mcg/mL) | Disk Diffusion (zone diameters in mm) |
|---|---|---|
| ATCC = American Type Culture Collection | ||
| 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 |
13 NONCLINICAL TOXICOLOGY
13.1 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.
13.2 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.
14 CLINICAL STUDIES
14.1 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 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.
14.2 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 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.
| TYGACILa
n/N (%) | Imipenem/Cilastatinb
n/N (%) |
|
|---|---|---|
| a 100 mg initially, followed by 50 mg every 12 hours | ||
| 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) |
14.3 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 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.
To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:
- Age ≥50 years
- PSI score ≥3
- Streptococcus pneumoniae bacteremia
The results of this analysis are shown in Table 12. Age ≥50 was the most common risk factor in the higher-risk group.
15 REFERENCES
- 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.
- Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests – 10th ed. Approved Standard, CLSI document M02-A10, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2009.
- Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – 7th ed. Approved Standard, CLSI document M11-A7, CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898. January 2007.
- 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass or 10 mL glass vial, each vial containing 50 mg tigecycline lyophilized powder for reconstitution.
5 mL - 10 vials/box. NDC 0008-4990-02
10 mL - 10 vials/box. NDC 0008-4990-20
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.
U.S. Patent Numbers: RE40086; RE40183; 5,284,963; 5,530,117; 5,675,030; and 7,365,087.
17 PATIENT COUNSELING INFORMATION
- 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.
 | 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. |  |
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - VIAL LABEL
Contains 100 mg lactose monohydrate;
pH adjusted with HCl and if necessary, NaOH.
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - CARTON
RECONSTITUTED SOLUTION MUST BE FURTHER DILUTED FOR I.V. INFUSION
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - VIAL LABEL
Contains 100 mg lactose monohydrate;
pH adjusted with HCl and if necessary, NaOH.
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - CARTON
RECONSTITUTED SOLUTION MUST BE FURTHER DILUTED FOR I.V. INFUSION
| TYGACIL
tigecycline injection, powder, lyophilized, for solution |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA021821 | 06/01/2005 | |
| Labeler - Wyeth Pharmaceuticals Company (071170729) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Patheon Italia S.p.A. | 338336589 | MANUFACTURE, ANALYSIS | |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Wyeth Parenterals Division of Wyeth Holdings Corporation | 828832100 | MANUFACTURE, ANALYSIS | |