Tygacil

Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TYGACIL safely and effectively. See full prescribing information for TYGACIL. TYGACIL (tigecycline) FOR INJECTION for intravenous use Initial U.S. Approval: 2005BOXED WARNING WARNING: ALL-CAUSE MORTALITY See full prescribing information for complete boxed warning. All-cause mortality was higher in patients treated with TYGACIL than comparators in a meta-analysis of clinical trials. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. TYGACIL should be reserved for use in situations when alternative treatments are not suitable [see Indications and Usage (1.4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. RECENT MAJOR CHANGES Boxed Warning 09/2013 Indications and Usage, Limitations of Use (1.4) 09/2013 Dosage and Administration, Preparation and Handling (2.4) 11/2012 Warnings and Precautions, All-Cause Mortality (5.1) 09/2013 INDICATIONS AND USAGETYGACIL is a tetracycline-class antibacterial drug indicated in patients 18 years of age and older for: Complicated skin and skin structure infections (1.1) Complicated intra-abdominal infections (1.2) Community-acquired bacterial pneumonia (1.3) Limitations of Use: TYGACIL is not indicated for treatment of diabetic foot infection or hospital-acquired pneumonia, including ventilator-associated pneumonia (1.4).DOSAGE AND ADMINISTRATION Initial dose of 100 mg, followed by 50 mg every 12 hours administered intravenously over approximately 30 to 60 minutes. (2.1) Severe hepatic impairment (Child Pugh C): Initial dose of 100 mg followed by 25 mg every 12 hours. (2.2) DOSAGE FORMS AND STRENGTHS50 mg lyophilized powder for reconstitution in a single-dose 5 mL vial or 10 mL vial. (3) CONTRAINDICATIONS Known hypersensitivity to tigecycline. (4) WARNINGS AND PRECAUTIONS A meta-analysis of Phase 3 and 4 clinical trials demonstrated an increase in all-cause mortality in TYGACIL-treated patients compared to controls with a risk difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase has not been established. An increase was also seen in a meta-analysis limited to the approved indications [0.6% (95% CI 0.0, 1.2)]. The greatest difference in mortality was seen in TYGACIL-treated patients with ventilator-associated pneumonia (5.1, 5.2). Anaphylaxis/anaphylactoid reactions have been reported with TYGACIL, and may be life-threatening. Exercise caution in patients with known hypersensitivity to tetracyclines. (5.3) Hepatic dysfunction and liver failure have been reported with TYGACIL. (5.4) Pancreatitis, including fatalities, has been reported with TYGACIL. If pancreatitis is suspected, then consider stopping TYGACIL. (5.5) TYGACIL may cause fetal harm when administered to a pregnant woman. (5.6) The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. (5.7) Clostridium difficile associated diarrhea: evaluate if diarrhea occurs. (5.8) Side EffectsThe most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Suitable anticoagulation test should be monitored if TYGACIL is administered to patients receiving warfarin. (7.1) USE IN SPECIFIC POPULATIONS Pediatrics: Use in patients under 18 years of age is not recommended. Pediatric trials were not conducted because of the higher risk of mortality seen in adult trials (8.4) Microbiology 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 bacteria.

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 TYGACIL INDICATIONS AND USAGE
  • 1.1 Complicated Skin and Skin Structure Infections
  • 1.2 Complicated Intra-abdominal Infections
  • 1.3 Community-Acquired Bacterial Pneumonia
  • 1.4 Limitations of Use
• 2 TYGACIL DOSAGE AND ADMINISTRATION
  • 2.1 General Dosage and Administration
  • 2.2 Patients With Hepatic Impairment
  • 2.3 Pediatric Patients
  • 2.4 Preparation and Handling
• 3 DOSAGE FORMS AND STRENGTHS
• 4 TYGACIL CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 All-Cause Mortality
  • 5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia
  • 5.3 Anaphylaxis/Anaphylactoid Reactions
  • 5.4 Hepatic Effects
  • 5.5 Pancreatitis
  • 5.6 Use During Pregnancy
  • 5.7 Tooth Development
  • 5.8Associated Diarrhea
  • 5.9 Patients With Intestinal Perforation
  • 5.10 Tetracycline-Class Effects
  • 5.11 Superinfection
  • 5.12 Development of Drug-Resistant Bacteria
• 6 TYGACIL ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Post-Marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Warfarin
  • 7.2 Oral Contraceptives
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
• 10 OVERDOSAGE
• 11 TYGACIL DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
  • 14.1 Complicated Skin and Skin Structure Infections
  • 14.2 Complicated Intra-abdominal Infections
  • 14.3 Community-Acquired Bacterial Pneumonia
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

TYGACIL is a tetracycline-class antibacterial drug 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 Limitations of Use

TYGACIL is not indicated for the treatment of diabetic foot infections. A clinical trial failed to demonstrate non-inferiority of TYGACIL for treatment of diabetic foot infections.

TYGACIL is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia. In a comparative clinical trial, greater mortality and decreased efficacy were reported in TYGACIL-treated patients [see Warnings and Precautions (5.2)].

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 Pediatric Patients

The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline in adult patients. Tigecycline should not be used in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested:

• Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
• Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours,

The proposed pediatric doses of tigecycline were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

2.4 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 (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25°C (77°F) after reconstitution, tigecycline should be used immediately. 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, metoclopramide, 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, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

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 All-Cause Mortality

An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in TYGACIL-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. TYGACIL should be reserved for use in situations when alternative treatments are not suitable [see Indications and Usage (1.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia

A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of TYGACIL. In this trial, 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).

In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received TYGACIL (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1)]. Particularly high mortality was seen among TYGACIL-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).

5.3 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.

5.4 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.

5.5 Pancreatitis

Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions (6.2)].

5.6 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)].

5.7 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.

5.8Associated 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.

5.9 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.

5.10 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 [see Warnings and Precautions (5.5)].

5.11 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.

5.12 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.

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)	ComparatorsVancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid. (N=2307)
Body as a Whole
Abdominal pain	6	4
Abscess	2	2
Asthenia	3	2
Headache	6	7
Infection	7	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	5	6
Metabolic and Nutritional
Alkaline Phosphatase Increased	3	3
Amylase Increased	3	2
Bilirubinemia	2	1
BUN Increased	3	1
Healing Abnormal	3	2
Hyponatremia	2	1
Hypoproteinemia	5	3
SGOT IncreasedLFT 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.	4	5
SGPT IncreasedLFT 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.	5	5
Respiratory System
Pneumonia	2	2
Nervous System
Dizziness	3	3
Skin and Appendages
Rash	3	4

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type

	TYGACIL		Comparator		Risk DifferenceThe difference between the percentage of patients who died in TYGACIL and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.
Infection Type	n/N	%	n/N	%	% (95% CI)
CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.
Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).
cSSSI	12/834	1.4	6/813	0.7	0.7 (-0.3, 1.7)
cIAI	42/1382	3.0	31/1393	2.2	0.8 (-0.4, 2.0)
CAP	12/424	2.8	11/422	2.6	0.2 (-2.0, 2.4)
HAP	66/467	14.1	57/467	12.2	1.9 (-2.4, 6.3)
Non-VAPThese are subgroups of the HAP population.	41/336	12.2	42/345	12.2	0.0 (-4.9, 4.9)
VAPThese are subgroups of the HAP population.	25/131	19.1	15/122	12.3	6.8 (-2.1, 15.7)
RP	11/128	8.6	2/43	4.7	3.9 (-4.0, 11.9)
DFI	7/553	1.3	3/508	0.6	0.7 (-0.5, 1.8)
Overall Adjusted	150/3788	4.0	110/3646	3.0	0.6 (0.1, 1.2)Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.

An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (315, 400, 900) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

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 (5.9)].

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

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

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval 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
• severe skin reactions, including Stevens-Johnson Syndrome
• symptomatic hypoglycemia in patients with and without diabetes mellitus

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 (5.6)]

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 reductions in fetal weights and an increased incidence of 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 (5.7)].

8.4 Pediatric Use

Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in tigecycline-treated adult patients in clinical trials, pediatric trials of tigecycline to evaluate the safety and efficacy of tigecycline were not conducted.

In situations where there are no other alternative antibacterial drugs, pediatric dosing has been proposed based on data from pediatric pharmacokinetic studies [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Because of effects on tooth development, use in patients under 8 years of age is not recommended [see Warnings and Precautions (5.7)].

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)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

No significant effect of a single intravenous dose of TYGACIL 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.

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.

Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline

	Single Dose 100 mg (N=224)	Multiple Dose100 mg initially, followed by 50 mg every 12 hours 50 mg every 12h (N=103)
Cmax (mcg/mL)30-minute infusion	1.45 (22%)	0.87 (27%)
Cmax (mcg/mL)60-minute infusion	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 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 (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)].

Pediatric Patients

A single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged 8–16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or 2 mg/kg. The study showed that for children aged 12–16 years (n = 16) a dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults with the approved dosing regimen. Large variability observed in children aged 8 to 11 years of age (n = 8) required additional study to determine the appropriate dosage.

A subsequent tigecycline dose-finding study was conducted in 8–11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n = 17), 1 mg/kg (n = 21), and 1.25 mg/kg (n=20). This study showed that for children aged 8–11 years, a 1.2 mg/kg dose would likely result in exposures comparable to those observed in adults resulting with the approved dosing regimen [see Dosage and Administration (2.3)].

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 co-administered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the C_max of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in C_max did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment 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 C_max 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 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 baumanniiThere 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.

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

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 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 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.

Table 4. Susceptibility Test Result Interpretive Criteria for Tigecycline

	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion (zone diameters in mm)
Pathogen	S	I	R	S	I	R
Staphylococcus aureus (including methicillin-resistant isolates)	≤0.5The 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.	-	-	≥19	-	-
Streptococcus spp. other than S. pneumoniae	≤0.25The 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.	-	-	≥19	-	-
Streptococcus pneumoniae	≤0.06The 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.	-	-	≥19	-	-
Enterococcus faecalis (vancomycin-susceptible isolates)	≤0.25The 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.	-	-	≥19	-	-
EnterobacteriaceaeTigecycline has decreased in vitro activity against Morganella spp., Proteus spp. and Providencia spp.	≤2	4	≥8	≥19	15–18	≤14
Haemophilus influenzae	≤0.25The 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.	-	-	≥19	-	-
AnaerobesAgar dilution	≤4	8	≥16	n/a	n/a	n/a

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.

Table 5. Acceptable Quality Control Ranges for Susceptibility Testing

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 fragilis Agar dilution ATCC 25285	0.12–1	Not Applicable
Bacteroides thetaiotaomicron Agar dilution ATCC 29741	0.5–2	Not Applicable
Eubacterium lentum Agar dilution ATCC 43055	0.06–0.5	Not Applicable
Clostridium difficile Agar dilution 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.

Table 6. Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy

	TYGACIL100 mg initially, followed by 50 mg every 12 hours n/N (%)	Vancomycin/AztreonamVancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours) 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)

Table 7. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure InfectionsTwo cSSSI pivotal studies and two Resistant Pathogen studies

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.Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus	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)

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.

Table 8. Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy

	TYGACIL100 mg initially, followed by 50 mg every 12 hours n/N (%)	Imipenem/CilastatinImipenem/Cilastatin (500 mg every 6 hours) 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)

Table 9. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal InfectionsTwo cIAI pivotal studies and two Resistant Pathogen studies

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.Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus	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)

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.

Table 10. Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy

	TYGACIL100 mg initially, followed by 50 mg every 12 hours n/N (%)	LevofloxacinLevofloxacin (500 mg intravenous every 12 or 24 hours) n/N (%)	95% CI95% confidence interval for the treatment difference
Study 308After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.
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)

Table 11. Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial PneumoniaTwo CABP studies

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)Includes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for TYGACIL and levofloxacin respectively]	44/46 (95.7)	39/44 (88.6)

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.

Table 12. Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of MortalityPatients 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

	TYGACIL n/N (%)	Levofloxacin n/N (%)	95% CI95% confidence interval for the treatment difference
Study 308After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.
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)

15 REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement. CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

16 HOW SUPPLIED/STORAGE AND HANDLING

TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass vial or 10 mL glass vial, each containing 50 mg tigecycline lyophilized powder for reconstitution.

Supplied:

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 (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25°C (77°F) after reconstitution, tigecycline should be used immediately. 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.

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.

LAB-0458-5.0

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - VIAL LABEL

Tygacil ^®
(tigecycline) for injection

50 mg tigecycline per vial

For I.V. Infusion Only

Contains 100 mg lactose monohydrate;
pH adjusted with HCl and if necessary, NaOH.
No preservatives.
Mfg. for: Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101

Wyeth ^®

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 50 MG - CARTON

Tygacil ^®
(tigecycline)
for injection

Rx only

RECONSTITUTED SOLUTION MUST BE
FURTHER DILUTED FOR I.V. INFUSION

NDC 0008-4990-20

50 mg

tigecycline
per vial
10 Single Use Vials

Wyeth ^®