1.1 Complicated Skin and Skin Structure Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of 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

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates of 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

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae , and Legionella pneumophila.

1.4 Limitations of Use

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

Tigecycline for injection 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 tigecycline for injection -treated patients [see Warnings and Precautions (5.2)].

1.5 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of tigecycline for injection and other antibacterial drugs, tigecycline for injection should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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

2.1 Recommended Adult Dosage

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

The recommended duration of treatment with tigecycline for injection for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with tigecycline for injection 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 Dosage in 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 tigecycline for injection 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 Dosage in 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 for injection in adult patients. Avoid use of tigecycline for injection 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 for injection every 12 hours intravenously to a maximum dose of 50 mg of tigecycline for injection every 12 hours.
• Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline for injection every 12 hours.

The proposed pediatric doses of tigecycline for injection 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)] .

There are no data to provide dosing recommendations in pediatric patients with hepatic impairment.

2.4 Monitoring of Blood Coagulation Parameters

Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline for Injection [see Warnings and Precautions (5.7)]. .

2.5 Preparation and Administration

There are different formulations of tigecycline for Injection that have differences concerning the presence of maltose in the formulation. If this tigecycline for Injection that contains maltose is substituted for another tigecycline formulation, glucose testing methods that do not react with maltose should be used [see Boxed Warning and Warnings and Precautions (5.3)].

Each vial of tigecycline for injection 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. Reconstituted solution must be transferred and further diluted for intravenous infusion. 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, tigecycline for injection 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, Tigecycline for injection 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.

Tigecycline for injection may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline for injection 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.

2.6 Drug 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, tigecycline for injection 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.

2.7 Drug Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as tigecycline for injection: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

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 tigecycline for injection-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 tigecycline for injection 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 tigecycline 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. Tigecycline for injection should be reserved for use in situations when alternative treatments are not suitable [see Boxed Warning, 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 tigecycline for injection. In this trial, patients were randomized to receive tigecycline for injection (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 tigecycline for injection 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 tigecycline for injection (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions (6.1)] . Particularly high mortality was seen among tigecycline for injection-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 Unrecognized Hypoglycemia Due to Interference with Blood Glucose Testing

This formulation of tigecycline for injection contains maltose and may result in falsely elevated glucose readings leading to unrecognized hypoglycemia or inappropriate insulin administration. Glucose testing methods that do not react with maltose should be used when patients are receiving this formulation of tigecycline for injection [see Drug Interactions (7.3)] .

Interference with blood glucose testing may not be associated with other tigecycline products that do not contain maltose.

5.4 Anaphylactic Reactions

Anaphylactic reactions have been reported with nearly all antibacterial agents, including tigecycline for injection, and may be life-threatening. Tigecycline for injection is structurally similar to tetracycline-class antibiotics and should be avoided in patients with known hypersensitivity to tetracycline-class antibiotics.

5.5 Hepatic Adverse 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. Hepatic dysfunction may occur after the drug has been discontinued.

5.6 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)] .

5.7 Monitoring of Blood Coagulation Parameters

Hypofibrinogenemia has been reported in patients treated with tigecycline for injection [see Adverse Reactions (6.2)] . Obtain baseline blood coagulation parameters, including fibrinogen, andcontinue to monitor regularly during treatment with tigecycline for injection.

5.8 Tooth Discoloration and Enamel Hypoplasia

The use of tigecycline for injection 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). This adverse reaction is more common during long-term use of tetracyclines, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)] .

5.9 Inhibition of Bone Growth

The use of tigecycline for injection during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the tetracycline was discontinued. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)] .

5.10 Clostridioides difficile-Associated Diarrhea

Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline for injection, 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.

5.11 Sepsis/Septic Shock in Patients With Intestinal Perforation

Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with tigecycline for injection and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline for injection 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.

5.12 Tetracycline-Class Adverse Effects

Tigecycline for injection is structurally similar to tetracycline-class antibacterial drugs 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).

5.13 Development of Drug-Resistant Bacteria

Prescribing tigecycline for injection 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.

6.1 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 tigecycline for injection. Tigecycline for injection was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

aVancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.

bLFT abnormalities in tigecycline for injection-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy.

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline for injection 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 tigecycline for injection 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.

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.

* The difference between the percentage of patients who died in tigecycline for injection and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.

** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.

a These are subgroups of the HAP population.

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).

An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - 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 reactions were more frequently reported for subjects treated with tigecycline for injection (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with tigecycline for injection (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 (5.11)] .

The most common 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 tigecycline for injection and comparators were either mild or moderate in severity. In patients treated with tigecycline for injection, 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 tigecycline for injection and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline for injection and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline for injection and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline for injection and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline for injection and 8% for levofloxacin; vomiting incidence was 16% for tigecycline for injection and 6% for levofloxacin.

Discontinuation from tigecycline for injection 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 (<2%) in patients receiving tigecycline for injection 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: prolonged activated 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 tigecycline for injection. 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.

• anaphylactic reactions
• acute pancreatitis
• hepatic cholestasis, and jaundice
• severe skin reactions, including Stevens-Johnson Syndrome
• symptomatic hypoglycemia in patients with and without diabetes mellitus
• hypofibrinogenemia [see Warnings and Precautions (5.7)]

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 Calcineurin Inhibitors

Concomitant use of tigecycline for injection and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Therefore, serum concentrations of the calcineurin inhibitor should be monitored during treatment with tigecycline for injection to avoid drug toxicity.

7.3 Oral Contraceptives

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

7.4 Blood Glucose Testing

This formulation of tigecycline for injection contains maltose and may result in falsely elevated glucose readings due to interference with blood glucose testing, leading to unrecognized hypoglycemia or inappropriate insulin administration. Blood glucose monitors or strips using glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ), glucose-dye-oxidoreductase (GDO), or some glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD)-based methods must not be used because the presence of maltose can interfere with their readings.

Methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase should be used when this formulation of tigecycline for injection is administered. [see Warnings and Precautions (5.3)] .

8.1 Pregnancy

8.2 Lactation

Risk Summary

There are no data on the presence of tigecycline in human milk; however, tetracycline-class antibacterial drugs are present in breast milk. It is not known whether tigecycline has an effect on the breastfed infant or on milk production. Tigecycline has low oral bioavailability; therefore, infant exposure is expected to be low. Tigecycline is present in rat milk with little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tigecycline for injection and any potential adverse effects on the breastfed child from tigecycline for injection or from the underlying maternal condition (see Clinical Considerations).

Clinical Considerations

Because of the theoretical risk of dental discoloration and inhibition of bone growth, avoid breastfeeding if taking tigecycline for injection for longer than three weeks. A lactating woman may also consider interrupting breastfeeding and pumping and discarding breastmilk during administration of tigecycline for injection and for 9 days (approximately 5 half-lives) after the last dose in order to minimize drug exposure to a breastfed infant.

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 for injection-treated adult patients in clinical trials, pediatric trials of tigecycline to evaluate the safety and efficacy of tigecycline for injection were not conducted.

In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients 8 to 17 years of age 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 tigecycline for injection in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No 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)] .

12.1 Mechanism of Action

Tigecycline is a tetracycline class antibacterial [see Microbiology (12.4)].

12.2 Pharmacodynamics

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.

a 100 mg initially, followed by 50 mg every 12 hours

b 30-minute infusion

c 60-minute infusion

12.4 Microbiology

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.

14.1 Complicated Skin and Skin Structure Infections

Tigecycline for injection 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 1 and 2). These studies compared tigecycline for injection (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 4. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 5.

a100 mg initially, followed by 50 mg every 12 hours

bVancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)

aTwo cSSSI pivotal studies and two Resistant Pathogen studies

bIncludes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

14.2 Complicated Intra-abdominal Infections

Tigecycline for injection was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared tigecycline for injection (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 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

a100 mg initially, followed by 50 mg every 12 hours

bImipenem/Cilastatin (500 mg every 6 hours)

aTwo cIAI pivotal studies and two Resistant Pathogen studies

bIncludes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

14.3 Community-Acquired Bacterial Pneumonia

Tigecycline for injection was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 1 and 2). These studies compared tigecycline for injection (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In Study 1, 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 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

a100 mg initially, followed by 50 mg every 12 hours

bLevofloxacin (500 mg intravenous every 12 or 24 hours)

c95% confidence interval for the treatment difference

dAfter at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1.

aTwo CABP studies

bIncludes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for tigecycline and levofloxacin respectively]

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

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

The results of this analysis are shown in Table 10. Age ≥50 was the most common risk factor in the higher-risk group.

a Patients at higher risk of death include patients with any one of the following: ≥50 year of age; PSI score ≥3; or

   bacteremia due to Streptococcus pneumoniae

b 95% confidence interval for the treatment difference

c After at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 1.

Supplied:

10 mL -10 vials/box. NDC 16729-364-68

Storage:

Prior to reconstitution, tigecycline for injection USP should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] The reconstituted solution of tigecycline for injection USP 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) [see Dosage and Administration (2.4)].