`7/2010
`7/2010
`
`7/2010
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These 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: 2005
`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.
`———————— RECENT MAJOR CHANGES ————————
`
`Warnings and Precautions
` All-Cause Mortality (5.1)
`
`
` Mortality Imbalance and Lower Cure Rates in
`
` Ventilator-Associated Pneumonia (5.4)
`
` Pancreatitis (5.5)
`
`
`sp;
`———————— INDICATIONS AND USAGE ————————
`TYGACIL is a tetracycline class antibacterial 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)
`
`——————— 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 STRENGTHS ——————
`
`50 mg lyophilized powder for reconstitution in a single-dose 5 mL vial. (3)
`————————— CONTRAINDICATIONS ————————
`Known hypersensitivity to tigecycline. (4)
` ——————— WARNINGS AND PRECAUTIONS ——————
`
`
`• An increase in all-cause mortality has been observed across Phase
`
`
`3 and 4 clinical trials in TYGACIL-treated patients versus
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Complicated Skin and Skin Structure Inf ctions e
`
`1.2 Complicated Intra-abdominal Infections
`
`
`1.3 Comm nity-Acquired Bacterial Pneumoniau
`
`1.4 Usage
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosage and Administration
`
`2.2 Patients With Hepatic Impairment
`
`2.3 Preparation and Handling
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 All-Cause Mortality
`
`5.2 Anaphylaxis/Anaphylactoid Reactions
`
`5.3 Hepatic Effects
`5.4 Mortality Imbalance and Lower Cure Rates in Ventilator-Associated
`
`
`Pneumonia
`
`
`5.5 Pancreatitis
`
`5.6 Use During Pregnancy
`
`5.7 Tooth Development
`
`5.8 Clostridium difficile Associated Di rrheaa
`
`
`5.9 Patients With Intestinal Perforation
`
`5.10 Tetracycline-Class Effects
`
`5.11 Superinfection
`
`5.12 Development of Drug-Resistant Bacteria
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Post-Marketing Experience
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`1
`
`
`comparator. The cause of this increase has not been established.
`This increase in all-cause mortality should be considered when
`
`selecting among treatment options. (5.1)
`• Anaphylaxis/anaphylactoid reactions have been reported with
`
`TYGACIL, and may be life-threatening. Exercise caution in
`patients with known hypersensitivity to tetracyclines. (5.2)
`• Hepatic dysfunction and liver failure have been reported with
`
`
`TYGACIL. (5.3)
`• Lower cure rates and higher mortality were seen when patients
`
`
`with ventilator-associated pneumonia were treated 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)
`————————— ADVERSE REACTIONS —————————
`The 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. (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION
`Revised: 07/2010
`
`
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`7.1 Warfarin
`
`7.2 Oral Contraceptives
`
`8 USE IN SPEC FIC POPULATIONS I
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`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 indicated for the treatment of infections caused
`by susceptible isolates of the designated microorganisms in the conditions listed below for
`patients 18 years of age and older:
`
`1.1 Complicated Skin and Skin Structure Infections
`
`Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus
`faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and
`-resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S.
`anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae,
`Klebsiella pneumoniae, and Bacteroides fragilis.
`
`
`1.2 Complicated Intra-abdominal Infections
`
`Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae,
`
`Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis
`
`(vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and
`-resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S.
`constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis,
`Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
`
`
`1.3 Community-Acquired Bacterial Pneumonia
`
`Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-
`susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae
`
`(beta-lactamase negative isolates), and Legionella pneumophila.
`
`1.4 Usage
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of
`
`TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat or prevent
`infections that are proven or strongly suspected to be caused by susceptible bacteria. When
`culture and susceptibility information are available, they should be considered in selecting or
`modifying antibacterial therapy. In the absence of such data, local epidemiology and
`susceptibility patterns may contribute to the empiric selection of therapy.
`
`
`Appropriate specimens for bacteriological examination should be obtained in order to isolate
`and identify the causative organisms and to determine their susceptibility to tigecycline.
`TYGACIL may be initiated as empiric monotherapy before results of these tests are known.
`
`
`
`2
`
`
`

`

`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosage and Administration
`
`The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by
`
`50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over
`approximately 30 to 60 minutes every 12 hours.
`
`The recommended duration of treatment with TYGACIL for complicated skin and skin
`structure infections or for complicated intra-abdominal infections is 5 to 14 days. The
`recommended duration of treatment with TYGACIL for community-acquired bacterial
`pneumonia is 7 to 14 days. The duration of therapy should be guided by the severity and site of
`the infection and the patient’s clinical and bacteriological progress.
`
`2.2 Patients With Hepatic Impairment
`
`No dosage adjustment is warranted in patients with mild to moderate hepatic impairment
`(Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C),
`the initial dose of TYGACIL should be 100 mg followed by a reduced maintenance dose of
`25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be
`treated with caution and monitored for treatment response [see Clinical Pharmacology (12.3)
`and Use in Specific Populations (8.6)].
`
`2.3 Preparation and Handling
`
`Each vial of TYGACIL should be reconstituted with 5.3 mL of 0.9% Sodium Chloride
`Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer’s Injection, USP to achieve a
`concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL
`
`of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled
`until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a
`100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg
`dose, reconstitute one vial). The maximum concentration in the intravenous bag should be
`1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution
`should be discarded. Parenteral drug products should be inspected visually for particulate
`matter and discoloration (e.g., green or black) prior to administration. Once reconstituted,
`TYGACIL may be stored at room temperature for up to 24 hours (up to 6 hours in the vial and
`the remaining time in the intravenous bag). Alternatively, TYGACIL mixed with 0.9% Sodium
`
`Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C
`(36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into
`the intravenous bag.
`
`TYGACIL may be administered intravenously through a dedicated line or through a Y-site. If
`the same intravenous line is used for sequential infusion of several drugs, the line should be
`flushed before and after infusion of TYGACIL with 0.9% Sodium Chloride Injection, USP, 5%
`
`Dextrose Injection, USP or Lactated Ringer’s Injection, USP. Injection should be made with an
`infusion solution compatible with tigecycline and with any other drug(s) administered via this
`
`common line.
`
`
`
`3
`
`
`

`

`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 across 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, an adjusted risk
`difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and
`comparator-treated patients. The cause of this increase has not been established. This
`increase in all-cause mortality should be considered when selecting among treatment
`options [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
`
`5.2 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.
`
`
`
`4
`
`
`

`

`5.3 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.
`
`5.4 Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia
`
`A trial of patients with hospital acquired 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).
`
`5.5 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
`
`
`
`5
`
`
`

`

`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.
`
`5.8 Clostridium difficile Associated Diarrhea
`
`Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
`antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal
`colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
`overgrowth of C. difficile.
`
`C. difficile produces toxins A and B which contribute to the development of CDAD.
`Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these
`infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
`
`be considered in all patients who present with diarrhea following antibiotic use. Careful
`medical history is necessary since CDAD has been reported to occur over two months after the
`administration of antibacterial agents.
`
`If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may
`need to be discontinued. Appropriate fluid and electrolyte management, protein
`supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted
`as clinically indicated.
`
`5.9 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.
`
`
`
`6
`
`
`

`

`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
`
`TYGACIL
`(N=2514)
`
`6
`3
`3
`6
`8
`
`3
`
`12
`2
`26
`18
`
`4
`
`
`
`Comparatorsa
`
`(N=2307)
`
`4
`3
`2
`7
`5
`
`4
`
`11
`2
`13
`9
`
`5
`
`Body System
`
`Adverse Reactions
`Body as a Whole
`
` Abdominal pain
`Abscess
`Asthenia
`Headache
`Infection
`Cardiovascular System
`
` Phlebitis
`Digestive System
` Diarrhea
`Dyspepsia
`Nausea
` Vomiting
`Hemic and Lymphatic System
` Anemia
`
`
`
`
`
`
`
`7
`
`
`

`

`Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of
`
`Patients Treated in Clinical Studies
`
`
`TYGACIL
`(N=2514)
`
`4
`
`Comparatorsa
`
`(N=2307)
`
`3
`
`
`
`Body System
`
`Adverse Reactions
`Metabolic and Nutritional
` Alkaline Phosphatase
`Increased
`3
` Amylase Increased
`2
` Bilirubinemia
`3
`BUN Increased
`4
` Healing Abnormal
` Hypoproteinemia
`5
`SGOT Increasedb
`
`4
`SGPT Increasedb
`
`5
`Nervous System
`
`
`3
` Dizziness
`Skin and Appendages
`
`3
` Rash
`a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.
`
`b LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post
`
`therapy period than those in comparator-treated patients, which occurred more often on therapy.
`
` 
`In 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.
`
`
`2
`1
`1
`3
`3
`5
`5
`
`3
`
`4
`
`
`
`
`
`8
`
`
`

`

` Table 2. Patients with Outcome of Death by Infection Type
`
`Comparator
`TYGACIL
`Risk Difference*
`
`
`%
`%
`n/N
`n/N
`% (95% CI)
`Infection Type
`12/834
`cSSSI
`0.7
`0.7 (-0.3, 1.7)
`6/813
`1.4
`42/1382
`cIAI
`2.2
`0.8 (-0.4, 2.0)
`31/1393
`3.0
`12/424
`CAP
`2.6
`0.2 (-2.0, 2.4)
`11/422
`2.8
`66/467
`HAP
`12.2
`1.9 (-2.4, 6.3)
`57/467
`14.1
`Non-VAPa
`41/336
`
`12.2
`0.0 (-4.9, 4.9)
`42/345
`12.2
`
` VAPa
`12.3
`6.8 (-2.1, 15.7)
`15/122
`19.1
`25/131
`4.7
`3.9 (-4.0, 11.9)
`2/43
`8.6
`11/128
`RP
`0.6
`0.7 (-0.5, 1.8)
`3/508
`1.3
`7/553
`DFI
`3.0
`0.6 (0.1, 1.2)**
`110/3646
`4.0
`150/3788
`Overall Adjusted
`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 TYGACIL 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).
`
` 
`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),
`
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`nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was
`
`16% for TYGACIL and 6% for levofloxacin.
`
`
`Discontinuation from tigecycline was most frequently associated with nausea (1%) and
`
`vomiting (1%). For comparators, discontinuation was most frequently associated with nausea
`
`(<1%).
`
`
`The following adverse reactions were reported infrequently (<2%) in patients receiving
`
`
`TYGACIL in clinical studies:
`
`
`Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic
`
`shock, allergic reaction, chills, injection site edema, injection site phlebitis
`
`
`Cardiovascular System: thrombophlebitis
`
`Digestive System: anorexia, jaundice, abnormal stools
`
`Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia,
`hyponatremia
`
`Special Senses: taste perversion
`
`Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time
`(PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia
`
`Skin and Appendages: pruritus
`
`Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
`
`6.2 Post-Marketing Experience
`
`The following adverse reactions have been identified during postapproval use of TYGACIL.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish causal relationship to drug
`exposure.
`
`• anaphylaxis/anaphylactoid reactions
`
`• acute pancreatitis
`
`• hepatic cholestasis, and jaundice
`
`
`7 DRUG INTERACTIONS
`
`7.1 Warfarin
`
`Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is
`administered with warfarin [see Clinical Pharmacology (12.3)].
`
`
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`10
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`

`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 slight reductions in fetal weights and an
`increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of
`5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively
`(28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss
`was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.
`
`There are no adequate and well-controlled studies of tigecycline in pregnant women.
`TYGACIL should be used during pregnancy only if the potential benefit justifies the potential
`risk to the fetus.
`
`8.3 Nursing Mothers
`
`Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted
`readily via the milk of lactating rats. Consistent with the limited oral bioavailability of
`tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of
`exposure via maternal milk.
`
`It is not known whether this drug is excreted in human milk. Because many drugs are excreted
`in human milk, caution should be exercised when TYGACIL is administered to a nursing
`woman [see Warnings and Precautions (5.7)].
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients below the age of 18 years have not been
`established. Because of effects on tooth development, use in patients under 8 years of age is not
`recommended [see Warnings and Precautions (5.7)].
`
`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.
`
`
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`

`

`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.
`
`
`
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`

`

`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Tigecycline is an antibacterial drug [see Clinical Pharmacology (12.4)].
`
`
`12.3 Pharmacokinetics
`
`The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous
`doses based on pooled data from clinical pharmacology studies are summarized in Table 3.
`Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.
`
`Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline
`
`Multiple Dosea
`
`
`Single Dose
`
`50 mg every 12h
`100 mg
`
`(N=224)
`(N=103)
`Cmax (mcg/mL)b
`
`1.45 (22%)
`0.87 (27%)
`Cmax (mcg/mL)c
`0.90 (30%)
`0.63 (15%)
`
`5.19 (36%)
`- -
`AUC (mcg·h/mL)
`- -
`4.70 (36%)
`AUC0-24h (mcg·h/mL)
`- -
`0.13 (59%)
`Cmin (mcg/mL)
`27.1 (53%)
`42.4 (83%)
`t½ (h)
`21.8 (40%)
`23.8 (33%)
`CL (L/h)
`38.0 (82%)
`51.0 (58%)
`CLr (mL/min)
`568 (43%)
`639 (48%)
`Vss (L)
`a 100 mg initially, followed by 50 mg every 12 hours
`b 30-minute infusion
`c 60-minute infusion
`&nbsp;
`
`Distribution
`
`The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at
`concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of
`distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is
`extensively distributed beyond the plasma volume and into the tissues.
`
`Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to
`33 healthy volunteers, the tigecycline AUC0-12h (134 mcg·h/mL) in alveolar cells was
`approximately 78-fo