`
`
`
` 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 ————————
` Preparation and Handling (2.3) 11/2012
`
`
`
`
`
`
`
`
`
`———————— 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
`
`
`
`
` comparator. The cause of this increase has not been established.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`
`1 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 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 Diarrhea
`
`
`
`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
`
`
`
`
`Reference ID: 3313203
`
`
`
` 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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: 11/2012
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 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.
`
`
`
`
`
`Reference ID: 3313203
`
`
`
` 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 (not to exceed 25ºC/77ºF) 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 25ºC (77ºF) 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.
`
`
`
`Reference ID: 3313203
`
`
`
` 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.
`
`
`
`Reference ID: 3313203
`
`
`
` 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)].
`
`
`Reference ID: 3313203
`
`
`
` 5
`
`
`

`

`
`
` 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.
`
`
`5.8 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)].
`
`
`
`Reference ID: 3313203
`
`
`
` 6
`
`
`

`

`
`
` 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
`
`
` TYGACIL
`
` (N=2514)
`
`6
`2
`3
`6
`7
`
`3
`
`12
`
`2
`
` 26
`
`18
`
`5
`
`
`
`
`
`
` Comparatorsa
`
`(N=2307)
`
`
`
`
`
`
`
`4
`
` 2
`2
`7
`5
`
`4
`
`11
`
`2
`13
`
`9
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`Reference ID: 3313203
`
`
`
` 7
`
`
`

`

`
`
`
`
` Body System
`
`
`
` Adverse Reactions
` Metabolic and Nutritional
`
`
` Alkaline Phosphatase
`
`
` Increased
`3
`
`
`
` Amylase Increased
`2
`
`
`
` Bilirubinemia
`
`3
`
`
` BUN Increased
`
` 3
`Healing Abnormal
`
`
` 2
`
`
` Hyponatremia
`5
`
` Hypoproteinemia
`
`
` SGOT Increasedb
`4
`
`
` SGPT Increasedb
`5
`
`
` Respiratory System
`
`
` 2
`
`
` Pneumonia
`
` 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.
`
`
`
` Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of
`
` Patients Treated in Clinical Studies
`
`
`
` TYGACIL
`
` (N=2514)
`
`3
`
`
`
`
`
`
` Comparatorsa
`
`(N=2307)
`
`3
`
`
`
`
`
`
`
`
`
`2
`1
`1
`2
`
` 1
`3
`5
`5
`
`
` 2
`
`3
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3313203
`
`
`
` 8
`
`
`

`

` Table 2. Patients with Outcome of Death by Infection Type
`
`
`
`
` Comparator
` TYGACIL
`
` Risk Difference*
`
` Infection Type
`
`
`
` n/N
` n/N
` % (95% CI)
`
` %
`
` %
` cSSSI
`
` 6/813
` 12/834
`
` 0.7 (-0.3, 1.7)
`
`
`
` 0.7
`
` 1.4
`
` cIAI
`
` 0.8 (-0.4, 2.0)
`
` 42/1382
`
` 31/1393
`
` 2.2
`
` 3.0
`
` CAP
`
` 0.2 (-2.0, 2.4)
`
` 12/424
`
` 11/422
`
` 2.6
`
` 2.8
`
` HAP
`
` 1.9 (-2.4, 6.3)
`
` 66/467
`
` 57/467
`
` 12.2
`
` 14.1
`
` Non-VAPa
`
`
` 0.0 (-4.9, 4.9)
`
` 41/336
`
` 42/345
`
` 12.2
`
` 12.2
`
` VAPa
`
`
` 6.8 (-2.1, 15.7)
`
` 25/131
`
` 15/122
`
` 12.3
`
` 19.1
` RP
`
`
` 3.9 (-4.0, 11.9)
`
` 11/128
`
` 2/43
`
` 4.7
`
` 8.6
` DFI
`
`
` 7/553
`
` 3/508
`
` 0.7 (-0.5, 1.8)
`
` 0.6
`
` 1.3
` Overall Adjusted
` 0.6 (0.1, 1.2)**
` 150/3788
` 110/3646
`
` 3.0
`
`
` 4.0
`
`
`
`
` 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),
`
`
`
`Reference ID: 3313203
`
`
`
` 9
`
`
`

`

`
`
` 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 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
`
` • severe skin reactions, including Stevens-Johnson Syndrome
`
`
`
`
`
`
` 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)].
`
`
`
`Reference ID: 3313203
`
`
`
` 10
`
`
`

`

`
`
` 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.
`
`
`Reference ID: 3313203
`
`
`
` 11
`
`
`

`

` 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