`
`
`
`
`
`
`
`
`
`
`
` ——————— WARNINGS AND PRECAUTIONS ——————
`
` • All-Cause Mortality: A meta-analysis of Phase 3 and 4 clinical
`
`
`
`trials demonstrated an increase in all-cause mortality in
`
`
`
`
`
`TYGACIL-treated patients compared to controls with a risk
`
`difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase
`
`
`has not been established. An increase was also seen in a meta­
`
`
`
`
`
`
`analysis limited to the approved indications [0.6% (95% CI 0.0,
`
`
`
`1.2)]. The greatest difference in mortality was seen in TYGACIL-
`
`treated patients with ventilator-associated pneumonia (5.1, 5.2).
`
`
`
`
` • Anaphylactic Reactions: have been reported with TYGACIL, and
`
`may be life-threatening. Avoid use in patients with known
`
`
`
`hypersensitivity to tetracyclines. (5.3)
`
`
` • Hepatic Adverse Effects: have been reported with TYGACIL.
`Patients who develop abnormal liver function tests during
`
`
`
`TYGACIL therapy should be monitored for evidence of
`
`
`worsening hepatic function and evaluated for risk/benefit of
`
`continuing tigecycline therapy. (5.4)
`
`
`
`
` • Pancreatitis, including fatalities, has been reported with
`
`
`TYGACIL. If pancreatitis is suspected, then consider stopping
`
`
`
`
`TYGACIL. (5.5)
`
`
` • Fetal Harm: TYGACIL may cause fetal harm when administered
`to a pregnant woman. (5.6)
`
`
`
` • Tooth Discoloration: The use of TYGACIL during tooth
`
`
`development may cause permanent discoloration of the teeth.
`
`(5.7)
`
`
`
` • Clostridium difficile associated Diarrhea (CDAD): 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 Pfizer Inc.
`
`
`at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`————————— DRUG INTERACTIONS —————————
`
`
`
`
` • Suitable anticoagulation test should be monitored if TYGACIL is
`
`
`
`
` administered to patients receiving warfarin. (7.1)
`
`
` ——————— USE IN SPECIFIC POPULATIONS ——————
`
`
`
` • Pediatrics: Use in patients under 18 years of age is not
`
`
`
` recommended. Pediatric trials were not conducted because of the
`
`
` higher risk of mortality seen in adult trials (8.4)
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION
`
`
`
` Revised: 12/2015
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`WARNING: ALL-CAUSE MORTALITY
`See full prescribing information for complete boxed warning.
`
`
`
`
`All-cause mortality was higher in patients treated with TYGACIL than
`
`
`
`
`
`comparators in a meta-analysis of clinical trials. The cause of this
`
`
`
`
`mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been
`
`
`
`
`established. TYGACIL should be reserved for use in situations when
`
`
`alternative treatments are not suitable (1.4, 5.1, 5.2, 6.1).
`
`
`
`———————— 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)
`
`
`
`
`
`
`
`
` Limitations of Use: TYGACIL is not indicated for treatment of diabetic
` foot infection or hospital-acquired pneumonia, including ventilator-
`
`
` associated pneumonia (1.4).
`
`
`
` 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 infections that are proven or strongly suspected to be
`
`
` caused by bacteria.
`
` ——————— 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 ——————
`
`
` For Injection: 50 mg, lyophilized powder for reconstitution in a single-dose
`
`
`
` 5 mL vial or 10 mL vial. (3)
`
`
`
`
`
` ————————— CONTRAINDICATIONS ————————
`
`
`• Known hypersensitivity to tigecycline. (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 1
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS *
`
` WARNING: ALL-CAUSE MORTALITY
`
`
`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 Limitations of Use
`
`
`
`
`1.5 Usage
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Adult Dosage
`
`
`
`
`2.2 Dosage in Patients With Hepatic Impairment
`
`
`
`2.3 Dosage in Pediatric Patients
`
`
`
`
`2.4 Preparation and Administration
`
`
`
`
`2.5 Drug Compatibilities
`
`
`
`
`2.6 Drug Incompatibilities
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 All-Cause Mortality
`
`5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired
`
`
`
`
`
`
`
`Pneumonia
`
`
`5.3 Anaphylactic Reactions
`
`
`
`
`5.4 Hepatic Adverse Effects
`
`
`
`
`5.5 Pancreatitis
`
`
`5.6 Fetal Harm
`
`
`
`5.7 Tooth Discoloration
`
`
`
`
`5.8 Clostridium difficile Associated Diarrhea
`
`
`
`
`5.9 Sepsis/Septic Shock in Patients With Intestinal Perforation
`
`
`
`
`5.10 Tetracycline-Class Adverse Effects
`
`
`
`5.11 Development of Drug-Resistant Bacteria
`
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Post-Marketing Experience
`
`
`7 DRUG INTERACTIONS
`
`7.1 Warfarin
`
`
`7.2 Oral Contraceptives
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`12.4 Microbiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`14.1 Complicated Skin and Skin Structure Infections
`
`
`
`
`14.2 Complicated Intra-abdominal Infections
`
`
`14.3 Community-Acquired Bacterial Pneumonia
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: ALL-CAUSE MORTALITY
`
`
`An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4
`
`
`clinical trials in TYGACIL-treated patients versus comparator. The cause of this
`
`
`mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. TYGACIL
`should be reserved for use in situations when alternative treatments are not suitable [see
`
`
`
`Indications and Usage (1.4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions
`
` (6.1)].
`
`
`
`1 INDICATIONS AND USAGE
`
`
`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
`
`
`TYGACIL is not indicated for the treatment of diabetic foot infections. A clinical trial failed to
`
`demonstrate non-inferiority of TYGACIL for treatment of diabetic foot infections.
`
`
`
`Reference ID: 3874843
`
`
`
` 3
`
`
`

`

` TYGACIL is not indicated for the treatment of hospital-acquired or ventilator-associated
`
`
`
`
` pneumonia. In a comparative clinical trial, greater mortality and decreased efficacy were
` reported in TYGACIL-treated patients [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
` 1.5 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 infections that
`
`are proven or strongly suspected to be caused by susceptible bacteria. When culture and
`susceptibility information are available, they should be considered in selecting or modifying
`
`antibacterial therapy. In the absence of such data, local epidemiology and susceptibility
`
`patterns may contribute to the empiric selection of therapy.
`
`
`Appropriate specimens for bacteriological examination should be obtained in order to isolate
`
`and identify the causative organisms and to determine their susceptibility to tigecycline.
`
`TYGACIL may be initiated as empiric monotherapy before results of these tests are known.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Adult Dosage
`
`
`
`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 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 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 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 in adult patients. Avoid use of
`
`
`
`tigecycline in pediatric patients unless no alternative antibacterial drugs are available. Under
`
`
`
`
`
`these circumstances, the following doses are suggested:
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 4
`
`
`

`

`
`
`
` • Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours
`
` intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
`
`
`
` • Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours.
`
`
`
`
`
`
`
` The proposed pediatric doses of tigecycline were chosen based on exposures observed in
`
`
` pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific
`
` Populations (8.4) and Clinical Pharmacology (12.3)].
`
`
`
`
` 2.4 Preparation and Administration
`
`
`
`
`
`
`
`
` 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. 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,
`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.
`
`
`2.5 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,
`
`
`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.
`
`
`
`Reference ID: 3874843
`
`
`
` 5
`
`
`

`

`
`
` 2.6 Drug 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
`
` For Injection: 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. Reactions have included anaphylactic reactions [see Warnings and Precautions
`
`
`
`(5.3) and Adverse Reactions (6.2)].
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 All-Cause Mortality
`
`
`An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4
`
`
`clinical trials in TYGACIL-treated patients versus comparator-treated patients. In all 13 Phase
`
`
`3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients
`
`receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled
`
`analysis of these trials, based on a random effects model by trial weight, the adjusted risk
`
`
`
`difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and
`
`comparator-treated patients. An analysis of mortality in all trials conducted for approved
`
`indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted
`
`
`
`mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator,
`
`
`
`
`
`
`
`respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95%
`
`
`
`CI 0.0, 1.2).
`
`
`The cause of this mortality difference has not been established. Generally, deaths were the
`
`
`result of worsening infection, complications of infection or underlying co-morbidities.
`
`
`TYGACIL should be reserved for use in situations when alternative treatments are not suitable
`
`[see 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 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).
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 6
`
`
`

`

`
`
` In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who
` received TYGACIL (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients)
`
`
`
`
` [see Adverse Reactions (6.1)]. Particularly high mortality was seen among TYGACIL-treated
`
` patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus
`
`
`
` 1/13 [7.7%] in comparator-treated patients).
`
`
`
`
`
` 5.3 Anaphylactic Reactions
`
`
`
`
`
` Anaphylactic 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 avoided in patients with known hypersensitivity to tetracycline-class
`
`
`
` antibiotics.
`
`
`
` 5.4 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.
`
`
`
`
`
` 5.5 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 Fetal Harm
`
` 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: 3874843
`
`
`
` 7
`
`
`

`

`
`
` 5.7 Tooth Discoloration
`
`
`
` 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 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 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 Adverse Effects
`
`
`TYGACIL 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).
`
`
`
`
`Reference ID: 3874843
`
`
`
` 8
`
`
`

`

`
`
` 5.11 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
`
`
`The following serious adverse reactions are described elsewhere in the labeling:
`
`
`• All-Cause Mortality [see Boxed Warning and Warnings and Precautions (5.1)]
`
`
`
`
`• Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see
`
`
`
`
`Warnings and Precautions (5.2)]
`
`
`
`• Anaphylaxis [Warning and Precautions (5.3)]
`
`
`
`
`• Hepatic Adverse Effects [Warnings and Precautions (5.4)]
`
`
`
`• Pancreatitis [Warnings and Precautions (5.5)]
`
`
`
`
`
`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 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
`
`
`
`
`
`
`
` Comparatorsa
`
` (N=2307)
`
`
`
`
`
`
`
`
`
`4
`
` 2
`2
`7
`5
`
`4
`
`11
`
`2
`13
`
`9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 9
`
`
`

`

`
`
`
`
`
`
`
` Body System
` Adverse Reactions
`
`
`
`Anemia
` 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)
`
`5
`
`3
`
`
`
`
`
`
` Comparatorsa
`
` (N=2307)
`
`6
`
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`1
`1
`2
`
` 1
`3
`5
`5
`
`
` 2
`
`3
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 10
`
`
`

`

` 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
` 42/1382
`
`
` 0.8 (-0.4, 2.0)
`
` 31/1393
`
` 2.2
`
` 3.0
`
` CAP
` 12/424
`
`
` 0.2 (-2.0, 2.4)
`
` 11/422
`
` 2.6
`
` 2.8
`
` HAP
`
` 66/467
`
` 1.9 (-2.4, 6.3)
`
` 57/467
`
` 12.2
`
` 14.1
` Non-VAPa
`
`
` 41/336
`
` 0.0 (-4.9, 4.9)
`
` 42/345
`
` 12.2
`
` 12.2
`
` VAPa
`
` 25/131
`
` 6.8 (-2.1, 15.7)
`
` 15/122
`
` 12.3
`
` 19.1
`
` RP
`
` 11/128
`
` 3.9 (-4.0, 11.9)
`
` 2/43
`
` 4.7
`
` 8.6
` DFI
`
` 7/553
`
`
` 3/508
`
` 0.7 (-0.5, 1.8)
`
` 0.6
`
` 1.3
` Overall Adjusted
` 150/3788
` 0.6 (0.1, 1.2)**
` 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).
`
`
`
`
`
` 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 TYGACIL (7%) versus comparators (6%). Serious adverse
`
`
` reactions 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 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).
`
`
`
`
`
`
`Reference ID: 3874843
`
`
`
` 11
`
`
`

`

`
` In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence
` was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for
`
`
`
` TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra­
`
` abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for
`
`
` imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for
`
`
`
` imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP),
`
` nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16%
`
`
`
` for TYGACIL and 6% for levofloxacin.
`
`
`
`
` Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting
`
`
` (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).
`
`
` The following adverse reactions were reported (<2%) in patients receiving TYGACIL in clinical
`
`studies:
`
`
`
`
`
` Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic
`
`
` shock, allergic reaction, chills, injection site edema, injection site phlebitis
`
`
`
` Cardiovascular System: thrombophlebitis
`
`
`
` Digestive System: anorexia, jaundice, abnormal stools
`
`
`
`
`
` Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia
`
`Special Senses: taste perversion
`
`
`
`
`
` Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time
`
` (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia
`
`
`
` Skin and Appendages: pruritus
`
`
`
` Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
`
`6.2 Post-Marketing Experience
`
`
`
` The following adverse reactions have been identified during post-approval use of TYGACIL.
`
`
`
` Because these reactions are re