
`
`
`
`----------------------- 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)
`Monitoring Blood Coagulation Parameters: Hypofibrinogenemia has
`been reported with TYGACIL. Monitor blood coagulation parameters,
`including fibrinogen, at baseline and regularly during treatment with
`TYGACIL. (5.6)
`Tooth Discoloration and Enamel Hypoplasia: 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) and enamel hypoplasia. (5.7)
`Inhibition of Bone Growth: The use of TYGACIL during the second and
`third trimester of pregnancy, infancy, and childhood up to the age of
`8 years may cause reversible inhibition of bone growth. (5.8)
`Clostridioides difficile-Associated Diarrhea (CDAD): evaluate if
`diarrhea occurs. (5.9)
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ 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-------------------------------
` Warfarin: Suitable anticoagulation test should be monitored if
`TYGACIL is administered to patients receiving warfarin. (7.1)
`Calcineurin Inhibitors: Serum concentrations of calcineurin inhibitors
`(e.g., tacrolimus, cyclosporine) should be monitored during treatment
`with TYGACIL due to risk of toxicity. (7.2)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Lactation: Avoid breastfeeding for longer than 3 weeks while taking
`
`TYGACIL. A lactating woman may also pump and discard breast milk
`during treatment and for 9 days after the last dose of TYGACIL (8.2)
`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: 6/2020
`
`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).
`
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Dosage and Administration, Monitoring of Blood
`Coagulation Parameters (2.4)
`Warnings and Precautions, Monitoring of Blood
`Coagulation Parameters (5.6)
`Warnings and Precautions, Tooth Discoloration and
`Enamel Hypoplasia (5.7)
`Warnings and Precautions, Inhibition of Bone Growth (5.8)
`
`6/2020
`
`1/2020
`1/2020
`
`6/2020
`
`--------------------------- 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 (1.5).
`
`
`
`-----------------------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)
`Obtain baseline blood coagulation parameters, including fibrinogen, and
`continue to monitor regularly during treatment with TYGACIL. (2.4,
`5.6)
`
`
`
`--------------------- 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: 4629744
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS *
`
`2
`
`3
`4
`5
`
`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
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Adult Dosage
`2.2
`Dosage in Patients With Hepatic Impairment
`2.3
`Dosage in Pediatric Patients
`2.4
`Monitoring of Blood Coagulation Parameters
`2.5
`Preparation and Administration
`2.6
`Drug Compatibilities
`2.7
`Drug Incompatibilities
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`All-Cause Mortality
`5.2
`Mortality Imbalance and Lower Cure Rates in
`Hospital-Acquired Pneumonia
`Anaphylactic Reactions
`Hepatic Adverse Effects
`Pancreatitis
`Monitoring of Blood Coagulation Parameters
`Tooth Discoloration and Enamel Hypoplasia
`Inhibition of Bone Growth
`Clostridioides difficile-Associated Diarrhea
`Sepsis/Septic Shock in Patients With Intestinal Perforation
`Tetracycline-Class Adverse Effects
`Development of Drug-Resistant Bacteria
`
`6
`
`7
`
`8
`
`10
`11
`12
`
`13
`
`14
`
`16
`17
`
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Post-Marketing Experience
`DRUG INTERACTIONS
`7.1
`Warfarin
`7.2
`Calcineurin Inhibitors
`7.3
`Oral Contraceptives
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`12.4 Microbiology
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2
`Animal Toxicology and/or Pharmacology
`CLINICAL STUDIES
`14.1
`Complicated Skin and Skin Structure Infections
`14.2
`Complicated Intra-abdominal Infections
`14.3
`Community-Acquired Bacterial Pneumonia
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not
`listed.
`
`5.3
`5.4
`5.5
`5.6
`5.7
`5.8
`5.9
`5.10
`5.11
`5.12
`
`Reference ID: 4629744
`
`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: 4629744
`
`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 TYGACIL in adult patients. Avoid use of
`TYGACIL in pediatric patients unless no alternative antibacterial drugs are available. Under
`these circumstances, the following doses are suggested:
`
`Reference ID: 4629744
`
`4
`
`

`

` Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of TYGACIL every
`12 hours intravenously to a maximum dose of 50 mg of TYGACIL every 12 hours.
` Pediatric patients aged 12 to 17 years should receive 50 mg of TYGACIL every 12 hours.
`
`The proposed pediatric doses of TYGACIL were chosen based on exposures observed in
`pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific
`Populations (8.4) and Clinical Pharmacology (12.3)].
`
`There are no data to provide dosing recommendations in pediatric patients with hepatic
`impairment.
`
`2.4 Monitoring of Blood Coagulation Parameters
`
`Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor
`regularly during treatment with TYGACIL [see Warnings and Precautions (5.6)].
`
`2.5 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.
`
`Reference ID: 4629744
`
`5
`
`

`

`2.6 Drug Compatibilities
`
`Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose
`Injection, USP, and Lactated Ringer’s Injection, USP. When administered through a Y-site,
`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.
`
`2.7 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
`
`Reference ID: 4629744
`
`6
`
`

`

`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).
`
`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
`antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-
`class antibacterial drugs.
`
`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)].
`
`Reference ID: 4629744
`
`7
`
`

`

`5.6 Monitoring of Blood Coagulation Parameters
`
`Hypofibrinogenemia has been reported in patients treated with TYGACIL [see Adverse
`Reactions (6.2)]. Obtain baseline blood coagulation parameters, including fibrinogen, and
`continue to monitor regularly during treatment with TYGACIL.
`
`5.7 Tooth Discoloration and Enamel Hypoplasia
`
`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). This
`adverse reaction is more common during long-term use of tetracyclines, but it has been observed
`following repeated short-term courses. Enamel hypoplasia has also been reported. Advise the
`patient of the potential risk to the fetus if TYGACIL is used during the second or third trimester
`of pregnancy [see Use in Specific Populations (8.1, 8.4)].
`
`5.8 Inhibition of Bone Growth
`
`The use of TYGACIL during the second and third trimester of pregnancy, infancy and childhood
`up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a
`stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been
`observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This
`reaction was shown to be reversible when the tetracycline was discontinued. Advise the patient
`of the potential risk to the fetus if TYGACIL is used during the second or third trimester of
`pregnancy [see Use in Specific Populations (8.1, 8.4)].
`
`5.9 Clostridioides difficile-Associated Diarrhea
`
`Clostridioides 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 antibacterial drug 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 antibacterial drug use not directed against C.
`difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein
`supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be
`instituted as clinically indicated.
`
`Reference ID: 4629744
`
`8
`
`

`

`5.10 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.
`
`5.11 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).
`
`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
`
`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.
`
`Reference ID: 4629744
`
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`
`

`

`Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of
`Patients Treated in Clinical Studies
`TYGACIL
`(N=2514)
`
`Comparatorsa
`(N=2307)
`
`4
`2
`2
`7
`5
`
`4
`
`11
`2
`13
`9
`
`6
`
`3
`
`2
`1
`1
`2
`1
`3
`5
`5
`
`2
`
`3
`
`4
`
`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
`Metabolic and Nutritional
`Alkaline Phosphatase
` Increased
`Amylase Increased
`Bilirubinemia
`BUN Increased
`Healing Abnormal
`Hyponatremia
`Hypoproteinemia
`SGOT Increasedb
`SGPT Increasedb
`Respiratory System
`Pneumonia
`Nervous System
`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.
`
`6
`2
`3
`6
`7
`
`3
`
`12
`2
`26
`18
`
`5
`
`3
`
`3
`2
`3
`3
`2
`5
`4
`5
`
`2
`
`3
`
`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
`
`Reference ID: 4629744
`
`10
`
`

`

`difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and
`comparator-treated patients (see Table 2). The cause of the imbalance has not been established.
`Generally, deaths were the result of worsening infection, complications of infection or
`underlying co-morbidities.
`
`Table 2. Patients with Outcome of Death by Infection Type
`TYGACIL
`Comparator
`Risk Difference*
`%
`%
`n/N
`n/N
`% (95% CI)
`Infection Type
`0.7
`1.4
`12/834
`6/813
`0.7 (-0.3, 1.7)
`cSSSI
`2.2
`3.0
`42/1382
`31/1393
`0.8 (-0.4, 2.0)
`cIAI
`2.6
`2.8
`12/424
`11/422
`0.2 (-2.0, 2.4)
`CAP
`12.2
`14.1
`66/467
`57/467
`1.9 (-2.4, 6.3)
`HAP
`12.2
`12.2
`41/336
`42/345
`0.0 (-4.9, 4.9)
`Non-VAPa
`12.3
`19.1
`25/131
`15/122
`6.8 (-2.1, 15.7)
`VAPa
`4.7
`8.6
`11/128
`2/43
`3.9 (-4.0, 11.9)
`RP
`0.6
`1.3
`7/553
`3/508
`0.7 (-0.5, 1.8)
`DFI
`3.0
`4.0
`150/3788
`110/3646
`0.6 (0.1, 1.2)**
`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).
`
`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 (5.10)].
`
`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: 4629744
`
`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 TYGACIL 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: prolonged activated partial thromboplastin time (aPTT),
`prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR),
`thrombocytopenia
`
`Skin and Appendages: pruritus
`
`Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
`
`6.2 Post-Marketing Experience
`
`The following adverse reactions have been identified during post-approval use of 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