TYGACIL- tigecycline injection, powder, lyophilized, for solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TIGECYCLINE (UNII: 70JE2N95KR) (TIGECYCLINE - UNII:70JE2N95KR)
Available from:
Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.
INN (International Name):
TIGECYCLINE
Composition:
TIGECYCLINE 50 mg in 5 mL
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. 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,
Product summary:
TYGACIL (tigecycline) for injection is supplied in a single-dose 5 mL glass vial or 10 mL glass vial, each containing 50 mg tigecycline lyophilized powder for reconstitution. Supplied: 5 mL - 10 vials/box. NDC 0008-4990-02 10 mL - 10 vials/box. NDC 0008-4990-20 Prior to reconstitution, TYGACIL should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] The reconstituted solution of TYGACIL may be stored at room temperature (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag) [see Dosage and Administration (2.5)] .
Authorization status:
New Drug Application
Authorization number:
0008-4990-01, 0008-4990-02, 0008-4990-19, 0008-4990-20

TYGACIL- tigecycline injection, powder, lyophilized, for solution

Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.

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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)

6/2020

Warnings and Precautions, Monitoring of Blood Coagulation Parameters (5.6)

6/2020

Warnings and Precautions, Tooth Discoloration and Enamel Hypoplasia (5.7)

1/2020

Warnings and Precautions, Inhibition of Bone Growth (5.8)

1/2020

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)

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: 7/2020

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 Monitoring of Blood Coagulation Parameters

2.5 Preparation and Administration

2.6 Drug Compatibilities

2.7 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 Monitoring of Blood Coagulation Parameters

5.7 Tooth Discoloration and Enamel Hypoplasia

5.8 Inhibition of Bone Growth

5.9 Clostridioides difficile-Associated Diarrhea

5.10 Sepsis/Septic Shock in Patients With Intestinal Perforation

5.11 Tetracycline-Class Adverse Effects

5.12 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 Calcineurin Inhibitors

7.3 Oral Contraceptives

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

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

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

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.

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:

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 25°C/77°F) for up to 24 hours (up to 6

hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25°C

(77°F) after reconstitution, tigecycline should be used immediately. Alternatively, 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.

2.6 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 Warning,

Indications and Usage (1.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

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)].

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.

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.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure

Reported in ≥ 2% of Patients Treated in Clinical Studies

Body System

Adverse Reactions

TYGACIL

(N=2514)

Comparators

(N=2307)

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 Increased

SGPT Increased

Respiratory System

Pneumonia

Nervous System

Dizziness

Skin and Appendages

Rash

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

*

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

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.

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 2. Patients with Outcome of Death by Infection Type

TYGACIL

Comparator

Risk Difference

Infection Type

n/N

%

n/N

%

% (95% CI)

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.

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).

cSSSI

12/834

6/813

0.7 (-0.3, 1.7)

cIAI

42/1382

31/1393

0.8 (-0.4, 2.0)

12/424

11/422

0.2 (-2.0, 2.4)

66/467

14.1

57/467

12.2

1.9 (-2.4, 6.3)

Non-VAP

41/336

12.2

42/345

12.2

0.0 (-4.9, 4.9)

25/131

19.1

15/122

12.3

6.8 (-2.1, 15.7)

11/128

2/43

3.9 (-4.0, 11.9)

7/553

3/508

0.7 (-0.5, 1.8)

Overall Adjusted

150/3788

110/3646

0.6 (0.1, 1.2)

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).

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

*

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.

These are subgroups of the HAP population.

Overall adjusted (random effects model by trial weight) risk difference estimate and

95% CI.

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