CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`21-821/S026/S031
`
`
`
`
`
`
`
`
`
`
`Tygacil
`Trade Name:
`
`
`tigecycline
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`
`
`9/26/2013
`
`
`
`PF PRISM C.V.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-821/S026/S031
`
`
`
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`21-821/S026/S031
`21-821/8026/8031
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

` PF PRISM C.V.
`
`
` c/o Pfizer Inc.
` Attention: Nadia Kirzecky
`
` Director, Worldwide Safety and Regulatory
`
`235 East 42nd Street
`
`
`
`New York, NY 10017-5755
`
`
`
`Dear Ms. Kirzecky:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) submitted under section
`
`
`
`
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
` NDA#/Drug Name
`
`
`
`
`
` Supplement
`
` Number
`
`
`
` Submission Date Date Received
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 21-821/S-026 and S-031
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
`
`
`
`
`
`
`
` S-026
`
`
`S-031
`
`
`
` September 30, 2009
`
`
`February 11, 2011
`
`
`
` September 30, 2009
`
`
`February 11, 2011
`
`
`
` NDA 21-821/Tygacil
`
` (tigecycline) for
`
`
` Injection
`
`
`
`
`
`We acknowledge receipt of your amendments to these supplemental applications dated
`
`
`
`
`November 29, 2011, February 7, 2012 [S-031 only], and February 13, July 3, and September 23,
`
`2013.
`
`
`
`
`
`Supplemental application S-026 is a “Prior Approval” supplement that provides for changes to
`
`the INDICATIONS AND USAGE section stating that Tygacil is not indicated for the treatment
`
`
`
`of diabetic foot infections.
`
`
`
`
`Supplemental application S-031 is a “Changes Being Effected” supplement that provides for
`changes to the ADVERSE REACTIONS section of the labeling to include the adverse reactions
`
`
`
`
`
`
`of pneumonia and severe skin reactions, including Stevens-Johnson syndrome.
`
`
`
`
`In addition to the changes requested in the above supplements, the attached labeling also
`
`
`
`
`
`
`
`includes the following changes as discussed with you via multiple electronic communications
`
`
`(e-mails) and finalized in your submission containing revised draft labeling on September 23,
`
`2013.
`
`
`
`Reference ID: 3379756
`
`

`

`
`
` NDA 21-821/S-026 and S-031
`
`
` P a g e | 2
`
`
`
`
` • Addition of a “BOXED WARNING” to include information from meta-analysis of
`
`
` clinical trials that showed an increased risk of mortality in Tygacil-treated patients and to
`
`
`
`
` reserve Tygacil for use in situations when alternative treatments are not suitable.
`
`
` • Addition of Limitations of Use (1.4) to include information that Tygacil is not indicated
`
`
`
`
`
`
` for the treatment of diabetic foot infections and hospital-acquired or ventilator-associated
`
`
` pneumonia.
`
`
`
` • Revisions of the DOSAGE AND ADMINISTRATION section (2), Pediatric Patients
`
`
`
`
`
` subsection (2.3) and USE IN SPECIFIC POPULATIONS section (8.0), Pediatric Use
`
`
`
`
` subsection (8.4) to include information about use in the pediatric population.
`
`
`
`
`
`
` • Revisions to the WARNINGS AND PRECAUTIONS section (5), All-Cause Mortality
`
`
`
` subsection (5.1) regarding the increased risk of mortality.
`
` • The following revisions to the ADVERSE REACTIONS section (6):
`
`
`
`
`
`o Clinical Trials Experience subsection (6.1) to include information about an
`
`
`
`
` increase in mortality in trials conducted for approved indications
`
`
`o Post-Marketing Experience subsection (6.2), to include adverse reactions of
`
`
`
` Stevens-Johnson syndrome and symptomatic hypoglycemia
`
`o Revised the incidence of adverse reactions in Table 1.
`
`
`
`
`
`
` • Addition of a Pharmacodynamics subsection (12.2), Cardiac Electrophysiology, to the
`
`
`
` CLINICAL PHARMACOLOGY section (12).
`
`
` • Minor editorial changes including updates to the REFERENCES (15) section.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`APPROVAL & LABELING
`
`
`We have completed our review of these supplemental applications, as amended. They are
`
`
`
`
`
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`
`upon labeling text.
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`
`
`
`
`
`automated drug registration and listing system (eLIST), as described at
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`
`of labeling must be identical to the enclosed labeling text for package insert, with the addition of
`
`
`any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as
`
`
`
`
`annual reportable changes not included in the enclosed labeling.
`
`
`Reference ID: 3379756
`
`

`

`
`
`
`
`
`
` NDA 21-821/S-026 and S-031
`
`
` P a g e | 3
`
`
`
`
` Information on submitting SPL files using eList may be found in the guidance for industry titled
` “SPL Standard for Content of Labeling Technical Qs and As at
`
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
` The SPL will be accessible from publicly available labeling repositories.
`
`
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`
`
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
`
`
`
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`changes approved in these supplemental applications, as well as annual reportable changes and
`
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`
`should provide appropriate annotations, including supplement number(s) and annual report
`
`date(s).
`
`
`PROMOTIONAL MATERIALS
`
`All promotional materials that include representations about your drug product must be promptly
`
`
`revised to be consistent with the labeling changes approved in this supplement, including any
`
`
`
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`
`
`
`should include prominent disclosure of the important new safety information that appears in the
`
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`If you have any questions, call Carmen DeBellas, PharmD, R.Ph., Regulatory Project Manager,
`
`
`
`
`at (301) 796-1203.
`
`
`
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`
`Sumathi Nambiar, MD, MPH
`
`Acting Director
`
`
`Division of Anti-Infective Products
`
`Office of Antimicrobial Products
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE:
`
`Content of Labeling
`
`
`
`Reference ID: 3379756
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUMATHI NAMBIAR
`09/26/2013
`
`Reference ID: 3379756
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`21-821/S026/S031
`21-821/8026/8031
`
`
`
`APPLICA TION NUMBER:
`
`
`LABELING
`LABELING
`
`
`
`
`
`
`
`

`

`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 [see Indications and Usage (1.4),
`Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
`
`To reduce the development of drug-resistant bacteria and maintain the
`effectiveness of TYGACIL and other antibacterial drugs, TYGACIL
`should be used only to treat or prevent infections that are proven or
`strongly suspected to be caused by bacteria.
`———————— RECENT MAJOR CHANGES ————————
`Boxed Warning
`09/2013
`Indications and Usage, Limitations of Use (1.4)
`09/2013
`Dosage and Administration, Preparation and Handling (2.4) 11/2012
`Warnings and Precautions, All-Cause Mortality (5.1)
`09/2013
`
`———————— INDICATIONS AND USAGE ————————
`TYGACIL is a tetracycline-class antibacterial drug 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).
`——————— 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 ——————
`
`FULL PRESCRIBING INFORMATION: CONTENTS *
`1 INDICATIONS AND USAGE
`1.1 Complicated Skin and Skin Structure Infections
`1.2 Complicated Intra-abdominal Infections
`1.3 Community-Acquired Bacterial Pneumonia
`1.4 Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosage and Administration
`2.2 Patients With Hepatic Impairment
`2.3 Pediatric Patients
`2.4 Preparation and Handling
`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 Anaphylaxis/Anaphylactoid Reactions
`5.4 Hepatic Effects
`5.5 Pancreatitis
`5.6 Use During Pregnancy
`5.7 Tooth Development
`5.8 Clostridium difficile Associated Diarrhea
`5.9 Patients With Intestinal Perforation
`5.10 Tetracycline-Class Effects
`5.11 Superinfection
`
`Reference ID: 3379756
`
`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 ——————
` 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).
` Anaphylaxis/anaphylactoid reactions have been reported with
`TYGACIL, and may be life-threatening. Exercise caution in
`patients with known hypersensitivity to tetracyclines. (5.3)
` Hepatic dysfunction and liver failure have been reported with
`TYGACIL. (5.4)
` Pancreatitis, including fatalities, has been reported with
`TYGACIL. If pancreatitis is suspected, then consider stopping
`TYGACIL. (5.5)
` TYGACIL may cause fetal harm when administered to a pregnant
`woman. (5.6)
` The use of TYGACIL during tooth development may cause
`permanent discoloration of the teeth. (5.7)
` Clostridium difficile associated diarrhea: evaluate if diarrhea
`occurs. (5.8)
`————————— ADVERSE REACTIONS —————————
`The most common adverse reactions (incidence >5%) are nausea, vomiting,
`diarrhea, abdominal pain, headache, and increased SGPT. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Wyeth
`Pharmaceuticals Inc. at 1-800-934-5556 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`————————— DRUG INTERACTIONS —————————
` Suitable anticoagulation test should be monitored if TYGACIL is
`administered to patients receiving warfarin. (7.1)
`——————— USE IN SPECIFIC POPULATIONS ——————
` Pediatrics: Use in patients under 18 years of age is not
`recommended. 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: 09/2013
`
`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 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
`
`1
`
`

`

`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: 3379756
`
`
`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
`
`TYGACIL is a tetracycline-class antibacterial drug indicated for the treatment of infections
`caused by susceptible isolates of the designated microorganisms in the conditions listed below
`for patients 18 years of age and older:
`
`1.1 Complicated Skin and Skin Structure Infections
`
`Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus
`
`faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and
`-resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S.
`anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae,
`Klebsiella pneumoniae, and Bacteroides fragilis.
`
`1.2 Complicated Intra-abdominal Infections
`
`Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae,
`
`Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis
`(vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and
`-resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S.
`constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis,
`Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
`
`1.3 Community-Acquired Bacterial Pneumonia
`
`Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-
`susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae
`(beta-lactamase negative isolates), and Legionella pneumophila.
`
`1.4 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: 3379756
`
`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)].
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of
`TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat or prevent
`infections that are proven or strongly suspected to be caused by susceptible bacteria. When
`culture and susceptibility information are available, they should be considered in selecting or
`modifying antibacterial therapy. In the absence of such data, local epidemiology and
`susceptibility patterns may contribute to the empiric selection of therapy.
`
`Appropriate specimens for bacteriological examination should be obtained in order to isolate
`and identify the causative organisms and to determine their susceptibility to tigecycline.
`TYGACIL may be initiated as empiric monotherapy before results of these tests are known.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosage and Administration
`
`The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by
`50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over
`approximately 30 to 60 minutes every 12 hours.
`
`The recommended duration of treatment with TYGACIL for complicated skin and skin
`structure infections or for complicated intra-abdominal infections is 5 to 14 days. The
`recommended duration of treatment with TYGACIL for community-acquired bacterial
`pneumonia is 7 to 14 days. The duration of therapy should be guided by the severity and site of
`the infection and the patient’s clinical and bacteriological progress.
`
`2.2 Patients With Hepatic Impairment
`
`No dosage adjustment is warranted in patients with mild to moderate hepatic impairment
`(Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C),
`the initial dose of TYGACIL should be 100 mg followed by a reduced maintenance dose of
`25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be
`treated with caution and monitored for treatment response [see Clinical Pharmacology (12.3)
`and Use in Specific Populations (8.6)].
`
`2.3 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. Tigecycline
`should not be used 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 tigecycline every 12 hours
`intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
`
`
`Reference ID: 3379756
`
`4
`
`
`

`

` 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 Handling
`
`Each vial of TYGACIL should be reconstituted with 5.3 mL of 0.9% Sodium Chloride
`Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer’s Injection, USP to achieve a
`concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL
`
`of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled
`until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a
`100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg
`dose, reconstitute one vial). The maximum concentration in the intravenous bag should be
`1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution
`should be discarded. Parenteral drug products should be inspected visually for particulate
`matter and discoloration (e.g., green or black) prior to administration. Once reconstituted,
`TYGACIL may be stored at room temperature (not to exceed 25ºC/77ºF) for up to 24 hours (up
`to 6 hours in the vial and the remaining time in the intravenous bag). If the storage conditions
`exceed 25ºC (77ºF) after reconstitution, tigecycline should be used immediately. Alternatively,
`TYGACIL mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP
`may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate
`transfer of the reconstituted solution into the intravenous bag.
`
`TYGACIL may be administered intravenously through a dedicated line or through a Y-site. If
`the same intravenous line is used for sequential infusion of several drugs, the line should be
`flushed before and after infusion of TYGACIL with 0.9% Sodium Chloride Injection, USP, 5%
`Dextrose Injection, USP or Lactated Ringer’s Injection, USP. Injection should be made with an
`infusion solution compatible with tigecycline and with any other drug(s) administered via this
`common line.
`
`Compatibilities
`
`Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose
`Injection, USP, and Lactated Ringer’s Injection, USP. When administered through a Y-site,
`TYGACIL is compatible with the following drugs or diluents when used with either 0.9%
`Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine,
`dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine HCl, metoclopramide,
`morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride,
`propofol, ranitidine HCl, theophylline, and tobramycin.
`
`Incompatibilities
`
`The following drugs should not be administered simultaneously through the same Y-site as
`TYGACIL: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and
`omeprazole.
`
`Reference ID: 3379756
`
`5
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`Each single-dose 5 mL glass vial and 10 mL glass vial contain 50 mg of tigecycline as an
`orange lyophilized powder for reconstitution.
`
`4 CONTRAINDICATIONS
`
`TYGACIL is contraindicated for use in patients who have known hypersensitivity to
`tigecycline.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 All-Cause Mortality
`
`An increase in all-cause mortality has been observed 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 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).
`
`Reference ID: 3379756
`
`6
`
`
`

`

`5.3 Anaphylaxis/Anaphylactoid Reactions
`
`Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents,
`including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to
`tetracycline-class antibiotics and should be administered with caution in patients with known
`hypersensitivity to tetracycline-class antibiotics.
`
`5.4 Hepatic Effects
`
`Increases in total bilirubin concentration, prothrombin time and transaminases have been seen
`in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic
`failure have been reported in patients being treated with tigecycline. Some of these patients
`were receiving multiple concomitant medications. Patients who develop abnormal liver
`function tests during tigecycline therapy should be monitored for evidence of worsening
`hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse
`events may occur after the drug has been discontinued.
`
`5.5 Pancreatitis
`
`Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment.
`The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who
`develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis.
`Cases have been reported in patients without known risk factors for pancreatitis. Patients usually
`
`improve after tigecycline discontinuation. Consideration should be given to the cessation of the
`treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse
`Reactions (6.2)].
`
`5.6 Use During Pregnancy
`
`TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient
`becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard
`to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found
`in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification)
`and fetal loss in rabbits have been observed with tigecycline [see Use in Specific Populations
`(8.1)].
`
`5.7 Tooth Development
`
`The use of TYGACIL during tooth development (last half of pregnancy, infancy, and
`childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-
`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
`
`Reference ID: 3379756
`
`7
`
`
`

`

`colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
`overgrowth of C. difficile.
`
`C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
`producing strains of C. difficile cause increased morbidity and mortality, as these infections can
`be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in
`all patients who present with diarrhea following antibiotic use. Careful medical history is
`necessary since CDAD has been reported to occur over two months after the administration of
`antibacterial agents.
`
`If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may
`
`need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation,
`antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically
`indicated.
`
`5.9 Patients With Intestinal Perforation
`
`Caution should be exercised when considering TYGACIL monotherapy in patients with
`complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal
`perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated
`with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic
`shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13)
`versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to
`differences in baseline APACHE II scores between treatment groups and small overall numbers,
`the relationship of this outcome to treatment cannot be established.
`
`5.10 Tetracycline-Class Effects
`
`TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse
`effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic
`action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with
`tetracyclines, pancreatitis has been reported with the use of TYGACIL [see Warnings and
`Precautions (5.5)].
`
`5.11 Superinfection
`
`As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible
`organisms, including fungi. Patients should be carefully monitored during therapy. If
`superinfection occurs, appropriate measures should be taken.
`
`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.
`
`Reference ID: 3379756
`
`8
`
`
`

`

`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.
`
`In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to
`adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the
`incidence of treatment-emergent adverse reactions through test of cure reported in ≥2% of
`patients in these trials.
`
`Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of
`Patients Treated in Clinical Studies
`TYGACIL
`(N=2514)
`
`Comparatorsa
`(N=2307)
`
`6
`2
`3
`6
`7
`
`3
`
`12
`2
`26
`18
`
`5
`
`3
`
`3
`2
`3
`3
`2
`5
`4
`5
`
`4
`2
`2
`7
`5
`
`4
`
`11
`2
`13
`9
`
`6
`
`3
`
`2
`1
`1
`2
`1
`3
`5
`5
`
`Body System
`Adverse Reactions
`Body as a Whole
`Abdominal pain
`Abscess
`Asthenia
`Headache
`Infection
`Cardiovascular System
`Phlebitis
`Digestive System
`Diarrhea
`Dyspepsia
`Nausea
`Vomiting
`Hemic and Lymphatic System
`Anemia
`Metabolic and Nutritional
`Alkaline Phosphatase
`Increased
`Amylase Increased
`Bilirubinemia
`BUN Increased
`Healing Abnormal
`Hyponatremia
`Hypoproteinemia
`SGOT Increasedb
`SGPT Increasedb
`Respiratory System
`
`
`
`Ref