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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`NDA 021821/S-021
`NDA 021821/S-025
`NDA 021821/S-027
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`Pfizer Pharmaceuticals, Inc.
`Attention: Nia Tatsis, Ph.D.
`Senior Manager
`P.O. Box 8299
`Philadelphia, PA 19101-8299
`
`
`Dear Dr. Tatsis:
`
`Please refer to your supplemental new drug applications dated February 23 (S-021), August 5,
`2009 (S-025), and January 21, 2010 (S-027), received February 24, August 5, 2009 and January
`21, 2010, respectively, submitted under 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Tygacil (tigecycline).
`
`We acknowledge receipt of your amendments to supplemental applications S-021 and S-025
`dated March 27 and September 11, 2009, May 10, July 13 and July 15, 2010.
`
`Supplemental application S-021 is a “Changes Being Effected” supplemental new drug
`application that provides for changes to the WARNINGS AND PRECAUTIONS and
`ADVERSE REACTIONS sections of the labeling concerning a mortality imbalance in Tygacil
`(tigecycline) Phase 3 trials.
`
`Supplemental application S-025 is a Prior Approval supplemental new drug application that
`provides for changes to the Preparation and Handling section and the Compatibilities and
`Incompatibilities subsections of the labeling as follows:
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`• “The reconstitution solution should be yellow to orange in color; if not, the solution
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`should be discarded” added to Preparation and Handling section
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`• “metoclopromide” added to the Compatibilities subsection
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`• “amphotericin B lipid complex, esomeprazole and omeprazole” added to the
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`Incompatibilities subsection
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`Supplemental application S-027 is a Prior Approval supplemental new drug application that
`provides for changes to the WARNINGS AND PRECAUTIONS section describing pancreatitis
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` with the use of Tygacil (tigecycline).
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`

`

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` NDA 021821/S-021
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` NDA 021821/S-025
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` NDA 021821/S-027
`Page 2
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`We have completed our review of these applications, as amended. They are approved, effective
`on the date of this letter, for use as recommended in the agreed-upon labeling text and with the
`minor editorial revisions listed below.
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`
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`1. The dates of major recent changes and the revision date in the Highlight section of the
`label were changed to 07/2010.
`2. Bolding was removed from text in the first bullet of the WARNINGS AND
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`PRECAUTIONS in the Highlight section.
`3. In the last sentence of section 5.4 the “)” was moved to include the phrase “in
`comparator-treated patients”.
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`CONTENT OF LABELING
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`Within 14 days from the date of this letter, please amend all pending supplemental applications
`for this NDA, including pending "Changes Being Effected" (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
`structured product labeling (SPL) format that includes the changes approved in this supplemental
`application.
`
`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
`
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
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`purposes, if FDA makes certain findings required by the statute.
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`Since Tygacil (tigecycline) was approved on June 15, 2005, we have become aware of increased
`mortality among Tygacil (tigecycline)-treated patients from the accumulating data from phase 3
`and phase 4 clinical trials. In addition, in some trials, QT prolongation occurred more frequently
`in the Tygacil (tigecycline) arm compared to the comparator groups. Therefore, we consider the
`observed increased mortality in Tygacil (tigecycline)-treated patients to be “new safety
`information” as defined in section 505-1(b)(3) of the FDCA.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of the serious
`risk of increased mortality in patients treated with Tygacil (tigecycline).
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious
`risk.
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`

`

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`October, 2010
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`May, 2011
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`October, 2011
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`Submit the protocol to your IND 56,518, with a cross-reference letter to NDA 21-821. Submit all
`final reports to your NDA 21-821. Prominently identify the submission with the following
`wording in bold capital letters at the top of the first page of the submission, as appropriate:
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` NDA 021821/S-021
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` NDA 021821/S-025
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` NDA 021821/S-027
`Page 3
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of the serious risk of increased mortality in patients
`treated with Tygacil (tigecycline).
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`Therefore, based on appropriate scientific data, FDA has determined that you are required, to
`conduct the following:
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`1665-1: A thorough QTc clinical trial in patients treated with Tygacil (tigecycline).
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`The timetable you submitted on June 29, 2010 states that you will conduct this trial
`according to the following schedule:
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`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
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`• REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
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`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
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`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
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`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We remind
`you that to comply with 505(o), your annual report must also include a report on the status of any
`study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an
`annual report for studies or clinical trials required under 505(o) on the date required will be
`considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
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`
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`
`

`

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` NDA 021821/S-021
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` NDA 021821/S-025
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` NDA 021821/S-027
`Page 4
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`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`the letter to both this NDA and to the following address:
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`
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`MedWatch
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`Food and Drug Administration
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`5600 Fishers Lane, Room 12B05
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`Rockville, MD 20857
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Carmen DeBellas, PharmD, Project Manager at (301) 796-1203.
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`Sincerely,
`
`{See appended electronic signature page}
`
`
`Sumathi Nambiar M.D. M.P.H.
`Deputy Director for Safety
`Division of Anti-Infective and Ophthalmology Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`Enclosure:
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`

`

`Application
`Type/Number
`--------------------
`NDA-21821
`
`Submission
`Type/Number
`--------------------
`SUPPL-27
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`NDA-21821
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`SUPPL-25
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`NDA-21821
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`SUPPL-21
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`Submitter Name
`
`Product Name
`
`--------------------
`WYETH
`PHARMACEUTICA
`LS INC
`WYETH
`PHARMACEUTICA
`LS INC
`WYETH
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`TYGACIL
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`TYGACIL
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`TYGACIL
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`---------------------------------------------------------------------------------------------------------
`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
`07/16/2010
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