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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 21-083/S-042 and S-043
`NDA 21-110/S-053 and S-054
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`Wyeth Pharmaceuticals, Inc.
`Attention: David K. Ellis, PhD
` Assistant Vice President, Regulatory Affairs
`P. O. Box 8299
`Philadelphia, PA 19101-8299
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`Dear Dr. Ellis:
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`Please refer to your Supplemental New Drug Applications (sNDAs), submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) as follows:
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`Received on
`NDA/Supplement # Drug name Dosage Form Dated
`NDA 21-083/S-042 Rapamune (sirolimus)
`August 18, 2009 August 18, 2009
`Oral Solution
`NDA 21-083/S-043 Rapamune (sirolimus)
`Oral Solution
`NDA 21-110/S-053 Rapamune (sirolimus)
`Tablets
`NDA 21-110/S-054 Rapamune (sirolimus)
`Tablets
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`October 26, 2009 October 27, 2009
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`August 18, 2009 August 18, 2009
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`October 26, 2009 October 27, 2009
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`We acknowledge receipt of your submission dated April 21, 2010, which constitutes a complete
`response to our Complete Response letter dated February 11, 2010 (for NDA 21-083/S-042 and
`NDA 21-110/S-053). This submission also contains revised labeling for NDA 21-083/S-043 and
`NDA 21-110/S-054.
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`These “Changes Being Effected” supplemental new drug applications provide for the following
`revisions to the content of labeling (added text is reflected with underline, deleted text is
`reflected with strikethrough).
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` Page 2
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` NDA 21-083/S-042 and S-043
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` NDA 21-110/S-053 and S-054
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` NDA 21-083/S-042 and NDA 21-110/S-053
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`1. Under RECENT MAJOR CHANGES, the Warnings and Precautions subsection is
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` revised as follows:
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`Warnings and Precautions
`Liver Transplantation (5.2)
`Fluid Accumulation and Wound Healing (5.6)
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`Latent Viral Infections (5.10)
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`FULL PRESCRIBING INFORMATION
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`2.
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`9/2009
`4/2010
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`10/2009
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`In section 5 WARNINGS AND PRECAUTIONS, 5.6 Fluid Accumulation and Wound
`Healing the second paragraph is revised as follows:
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`There have also been reports of fluid accumulation, including peripheral edema,
`lymphedema, pleural effusion, ascites and pericardial effusions (including
`hemodynamically significant effusions and tamponade requiring intervention in children
`and adults), in patients receiving Rapamune.
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`In section 6 ADVERSE REACTIONS, at the beginning of the 6.6 Postmarketing
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`Experience section, the Cardiovascular subsection is revised and a new Digestive System
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`subsection is added as follows:
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`• Body as a Whole – Lymphedema.
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`• Cardiovascular – Pericardial effusion (including hemodynamically significant
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`effusions and tamponade requiring intervention in children and adults) and fluid
`accumulation.
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`3.
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`NDA 21-083/S-043 and NDA 21-110/S-054
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`4. Under RECENT MAJOR CHANGES, the Dosage and Administration and Warnings
`and Precautions subsections are revised as follows:
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`• Digestive System-Ascites
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`Dosage and Administration
`Therapeutic Drug Monitoring (2.3)
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`4/2010
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` NDA 21-083/S-042 and S-043
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` NDA 21-110/S-053 and S-054
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`Warnings and Precautions
`Liver Transplantation (5.2)
`Latent Viral Infections (5.10)
`Assay for Sirolimus Therapeutic Drug Monitoring (5.15)
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`9/2009
`10/2009
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`4/2010
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`FULL PRESCRIBING INFORMATION
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`5.
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`In section 2 DOSAGE AND ADMINISTRATION, the last paragraph of the 2.3
`Therapeutic Drug Monitoring subsection is revised as follows:
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`The above recommended 24-hour trough concentration ranges for sirolimus are based on
`chromatographic methods. On average, chromatographic methods (HPLC UV or
`LC/MS/MS) yield results that are approximately 20% lower that the immunoassay for
`whole blood concentration determination. Currently in clinical practice, sirolimus whole
`blood concentrations are being measured by both chromatographic and immunoassay
`methodologies. Because the measured sirolimus whole blood concentrations depend on
`the type of assay used, the concentrations obtained by these different methodologies are
`not interchangeable [see Warnings and Precautions (5.15 5.15 , Clinical Pharmacology
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`(12.3)]. Adjustments to the targeted range should be made according to the assay utilized
`to determine sirolimus trough concentrations. Since results are assay and laboratory
`dependent, and the results may change over time, adjustments to the targeted therapeutic
`range must be made with a detailed knowledge of the site-specific assay used. Therefore
`communication should be maintained with the laboratory performing the assay. A
`discussion of different assay methods is contained in Clinical Therapeutics, Volume 22,
`Supplement B, April 2000 [see References (15)].
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`In the 5 WARNINGS AND PRECAUTIONS section, the 5.15 Assay for Sirolimus
`Therapeutic Drug Monitoring subsection as been revised as follows:
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`The label-recommended 24-hour trough concentration ranges for sirolimus are based on
`chromatographic methods. Currently in clinical practice, sirolimus whole blood
`concentrations are being measured by both chromatographic and immunoassay
`methodologies. These concentration values are not interchangeable [see Dosage and
`Administration (2.3), Clinical Pharmacology (12.3)].Currently in clinical practice,
`sirolimus whole blood concentrations are being measured by various chromatographic
`and immunoassay methodologies. Patient sample concentration values from different
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`assays may not be interchangeable [see Dosage and Administration(2.3)].
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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 enclosed, agreed upon labeling text,
`which is identical to the content of labeling submitted on April 21, 2010.
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`6.
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` Page 4
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` NDA 21-083/S-042 and S-043
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` NDA 21-110/S-053 and S-054
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`We also note that you have updated the following sections of the FULL PRESCRIBING
`INFORMATION of the content of labeling to provide consistency with cross-reference
`numbers.
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`7.
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`In the 1 INDICATIONS AND USAGE, the 1.1 Prophylaxis of Organ Rejection in Renal
`Transplantation section, In patients at high immunologic risk subsection, the reference
`in the [see …Clinical Studies] is revised as follows:
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`In patients at high-immunologic risk (defined as Black recipients and/or repeat renal
`transplant recipients who lost a previous allograft for immunologic reason and/or patients
`with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended
`that Rapamune be used in combination with cyclosporine and corticosteroids for the first
`year following transplantation [see Dosage and Administration (2.2), Clinical Studies
`(14.214.3)]
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`In the 1 INDICATIONS AND USAGE, the 1.2 Limitations of Use section, last paragraph,
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`the reference in the [see Clinical studies] is revised as follows:
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`The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in
`maintenance renal transplant patients has not been established [see Clinical Studies (14.2)
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`(14.4)]
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`Safety and efficacy information from a controlled clinical trial in pediatric and
`adolescent (< 18 years of age) renal transplant patients judged to be at high-
`immunologic risk, defined as a history of one or more acute rejection episodes and/or the
`presence of chronic allograft nephropathy, do not support the chronic use of Rapamune
`Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids,
`due to the higher incidence of lipid abnormalities and deterioration of renal function
`associated with these immunosuppressive regimens compared to calcineurin inhibitors,
`without increased benefit with respect to acute rejection, graft survival, or patient survival
`[see Clinical Studies (14.514.6)]
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`8.
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`9.
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`In the 2 DOSAGE AND ADMINISTRATION, the 2.2 Patients at High-Immunologic
`Risk section, first paragraph, first sentence, the reference in the [see Clinical Studies] is
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`revised as follows:
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`In patients with high-immunologic risk, it is recommended that Rapamune be used in
`combination with cyclosporine and corticosteroids for the first 12 month following
`transplantation [see Clinical Studies (14.2) (14.3)].
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`10. In the 8 USE IN SPECIFIC POPULATIONS, the last paragraph of the 8.4 Pediatric Use
`section, the reference in the [see Clinical Studies] is revised as follows:
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` Page 5
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` NDA 21-083/S-042 and S-043
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` NDA 21-110/S-053 and S-054
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` CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format, as described
`at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed content of labeling (text for the package insert and patient labeling),
`which was submitted on April 21, 2010. For administrative purposes, please designate this
`submission, “SPL for NDA 21-083/S-042 and S-043 and NDA 21-110/S-053 and S-054.”
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`Also, within 14 days from the date of this letter, please amend all pending supplemental
`applications for these NDAs, 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 these supplemental applications.
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`PROMOTIONAL MATERIALS
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`All promotional materials for your drug product that include representations about your drug
`product must be promptly revised to make it consistent with the labeling changes approved in
`this supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions to
`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 following address or
`by facsimile at 301-847-8444:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`In addition, as required under 21 CFR 314.81(b)(3)(i), you must submit your updated final
`promotional materials, and the package insert(s), at the time of initial dissemination or
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`publication, accompanied by a Form FDA-2253, directly to the above address. For instruction
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`on completing the Form FDA 2253, see page 2 of the Form. For more information about
`submission of promotional materials to the Division of Drug Marketing, Advertising, and
`Communications (DDMAC), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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` Page 6
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` NDA 21-083/S-042 and S-043
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` NDA 21-110/S-053 and S-054
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` LETTERS TO HEALTH CARE PROFESSIONALS
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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
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` the letter to both this NDA and to the following address:
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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 Christine Lincoln, RN, MPH, Regulatory Project Manager, at
`(301) 796-1600
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`Sincerely,
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`{See appended electronic signature page}
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`
`Ozlem Belen, MD, MPH
`Deputy Director for Safety
`Division of Special Pathogen and Transplant Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`Enclosure: Content of Labeling
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`Application
`Type/Number
`--------------------
`NDA-21110
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`Submission
`Type/Number
`--------------------
`SUPPL-54
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`NDA-21110
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`SUPPL-53
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`NDA-21083
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`SUPPL-43
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`NDA-21083
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`SUPPL-42
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`Submitter Name
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`Product Name
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`------------------------------------------
`--------------------
`RAPAMUNE (SIROLIMUS) 1MG
`WYETH
`PHARMACEUTICA TABLETS
`LS INC
`RAPAMUNE (SIROLIMUS) 1MG
`WYETH
`PHARMACEUTICA TABLETS
`LS INC
`RAPAMUNE
`WYETH
`PHARMACEUTICA (SIROLIMUS)1MG/ML ORAL
`LS INC
`SOLUTION
`WYETH
`RAPAMUNE
`PHARMACEUTICA (SIROLIMUS)1MG/ML ORAL
`LS INC
`SOLUTION
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`OZLEM A BELEN
`04/22/2010
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`