DEPARTMENT OF HEALTH & HUMAN
`
` SERVICES
`
`
`
`
`
`
`
`
`NDA 21083/S-044 and S-047
`NDA 21110/S-055 and S-057
`
`Public Health Service
`
`
`
` Food and Drug Administration
`Rockville, MD 20857
`
`
` SUPPLEMENT APPROVAL
`
` FULFILLMENT OF POSTMARKETING COMMITMENT
`
`
`
`Wyeth Pharmaceuticals, Inc.
`Attention: Sharon Pfleger, M.S., RAC
`
`Manager, Global Regulatory Affairs
`PO Box 8299
`Philadelphia, PA 19101-8299
`
`
`Dear Ms. Pfleger:
`
`Please refer to your Supplemental New Drug Applications submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
`
`Name of Drug Product
`
`NDA
`Number
`021083 Rapamune® (sirolimus) Oral
`Solution, 1 mg/mL
`021110 Rapamune® (sirolimus) Tablets,
`1 mg, 2 mg, and 5 mg
`
`Date of
`Supplement
`September 8,
`2010
`September 8,
`2010
`
`Date of
`Receipt
`September 8,
`2010
`September 8,
`2010
`
`
`
`Supplement
`Number
`S-044
`
`S-055
`
`
`We acknowledge receipt of your amendments dated November 22, 2010.
`
`The September 8, 2010, submission constituted a complete response to our August 9, 2010,
`action letter. These supplemental applications consist of the proposed Risk Evaluation and
`Mitigation Strategy (REMS).
`
`
`Name of Drug Product
`
`NDA
`Number
`021083 Rapamune® (sirolimus) Oral
`Solution, 1 mg/mL
`021110 Rapamune® (sirolimus) Tablets,
`1 mg, 2 mg, and 5 mg
`
`Supplement
`Number
`S-047
`
`S-057
`
`Date of
`Supplement
`September 7,
`2010
`September 7,
`2010
`
`Date of
`Receipt
`September 7,
`2010
`September 7,
`2010
`
`
`We acknowledge receipt of your amendments dated November 17, 2010.
`
`These supplemental applications provide for revisions to the labeling for Rapamune® (sirolimus)
`and proposed medication guide.
`
`Reference ID: 2868138
`
`

`

`
`
`NDA 21083/S-044 and S-047
`
`NDA 21110/S-055 and S-057
`
`Page 2
`
`
`
` A. SAFETY LABELING CHANGE
`
`We also refer to our letter dated August 9, 2010 , notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for
`Rapamune® (sirolimus). This information pertains to serious risk of hyperlipidemia that required
`treatment in up to 90% of patients and where lipid levels in a substantial number of patients
`exceeded the recommended normal target levels for cholesterol and trigylcerides despite antilipid
`management.
`
`Your supplemental new drug applications NDA 21083/S-047 and NDA 21110/S-057 provide for
`revisions to the labeling for Rapamune® (sirolimus). The agreed upon changes to the language
`included in our August 9, 2010, letter are as follows (additions are noted by underline and
`deletion are noted by strikethrough).
`
`
`
`1. In the highlights section, the following has been revised as follows:
`
`
`-------—— RECENT MAJOR CHANGES ————————
`Dosage and Administration
`
`• Therapeutic Drug Monitoring
`
`(2.3)
` Warnings and Precautions
`
` • Liver Transplantation (5.2)
`
`
`• Fluid Accumulation and
`
`Wound Healing (5.6)
`
` • Hyperlipidemia (5.7)
`
`• Latent Viral infections (5.10)
`
`• Assay for Sirolimus
`
`Therapeutic Drug Monitoring
`(5.15)
`
`04/2010
`
`09/2009
`04/2010
`
`09/2010
`07/2010
`04/2010
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved
`patient labelingMedication Guide.
`
`
`2. 5 WARNINGS AND PRECAUTIONS
`5.7 Hyperlipidemia
`
`Increased serum cholesterol and triglycerides requiring treatment occurred more
`
`frequently in patients treated with Rapamune compared with azathioprine or placebo
`controls in Studies 1 and 2 [see Adverse Reactions (6.1)]. There were increased
`incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) in
`patients receiving Rapamune compared with placebo controls (each 23%). The
`risk/benefit should be carefully considered in patients with established hyperlipidemia
`before initiating an immunosuppressive regimen including Rapamune.
`
`
`Reference ID: 2868138
`
`

`

`NDA 21083/S-044 and S-047
`
`NDA 21110/S-055 and S-057
`
`Page 3
`
`
`
`Any patient who is administered Rapamune should be monitored for hyperlipidemia. If
`detected, interventions such as diet, exercise, and lipid-lowering agents should be
`initiated as outlined by the National Cholesterol Education Program guidelines.
`
`In clinical trials, of patients receiving Rapamune plus cyclosporine or Rapamune after
`cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and
`hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid
`management, up to 50% of patients had fasting serum cholesterol levels > 240 mg/dL and
`triglycerides above recommended target levels. Thethe concomitant administration of
`Rapamune and HMG-CoA reductase inhibitorsand/or fibrates appeared to be well-
`tolerated. resulted in adverse events such as CPK elevations (3%), myalgia (6.7%) and
`rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration
`of follow-up too short to evaluate the long-term impact of Rapamune on cardiovascular
`mortality.
`
`
`During Rapamune therapy with or without cyclosporine, patients who should be
`monitored for elevated lipids, and patients administered an HMG-CoA reductase
`inhibitor and/or fibrate should be monitored for the possible development of
`rhabdomyolysis and other adverse effects, as described in the respective labeling for
`these agents.
`
`
`3. 6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal
`Transplantation
`
`Increased Serum Cholesterol and Triglycerides
`
`The use of Rapamune in renal transplant patients was associated with increased serum
`
`cholesterol and triglycerides that may require treatment.
`
`In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting,
`
`total serum cholesterol < 200 mg/dL or fasting, total serum triglycerides < 200 mg/dL,
`
`there was an increased incidence of hypercholesterolemia (fasting serum cholesterol >
`
`240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL),
`
`respectively, in patients receiving both Rapamune 2 mg and Rapamune 5 mg compared
`
`with azathioprine and placebo controls.
`
`
`Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in
`42-52% of patients enrolled in the Rapamune arms of Studies 1 and 2 compared with
`16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other
`Rapamune renal transplant studies, up to 90% of patients required treatment for
`hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates).
`Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels
`> 240 mg/dL and triglycerides above recommended target levels [see Warnings and
`
`Precautions (5.7)].
`
`4. 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`Reference ID: 2868138
`
`

`

`NDA 21083/S-044 and S-047
`
`NDA 21110/S-055 and S-057
`
`Page 3
`
`
`
`Since Rapamune is not absorbed through the skin, there are no special precautions.
`However, if direct contact of the oral solution occurs with the skin or eyesmucous
`membranes occurs, wash skin thoroughly with soap and water; rinse eyes with plain
`water.
`
`Do not use RAPAMUNE after the expiration date that is located on the blister and carton.
`The expiration date refers to the last day of that month.
`
`
`
`5. 17 PATIENT COUNSELING INFORMATION
`
`Advise patients, their families, and their caregivers to read the Medication Guide and
`assist them in understanding its contents. The complete text of the Medication Guide is
`
`reprinted at the end of the document.
`See FDA-Approved Patient Labeling (17.4) Medication Guide.
`
`17.1 Dosage
`
`Patients should be given complete dosage instructions [see FDA-Approved Medication
`GuidePatient Counseling Information (17.4)]
`
`17.4 FDA-Approved Patient Labeling
`
`
`6. The medication guide has been agreed upon as attached in the letter.
`
`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, using the FDA
`automated drug registration and listing system (eLIST), 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 labeling (text for the package insert, Medication Guide, and Instructions
`for use) and include the labeling changes proposed in any pending “Changes Being Effected”
`(CBE) supplements. 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 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 MS Word format that
`includes the changes approved in this supplemental application.
`
`Reference ID: 2868138
`
`

`

`
`
`NDA 21083/S-044 and S-047
`NDA 21110/S-055 and S-057
`Page 4
`
`
` CARTON AND IMMEDIATE CONTAINER LABELS
`
`We acknowledge your September 7, 2010, submission containing proposed carton and container
`labels. Submit final printed carton and container labels that are identical to the carton and
`immediate container labels submitted on November 17, 2010, as soon as they are available, but
`no more than 30 days after they are printed.
`
`Please submit these labels electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Product
`Correspondence – Final Printed Carton and Container Labels for approved NDA 21083/S-
`
`047 and NDA 21110/ S-057.” Approval of this submission by FDA is not required before the
`labeling is used.
`
`B. RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS) if FDA becomes aware of new safety information and makes a
`determination that such a strategy is necessary to ensure that the benefits of the drug outweigh
`the risks (section 505-1(a)). The details of the REMS requirements were outlined in our REMS
`notification and complete response letter dated August 9, 2010.
`
`Since Rapamune® (sirolimus) was approved on September 15, 1999 (NDA 21083, Oral
`Solution) and August 20, 2000 (NDA 21110, Tablets), we have become aware of the serious risk
`of hyperlipidemia which required treatment in up to 90% of patients and where lipid levels in a
`substantial number of patients exceeding the recommended normal target levels for cholesterol
`and triglycerides despite antilipid management. This information was submitted and received
`November 16, 2009 in response to a post marketing commitment trial. We consider this
`information to be “new safety information” as defined in section 505-1(b)(3) of the FDCA.
`
`Your proposed REMS, submitted on November 11, 2010, and appended to this letter, is
`approved. The REMS consists of the Medication Guide included with this letter and the
`timetable for submission of assessments of the REMS.
`
`
`The REMS assessment plan should include but is not limited to the following:
`
`
`
`a. An evaluation of patients’ understanding of the serious risks of Rapamune®
`(sirolimus)
`
`b. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24
`
`c. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance
`
`
`
`Reference ID: 2868138
`
`

`

`NDA 21083/S-044 and S-047
`NDA 21110/S-055 and S-057
`Page 5
`
`Assessments of an approved REMS must include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. With respect to any such postapproval
`study, you must include the status of such study, including whether any difficulties completing
`the study have been encountered. With respect to any such postapproval clinical trial, you must
`include the status of such clinical trial, including whether enrollment has begun, the number of
`participants enrolled, the expected completion date, whether any difficulties completing the
`clinical trial have been encountered, and registration information with respect to requirements
`under subsections (i) and (j) of section 402 of the Public Health Service Act. You can satisfy
`these requirements in your REMS assessments by referring to relevant information included in
`the most recent annual report required under section 506B and 21 CFR 314.81(b)(2)(vii) and
`including any updates to the status information since the annual report was prepared. Failure to
`comply with the REMS assessments provisions in section 505-1(g) could result in enforcement
`action.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of FDCA.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 21083 and NDA 21110 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 21083 and NDA 21110
`
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`FOR NDA 21083 and NDA 21110
`
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
`
`C. FULFILLMENT OF POSTMARKETING COMMITMENT
`
`
`We have received your submission on November 16, 2009 reporting on the following
`postmarketing commitment (PMC):
`
`
`
`
`Reference ID: 2868138
`
`

`

`NDA 21083/S-044 and S-047
`NDA 21110/S-055 and S-057
`Page 6
`
`
`PMC 933-2
`You will conduct an appropriate study or studies to better define the type and duration of
`hyperlipidemia associated with the use of sirolimus. In particular, you will measure and
`analyze total fasting serum cholesterol and triglycerides, as well as high density
`lipids/low-density lipids, and lipoprotein A. Transplant recipients with and without a lipid
`disorder prior to transplant will be included, and the use of lipid lowering agents and
`other specific interventions will be evaluated.
`
`
`We have reviewed your submissions and conclude that the above commitment was fulfilled.
`This completes all of your postmarketing commitments acknowledged in our September 15,
`1999 letter.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`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
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.(b)(3)(i)]. Form FDA
`2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html; instructions
`are provided on page 2 of the form. For more information about submission of promotional
`materials to the Division of Drug Marketing, Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`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.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`
`If you decide to 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, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA to the following
`address:
`
`Reference ID: 2868138
`
`

`

`NDA 21083/S-044 and S-047
`NDA 21110/S-055 and S-057
`Page 7
`
`
` MedWatch Program
`
`
`Office of Special Health Issues
`
`
`Food and Drug Administration
`
`10903 New Hampshire Ave
`
`Building 32, Mail Stop 5353
`
`
`Silver Spring, MD 20993
`
`
`
`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 Hyun Son, Pharm.D., Safety Regulatory Project Manager,
`at (301) 796-1600.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Ozlem Belen, M.D., MPH
`Deputy Director for Safety
`Division of Special Pathogen and Transplant Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`REMS
`
`
`
`Reference ID: 2868138
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`11/23/2010
`
`Reference ID: 2868138
`
`