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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021073/S-043, 044
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`NDA 021842/S-014, 015
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`NDA 022024/S-008, 007
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`NDA 021925/S-010, 011
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`Food and Drug Administration
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`Silver Spring MD 20993
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`SUPPLEMENT APPROVALS
`
`
`Takeda Global Research & Development Center, Inc.
`
`Attention: Jessie Y. Lee, Ph.D.
`
`Manager, Regulatory Affairs
`
`One Takeda Parkway
`
`Deerfield, IL 60015-2235
`
`
`Dear Dr. Lee:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated July 7, 2011, received
`July 8, 2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for:
`
`• ACTOS (pioglitazone hydrochloride) Tablets (sNDA 21-073/S-043),
`
`• ACTOPLUS MET (pioglitazone hydrochloride and metformin hydrochloride) fixed-dose
`combination Tablets (sNDA 21-842/S-014),
`
`• ACTOPLUS MET XR (pioglitazone hydrochloride and metformin hydrochloride
`extended-release) fixed-dose combination Tablets (sNDA 22-024/S-008), and
`
`• DUETACT (pioglitazone hydrochloride and glimepiride) fixed-dose combination
`Tablets (sNDA 21-925/S-010).
`
`
`Please also refer to your sNDAs dated and received July 8, 2011 for ACTOS (sNDA 21-073/S-
`044), ACTOPLUS MET (sNDA 21-842/S-015), ACTOPLUS MET XR (sNDA 22-024/S-007),
`and DUETACT (sNDA 21-925/S-011).
`
`We acknowledge receipt of your amendments dated August 1 and 3, 2011, for ACTOS,
`ACTOPLUS MET, ACTOPLUS MET XR, and DUETACT, and your risk evaluation and
`mitigation strategy (REMS) assessments submitted on March 7, 2011, for ACTOS and
`DUETACT, and on November 4, 2010, for ACTOPLUS MET and ACTOPLUS MET XR.
`
`We also refer to our letter dated June 9, 2011, notifying you of new safety information that we
`believe should be included in the labeling for ACTOS, ACTOPLUS MET, ACTOPLUS MET
`XR, and DUETACT under Section 505(o)(4) of the FDCA, notifying you that you must submit a
`proposed REMS modification under Section 505-1, and notifying you of a requirement for a
`postmarketing study under Section 505(o)(3). The new safety information pertains to a dose-
`and duration-dependent increase in the risk of bladder cancer in subjects exposed to pioglitazone
`hydrochloride compared to subjects never exposed to pioglitazone hydrochloride.
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
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`
` NDA 021842/S-014, 015
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`
` NDA 022024/S-007, 008
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` NDA 021925/S-010, 011
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`Page 2
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`
`
`
`Supplemental new drug applications (sNDA 21-073/S-044, sNDA 21-842/S-015,
`sNDA 22-024/S-007, and sNDA 21-925/S-011) provide for revisions to the labeling for ACTOS,
`ACTOPLUS MET, ACTOPLUS MET XR, and DUETACT, respectively. The agreed upon
`changes to the language included in our June 9, 2011, letter are as follows (additions are noted
`by underline and deletions are noted by strikethrough).
`
`For ACTOS:
`
`On the Highlights page, under WARNINGS AND PRECAUTIONS:
`
`
`Bladder cancer: Preclinical and clinical trial data, and results from an observational study
`suggest an increased risk of bladder cancer in pioglitazone users. The observational data
`indicate further suggest that the risk increases with duration of use. Do not use in patients with
`
`active bladder cancer. Use caution when using in patients with a prior history of bladder cancer
`
`(5.5)
`
`In the Full Prescribing Information, under WARNINGS AND PRECAUTIONS, 5.5 Urinary
`Bladder Tumors:
`
`
`A five-year interim report of an ongoing 10-year observational cohort study found a
`nonsignificant increase in the risk for bladder cancer in subjects ever exposed to ACTOS,
`compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared
`to never exposure, a duration of ACTOS therapy longer than 12 months was associated
`with an 40% increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical
`significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim
`
`results from this study suggested that taking ACTOS A duration of therapy longer than 12
`
`months increased the relative risk of developing bladder cancer in any given year by 40% which
`equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without
`ACTOS] to approximately 10 in 10,000 [with ACTOS]) was associated with 27.5 excess cases of
`
`bladder cancer per 100,000 person-years of follow-up, compared to never use of ACTOS.
`
`In the Full Prescribing Information, under PATIENT COUNSELING INFORMATION,
`Instructions:
`
`Tell patients to promptly report any signs of macroscopic hematuria or other symptoms of blood
`
`in the urine, such as dysuria or urinary urgency that develop or increase during treatment urinary
`
`urgency, pain on urination, back or abdominal pain as these may be due to bladder cancer.
`
`To the Medication Guide, under “What are the possible side effects of ACTOS? ACTOS may
`cause serious side effects including”:
`
`
`Reference ID: 2983732
`
`

`

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` NDA 021073/S-043, 044
`
`
` NDA 021842/S-014, 015
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` NDA 022024/S-007, 008
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` NDA 021925/S-010, 011
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`Page 3
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`
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`• bladder cancer. There may be an increased chance of having bladder cancer when
`
`you take ACTOS. You should not take ACTOS if you are receiving treatment for
`bladder cancer. Tell your doctor right away if you have any of the following
`symptoms of bladder cancer:
`o you see blood or a red color in your urine.
`
`o you have an increased urgent need to urinate or pain while urinating
`
`
`o you have pain in your back or lower abdomen
`
`
`o pain while you urinate
`
`
`
`
`For ACTOPLUS MET:
`
`
`Under PRECAUTIONS, General: Pioglitazone hydrochloride:
`
`A five-year interim report of an ongoing 10-year observational cohort study found a
`nonsignificant increase in the risk for bladder cancer in subjects ever exposed to ACTOS,
`compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never
`exposure, a duration of ACTOS therapy longer than 12 months was associated with an 40%
`increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more
`than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study
`suggested that taking ACTOS A duration of therapy longer than 12 months increased the relative
`risk of developing bladder cancer in any given year by 40% which equates to an absolute
`increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without ACTOS] to
`approximately 10 in 10,000 [with ACTOS]) was associated with 27.5 excess cases of bladder
`
`cancer per 100,000 person-years of follow-up, compared to never use of ACTOS.
`
`
`Under Information for Patients:
`
`Patients should be told to promptly report any signs of macroscopic hematuria or other
`
`
`symptoms such as dysuria or urinary urgency that develop or increase during treatment of blood
`
`in the urine, urinary urgency, pain on urination, back or abdominal pain as these may be due to
`
`bladder cancer.
`
`To the Medication Guide, under “What are the possible side effects of ACTOPLUS MET?
`ACTOPLUS MET may cause serious side effects including”:
`
`
`• Bladder cancer. There may be an increased chance of having bladder cancer when you take
`ACTOPLUS MET. You should not take ACTOPLUS MET if you are receiving treatment for
`bladder cancer. Tell your doctor right away if you have any of the following symptoms of
`bladder cancer:
`o you see blood or a red color in your urine.
`
`o you have an increased urgent need to urinate or pain while urinating
`
`
`o you have pain in your back or lower abdomen
`
`
`o pain while you urinate
`
`
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
`
` NDA 021842/S-014, 015
`
` NDA 022024/S-007, 008
`
` NDA 021925/S-010, 011
`Page 4
`
`
`
`In studies of pioglitazone (one of the medicines in ACTOPLUS MET), bladder cancer occurred
`in a few more people who were taking pioglitazone than in people who were taking other
`diabetes medicines. There were too few cases to know if the bladder cancer was related to
`pioglitazone.
`
`
`For ACTOPLUS MET XR:
`
`Under PRECAUTIONS, General: Pioglitazone:
`
`A five-year interim report of an ongoing 10-year observational cohort study found a non-
`significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared
`to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure,
`a duration of ACTOS therapy longer than 12 months was associated with an 40% increase in risk
`(HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of
`ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking
`ACTOS A duration of therapy longer than 12 months increased the relative risk of developing
`bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in
`10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with
`ACTOS]) was associated with 27.5 excess cases of bladder cancer per 100,000 person-years of
`
`follow-up, compared to never use of ACTOS.
`
`
`Under Information for Patients:
`
`Patients should be told to promptly report any signs of macroscopic hematuria or other
`
`
`symptoms such as dysuria or urinary urgency that develop or increase during treatment of blood
`
`in the urine, urinary urgency, pain on urination, back or abdominal pain as these may be due to
`
`bladder cancer.
`
`To the Medication Guide, under “What are the possible side effects of ACTOPLUS MET
`XR? ACTOPLUS MET XR may cause serious side effects including”:
`
`
`• Bladder cancer. There may be an increased chance of having bladder cancer when you take
`ACTOPLUS MET XR. You should not take ACTOPLUS MET XR if you are receiving
`treatment for bladder cancer. Tell your doctor right away if you have any of the following
`symptoms of bladder cancer:
`o you see blood or a red color in your urine.
`
`o you have an increased urgent need to urinate or pain while urinating
`
`
`o you have pain in your back or lower abdomen
`
`
`o pain while you urinate
`
`
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
`
`
` NDA 021842/S-014, 015
`
`
` NDA 022024/S-007, 008
`
`
` NDA 021925/S-010, 011
`
`Page 5
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`
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`
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`In studies of pioglitazone (one of the medicines in ACTOPLUS MET XR), bladder cancer
`occurred in a few more people who were taking pioglitazone than in people who were taking
`other diabetes medicines. There were too few cases to know if the bladder cancer was related to
`pioglitazone.
`
`
`For DUETACT:
`
`Under PRECAUTIONS, General: Pioglitazone hydrochloride:
`
`A five-year interim report of an ongoing 10-year observational cohort study found a non-
`significant increase in the risk for bladder cancer in subjects ever exposed to ACTOS, compared
`to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure,
`a duration of ACTOS therapy longer than 12 months was associated with an 40% increase in risk
`(HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of
`ACTOS use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking
`ACTOS A duration of therapy longer than 12 months increased the relative risk of developing
`bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in
`10,000 (from approximately 7 in 10,000 [without ACTOS] to approximately 10 in 10,000 [with
`ACTOS]) was associated with 27.5 excess cases of bladder cancer per 100,000 person-years of
`
`follow-up, compared to never use of ACTOS.
`
`
`Under Information for Patients:
`
`Patients should be told to promptly report any signs of macroscopic hematuria or other
`
`symptoms such as dysuria or urinary urgency that develop or increase during treatment of blood
`
`in the urine, urinary urgency, pain on urination, back or abdominal pain as these may be due to
`bladder cancer.
`
`To the Medication Guide, under “What are other possible side effects of DUETACT?
`DUETACT can cause other serious side effects including”:
`
`
`• Bladder cancer. There may be an increased chance of having bladder cancer when you take
`DUETACT. You should not take DUETACT if you are receiving treatment for bladder
`cancer. Tell your doctor right away if you have any of the following symptoms of bladder
`cancer:
`o you see blood or a red color in your urine.
`
`o you have an increased urgent need to urinate or pain while urinating
`
`
`o you have pain in your back or lower abdomen
`
`
`o pain while you urinate
`
`
`
`
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
`
`
` NDA 021842/S-014, 015
`
`
` NDA 022024/S-007, 008
`
`
` NDA 021925/S-010, 011
`
`Page 6
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`
`
`In studies of pioglitazone (one of the medicines in DUETACT), bladder cancer occurred in a few
`more people who were taking pioglitazone than in people who were taking other diabetes
`medicines. There were too few cases to know if the bladder cancer was related to pioglitazone.
`
`
`Supplemental new drug applications (sNDA 21-073/S-043, sNDA 21-842/S-014, (sNDA
`22-024/S-008, and sNDA 21-925/S-010) provide for proposed REMS modifications consisting
`of revisions to the Medication Guides and timetables for submission of assessments of the REMS
`for ACTOS, ACTOPLUS MET, ACTOPLUS MET XR, and DUETACT, respectively.
`
`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 (texts for the package inserts and
`
`Medication Guides), 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.
`
`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 these NDAs, 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 submissions, provide a highlighted or marked-up copies that shows all
`changes, as well as clean Microsoft Word versions. The marked-up copies should provide
`appropriate annotations, including supplement numbers and annual report dates.
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`
`Reference ID: 2983732
`
`

`

`
`
`
` NDA 021073/S-043, 044
`
` NDA 021842/S-014, 015
`
` NDA 022024/S-007, 008
`
` NDA 021925/S-010, 011
`Page 7
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`
` POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`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
`purposes, if FDA makes certain findings required by the statute.
`
`Since ACTOS was approved on July 15, 1999, ACTOPLUS MET was approved on
`August 29, 2005, ACTOPLUS MET XR was approved on May 12, 2009, and DUETACT was
`
` approved on July 28, 2006, we have become aware of a 5-year interim report of your
`epidemiological study entitled, "Cohort Study of Pioglitazone and Bladder Cancer in Patients
`with Diabetes," which showed a dose- and duration-dependent increase in the risk of bladder
`cancer in subjects exposed to pioglitazone hydrochloride compared to subjects never exposed to
`pioglitazone hydrochloride. We considered this information to be “new safety information” as
`defined in section 505-1(b)(3) of the FDCA.
`
`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 the signal of a serious
`risk of bladder cancer.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`1783-1
`
`Continuation and modification of your ten-year epidemiological study assessing
`whether treatment with pioglitazone hydrochloride is associated with an increased
`
`risk of bladder cancer in men and women with diabetes.
`
`
`The timetable you submitted on July 29, 2011, states that you will conduct this study according
`to the following schedule:
`
`
`Final Protocol Amendment Submission:
`4th Interim Report Submission:
`
`
`
`
`Study Completion:
`
`
`Final Report Submission:
`
`December 16, 2011
`June 30, 2012
`December 31, 2012
`December 31, 2013
`
`
`Submit the protocol to your IND 33729, with a cross-reference letter to your NDA for ACTOS.
`Submit the final report to the NDA for ACTOS. Prominently identify each submission with the
`following wording in bold capital letters at the top of the first page of the submission, as
`appropriate: “Required Postmarketing Protocol Under 505(o)”, “Required Postmarketing
`
`Final Report Under 505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
`
` NDA 021842/S-014, 015
`
` NDA 022024/S-007, 008
`
` NDA 021925/S-010, 011
`Page 8
`
`
`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
`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.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`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.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`The REMS for ACTOS was originally approved on September 9, 2009, and modified on
`February 3, 2011. The REMS for ACTOPLUS MET was originally approved on
`September 14, 2009, and modified on October 21, 2009. The REMS for ACTOPLUS MET XR
`was originally approved on May 12, 2009, and modified on December 22, 2010. The REMS for
`DUETACT was originally approved on September 9, 2009. These REMS consist of a
`Medication Guide and a timetable for submission of assessments of these REMS. Your
`proposed modification to these REMS consists of revised Medication Guides to include
`information about the risk of bladder cancer, and revised timetables for submission of
`assessments of these REMS.
`
`Your proposed modified REMS, submitted on July 7, 2011, received on July 8, 2011, and
`appended to this letter, are approved.
`
`There are no changes to the REMS assessment plan described in our original REMS approval
`letters for these products.
`
`We remind you that assessments of an approved REMS must also 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.
`
`Reference ID: 2983732
`
`

`

`
` NDA 021073/S-043, 044
`
` NDA 021842/S-014, 015
`
` NDA 022024/S-007, 008
`
` NDA 021925/S-010, 011
`Page 9
`
`
`
`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 material or
`significant 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.
`
`In addition to the assessments submitted according to the timetable included in these approved
`REMS, you must submit a REMS assessment and may propose a modification to these 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.
`
`If you currently distribute or plan to distribute an authorized generic product under this NDA,
`you must submit a complete proposed REMS that relates only to the authorized generic product.
`Submit a proposed REMS, REMS supporting document, and any required appended documents
`as a prior approval supplement. Approval of the proposed REMS is required before you may
`market your authorized generic product.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submissions as appropriate:
`
`
`NDA 021073/ NDA 021842/NDA 022024/NDA 021925 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 021073/ NDA 021842/NDA 022024/NDA 021925
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`FOR NDA 021073/ NDA 021842/NDA 022024/NDA 021925
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`
`
`
`Reference ID: 2983732
`
`

`

`
`
`
` NDA 021073/S-043, 044
`
` NDA 021842/S-014, 015
`
` NDA 022024/S-007, 008
`
` NDA 021925/S-010, 011
`Page 10
`
`
` 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 inserts, accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(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 products must be
`promptly revised to be consistent with the labeling changes approved in these supplements,
`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 Ms. Jena Weber, Regulatory Project Manager, at
`
`301-796-1306.
`
`
`
`Sincerely,
`{See appended electronic signature page}
`
`Amy G. Egan, M.D., M.P.H.
`Deputy Director for Safety
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation II
`
`ENCLOSURES:
`Content of Labeling
`REMS
`
`
`Reference ID: 2983732
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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.
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`AMY G EGAN
`08/04/2011
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`Reference ID: 2983732
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