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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 202343/S-005 and S-007
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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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`Merck Sharp & Dohme Corp.
`Attention: Lou Ann Eader, Ph.D.
`Director, Regulatory Affairs
`P.O. Box 1000, UG2C-50
`North Wales, PA 19454-1099
`
`Dear Dr. Eader:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received July 18,
`2012 (S-005) and September 21, 2012 (S-007), submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act (FDCA) for Juvisync (sitagliptin/simvastatin) Tablets.
`
`We acknowledge receipt of your amendments dated October 2 (S-005), October 15 (S-005 and
`S-007), and October 22 (S-005 and S-007), 2012.
`
`Supplemental new drug application, S-005, provides information regarding the concomitant use
`of Juvisync and dronedarone, the co-administration of Juvisync with voriconazole, and updated
`information on the concomitant use of grapefruit juice to the package insert for Juvisync. This
`was submitted in response to our Prior Approval Supplement Request letter for Zocor
`(simvastatin) dated June 5, 2012.
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`We also refer to our letter dated August 22, 2012, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for
`Juvisync. This information pertains to the risk of immune-mediated necrotizing myopathy
`(IMNM).
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`Supplemental new drug application, S-007, provides for revisions to the labeling for Juvisync.
`The agreed upon changes to the language included in our August 22, 2012, letter are as follows
`(additions are noted by underline and deletions are noted by strikethrough).
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`In the Full Prescribing Information, under WARNINGS AND PRECAUTIONS, 5.2
`Myopathy/Rhabdomyolysis:
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`
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`Reference ID: 3210297
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`

`

`NDA202343/S-005; S-007
`Page2
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`There have been rare rep01is of *immune-mediated necrotizing myopathy (IMNM), an
`-~bn4I
`autoimmlme myopathy, associated with
`4
`4)IMNM
`- statin ~~~
`(b)(
`(bH
`1
`.is characterized by: proximal muscle weakness and elevated semm creatine
`'.-.· - - -:
`kinase. which persist despite discontinuation of statin treatment: muscle biopsy showing
`necrotizing myopathy without significant inflammation: improvement with
`immunosuppressive agents.
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`r----------------------------------.(1))(4~
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`In the Full Prescribing Infonnation, under ADVERSE REACTIONS, 6.2 Postmarketing
`Experience:
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`Anemia; depression; headache; dizziness; paresthesia; peripheral nemopathy; interstitial
`lung disease; pancreatitis; acute pancreatitis, including fatal and non-fatal hemonhagic
`and necrotizing pancreatitis [see Indications and Usage (1.3); Warnings and Precautions
`(5.1 )} ; constipation; vomiting; hepatitis/jaundice; fatal and non-fatal hepatic failme;
`hepatic enzyme elevations; pmritus; alopecia; a variety of skin changes (e.g., nodules,
`discoloration, dtyness of skin/mucous membranes, changes to hair/nails); muscle cramps;
`4
`> _worsening renal
`myalgia; rhabdomyolysis
`(bH
`function, including acute renal failure (sometimes requiring dialysis); erectile
`dysfunction.
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`There have been rare rep01is of immune-mediated necrotizing myopathy associated with
`statin use [see Warnings and Precau tions (5.2) .
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`In the Medication Guide, under What are the possible side effects of JUVISYNC?, Serious
`side effects have happened in people taking JUVISYNC., myopathy (muscle weakness) and
`rhabdomyolysis (muscle breakdown):
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`41!f you have muscle problems that do not go away even after your doctor
`(bH
`"h--a-s -a•d·v- 1··-s-ed--.-y-o-u~to stop (b)(4) taking JUVISYNC. notify your doctor. Your doctor may do
`fmiher tests to diagnose the cause of your muscle problems.
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`Reference ID: 3210297
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` NDA202343/S-005; S-007
`Page 3
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`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.
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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, 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 the package insert and Medication
`Guide), 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.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications 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 this
`supplemental application, 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).
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`PROMOTIONAL MATERIALS
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`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:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`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
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`Reference ID: 3210297
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` NDA202343/S-005; S-007
`Page 4
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`promotional materials to the Office of Prescription Drug Promotion (OPDP), 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.
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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 Raymond Chiang, Regulatory Project Manager, at (301) 796-
`1940.
`
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`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
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Package Insert
`Medication Guide
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`Reference ID: 3210297
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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/
`----------------------------------------------------
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`AMY G EGAN
`10/31/2012
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`Reference ID: 3210297
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