DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`REMS RETRACTION
`
`Abbott Laboratories
`Attention: Jeremy M. McCumber
` Manager, Regulatory Affairs, Pharmaceuticals Products Group
`200 Abbott Park Road
`Dept PA 76 Bldg AP30-1
`Abbott Park, Illinois 60064-6157
`
`Dear Mr. McCumber:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for the following:
`
`Application
`
`Drug Product
`
`NDA 018081/S-046
`NDA 018082/S-031
`NDA 018723/S-037
`
`Submitted
`on:
`12/28/2007
`
`Received
`on:
`12/31/2007
`
`Depakene (valproic acid) Capsules
`Depakene (valproic acid) Oral Solution
`Depakote (divalproex sodium)
`Delayed Release Tablets
`Depakote Sprinkle Capsules
`(divalproex sodium coated particles in capsules)
`Depacon (valproate sodium) Injection
`Depakote ER (divalproex sodium)
`Extended Release Tablets
`These “Changes Being Effected” supplements provide for:
`• Addition of information in Precautions section regarding Hypothermia
`• Revision to the Precautions subsections - Hyperammonemia and Hyperammonemia and Encephalopathy
`associated with Concomitant Topiramate Use
`• Revision of the Drug Interactions, Topiramate subsection
`• Addition of information in Warnings section regarding drug interactions with Carbapenem Antibiotics
`
`NDA 019680/S-025
`
`NDA 020593/S-016
`NDA 021168/S-016
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`Page 2
`
`Submitted
`on:
`01/14/2009
`
`Received
`on:
`01/15/2009
`
`Application
`NDA 018081/S-048
`NDA 018082/S-033
`NDA 018723/S-040
`NDA 019680/S-027
`
`Drug Product
`Depakene (valproic acid) Capsules
`Depakene (valproic acid) Oral Solution
`Depakote (divalproex sodium) Delayed Release Tablets
`Depakote Sprinkle Capsules
`(divalproex sodium coated particles in capsules)
`Depakote ER (divalproex sodium)
`Extended Release Tablets
`These “Prior Approval” supplements provide for:
`• Proposed REMS including Medication Guides
`• Inclusion of NAAED Pregnancy Registry information
`
`NDA 021168/S-017
`
`Application
`NDA 018081/S-050
`NDA 018082/S-035
`NDA 018723/S-043
`NDA 019680/S-029
`
`NDA 020593/S-020
`NDA 021168/S-020
`
`Submitted
`on:
`11/18/2009
`
`Drug Product
`Depakene (valproic acid) Capsules
`Depakene (valproic acid) Oral Solution
`Depakote (divalproex sodium) Delayed Release Tablets
`Depakote Sprinkle Capsules
`(divalproex sodium coated particles in capsules)
`Depacon (valproate sodium) Injection
`Depakote ER (divalproex sodium)
`Extended Release Tablets
`These “Changes Being Effected” supplements provide for:
`
`Received
`on:
`11/18/2009
`
`Information regarding the risk of developmental delay in the offspring of women exposed to valproate during
`pregnancy
`
`Application
`NDA 018081/S-052
`NDA 018082/S-037
`NDA 018723/S-045
`NDA 020593/S-023
`
`Drug Product
`Depakene (valproic acid) Capsules
`Depakene (valproic acid) Oral Solution
`Depakote (divalproex sodium) Delayed Release Tablets
`Depacon (valproate sodium) Injection
`These “Prior Approval” supplements provide for:
`Revised product labeling to PLR format
`
`Submitted
`on:
`03/05/2010
`
`Received
`on:
`03/05/2010
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`Page 3
`
`Application
`
`NDA 018723/S-046
`NDA 019680/S-031
`
`NDA 021168/S-022
`
`Drug Product
`
`Depakote (divalproex sodium) Delayed Release Tablets
`Depakote Sprinkle Capsules
`(divalproex sodium coated particles in capsules)
`Depakote ER (divalproex sodium)
`Extended Release Tablets
`These “Prior Approval” supplements provide for:
`
`Submitted
`on:
`04/30/2010
`
`Received
`on:
`04/30/2010
`
`Warnings and Precautions section to include information regarding the potential for medication residue
`
`We acknowledge receipt of your amendments as follows:
`
`Application
`NDA 018081/S-048
`NDA 018082/S-033
`NDA 018723/S-040
`NDA 019680/S-027
`NDA 021168/S-017
`
`Amendments Dated:
`
`February 05, 2009 and April 16, 2009
`
`February 05, 2009, February 26, 2009,
`and April 16, 2009
`
`We have completed our review of these supplemental applications, and our review of labeling
`revisions for all aforementioned NDAs, as amended, as follows: adding information regarding the
`North American Antiepilepsy Drug Pregnancy Registry and strengthening language related to the risk
`for neural tube defects and other congenital malformations following in utero exposure to
`valproate (and cautioning against the treatment of women of childbearing potential as well as
`pregnant women with valproate due to these risks). These supplemental applications are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`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
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`Page 4
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, 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.
`
`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 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).
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`In our letter dated December 16, 2008, we notified you that a risk evaluation and mitigation
`strategy (REMS) is required for Depakene (valproic acid), Depakote (divalproex sodium), and
`Depacon (valproate sodium) to ensure that the benefits of the drug outweigh the increased risk of
`suicidal thoughts and behavior associated with the class of antiepileptic drugs (AEDs), of which
`Depakene (valproic acid), Depakote (divalproex sodium), and Depacon (valproate sodium) are
`members. We indicated that your REMS must include a Medication Guide and a timetable for
`submission of assessments of the REMS.
`
`We acknowledge receipt of your proposed REMS as described in your January 15, 2009,
`February 6 and 27, 2009, and April 16, 2009 submissions. The proposed REMS, as amended,
`contains a Medication Guide and a timetable for submission of assessments of the REMS.
`
`We have determined that maintaining the Medication Guide as part of the approved labeling is
`adequate to address the serious and significant public health concern and meets the standard in
`21 CFR 208.1. Therefore, it is no longer necessary to include the Medication Guide as an
`element of the REMS to ensure that the benefits of Depakene (valproic acid), Depakote
`(divalproex sodium), and Depacon (valproate sodium) outweigh their risks. Therefore, a REMS
`for Depakene (valproic acid), Depakote (divalproex sodium), and Depacon (valproate sodium) is
`not required. We will notify you if we become aware of new safety information and make a
`determination that a REMS is necessary.
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`Page 5
`
`We remind you that the Medication Guide will be part of the approved labeling in accordance
`with 21 CFR 208.
`
`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 314.81(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 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.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`NDA 018081/S-046/S-048/S-050/S-052
`NDA 018082/S-031/S-033/S-035/S-037
`NDA 018723/S-037/S-040/S-043/S-045/S-046
`NDA 019680/S-025/S-027/S-029/S-031
`NDA 020593/S-016/S-020/S-023
`NDA 021168/S-016/S-017/S-020/S-022
`Page 6
`
`If you have any questions, call Jacqueline H. Ware, PharmD, Senior Regulatory Project
`Manager, at (301) 796-1160.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell G. Katz, MD
`Director
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`ENCLOSURE:
`Content of Labeling
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306
`
`

`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`RUSSELL G KATZ
`10/07/2011
`
`Reference ID: 3026475
`
`AMN1014
`IPR of Patent No. 8,772,306