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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 022511/S-04
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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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`AstraZeneca LP
`Attention: Gary P. Horowitz, Ph.D.
`Executive Director, Regulatory Affairs
`1800 Concord Pike
`P.O. Box 8355
`Wilmington, DE 19803-8355
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`Dear Dr. Horowitz:
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`Please refer to your Supplemental New Drug Application (sNDA) dated March 28, 2011,
`received March 28, 2011, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Vimovo (naproxen/esomeprazole magnesium) Tablet.
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`We acknowledge receipt of your amendments dated April 26, 2011 and May 11, 2011.
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`We also refer to our letter dated March 1, 2011, notifying you, under Section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for proton
`pump inhibitors (PPIs). This information pertains to the risk of hypomagnesemia related to the
`use of proton pump inhibitors (PPIs) for at least three months, and in most cases after a year.
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`The agreed upon changes to the language included in our March 1, 2011, letter are as follows
`(additions are noted by underline and deletion are noted by strikethrough).
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`RECENT MAJOR CHANGES
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`WARNINGS AND PRECAUTIONS
`Hypomagnesemia (5.3)
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`WARNINGS AND PRECAUTIONS (add new bullet item)
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`May/2011
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`Hypomagnesemia has been noted reported rarely with prolonged treatment with PPIs
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`(5.19)
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`Reference ID: 2949897
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`Page 2 of 5
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` FULL PRESCRIBING INFORMATION: TABLE OF CONTENTS
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`5 WARNING AND PRECAUTIONS
`5.19 Hypomagnesemia
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` FULL PRESCRIBING INFORMATION
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`5 WARNING AND PRECAUTIONS
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`5.19 Hypomagnesemia
`Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients
`treated with proton-pump inhibitors PPIs for at least three months, in most cases after a
`year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In
`most patients, treatment of hypomagnesemia required magnesium replacement and
`discontinuation of the proton pump inhibitors PPI.
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`For patients expected to be on prolonged treatment or who take PPIs with medications
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`such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care
`professionals may consider monitoring magnesium levels prior to initiation of PPI
`treatment and periodically thereafter. [see Adverse Reactions (6.2)]
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`6.2 POSTMARKETING EXPERIENCE
`Metabolism and Nutritional Disorders: hypomagnesemia (symptoms may include tetany,
`arrythmias or seizures)
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`17 PATIENT COUNSELING INFORMATION
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`Advise patients to immediately report and seek care for any cardiovascular (e.g.,
`palpitations) or neurological symptoms including palpitations, dizziness, (e.g., seizures,
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`and tetany) as these may be signs of hypomagnesemia. [see Warnings and Precautions
`5.19]
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`FDA-APPROVED PATIENT MEDICATION GUIDE
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`What should I tell my doctor before taking DRUG NAME?
`Before you take DRUG NAME, tell your doctor if you:
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`• have been told that you have low magnesium levels in your blood
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`What are the possible side effects of DRUG NAME?
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`• Serious allergic reactions. Tell your doctor if you get any of the following
`symptoms with DRUG NAME.
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`rash
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`face swelling
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`throat tightness
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`• difficulty breathing
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`Reference ID: 2949897
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`Your doctor may stop DRUG NAME if these symptoms happen.
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`• Low magnesium levels in your body. This problem can be serious. Low
`magnesium can happen in some people who take a proton pump inhibitor
`medicine for at least 3 months. If low magnesium levels happen, it is usually after
`a year of treatment. You may or may not have symptoms of low magnesium.
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`Page 3 of 5
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`Tell your doctor right away if you have any of these symptoms of low magnesium levels:
`o seizures
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`o dizziness
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`o feeling your heart beat in your chest
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`o abnormal or fast heart beat, or skipped heartbeat
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`o
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`jitteriness
`o
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`jerking movements or shaking (tremors)
`o muscle weakness
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`o spasms of the hands and feet
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`o cramps or muscle aches
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`o spasm of the voice box
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`Your doctor may check the level of magnesium in your body before you start taking
`Vimovo, or during treatment; or if you will be taking Vimovo for a long period of time.
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`We have completed our review of this supplemental application, as amended. It is 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, text for the
`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
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`Reference ID: 2949897
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`[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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`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 Stacy Barley, Senior Regulatory Project Manager, at (301) 796-
`2137.
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`Sincerely,
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`{See appended electronic signature page}
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`Joyce Korvick, M.D., M.P.H.
`Deputy Director for Safety
`Division of Gastroenterology and Inborn Errors Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 2949897
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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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`JOYCE A KORVICK
`05/20/2011
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`Reference ID: 2949897
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