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`ADMINISTRAT I ON
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` NDA 22511-S28
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`SUPPLEMENT APPROVAL
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`Horizon Medicines LLC
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` Attention: Colleen Westerman
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` Manager, Regulatory Affairs
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` 1 Horizon Way
` Deerfield, IL 60015
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` Dear Ms. Westerman:
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` Please refer to your supplemental new drug application (sNDA) dated December 22,
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` 2022, received, and your amendments, submitted under section 505(b)(2) of the
` Federal Food, Drug, and Cosmetic Act (FDCA) for Vimovo (naproxen and
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` esomeprazole magnesium) delayed-release tablets.
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` We also refer to our letter dated November 22, 2021, notifying you, under Section
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` 505(o)(4) of the FDCA, of new safety informations that we believe should be included in
` the labeling for following risks:
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`• hypocalcemia and hypokalemia in patients treated with PPIs for at least three
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` months.
`• severe cutaneous adverse reactions which includes, acute generalized
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` exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and
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` systemic symptoms (DRESS).
`• hyponatremia.
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` This supplemental new drug application provides for revisions to the labeling for
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` Vimovo. The agreed upon changes to the language included in our November 22, 2021,
` letter are as follows (additions are noted by underline and deletion are noted by
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` strikethrough).
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` 5.24 Hypomagnesemia and Mineral Metabolism
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` Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients
` treated with PPIs for at least three months, in most cases after a year of therapy.
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` Serious adverse reactions include tetany, arrhythmias, and seizures. Hypomagnesemia
` may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying
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` hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia
` required magnesium replacement and discontinuation of the PPI.
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`Reference ID: 4947201
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

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` NDA 22511-S28
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` Page 2
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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
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` treatment and periodically [see Adverse Reactions (6.2)].
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` Consider monitoring magnesium and calcium levels prior to initiation of VIMOVO and
` periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g.,
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` hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If
` hypocalcemia is refractory to treatment, consider discontinuing the PPI.
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` APPROVAL & LABELING
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` We have completed our review of this application, as amended. It is approved, effective
` on the date of this letter, for use as recommended in the enclosed agreed-upon labeling
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` with minor editorial revision listed below and reflected in the enclosed labeling.
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`• Removed double underline in section 5.24.
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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
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` content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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` the FDA automated drug registration and listing system (eLIST), as described at
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` FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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` Prescribing Information, and Medication Guide), with the addition of any labeling
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`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
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` 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
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` industry SPL Standard for Content of Labeling Technical Qs and As.2
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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 that include labeling
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` changes for this NDA, including CBE supplements for which FDA has not yet issued an
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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` U.S. Food and Drug Administration
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` Silver Spring, MD 20993
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` www.fda.gov
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`Reference ID: 4947201
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`(b) (4)
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` NDA 22511-S28
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` Page 3
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` action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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` annual reportable changes. To facilitate review of your submission(s), provide a
` highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
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` Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
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` REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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` If you have any questions, call Jay Fajiculay, Pharm.D., Regulatory Project Manager, at
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` (301) 796-9007.
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` Sincerely,
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` {See appended electronic signature page}
`
` Joyce Korvick, M.D., M.P.H.
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` Deputy Director for Safety
` Division of Gastroenterology (DG)
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` Office of Immunology and Inflammation (OII)
` Center for Drug Evaluation and Research
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` ENCLOSURE(S):
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`• Content of Labeling
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`o Prescribing Information
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`o Medication Guide
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` U.S. Food and Drug Administration
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` Silver Spring, MD 20993
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` www.fda.gov
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`Reference ID: 4947201
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`

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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
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`JOYCE A KORVICK
`03/04/2022 12:26:27 PM
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`Reference ID: 4947201
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