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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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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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`NDA 21272/S-015
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`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`EVP, Regulatory Affairs and Compliance
`55 T.W. Alexander Drive
`PO Box 14186
`Research Triangle Park, NC 27709
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`Dear Mr. Bunce:
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`Please refer to your supplemental New Drug Application (sNDA) dated December 17, 2010,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Remodulin (treprostinil) 1, 2.5, 5, and 10 mg/mL Injection.
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`We also acknowledge receipt of your amendment dated January 28, 2011.
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`This Prior Approval sNDA provides for the following revisions to the labeling for Remodulin
`(treprostinil).
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`1. Under the first bullet in INDICATIONS AND USAGE, revise the following text
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`FROM
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`Remodulin is a prostacyclin vasodilator indicated for:
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`• Treatment of pulmonary arterial hypertension (PAH) in patients with NYHA
`Class II-IV symptoms, to diminish symptoms associated with exercise (1.1)
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`TO
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`Remodulin is a prostacyclin vasodilator indicated for:
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`• Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to diminish
`symptoms associated with exercise. Studies establishing effectiveness included
`patients with NYHA Functional Class II-IV symptoms and etiologies of
`idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-
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`Reference ID: 2902747
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` NDA 21272/S-015
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`Page 2
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`pulmonary shunts (23%), or PAH associated with connective tissue diseases
`(19%) (1.1)
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`Full Prescribing Information
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`2. In section 1.1 of INDICATIONS AND USAGE, revise the following text
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`FROM
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`1.1 Pulmonary Arterial Hypertension in Patients with NYHA
`Class II-IV Symptoms
`Remodulin is indicated for the treatment of pulmonary arterial hypertension in
`patients with NYHA Class II-IV symptoms [see Clinical Studies (14.1)] to diminish
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`symptoms associated with exercise. It may be administered as a continuous
`subcutaneous infusion or continuous intravenous infusion; however, because of the
`risks associated with chronic indwelling central venous catheters, including serious
`blood stream infections, continuous intravenous infusion should be reserved for
`patients who are intolerant of the subcutaneous route, or in whom these risks are
`considered warranted.
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`TO
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`1.1 Pulmonary Arterial Hypertension
`Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH)
`(WHO Group 1) to diminish symptoms associated with exercise. Studies establishing
`effectiveness included patients with NYHA Functional Class II-IV symptoms and
`etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital
`systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue
`diseases (19%) [see Clinical Studies (14.1)].
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`It may be administered as a continuous subcutaneous infusion or continuous
`intravenous infusion; however, because of the risks associated with chronic
`indwelling central venous catheters, including serious blood stream infections,
`continuous intravenous infusion should be reserved for patients who are intolerant of
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`the subcutaneous route, or in whom these risks are considered warranted.
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`Note that minor labeling revisions were made in section 14 of the labeling (CLINICAL
`STUDIES) to be consistent with the revisions made in section 1 (INDICATIONS AND
`USAGE).
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`3. In section 14.1 of CLINICAL STUDIES, revise the following text
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`Reference ID: 2902747
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` NDA 21272/S-015
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`Page 3
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` FROM
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`Two 12-week, multicenter, randomized, double-blind studies compared
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` continuous subcutaneous infusion of Remodulin to placebo in a total of 470
`patients with NYHA Class II-IV pulmonary arterial hypertension (PAH). PAH
`was primary in 58% of patients, associated with collagen vascular disease in 19%,
`and the result of congenital left to right shunts in 23%.
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`TO
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`Two 12-week, multicenter, randomized, double-blind studies compared
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`continuous subcutaneous infusion of Remodulin to placebo in a total of 470
`patients with NYHA Class II (11%), III (81%), or IV (7%) pulmonary arterial
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`hypertension (PAH). PAH was idiopathic/heritable in 58% of patients, associated
`with connective tissue diseases in 19%, and the result of congenital systemic-to-
`pulmonary shunts in 23%.
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`We note that you also revised the manufacturer information from “Remodulin
`manufactured by Baxter Pharmaceutical Solutions LLC” to “Remodulin manufactured
`for United Therapeutics Corp.”
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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, using the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert, Medication Guide) and include the
`labeling changes proposed in any pending “Changes Being Effected” (CBE) supplements.
`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
`pending “Changes Being Effected” (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.
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`Reference ID: 2902747
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` NDA 21272/S-015
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`Page 4
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`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
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`MedWatch Program
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`Office of Special Health Issues
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`Food and Drug Administration
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`10903 New Hampshire Ave
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`Building 32, Mail Stop 5353
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`Silver Spring, MD 20993
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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, please call Dan Brum, PharmD, BCPS, RAC, Regulatory Project
`Manager, at (301)796-0578.
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`Sincerely,
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`{See appended electronic signature page}
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`
`Norman Stockbridge, M.D., Ph.D.
`Director
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`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosure: Package Insert
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`Reference ID: 2902747
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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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`NORMAN L STOCKBRIDGE
`02/08/2011
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`Reference ID: 2902747
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