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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021272/S-020
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`United Therapeutics Corporation
`Attention: Rex Mauthe
`Associate VP, Regulatory Affairs
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`55 TW Alexander Drive
`P.O. Box 14186
`Research Triangle Park, NC 27709
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`Dear Mr. Mauthe:
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`Please refer to your Supplemental New Drug Application (sNDA) dated and received May 23, 2013,
`submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Remodulin
`(treprostinil) 20 mg, 50 mg, 100 mg, and 200 mg for Injection.
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`This “Prior Approval” supplemental new drug application provides for labeling revised as follows
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`(additions are marked as underlined text and deletions are marked as strikethrough text):
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`1. In HIGHLIGHTS, the following text was added/deleted:
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`Dosage and Administration (2.1)
`Warnings and Precautions (5.1)
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` 1/2010 09/2013
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` 1/2010 09/2013
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`2. In HIGHLIGHTS/DOSAGE AND ADMINISTRATION, the following text was
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`deleted from the first bullet:
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`
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`Initial dose for patients new to prostacyclin infusion therapy: 1.25 ng/kg/min
`(or 0.625 ng/kg/min if not tolerated); dose increase based on clinical response
`(increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment,
`later 2.5 ng/kg/min per week). Limited experience with doses > 40
`mg/kg/min. Abrupt cessation of infusion should be avoided. (2.2, 2.3)
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`3. In INDICATIONS AND USAGE/Pulmonary Arterial Hypertension, the following
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`text was added to the second paragraph of the first section:
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`It may be administered as a continuous subcutaneous infusion or continuous
`intravenous (IV) infusion; however, because of the risks associated with chronic
`indwelling central venous catheters, including serious blood stream infections
`(BSIs), continuous intravenous infusion should be reserved for patients who are
`intolerant of the subcutaneous route, or in whom these risks are considered
`warranted. [see Warnings and Precautions 5.1]
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`Reference ID: 3379327
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` NDA 021272/S-020
`Page 2
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`4.
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` Under DOSAGE AND ADMINISTRATION/General, the following text was
`added/deleted:
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`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of
`treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). Remodulin can be
`administered as supplied or diluted for intravenous infusion with Sterile Water for
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`Injection, 0.9% Sodium Chloride Injection, Sterile Diluent for Flolan, or Sterile
`Diluent for Epoprostenol Sodium for Injection prior to administration.
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`5. Under DOSAGE AND ADMINISTRATION/Dosage Adjustments, the following text
`was deleted from the second paragraph:
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`The infusion rate should be increased in increments of 1.25 ng/kg/min per week
`for the first four weeks of treatment and then 2.5 ng/kg/min per week for the
`remaining duration of infusion, depending on clinical response. Dosage
`adjustments may be undertaken more often if tolerated. There is little experience
`with doses > 40 mg/kg/min. Abrupt cessation of infusion should be avoided [see
`Warnings and Precautions (5.4)]. Restarting a Remodulin infusion within a few
`hours after an interruption can be done using the same dose rate. Interruptions for
`longer periods may require the dose of Remodulin to be re-titrated.
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`6. Under DOSAGE AND ADMINISTRATION/Intravenous Administration, the
`following text was added/deleted to the first, second, and sixth paragraphs:
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`Remodulin must be diluted with either Sterile Water for Injection, 0.9%
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`Sodium Chloride Injection, or Flolan Sterile Diluent for Flolan, or Sterile
`Diluent for Epoprostenol Sodium for Injection and is administered
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`intravenously by continuous infusion, via a surgically placed indwelling central
`venous catheter, using an infusion pump designed for intravenous drug delivery.
`If clinically necessary, a temporary peripheral intravenous cannula, preferably
`placed in a large vein, may be used for short term administration of Remodulin.
`Use of a peripheral intravenous infusion for more than a few hours may be
`associated with an increased risk of thrombophlebitis. To avoid potential
`interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and infusion sets. The ambulatory infusion pump used to
`administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no
`delivery, low battery, programming error and motor malfunction alarms, (3) have
`delivery accuracy of ±6% or better of the hourly dose, and (4) be positive pressure
`driven. The reservoir should be made of polyvinyl chloride, polypropylene or
`glass.
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`Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.
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`The calculated amount of Remodulin Injection is then added to the reservoir along
`with the sufficient volume of diluent (Sterile Water for Injection, 0.9% Sodium
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`Chloride Injection, or Flolan Sterile Diluent for Flolan, or Sterile Diluent for
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`Reference ID: 3379327
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` NDA 021272/S-020
`Page 3
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` Epoprostenol Sodium Injection) to achieve the desired total volume in the
`reservoir.
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`7. Under WARNINGS AND PRECAUTIONS/Risks Attributable to the Drug Delivery
`System, the following text was added to the first paragraph:
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`In an open-label study of IV treprostinil (n=47), there were seven catheter-related
`line infections during approximately 35 patient years, or about 1 BSI event per 5
`years of use. A CDC survey of seven sites that used IV treprostinil for the
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`treatment of PAH found approximately 1 BSI (defined as any positive blood
`culture) event per 3 years of use. Administration of IV Remodulin with a high pH
`glycine diluent such as Sterile Diluent for Flolan or Sterile Diluent for
`Epoprostenol Sodium has been associated with a lower incidence of BSIs
`compared to neutral diluents (sterile water, 0.9% sodium chloride) when used
`along with catheter care guidelines.
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`8. Under ADVERSE REACTIONS/Adverse Events during Chronic Dosing, the
`following text was added:
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`The safety of Remodulin was also studied in a long-term, open-label extension
`study in which 860 patients were dosed for a mean duration of 1.6 years, with a
`maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of
`at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic
`dosing study was similar to that observed in the 12-week placebo controlled study
`except for the following suspected adverse drug reactions (occurring in at least
`3%): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.
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`9. Under HOW SUPPLIED/STORAGE AND HANDLING, the following text was
`added/deleted from the second paragraph:
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`During use, a single reservoir (syringe) of undiluted Remodulin can be
`administered up to 72 hours at 37C. Diluted Remodulin Solution can be
`administered up to 48 hours at 37C when diluted to concentrations as low as
`0.004 mg/mL in Sterile Water for Injection, 0.9% Sodium Chloride Injection, or
`Flolan Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium
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`Injection. A single vial of Remodulin should be used for no more than 30 days
`after the initial introduction into the vial.
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`Remodulin Injection is supplied as:
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`10. Under PATIENT COUNSELING INFORMATION, the following text was
`added/deleted:
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`Patients receiving Remodulin should be given the following information:
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`Remodulin is infused continuously through a subcutaneous or surgically placed
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`indwelling central venous catheter, via an infusion pump. Patients should use an
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`Reference ID: 3379327
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`Page 4
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`infusion set with an in-line filter. Therapy with Remodulin will be needed for
`prolonged periods, possibly years, and the patient's ability to accept and care for a
`catheter and to use an infusion pump should be carefully considered. In order to
`reduce the risk of infection, aseptic technique must be used in the preparation and
`administration of Remodulin. Additionally, patients should be aware that
`subsequent disease management may require the initiation of an alternative
`intravenous prostacyclin therapy, Flolan (epoprostenol sodium).
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`US Patent No. 5,153,222 (Use Patent)
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`Copyright 20112013 United Therapeutics Corp. All rights reserved.
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`11. The revision date was updated.
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`There are no other changes from the last approved package insert.
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`We have completed our review of this supplemental application, and 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
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`[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), 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 titled “SPL
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`Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM0723
`92.pdf.
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`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
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`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
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`proposed materials in draft or mock-up form with annotated references, and (3) the package insert(s) to:
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`Reference ID: 3379327
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` NDA 021272/S-020
`Page 5
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`Food and Drug Administration
`Center for Drug Evaluation and Research
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`Division of Drug Marketing, Advertising, and Communications
`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 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.
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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
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`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, please call:
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`Lori Anne Wachter, RN, BSN
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`Regulatory Project Manager for Safety
`(301) 796-3975
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`Sincerely,
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`{See appended electronic signature page}
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`Mary Ross Southworth, PharmD.
`Deputy Director for Safety
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 3379327
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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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`MARY R SOUTHWORTH
`09/26/2013
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`Reference ID: 3379327
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