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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 203496/S-002
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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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` United Therapeutics Corporation
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` Attention: United Therapeutics Corporation
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` Attention: Rex Mauthe, MBA
` Assoc. VP, Regulatory Affairs
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` 55 TW Alexander Drive, P.O. Box 14186
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` 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 March 31, 2015,
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`received March 31, 2015, and your amendments, submitted under section 505(b) of the Federal
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`Food, Drug, and Cosmetic Act (FDCA) for Orenitram (treprostinil) Extended Release Tablets,
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`0.125 mg, 0.25 mg, 1 mg, and 2.5 mg.
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`This “Prior Approval” supplemental new drug application provides for revisions as follows
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`(additions noted in underline, deletions noted in strikethrough):
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`In the DOSAGE AND ADMINISTRATION section, new subsection 2.2 Transitioning from
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`Subcutaneous or Intravenous Routes of Administration of Treprostinil was added to the
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`package insert
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`2.2 Transitioning from Subcutaneous or Intravenous Routes of Administration of
`Treprostinil
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`Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram. The
`dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram
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`simultaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can
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`be used to estimate a comparable total daily dose of Orenitram in mg using a patient’s dose of
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`IV/SC treprostinil (in ng/kg/min) and weight (in kg).
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`Orenitram total daily dose (mg) = 0.0072 X Remodulin dose (ng/kg/min) X weight (kg)
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`In the DOSAGE AND ADMINISTRATION section, subsection 2.4 Interruptions and
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`Discontinuation was changed to subsection 2.5, with the following change:
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`If a dose of medication is missed, the patient should take the missed dose as soon as possible,
`with food. If a patient misses two or more doses, restart at a lower dose and re-titrate.
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`In the event of a planned short-term treatment interruption for patients unable to take oral
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`medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To
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`Reference ID: 3878392
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` NDA 203496/S-002
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` Page 2
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` calculate the total daily dose (mg) of treprostinil for the parenteral route divide the oral total
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` daily dose by 5 use the following equation
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` Remodulin (ng/kg/min) = 139 X Orenitram total daily dose (mg)
`weight (kg)
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` When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings
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` and Precautions (5.1)].
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`In the WARNINGS AND PRECAUTIONS section, subsection 5.3 Increased Exposure with
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`Alcohol was deleted.
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`In the ADVERSE REACTIONS section, subsection 6.1 Clinical Trials Experience, the
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`following paragraph was added to the end of the subsection:
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`The safety of Orenitram was also evaluated in an open-label study transitioning patients from
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`Remodulin. The safety profile during this study was similar to that observed in the three pivotal
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`studies.
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`In the DESCRIPTION section, the last sentence of the second paragraph was edited to read:
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`Orenitram tablets are formulated in four strengths, which contain 0.125 mg of treprostinil
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`(equivalent to 0.159 mg treprostinil diolamine), 0.25 mg of treprostinil (equivalent to 0.317 mg
`treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg treprostinil diolamine), or 2.5
`mg of treprostinil (equivalent to 3.17 mg treprostinil diolamine). The formulations also contain
`xylitol, maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose acetate, triethyl
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`citrate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In addition tablets
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`may contain colorants FD&C Blue #2, iron oxide yellow, and iron oxide red. The imprinting ink
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`contains shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl alcohol, and
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`propylene glycol, and ammonium hydroxide.
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`In the CLINICAL PHARMACOLOGY section, subsection 12.3 Pharmacokinetics,
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`subheading Absorption, the following sentence was added to the end of the first paragraph:
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`Absorption
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`The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil
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`concentrations occur between approximately 4 and 6 hours following Orenitram administration.
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`Time to reach steady-state concentrations for both BID and TID regimens is approximately 1 to
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`2 days.
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`In the NONCLINICAL TOXICOLOGY section, subsection 13.1 Carcinogenesis,
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`Mutagenesis, Impairment of Fertility, the following changes were made:
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`Treprostinil diolamine did not demonstrate any carcinogenic effects in mouse or rat
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`carcinogenicity studies. Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10
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`and 20 mg/kg/day in males and 0, 3, 7.5 and 15 mg/kg/day in females daily for 26 weeks did not
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`Reference ID: 3878392
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` Page 3
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` significantly increase the incidence of tumors. The exposures obtained at the highest dose levels
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` used in males and females are about 8- and 17-fold, respectively, the human exposure at the
` mean dose of 3.4 mg BID. Oral administration of treprostinil diolamine to Sprague Dawley rats
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`at 0, 1, 3 and 10 mg/kg/day daily for 104 weeks did not significantly increase the incidence of
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`tumors. The exposures obtained at the highest dose levels used in males and females are about
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`21- and 29-fold, respectively, the human exposure.
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`In vitro genotoxicity studies with high doses of treprostinil did not demonstrate any mutagenic or
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`clastogenic effects. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did
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`not induce an increased incidence of micronucleated polychromatic erythrocytes.
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` No adverse effect doses for fertility, fetal viability / growth, fetal development (teratogenicity),
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` and postnatal development were determined in rats. In pregnant rabbits, external fetal and soft
` tissue malformations and fetal skeletal malformation occurred with the no observed adverse
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` effect level for these adverse effects of 0.5 mg/kg/day (5 times the human exposure) [see Use in
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` Specific Populations (8.1)].
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` In the CLINICAL STUDIES section, subsection 14.1 Clinical Trials in Pulmonary Arterial
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` Hypertension (PAH), subheader “Remodulin to Orenitram Transition Study” was added, to read
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` as follows:
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` Remodulin to Orenitram Transition Study
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`A 24-week, multicenter, open-label study enrolled 33 WHO Group 1 patients on stable doses of
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`Remodulin. All patients received background therapy with a PDE-5 inhibitor and/or ERA.
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`Patients were WHO Functional Class I or II and hemodynamically stable at baseline with a
`cardiac index >2.2 L/m2, RAP<11 mmHg, and PVR<10 Woods units. The primary endpoint of
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`the study was the safety and tolerability of the transition. Successful transition was defined as
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`transition from Remodulin to Orenitram at Week 4 (no longer receiving Remodulin) and
`clinically maintained on Orenitram through Week 24 (as measured by 6MWD and
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`hemodynamics).
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`All patients transitioned from Remodulin to Orenitram (median time to transition of 3 days;)
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`with thirty-one patients (94%) completing transition in 5 days (range 2 to 29 days).Two subjects
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`discontinued Orenitram. The mean Orenitram total daily dose at the end of transition was 27 mg
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`± 12 mg compared to a mean Remodulin dose prior to transition of 59 ng/kg/min (25 to 111
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`ng/kg/min). The mean Orenitram total daily dose at Week 24 was 36 mg ± 16 mg.After 24 weeks
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`of treatment with Orenitram, 6MWD and hemodynamics remained stable. Without a control
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`group, these data must be interpreted cautiously.
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`In the PATIENT COUNSELING INFORMATION section, the last bullet was deleted as
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`follows:
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` Tell patients:
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` • Abrupt discontinuation of therapy could result in worsening of PAH symptoms.
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`Reference ID: 3878392
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` NDA 203496/S-002
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` Page 4
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` • Take Orenitram with food.
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` • Swallow Orenitram tablets whole. Do not split, chew, crush, or break. Do not take a tablet that is
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` damaged or broken.
` • The biologically inert components of the tablet remain intact during gastrointestinal transit and are
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` eliminated in the feces as an insoluble shell.
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`• Do not take Orenitram with alcohol.
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` APPROVAL & LABELING
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` We have completed our review of this supplemental application, as amended. It is approved,
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` effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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` 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
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
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`patient package insert), with the addition of any labeling changes in pending “Changes Being
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`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
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`labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
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`“SPL Standard for Content of Labeling Technical Qs and As at
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`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 that includes labeling changes
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`Reference ID: 3878392
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` NDA 203496/S-002
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` Page 5
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` REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
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`from this requirement.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
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`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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`CM443702.pdf ).
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
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`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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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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`Reference ID: 3878392
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` NDA 203496/S-002
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` Page 6
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` If you have any questions, call Wayne Amchin, Regulatory Project Manager, at (301) 796-0421.
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`Sincerely,
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`{See appended electronic signature page}
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`Norman Stockbridge, M.D., Ph.D.
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`Director
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`Division of Cardiovascular and Renal Products
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`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
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`Content of Labeling
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`Reference ID: 3878392
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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
`01/28/2016
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`Reference ID: 3878392
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