`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 022387/S-014
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`United Therapeutics Corporation
`Attention: Rex Mauthe, MBA
`Associate Vice President, Regulatory Affairs
`
`55 TW Alexander Drive
`PO Box 14186
`
`Research Triangle Park, NC 27709
`
`Dear Mr. Mauthe:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received December 4, 2015,
`
`submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Tyvaso
`(treprostinil) 0.6 mg/mL Inhalation Solution.
`
`
`This supplemental new drug application provides for labeling revised as follows (additions are marked as
`underlined text and deletions are marked as strikethrough text):
`
`
`
`
`
`1. In HIGHLIGHTS/WARNINGS AND PRECAUTIONS, the following text was added/deleted
`
`from the first and third bullet:
`
`
`
`
`
`
`
`
`
`
` Safety and eEfficacy hasve not been established in patients with significant
`underlying lung disease (such as asthma or chronic obstructive pulmonary disease).
`
`(5.1)
`
`
` Tyvaso may inhibits platelet aggregation and increases the risk of bleeding,
`particularly in patients receiving anticoagulants. (5.4, 7.2)
`
`
`2. Under WARNINGS AND PRECAUTIONS, the following sections were updated:
`
`
`Patients with Pulmonary Disease or Pulmonary Infections
`5.1
`
`The safety and efficacy of Tyvaso have has not been established in patients with
`significant underlying lung disease (e.g., asthma or chronic obstructive pulmonary
`disease). Patients with acute pulmonary infections should be carefully monitored to detect
`any worsening of lung disease and loss of drug effect.
`
`
`Risk of Bleeding
`5.4
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.Since
`Tyvaso inhibits platelet aggregation, there may be an increased risk of bleeding,
`
`particularly among patients receiving anticoagulant therapy.
`
`
`
`
`
`Reference ID: 3940956
`
`

`

`NDA 022387/S-014
`Page 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3. Under ADVERSE REACTIONS/Adverse reactions Identified in Clinical Trials, the
`following fourth paragraph was added:
`
`In a prospective, observational study comparing patients taking Tyvaso (958 patient-
`years of exposure) and a control group (treatment with other approved therapies for PAH;
`1094 patient-years), Tyvaso was associated with a higher rate of cough (16.2 per 100
`patient-years vs. 10.9 per 100 pt-years), throat irritation (4.5 per 100 pt-years vs. 1.2 per
`100 pt-years), nasal discomfort (2.6 per 100 pt-years vs. 1.3 per 100 pt-years), and
`haemoptysis (2.5 per 100 pt-years vs. 1.3 per 100 pt-years) compared to the control
`
`group.
`
`
`
`4. Under USE IN SPECIFIC POPULATIONS/Pregnancy, the following text was added to the
`first paragraph:
`
`Pregnancy Category B
`
`There are no adequate and well controlled studies with Tyvaso in pregnant
`
`women. Animal reproduction studies have not been conducted with treprostinil
`administered by the inhalation route. However, studies in pregnant rabbits using
`continuous subcutaneous (sc) infusions of treprostinil sodium at infusion rates higher
`
`than the recommended human sc infusion rate resulted in an increased incidence of fetal
`skeletal variations associated with maternal toxicity. Also, a study in pregnant rabbits
`administered oral treprostinil diolamine at exposures higher than those in humans
`resulted in external fetal and soft tissue malformations and fetal skeletal malformations
`[see Nonclinical Toxicology (13.3)]. Animal reproduction studies are not always
`
`predictive of human response.
`
`
`5. Under NONCLINCAL TOXICOLOGY/ Carcinogenesis, Mutagenesis, Impairment of
`Fertility, the following was added as paragraphs 2, 3, and 4:
`
`
`
`Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10 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
`
`
`
`significantly increase the incidence of tumors. The exposures, when based on AUC,
`obtained at the highest dose levels used in males and females are about 208- and 460-
`fold, respectively, the human exposure following a single at the target maintenance dose
`
`of 54 mcg daily.
`
`
`
`Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not
`induce an increased incidence of micronucleated polychromatic erythrocytes.
`
`
`6. Under NONCLINCAL TOXICOLOGY/Developmental Toxicity, the following text was
`added as the second paragraph:
`
`In studies with treprostinil diolamine, no adverse effect doses for fetal viability/growth,
`fetal development (teratogenicity), and postnatal development were determined in rats. In
`pregnant rats, no evidence of harm to the fetus was observed following oral
`administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which
`represents about 154 and 1479 times the human exposure, when based on Cmax and AUC
`
`Reference ID: 3940956
`
`

`

`NDA 022387/S-014
`Page 3
`
`
`
`following a single dose of 54 mcg, respectively. In pregnant rabbits, external fetal and
`soft tissue malformations and fetal skeletal malformation occurred. The dose at which no
`adverse effects were seen (0.5 mg/kg/day) represents about 9 and 145 times the human
` exposure, when based on Cmax and AUC following a single dose of 54 mcg, respectively.
`
`
`
`
`
`7. The revision date was updated.
`
`
`There are no other changes from the last approved package insert.
`
`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.
`
`CONTENT OF LABELING
`
`
`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), 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.
`
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL
`
`Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM0723
`92.pdf.
`
`
`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 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).
`
`PROMOTIONAL MATERIALS
`
`
`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
`proposed materials in draft or mock-up form with annotated references, and (3) the package insert(s) to:
`
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`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
`
`Reference ID: 3940956
`
`

`

`NDA 022387/S-014
`Page 4
`
`
`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.
`
`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.
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80
`
`and 314.81).
`
`If you have any questions, please call:
`
`Lori Anne Wachter, RN, BSN
`Regulatory Project Manager for Safety
`
`(301) 796-3975
`
`
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`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
`
`
`ENCLOSURE:
`
`Content of Labeling
`
`Reference ID: 3940956
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`Lori A WACHTER
`06/03/2016
`
`MARY R SOUTHWORTH
`06/06/2016
`
`Reference ID: 3940956
`
`