CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203496Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`203496 Orenitram (treprostinil) extended-release tablets
`
`Project Manager Overview
`
`NDA 203496 for Orenitram (treprostinil) extended-release tablets
`proposed indication: treatment of pulmonary arterial hypertension
`(PAH) (WHO Group 1) to improve exercise capacity
`PDUFA goal date: February 16, 2014
`Pharmacologic Class: prostacyclin analogue
`Type 3 NDA: New Dosage Form
`RPM: Wayne Amchin
`Class 2 Resubmission
`(6-month PDUFA review clock,
`21 CFR 314.110(b)(1))
`
`Regulatory Background
`
`Remodulin® (treprostinil) for subcutaneous (NDA 21272) and intravenous (NDA
`21272/s-002) administration was originally approved under Subpart H on May 21, 2002
`(NDA 21272) and November 24, 2004, respectively.
`
`Tyvaso® (treprostinil) inhalation solution (NDA 22387) was approved on July 30, 2009.
`
`NDA 203496 was submitted on December 24, 2011 and received on December 27,
`2011seeking to market a third dosage form of treprostinil diolamine (fourth route of
`administration). The original submission was reviewed under a standard 10-month
`review clock. Complete response actions on this NDA were taken on October 23, 2012
`and on March 22, 2013.
`
`The previous Complete Response was based on the finding that oral treprostinil had an
`effect on exercise capacity that was, by itself, too small to be clinically relevant when
`used alone. Orenitram had also failed to show even statistically significant effects on a
`background of another vasodilator in two studies of reasonable size.
`
`On December 21, 2012, a meeting was held between the DCRP and the applicant to
`discuss the clinical, statistical, and clinical pharmacology issues noted in the October
`23, 2012 Complete Response letter.
`
`In addition, on May 3, 2013, a meeting was held between the DCRP and the applicant to
`discuss the clinical and statistical issues noted in the March 22, 2013 Complete
`Response Letter.
`
`The Division Director’s review, dated December 20, 2013, states that those findings are
`still true and labeling reflects this. Oral administration avoids adverse consequences and
`inconveniences of currently approved intravenous, subcutaneous, and inhaled routes of
`administration, so replacing these uses—for which the efficacy data are no more
`compelling—seems useful. Thus labeling suggests such substitution while denying there
`are study data to support it. The current proposed label states to titrate the dose to
`tolerability, so getting the oral dose right should not be particularly difficult in such a
`1
`
`Reference ID: 3426539
`
`

`

`203496 Orenitram (treprostinil) extended-release tablets
`change of route of administration.
`
`Study number 302, conducted under IND number 71537
`
`The sponsor proposes the following four strengths of treprostinil extended-release tablets,
`0.125, 0.25, 1, and 2.5 mg.
`
`An orphan designation was granted on 02 November 1999 for the use of treprostinil in
`the treatment of pulmonary arterial hypertension. Pursuant to 21 CFR 314.55(d), drugs
`seeking approval for an orphan indication are exempt from PREA. Therefore, PeRC
`review was not necessary.
`
`The December 10, 2013 Product Quality review states on page 8 that the Office
`of Compliance has provided a final overall acceptable recommendation on December 9,
`2013, for all manufacturing and testing facilities for this NDA. The Office of
`Compliance Summary report is attached to the Product Quality report as pages 13-16.
`
`NDA Reviews and Memos
`
`Class 2 Resubmission (received August 16, 2013)
`
`Division Director/CDTL Memo
`Norman Stockbridge: December 20, 2013
`Dr. Stockbridge will sign the Approval letter.
`
`Product Quality Review
`Shastri Bhamidipati, December 10, 2013
`This was the only primary review for the current submission. It reaffirms
`approvability from the product quality perspective. No new data were reviewed
`
`DMEPA Proprietary Name Review
`Loretta Holmes and Irene Chan’s November 27, 2013 review deemed the proposed
`name acceptable.
`
`Labeling Reviews
`SEALD PI Review December 13, 2013
`OPDP/Patient Labeling PPI Joint Review on November 21, 2013
`DMEPA CCL Review, November 21, 2013
`OPDP CCL and PI reviews November 13, 2013 and October 18, 2013
`
`Reference ID: 3426539
`
`2
`
`

`

`203496 Orenitram (treprostinil) extended-release tablets
`Class 1 Resubmission (January 31, 2013)
`
`Division Director’s Memo
`
`Norman Stockbridge: March 22, 2013
`Dr. Stockbridge signed the complete response letter.
`
`CDTL Memo
`
`Abraham Karkowsky: March 5, 2013
`
`Dr. Karkowsky recommended taking a complete response.
`
`Clinical Review
`
`Maryann Gordon: June 17, 2013 (archived 9/16/13)
`
`This review highlighted the findings from previous reviews about the monotherapy
`and combination studies of treprostinil. No recommendation was made in this
`review.
`
`Product Quality Review
`
`Shastri Bhamidipati: March 22, 2013
`o)(4)
`In response to labeling issues identified by DMEPA
`and communicated in the CR letter, the sponsor has proposed to
`(m4) and change the color fihn-coat
`M0 to white. These changes were deemed
`
`eliminate
`for 0.125 mg strength tablet
`acceptable.
`
`Nonclinical Review
`
`Thomas Papoian: March 21, 2013
`
`This review summarized the carcinogenicity considerations and findings. It did not
`make an approvability recommendation.
`
`OSI Inspection Review
`
`Sharon Gershon, February 20, 2013
`This review of a foreign inspection concluded that the regulatory violations
`observed are minor and isolated, and unlikely to importantly impact the efficacy or
`safety of this study. The study appears to have been conducted adequately, and the
`data generated by this site appear acceptable in support of the respective indication.
`
`Original Submission (December 27, 2011)
`Division Director’s Memo
`
`Norman Stockbridge: October 23, 2012
`Dr. Stockbridge signed the complete response letter.
`
`CDTL Memo
`
`Abraham Karkowsky: October 18, 2012
`Dr. Karkowsky recommended taking a complete response.
`
`Clinical
`
`Maryann Gordon: October 3, 2012
`Dr. Gordon recommended taking a complete response action.
`3
`
`Reference ID: 3426539
`
`

`

`203496 Orenitram (treprostinil) extended-release tablets
`
`Biometrics
`John Lawrence: October 3, 2012 and October 10, 2012
`Dr. Lawrence recommended taking a complete response action.
`
`Reference ID: 3426539
`
`4
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`203496 Orenitram (treprostinil) extended-release tablets
`
`Clinical Pharmacology
`Sudharshan Hariharan: October 2 , 2012
`Dr. Hariharan recommended a thrice-daily dosing regimen, a regimen not used in the
`clinical studies.
`
`Nonclinical
`Xavier Joseph: October 3, 2012
`Dr. Joseph had no approvability issues.
`
`Biopharmaceutics
`Akm Khairuzzman: August 30, 2012
`Dr. Khairuzzaman had no approvability issues.
`
`CMC
`Shastri Bhamidipati: August 28, 2012 and October 19, 2012
`Dr. Bhamidipati had no approvability issues. The exclusion from environmental
`assessment was acceptable and facility inspections were acceptable.
`
`DMEPA
`Forest Ford, Irene Chan, and Kimberly Defronzo
`
`DMEPA rejected the following 3 proposed proprietary names:
`The sponsor submitted a fourth, Orenitram, that is under review. DMEPA
`provided comments on all aspects of labeling (e.g., carton, container, PI).
`
`Action Items:
`Approve the NDA
`
`Overview by Wayne Amchin
`December 20, 2013
`
`Reference ID: 3426539
`
`5
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WAYNE S AMCHIN
`12/20/2013
`
`Reference ID: 3426539
`
`

`

`Division of Cardiovascular and Renal Products
`
`REGULATORY PROJECT MANAGER LABELING REVIEW
`
`Application: NDA 203496
`
`Name of Drug: Orenitram (Treprostinil) Extended Release Tablets
`
`Applicant: United Therapeutics Corporation
`
`Labeling Reviewed
`
`Submission Date: December 18, 2013
`
`Receipt Date: December 18, 2013
`
`Background and Summary Description: NDA 203496 was originally submitted December 27,
`2011. A complete response action was taken on October 23, 2012. A class 1 resubmission was
`received on January 31, 2013, and a complete response action was taken on March 22, 2013. A
`class 2 resubmission was received on August 16, 2013.
`
`In response to the class 2 resubmission, labeling comments were conveyed to the applicant on
`November 5, 2013, by email. The applicant submitted a revised PI and PPI in response to those
`comments on November 12, 2013. The changes to the PPI were deemed acceptable and no
`further changes were requested.
`
`On December 13, 2013, SEALD completed their sign-off review of the End-of-Cycle Prescribing
`Information (PI). The SEALD review identified PLR format deficiencies and some other issues
`for DCRP to consider revisions to the Dosage and Administration Section and the Patient
`Counseling Information Section.
`
`On December 17, 2013, DCRP sent an information request to the applicant to request submission
`of an amended PI to address the PLR format deficiencies and additional edits DCRP requested to
`the Dosage and Administration Section and the Patient Counseling Information Section.
`
`Review
`
`On December 18, 2013, the applicant submitted an amendment with revisions to the PI to
`incorporate the changes requested by DCRP on December 17, 2013. This review compares the
`applicant’s December 18, 2013 PI submission to the PLR format changes requested and the PI
`with track changes provided in DCRP’s December 17, 2013 Information Request.
`
`The applicant made all the changes requested by DCRP. The applicant also proposed additional
`1
`
`Reference ID: 3426228
`
`

`

`minor formatting changes for consistency within the label. These changes involved header
`formatting case changes. The only issues I find in the 12/18/13 proposed PI are:
`1.
`In section 12.3, Pharmacokinetics, Subsection Special Populations, subheader Hepatic
`Impairment and Subheader Renal Impairment, the I in the word Impairment was changed
`to lower case i.
`In Section 17, Patient Counseling Information, a period is missing at the end of the
`opening statement “See FDA-approved patient labeling (Patient Package Insert)”.
`
`2.
`
`Recommendations
`I recommend approval of the labeling with correction to the two items above.
`
`Wayne Amchin
`Regulatory Project Manager
`
`12-19-13
`Date
`
`Reference ID: 3426228
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WAYNE S AMCHIN
`12/20/2013
`
`Reference ID: 3426228
`
`

`

`SEALD Director Sign-Off Review of the End-of-Cycle Prescribing Information:
`Outstanding Format Deficiencies
`
`
` Orenitram (treprostinil) Extended Release Tablets for oral
`
`
`.
`1
`administration
`Product Title
`
`Applicant
`United Therapeutics
`
`Application/Supplement Number
`NDA 203496
`Type of Application
`Original
`Indication(s)
`Treatment ofpuhnonary arterial hypertensron (PAH) ONHO Group 1)
`
`to improve exercrse capacrty
`
`
`I
`
`
`Office/Division
`ODE I/DCRP
`
`Division Pro'ect Mana er
`Wa
`e Amchin
`
`
`Date FDA Received Application
`August 16, 2013
`
`Goal Date
`February 16, 2014
`
`Date PI Received by SEALD
`December 11, 2013
`
`
`
`I
`i
`
`December 13, 2013
`SEALD Review Date
`
`SEALD Labeling Reviewer
`Elizabeth Donohoe
`
`Acting SEALD Division Director
`Sandra Kweder
`1 Product Title that appears in draft agreed-upon prescribing information (Pl)
`
`This Study Endpoints and Labeling Development (SEALD) Director sign-off review of the end-of-cycle,
`prescribing information (PI) for important format items reveals outstanding format deficiencies that
`should be corrected before taking an approval action. After these outstanding format deficiencies are
`corrected, the SEALD Director will have no objection to the approval of this PI.
`
`The Selected Requirements of Prescribing Information (SRPI) is a checklist of 42 important format PI
`items based on labeling regulations [21 CFR 201 .56(d) and 201.57] and guidances. The word “must”
`denotes that the item is a regulatory requirement, while the word “should” denotes that the item is
`based on guidance. Each SRPI item is assigned with one of the following three responses:
`
`0 NO: The PI does not meet the requirement for this item (deficiency).
`0 YES: The PI meets the requirement for this item (not a deficiency).
`
`0 N/A: This item does not apply to the specific PI under review (not applicable).
`
`Reference ID: 3421 626
`
`

`

`Selected Requirements of Prescribing Information
`
`
`
`
`
`Highlights
`See Appendix A for a sample tool illustrating the format for the Highlights.
`
`HIGHLIGHTS GENERAL FORMAT and HORIZONTAL LINES IN THE PI
`
`NO
`
`YES
`
`YES
`
`YES
`
`NO
`
`NO
`
`1. Highlights (HL) must be in a minimum of 8-point font and should be in two-column format, with
`½ inch margins on all sides and between columns.
`Comment: The top margin is less than 1/2 inch.
`2. The length of HL must be one-half page or less (the HL Boxed Warning does not count against
`the one-half page requirement) unless a waiver has been granted in a previous submission (e.g.,
`the application being reviewed is an efficacy supplement).
`Instructions to complete this item: If the length of the HL is one-half page or less, then select
`“YES” in the drop-down menu because this item meets the requirement. However, if HL is
`longer than one-half page:
` For the Filing Period:
` For efficacy supplements: If a waiver was previously granted, select “YES” in the drop-
`down menu because this item meets the requirement.
` For NDAs/BLAs and PLR conversions: Select “NO” because this item does not meet the
`requirement (deficiency). The RPM notifies the Cross-Discipline Team Leader (CDTL) of
`the excessive HL length and the CDTL determines if this deficiency is included in the 74-
`day or advice letter to the applicant.
` For the End-of-Cycle Period:
` Select “YES” in the drop down menu if a waiver has been previously (or will be) granted
`by the review division in the approval letter and document that waiver was (or will be)
`granted.
`Comment:
`3. A horizontal line must separate HL from the Table of Contents (TOC). A horizontal line must
`separate the TOC from the FPI.
`Comment:
`4. All headings in HL must be bolded and presented in the center of a horizontal line (each
`horizontal line should extend over the entire width of the column as shown in Appendix A). The
`headings should be in UPPER CASE letters.
`Comment:
`5. White space should be present before each major heading in HL. There must be no white space
`between the HL Heading and HL Limitation Statement. There must be no white space between
`the product title and Initial U.S. Approval. See Appendix A for a sample tool illustrating white
`space in HL.
`Comment: White space is missing before most major headings (it is present before I&U, DFS)
`6. Each summarized statement or topic in HL must reference the section(s) or subsection(s) of the
`Full Prescribing Information (FPI) that contain more detailed information. The preferred format
`is the numerical identifier in parenthesis [e.g., (1.1)] at the end of each summarized statement or
`topic.
`
`SRPI version 3: October 2013
`
`
`
`Page 2 of 10
`
`Reference ID: 3421626
`
`

`

`Selected Requirements of Prescribing Information
`
`Comment: A reference is missingfor the last paragraph under I&U.
`- 7. Section headings must be presented in the following order in HL:
`“——
`
`
`
`* RMC only applies to the BOED WARNING. INDICATIONS AND USAGE. DOSAGE AND
`ADMINISTRATION. CONTRAINDICATIONS. and WARNINGS AND PRECAUTIONS sections.
`
`Comment:
`
`HIGHLIGHTS DETAILS
`
`Highlights Heading
`
`- 8. At the beginning of I-IL, the following heading must be bolded and should appear in all UPPER
`CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”.
`
`Comment:
`
`Highlights Limitation Statement
`
`- 9. The bolded HL Limitation Statement must include the following verbatim statement: “These
`highlights do not include all the information needed to use (insert name of drug product)
`safely and effectively. See full prescribing information for (insert name of drug product)”
`The name of drug product should appear in UPPER CASE letters.
`
`Comment: The statement is not bolded and the name ofthe drugproduct is not in UPPER
`CASE.
`
`Product Title in Highlights
`- 10. Product title must be bolded.
`Comment:
`
`Initial U.S. Approval in Highlights
`- 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement “Initial U.S.
`Approvalz” followed by the 4-digit year.
`
`Comment:
`
`SRPI version 3: October 2013
`
`Reference ID: 3421626
`
`Page 3 0f 10
`
`

`

`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`
`
`Selected Requirements of Prescribing Information
`
`
`Boxed Warning (BW) in Highlights
`12. All text in the BW must be bolded.
`Comment:
`13. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if
`more than one warning, the term, “WARNING” and not “WARNINGS” should be used) and
`other words to identify the subject of the warning (e.g., “WARNING: SERIOUS
`INFECTIONS and ACUTE HEPATIC FAILURE”). The BW heading should be centered.
`Comment:
`14. The BW must always have the verbatim statement “See full prescribing information for
`complete boxed warning.” This statement should be centered immediately beneath the heading
`and appear in italics.
`Comment:
`15. The BW must be limited in length to 20 lines (this includes white space but does not include the
`BW heading and the statement “See full prescribing information for complete boxed
`warning.”).
`Comment:
`
`Recent Major Changes (RMC) in Highlights
`16. RMC pertains to only the following five sections of the FPI: BOXED WARNING,
`INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION,
`CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS. RMC must be listed in
`the same order in HL as the modified text appears in FPI.
`Comment:
`17. The RMC must include the section heading(s) and, if appropriate, subsection heading(s) affected
`by the recent major change, together with each section’s identifying number and date
`(month/year format) on which the change was incorporated in the PI (supplement approval date).
`For example, “Warnings and Precautions, Acute Liver Failure (5.1) --- 9/2013”.
`Comment:
`18. The RMC must list changes for at least one year after the supplement is approved and must be
`removed at the first printing subsequent to one year (e.g., no listing should be one year older than
`revision date).
`Comment:
`
`YES
`
`Indications and Usage in Highlights
`19. If a product belongs to an established pharmacologic class, the following statement is required
`under the Indications and Usage heading in HL: “(Product) is a (name of established
`pharmacologic class) indicated for (indication)”.
`Comment:
`
`N/A
`
`Dosage Forms and Strengths in Highlights
`20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted
`subheadings or tabular presentations of information should be used under the Dosage Forms and
`Strengths heading.
`
`SRPI version 3: October 2013
`
`
`
`Page 4 of 10
`
`Reference ID: 3421626
`
`

`

`YES
`
`NO
`
`NO
`
`
`
`
`
`Selected Requirements of Prescribing Information
`
`Comment:
`
`Contraindications in Highlights
`21. All contraindications listed in the FPI must also be listed in HL or must include the statement
`“None” if no contraindications are known. Each contraindication should be bulleted when there
`is more than one contraindication.
`Comment:
`
`Adverse Reactions in Highlights
`22. For drug products other than vaccines, the verbatim bolded statement must be present: “To
`report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at
`(insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch”.
`Comment: The proposed statement includes an email address; this should be deleted. See the
`Labeling Review Tool, page 10.
`
`Patient Counseling Information Statement in Highlights
`23. The Patient Counseling Information statement must include one of the following three bolded
`verbatim statements that is most applicable:
`If a product does not have FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION”
`If a product has FDA-approved patient labeling:
` “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling”
` “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide”
` Comment: The statement is not bolded and the words "PATIENT COUNSELING
`INFORMATION" are not in UPPER CASE.
`
`
`
`
`
`
`NO
`
`Revision Date in Highlights
`24. The revision date must be at the end of HL, and should be bolded and right justified (e.g.,
`“Revised: 9/2013”).
`Comment: The date is missing and should state: 12/2013
`
`SRPI version 3: October 2013
`
`
`
`Page 5 of 10
`
`Reference ID: 3421626
`
`

`

`
`
`Selected Requirements of Prescribing Information
`
`
`
`
`
`
` Contents: Table of Contents (TOC)
`See Appendix A for a sample tool illustrating the format for the Table of Contents.
`
`25. The TOC should be in a two-column format.
`Comment: Consider revising so the two columns are of equal length for improved readability.
`26. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING
`INFORMATION: CONTENTS”. This heading should be in all UPPER CASE letters and
`bolded.
`Comment: The heading is not bolded.
`27. The same heading for the BW that appears in HL and the FPI must also appear at the beginning
`of the TOC in UPPER CASE letters and bolded.
`Comment:
`28. In the TOC, all section headings must be bolded and should be in UPPER CASE.
`Comment:
`29. In the TOC, all subsection headings must be indented and not bolded. The headings should be in
`title case [first letter of all words are capitalized except first letter of prepositions (through),
`articles (a, an, and the), or conjunctions (for, and)].
`Comment: Subsection headings 16.1 and 16.2 are in UPPER CASE and should be in Title Case.
`30. The section and subsection headings in the TOC must match the section and subsection headings
`in the FPI.
`Comment: The heading for subsection 7.3 includes "on Treprostinil" in the TOC; this is missing
`from the FPI. Also, there is a dash "-" after 5.3 in the TOC that should be removed..
`31. In the TOC, when a section or subsection is omitted, the numbering must not change. If a section
`or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL
`PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the
`following statement must appear at the end of TOC: “*Sections or subsections omitted from the
`full prescribing information are not listed.”
`Comment:
`
`YES
`
`NO
`
`N/A
`
`YES
`
`NO
`
`NO
`
`YES
`
`SRPI version 3: October 2013
`
`
`
`Page 6 of 10
`
`Reference ID: 3421626
`
`

`

`
`
`
`
`
`
`Selected Requirements of Prescribing Information
`
`Full Prescribing Information (FPI)
`FULL PRESCRIBING INFORMATION: GENERAL FORMAT
`
`YES
`
`
`
`32. The bolded section and subsection headings in the FPI must be named and numbered in
`accordance with 21 CFR 201.56(d)(1) as noted below (section and subsection headings should
`be in UPPER CASE and title case, respectively). If a section/subsection required by regulation
`is omitted, the numbering must not change. Additional subsection headings (i.e., those not
`named by regulation) must also be bolded and numbered.
`
`
`
`BOXED WARNING
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`6 ADVERSE REACTIONS
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology (by guidance)
`12.5 Pharmacogenomics (by guidance)
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`Comment:
`33. The preferred presentation for cross-references in the FPI is the section (not subsection)
`heading followed by the numerical identifier. The entire cross-reference should be in italics and
`enclosed within brackets. For example, “[see Warnings and Precautions (5.2)]” or “[see
`Warnings and Precautions (5.2)]”.
`Comment:
`
`
`YES
`
`SRPI version 3: October 2013
`
`
`
`Page 7 of 10
`
`Reference ID: 3421626
`
`

`

`
`
`Selected Requirements of Prescribing Information
`
`
`34. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or
`subsections must be marked with a vertical line on the left edge.
`Comment:
`
`
`
`
`
`FULL PRESCRIBING INFORMATION DETAILS
`
`FPI Heading
`35. The following heading must be bolded and appear at the beginning of the FPI: “FULL
`PRESCRIBING INFORMATION”. This heading should be in UPPER CASE.
`Comment:
`BOXED WARNING Section in the FPI
`36. In the BW, all text should be bolded.
`Comment:
`37. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if
`more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and
`other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS
`INFECTIONS and ACUTE HEPATIC FAILURE”).
`Comment:
`CONTRAINDICATIONS Section in the FPI
`38. If no Contraindications are known, this section must state “None.”
`Comment:
`ADVERSE REACTIONS Section in the FPI
`39. When clinical trials adverse reactions data are included (typically in the “Clinical Trials
`Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or
`appropriate modification should precede the presentation of adverse reactions:
`
`“Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.”
`Comment:
`40. When postmarketing adverse reaction data are included (typically in the “Postmarketing
`Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or
`appropriate modification should precede the presentation of adverse reactions:
`
`“The following adverse reactions have been identified during post-approval use of (insert drug
`name). Because these reactions are reported voluntarily from a population of uncertain size, it is
`not always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.”
`Comment:
`PATIENT COUNSELING INFORMATION Section in the FPI
`41. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING
`INFORMATION section). The reference should appear at the beginning of Section 17 and
`
`
`
`
`
`
`
`
`
`N/A
`
`YES
`
`N/A
`
`N/A
`
`N/A
`
`YES
`
`N/A
`
`YES
`
`SRPI version 3: October 2013
`
`
`
`Page 8 of 10
`
`Reference ID: 3421626
`
`

`

`
`
`
`
`Selected Requirements of Prescribing Information
`
`YES
`
`include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Medication
`Guide, Instructions for Use).
`Comment:
`42. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for
`Use) must not be included as a subsection under section 17 (PATIENT COUNSELING
`INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon
`approval.
`Comment:
`
`
`SRPI version 3: October 2013
`
`
`
`Page 9 of 10
`
`Reference ID: 3421626
`
`

`

`Selected Requirements of Prescribing Information
`
`
`
`
`Appendix A: Format of the Highlights and Table of Contents
`
`
`
`
`
`
`
`
`SRPI version 3: October 2013 Page 10 of 10
`
`Reference ID: 3421626
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELIZABETH A DONOHOE
`12/13/2013
`
`ERIC R BRODSKY
`12/13/2013
`I agree. Eric Brodsky, SEALD labeling team leader, signing for Sandra Kweder, acting SEALD
`Division Director.
`
`Reference ID: 3421626
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Final Label Memorandum
`
`Date:
`
`November 21, 2013
`
`Reviewer:
`
`Team Leader:
`
`Janine Stewart, PharmD
`Division of Medication Error Prevention and Analysis
`Irene Z. Chan, PharmD, BCPS
`Division of Medication Error Prevention and Analysis
`Treprostinil Extended-release Tablets
`0.125 mg, 0.25 mg, 1 mg, 2.5 mg
`Application Type/Number: NDA 203496
`Applicant:
`United Therapeutics Corporation
`OSE RCM #:
`2013-2118
`
`Drug Name and Strengths:
`
`*** This document contains proprietary and confidential information that should not be released
`to the public. ***
`
`1
`
`Reference ID: 3410601
`
`

`

`INTRODUCTION
`1
`This memorandum evaluates the revised container labels for Treprostinil Extended- release
`Tablets, NDA 203496, submitted on October 29, 2013 (Appendix A). DMEPA previously
`reviewed the proposed labels and labeling under OSE Review # 2013-1345 dated October 17,
`2012.
`
`2 MATERIAL REVIEWED
`DMEPA reviewed the container labels submitted on October 29, 2013. We compared the
`revised labels against the recommendations contained in OSE Review # 2013-1345 dated
`October 17, 2012.
`
`3 CONCLUSIONS AND RECOMMENDATIONS
`The revised labels adequately address our concerns from a medication error perspective. We
`have no additional comments at this time.
`
`Please copy the Division of Medication Error Prevention and Analysis on any communication to
`the Applicant with regard to this review. If you have further questions or need clarifications,
`please contact OSE Regulatory Project Manager, Cherye Milburn, at 301-796-2048.
`
`2
`
`Reference ID: 3410601
`
`

`

`Appendix A: Retail Preferred Container Labels
`
`
`
`3
`
`Reference ID: 3410601
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JANINE A STEWART
`11/21/2013
`
`IRENE Z CHAN
`11/21/2013
`
`Reference ID: 3410601
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisional Agency Information****
`
`Memorandum
`
`Date:
`
`To:
`
`From:
`
`November 13, 2013
`
`Wayne Amchin
`Regulatory Project Manager
`Division of Cardiovascular and Renal Products(DCRP)
`
`Emily Baker, Pharm.D.
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Subject:
`
`NDA 203496
`OPDP Labeling Comments for Orenitram (treprostinil)
`Extended Release Tablets for oral administration
`
`OPDP has reviewed the proposed carton and container labeling submitted for
`consult on February 7, 2012, for Orenitram (treprostinil) Extended Release
`Tablets for oral administration. Our comments are based on the proposed
`labeling emailed to us on October 29, 2013.
`
`OPDP has no comments on the proposed carton and container labeling at this
`time.
`
`Thank you for the opportunity to comment on the proposed materials.
`
`If you have any questions, please contact Emily Baker at 301.796.7524 or
`emily.baker@fda.hhs.gov.
`
`Reference ID: 3406296
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a rep