CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`214324Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`DIVISION OF CARDIOLOGY AND NEPHROLOGY
`
`Regulatory Project Manager Review
`
`NDA:
`
`Drug:
`Class:
`Applicant:
`
`214324
`
`Tyvaso DPI (Ctreprostinil)inhalation powder
`prostacyclin
`United Therapeutics Corp.
`
`Proposed Indications:
`
`Treatment ofpulmonary arterial hypertension (PAH; WHOGroup1) to
`improve exercise ability
`
`Treatment ofpulmonary hypertension associated with interstitial lung
`disease (PH-ILD; WHO Group3) to improve exercise ability
`
`Resubmission Stamp Date:
`Action Date:
`
`December 23, 2021
`May 23, 2022
`
`* BACKGROUND
`NDA 214324 provides for a new dosage form oftreprostinil, a dry powder for oral inhalation, for the
`treatment of 1) pulmonary arterial hypertension (PAH; WHO Group1) to improve exerciseability and 2)
`pulmonary hypertension associated with interstitial lung disease (PHILD; WHO Group 3) to improve
`exerciseability.
`
`On July 8, 2021, a Citizens Petition (CP) was submitted concerning the safety of excipient fumaryl
`diketopiperazine (FDKP). The review team addressed the impact of FDKP in its reviewsas did the
`Division Director in his Memo dated October 14, 2021.
`
`On September 16, 2021, the Office ofPharmaceutical Quality notified the Division that the Applicant’s
`drug substanceanalyticaltestingsite,
` ( © wasclassified as
`Official Action Indicated (OAT) in 2020 and cGMP issues remain unresolved. The Division issued a
`Discipline Review Letter on September 24, 2021, notifying the Applicantofthis facility issue and
`conveyedthat *...per 21 CFR 314.125, all manufacturing and testing processes must be adequate to
`preservethe identity, strength, quality, purity, and stability of the material produced and the proposed
`facilities must comply with the current good manufacturing practice regulations. This problem could
`impede approval.”
`
`A Complete Response Letter was issued on October 15, 2021, due to the aforementionedfacility issue. A
`Type A Meeting washeld with the Applicant on November 17, 2021 (minutes dated December 2, 2021).
`The application was resubmitted on December 23, 2021 and wasfiled as a Class|I resubmission on
`January 14, 2022. This resubmitted NDA indicated the withdrawal of the
`®facility andits
`replacement with two alternate drug substancetesting facilities,
`and United Therapeutics Corporation (Silver Spring, MD).
`
`(b) (4)
`
`Reference ID: 4988012
`
`

`

`NDA214324 — RPM Overview
`Page 2 of 4
`
`Although the original reviewsdid not indicate a safety concern of FDKP,the Division issued an
`information request (IR) to the Applicant on February 15, 2022, requesting clarification how data
`obtained from Study No. TIP-PH-101 (BREEZE)supported the pulmonary safety of Tyvaso DPIfor the
`proposedindications. The Applicant provided their response on February 18, 2022, which constituted a
`major amendmentto this application. A Review Extension — Major Amendmentletter was issued on
`February 23, 2022, extending the user fee goal date to May 23, 2022.
`
`This review only provides a summary of information contained in the resubmission. See previous RPM
`review dated October 15, 2021, for details pertaining to the review ofthe original submission.
`
`** REGULATORY TIMELINE and APPLICATION DETAILS
`e Original NDA StampDate:
`April 16, 2021
`e Complete Response Date:
`October 15, 2021
`e Type A Meeting (post action):
`November17, 2021
`e Resubmission Stamp Date:
`December 23, 2021
`e Major Amendment:
`February 18, 2022
`e Original PDUFA GoalDate:
`February 23, 2022
`e Extended PDUFA Goal Date:
`May 23, 2022
`e Action Date:
`May 23, 2022
`
`User Fee
`This submission is a Class 1 resubmission to a previously filed application, therefore no User Fee is
`required.
`
`Facilities
`
`©facility andits replacementwith
`This resubmitted NDAindicated withdrawalofthe
`two alternate drug substanceanalyticaltesting facilities,
`and United Therapeutics Corporation (Silver Spring, MD). The Office of
`Pharmaceutical Manufacturing Assessment (OPMA/OPQ) recommendedapprovalfor these new
`listed facilities. At the time of approval,all listed facilities were in good standing. For more
`information, refer to Integrated Quality Review dated January 31, 2022.
`
`Proprietary Name
`A request for Proprietary Name review of Tyvaso DPI was submitted to the original NDA on
`April 22, 2021, and was deemed“conditionally acceptable” (Aidoo, June 17, 2021). The Applicant
`resubmitted their request on December 23, 2021, and DMEPA concluded that the Applicant’s
`proposed proprietary name wasagain “conditionally acceptable” (Straka/Mehta/Tu, February 17,
`2022). A letter granting the name was issued on February 22, 2022.
`
`¢,
`
`LABELING REVIEW
`Package Insert
`The Divisioninitiated labeling negotiations with the Applicant on September 24, 2021 (first review
`cycle) and concluded on April 14, 2022 (second review cycle). Upon review of the package insert
`during the second review cycle, the Division included a Bronchospasm warning statement under
`Warnings and Precautions. Both the Applicant and FDA agreedtothis addition.
`
`Instructions for Use (IFU)
`Labeling negotiations pertaining to the IFU were completed duringthe first review cycle (refer to
`submission dated September 29, 2021).
`
`Reference ID: 4988012
`
`

`

`NDA214324 — RPM Overview
`Page 3 of 4
`
`Carton and Container Labeling
`Duringthe first review cycle, the Applicant submitted revisions to carton and container labels on
`August 13, 2021, and additional revisions to carton labels on October 1, 2021. There were no further
`comments from FDAafter the Applicant’s October 1, 2021 response. Upon further review during the
`second review cycle, DMEPAprovidedadditional formatting and layout commentsto the
`October 1, 2021, submission, which were issued to the Applicant via email on February 11, 2022. The
`Applicant incorporated the requested revisions on February 17, 2022: however, due to a global supply
`chain issue, they requested to launch Tyvaso DPI with carton labeling printed from the previous
`review cycle on October 1, 2021. FDA agreedto this request and required the Applicant submit a
`formalnotification to the NDA whencarton labeling has been received and implemented. For
`additional information, please refer to DMEPA Memo(Mehta, 5/23/22).
`
`For purposesof the action letter, the agreed upon carton and container labeling from submissions
`dated April 16, 2021 (blister labels), August 13, 2021 (titration kit and maintenancetray labels), and
`February 17, 2022 (institutional kit, maintenance,and titration kit carton labels) were included.
`
`7
`Od REVIEWS
`The followingisalist of discipline reviews obtained during this review. For more detail on reviews
`completed from the previous review cycle, refer to RPM review in DARRTSdated 10/15/21.
`
`(May 23, 2022 — Southworth, Stockbridge
`Clinical/Decisional Memo
`Recommended Action: Approval
`During the original review cycle, the clinical reviewer recommended approval based on the submitted
`data (Psotka, September 23, 2021). No new clinical data were included within the resubmission:
`however, DCN became aware of a CP submitted during the original review cycle (regulations.gov:
`FDA-2021-P-0714) which raised concerns about FDKP,an excipient included in Tyvaso DPI. An
`assessmentof the Tyvaso DPI drug productin the originalclinical review did notindicate a safety
`concern.
`
`To understand more fully the pulmonary safety of Tyvaso DPI and implications for labeling, FDA’s
`Adverse Event Reporting system (FAERS) wassearchedfor cases of acute bronchospasm associated
`with marketed Tyvaso inhalation solution (IS-treprostinil solution), the drug substance in Tyvaso
`DPI. Several cases of acute bronchospasm shortly after Tyvaso IS use were identified (see
`postmarketing review dated 5/3/2022). Another prostaglandin (Ventavis, NDA 21779) is associated
`with bronchospasm. Despite the absence ofclinical cases with Tyvaso DPI at this time,
`bronchospasm has been identified as a potential risk for the class of inhaled prostaglandins; therefore,
`language to address bronchospasm wasincluded into the Warnings and Precautions section of
`labeling. Both the Applicant and FDA agreedto include this new warning statement.
`
`OPQ- Integrated Quality Review (January 31, 2022 - Multiple reviewers)
`Recommended Action: Approval
`OPQ provided an integrated review and concluded the complete response issues are now adequately
`resolved from a quality perspective; therefore, recommending approval of this NDA. Their review
`detailed the withdrawal of © drug substancetesting facility and replacement with two new
`testing facilities,
`©@ and United
`Therapeutics Corporation (Silver Spring, MD). In addition, their review states “These two new
`facilities will now be responsible to conduct the drug substancetesting for © content,
`endotoxin, and microbial limits. All these three compendial (USP) tests and their methods were
`appropriately transferred. The tests were conducted on the new drug substancebatchesat these new
`testing sites. The testing data demonstrated acceptable results.”
`
`Reference ID: 4988012
`
`

`

`NDA 214324 – RPM Overview
`Page 4 of 4
`
`The review also stated that an expiration period of 18 months for the product, when refrigerated at
`controlled temperature of 2°C to 8°C (36°F to 46°F) in the commercial packaging is granted. In
`addition, the drug product in unopened blister cards/strips is permitted to be stored up to 5 weeks at
`room temperature.
`
`UTC claimed categorical exclusion and OPQ found the exclusion acceptable.
`
`For additional information, please refer to the OPQ integrated review for the previous NDA review
`cycle, dated September 30, 2021.
`
` CONCLUSION
`After taking into consideration all primary and consult reviews during the original and resubmission
`review, the Division issued an approval letter, signed by Norman Stockbridge, Division Director for
`NDA 214324 on May 23, 2022.
`
`Reference ID: 4988012
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`BRIAN T COONEY
`05/23/2022 12:34:30 PM
`
`Reference ID: 4988012
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis 2 (DMEPA 2)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`May 23, 2022
`Requesting Office or Division: Division of Cardiology and Nephrology (DCN)
`Application Type and
`NDA 214324
`Number:
`Product Name and Strength:
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA 2 Team Leader:
`
`Tyvaso DPI (treprostinil) inhalation powder,
`16 mcg, 32 mcg, 48 mcg, and 64 mcg
`United Therapeutics Corp.
`2021-795-4
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant communicated on February 11, 2022 that their revised carton labeling received on
`February 17, 2022 for Tyvaso DPI will not be ready in time for launch if the NDA is approved.
`As such, they requested to launch their product with the original labeling from October 1, 2021
`until they obtain labels printed in
` which may be delayed until the
` due to
`supply chain issues.
`
` CONCLUSION
`2
`The Applicant will need to launch their product with the already printed carton labeling
`submitted on October 1, 2021 due to supply issues. The revised carton labeling received on
`February 17, 2022 will begin to be utilized once they are printed in
` The difference
`between the two carton labeling was to bring prominence to the strength and net contents
`statement. As there was no change to any other content on the labeling we find this proposal
`acceptable.
`
`Reference ID: 4987836
`
`1
`
`24 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`HINA S MEHTA
`05/23/2022 10:06:44 AM
`
`Reference ID: 4987836
`
`

`

`PLY U.S. FOOD & DRUG
`ADMINISTRATION
`
`Memorandum
`
`From:
`
`Mary Ross Southworth, PharmD
`Deputy Director for Safety
`Division of Cardiology and Nephrology
`Office of Cardiology, Hematology, Endocrinology, and Nephrology/CDER/FDA
`
`Date:
`
`May 3, 2022
`
`Subject:|Acute Bronchospasm andinhaled prostaglandins (Tyvaso Inhalation Solution 22-387)
`
`Tyvasoinhalation solution (IS) is approved to improve exercise ability for pulmonary arterial hypertension (WHO
`group 1) and PH-ILD; WHO Group3) patients. DCN reviewed cases of acute bronchospasm associated with
`Tyvasoinhalation solution (IS), prompted by a citizen petition (Dkt. No. FDA-2021-P-0714 at regulations.gov)
`submitted to the FDA whichraised issues related to the pulmonary safety of an inhaled product for pulmonary
`hypertension. The following postmarketing cases were retrieved from FAERSthat describe bronchospasm in
`patients receiving Tyvaso IS and were reviewed:
`
`(b) (6)
`
`(b) (6)
`
`9 yo female
`Difficulty getting deep breaths after treatments for 10 to 15 minutes. Evidence of FEV1 drop post dose.
`
`(b) (6)
`
`(b) (6)
`
`54 yo female
`Dyspnea and bronchospasmafter starting inhaled Tyvaso. Resolved upondiscontinuation
`
`(b) (6)
`
`(b) (6)
`
`59 yo male
`Increased shortness of breath and bronchial spasms. Hospitalized.
`
`(b) (6)
`
`(b) (6)
`
`71 yo male
`Dose decreased and then discontinued due to bronchospasm and cough.
`
`(b) (6)
`
`(b) (6)
`
`Elderly female
`
`www.fda.gov
`
`Reference ID: 4977682
`
`

`

`
`
`Interoffice Memorandum — (continued) Page 2 of 2 pages
`
`Bronchospasm, unrelieved by rescue inhaler. Decreased dose.
`
`(b) (6)
`
`(b) (6)
`
`43 yo female
`Bronchospasm uponinitiation. Hospitalized. Resolved upon discontinuation.
`
`(b) (6)
`
`(b) (6)
`
`50 yo female
`Experienced shortness of breath, wheezing, bronchospasm whenstarting Tyvaso. Drug discontinued.
`
`The temporal association betweeninhalation of Tyvaso IS and the bronchospasm event, supports causality. We
`also note that another inhaled prostaglandin for use in PAH WHO Group 1 (Ventavis, NDA 21779) includes the
`following warningin its label:
`
`5.3
`
`Bronchospasm
`
`VENTAVIS inhalation can induce bronchospasm. Bronchospasm may be more severe or
`frequent in patients with a history of hyperreactive airways. VENTAVIShas not been evaluated
`in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute
`pulmonary infections.
`
`The presence of similar cases for both of these inhaled products and the knownirritant properties of
`prostaglandins support the conclusion that bronchospasmis a potential risk for the class of inhaled
`prostaglandins.
`
`To reflect this risk, the following will be added to the label for Tyvaso Inhalation Solution.
`
`5.4 Bronchospasm
`Like other inhaled prostaglandins, Tyvaso inhalation solution may cause acute
`bronchospasm. Patients with asthmaor chronic obstructive pulmonary disease (COPD), or
`otherbronchial hyperreactivity are at increased risk for bronchospasm. Ensure that such
`patients are treated optimally for reactive airway disease prior to and during treatment with
`Tyvaso inhalation solution.
`
`
`SS 1004819 Tyvaso safety review for DARRTs.docx
`
`Reference ID: 4977682
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARY R SOUTHWORTH
`05/03/2022 07:35:39 AM
`
`Reference ID: 4977682
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis 2 (DMEPA 2)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`February 18, 2022
`Requesting Office or Division: Division of Cardiology and Nephrology (DCN)
`Application Type and
`NDA 214324
`Number:
`Product Name and Strength:
`
`Tyvaso DPI (treprostinil) inhalation powder,
`16 mcg, 32 mcg, 48 mcg, and 64 mcg
`Applicant/Sponsor Name:
`United Therapeutics Corp.
`OSE RCM #:
`2021-795-3
`DMEPA 2 Safety Evaluator: Maximilian Straka, PharmD, FISMP
`DMEPA 2 Team Leader:
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised carton labeling received on February 17, 2022 for Tyvaso DPI.
`We reviewed the revised carton labeling for Tyvaso DPI (Appendix A) to determine if it is
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`The Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Straka, M. Review of Revised Label and Labeling Memo for Tyvaso DPI (NDA 214324). Silver Spring (MD):
`FDA, CDER, OSE, DMEPA 2 (US); 2022 FEB 10. RCM No.: 2021-795-2.
`1
`
`Reference ID: 4940415
`
`24 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MAXIMILIAN STRAKA
`02/18/2022 10:05:13 AM
`
`HINA S MEHTA
`02/18/2022 11:03:54 AM
`
`Reference ID: 4940415
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis 2 (DMEPA 2)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`February 10, 2022
`Requesting Office or Division: Division of Cardiology and Nephrology (DCN)
`Application Type and
`NDA 214324
`Number:
`Product Name and Strength:
`
`Tyvaso DPI (treprostinil) inhalation powder,
`16 mcg, 32 mcg, 48 mcg, and 64 mcg
`Applicant/Sponsor Name:
`United Therapeutics Corp. (UTC)
`OSE RCM #:
`2021-795-2
`DMEPA 2 Safety Evaluator: Maximilian Straka, PharmD, FISMP
`DMEPA 2 Team Leader:
`Hina Mehta, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`UTC submitted a response to the Complete Response (CR) on December 23, 2021 for NDA
`214324 Tyvaso DPI (treprostinil) inhalation powder. NDA 214324 received a CR on October 15,
`2021 due to facility inspection issues. As part of the response to complete response, UTC
`resubmitted the Prescribing Information (PI), Instructions for Use (IFU) and referenced the
`carton labeling previously submitted on October 1, 2021.
`
` CONCLUSION
`2
`The carton labeling is unacceptable from a medication error perspective. We note the strength
`statement may cause confusion as currently presented it is only displayed with the number in the
`box and the unit of measure per cartridge is stated outside of the strength. The established name
`is difficult to read. In addition, the prominence of the contents statement and type of “kit” should
`be increased. We provide our recommendations below.
`
`3 RECOMMENDATIONS FOR UNITED THERAPEUTICS, CORP.
`We recommend the following be implemented prior to approval of this NDA:
`A. Carton Labeling
`a. As currently presented strength lacks prominence and the unit of measure per
`cartridge is stated outside of the colored box. We recommend increasing the
`
`Reference ID: 4936163
`
`1
`
`

`

`prominence of the strength and including the “mcg per cartridge” be stated in the
`colored box as the numerical strength.
`b. As currently presented the type of kit and contents of kit lacks prominence. We
`recommend increasing the prominence (i.e. increasing the font) of the kit type and
`contents.
`c. As currently presented the established name is difficult to read. Increase the
`prominence of the established name taking into account all pertinent factors,
`including typography, layout, contrast, and other printing features in accordance
`with 21 CFR 201.10(g)(2).
`
`Reference ID: 4936163
`
`2
`
`24 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MAXIMILIAN STRAKA
`02/10/2022 02:46:05 PM
`
`HINA S MEHTA
`02/10/2022 03:07:47 PM
`
`Reference ID: 4936163
`
`

`

`DIVISION OF CARDIOLOGY AND NEPHROLOGY
`
`Regulatory Project Manager Review
`
`NDA:
`Drug:
`Class:
`Applicant:
`
`Proposed Indications:
`
`214324
`Tyvaso DPI (treprostinil) inhalation powder
`Prostacyclin analogue
`United Therapeutics Corp. (UTC)
`
`Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to
`improve exercise ability
`Treatment of pulmonary hypertension associated with interstitial lung
`disease (PH-ILD; WHO Group 3) to improve exercise ability
`
`Received Date:
`Complete Response date:
`PDUFA date:
`
`April 16, 2021
`October 15, 2021
`October 16, 2021
`
` REVIEW TEAM
`
`Center for Drug Evaluation and Research
`
`Office of Cardiology, Hematology, Endocrinology and Nephrology, Division of Cardiology and
`Nephrology (DCN)
` Norman Stockbridge, MD, PhD – Division Director
` Mary Ross Southworth, PharmD – Deputy Director for Safety
` Michael Monteleone, MS, RAC – Associate Director for Labeling
`Fred Senatore, MD, PhD – Clinical Team Leader
`
` Mitchell Psotka, MD, PhD – Clinical Reviewer
`
`Office of Pharmaceutical Quality (OPQ)
`Office of New Drug Products
` Mohan Sapru, PhD – Cross-Disciplinary Team Leader (CDTL)
` Akm Khairuzzaman, PhD – Application Technical Lead/Drug Product Reviewer
` Daniel Jansen, PhD – Drug Substance Reviewer
`Office of Pharmaceutical Manufacturing Assessment
` Alex Gontcharov, PhD – Process and Facility Reviewer
`Parnali Chatterjee, PhD – Biopharmaceutics
`
` Amanda Buskirk, PhD – Microbiology Reviewer
`
`Division of Pharmacology/Toxicology for Cardiology, Hematology, Endocrinology, and Nephrology
` Xuan Chi, MD, PhD – Non-clinical Team Leader
` Baichun Yang, PhD – Non-clinical Reviewer
`
`Reference ID: 4873476
`
`

`

`NDA 214324 – RPM Overview
`Page 2 of 7
`
`Office of Clinical Pharmacology, Division of Cardiometabolic & Endocrine Pharmacology
` Manoj Khurana, PhD – Clinical Pharmacology Team Leader
` Xiaomeng Xu, PhD – Clinical Pharmacology Reviewer
`
`Office of Regulatory Operations, Division of Regulatory Operations for Cardiology, Hematology,
`Endocrinology, & Nephrology
` Brian Cooney, MS, PSM – Regulatory Health Project Manager
` Bridget Kane, MS – Sr. Regulatory Health Project Manager
` Alexis Childers, RAC – Sr. Regulatory Health Project Manager
`
`Office of Surveillance and Epidemiology (OSE)
`Division of Medical Error Prevention and Analysis (DMEPA)
` Lolita White, PharmD – Associate Director for Human Factors
` Chi-Ming (Alice) Tu, PharmD – Associate Director for Nomenclature and Labeling
` Colleen Little, PharmD – Team Lead
` Ebony Whaley, PharmD – Safety Evaluator
` Murewa Oguntimein, PhD – Human Factors Specialist
`Division of Risk Management
` Cynthia LaCivita, PharmD – Director
` Laura Zendel, PharmD – Team Leader
` Brian Caruth, PharmD – Reviewer
`
`Office of Medical Policy
`Office of Prescription Drug Promotion (OPDP)
`Jim Dvorsky, PharmD – Team Leader
`
` David Foss, PharmD – Regulatory Review Officer
`Office of Medical Policy Initiatives, Division of Medical Policy Programs, Patient Labeling Team
`(PLT)
` Barbara Fuller, RN, MSN, CWOCN – Team Lead
` Ruth Mayrosh, PharmD – Reviewer
`
`Center for Devices and Radiological Health (CDRH)
`
`Office of Product Evaluation and Quality (OPEQ), Office of Health Technology 1, Division of Health
`Technology 1 C (Anesthesia, Respiratory, & ENT Devices)
` Dongbo Wang, PhD – Team Lead
`John S. Bender, PhD - Chemist
`
`
` BACKGROUND
`Treprostinil, a prostacyclin vasodilator developed by United Therapeutics Corporation (UTC), was
`originally approved in May 2002 (Remodulin; NDA 021272) as an injection for the treatment of
`pulmonary arterial hypertension (PAH) in patients with NYHA Class II-IV symptoms to diminish
`symptoms associated with exercise. Subsequently, the following dosage forms were approved: a
`solution for inhalation [NDA 022387 (Tyvaso), July 2009], extended-release tablets for oral
`administration [NDA 203496 (Orenitram), December 2013].
`
`Tyvaso (treprostinil) inhalation solution is also currently approved for the treatment of PAH (WHO
`Group 1) to improve exercise ability and for the treatment of pulmonary hypertension associated
`with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability.
`
`Reference ID: 4873476
`
`

`

`NDA 214324 – RPM Overview
`Page 3 of 7
`
` In June 2010, Tyvaso was granted orphan drug designation (#04-1891) for the treatment of PAH.
`
`Under IND 134582, UTC developed a new dosage form, an inhalation powder - treprostinil dry
`powder for inhalation (DPI). Treprostinil DPI is a drug-device combination product comprised of
`single-use cartridges of 16, 32, 48, or 64 mcg of treprostinil dry powder to be used with a dry powder
`inhaler. The drug product and device are manufactured by MannKind Corporation (DMF
`
`
`UTC conducted the following studies to evaluate the safety and tolerability of treprostinil DPI and to
`demonstrate similar exposure when compared to Tyvaso (treprostinil) inhalation solution:
`
` MKC-475-001: a phase 1, open-label, single-ascending dose study in healthy normal
`volunteers conducted to assess the safety and tolerability of treprostinil inhalation powder
` TIP-PH-101: a multicenter phase 1b, safety and tolerability study in which PAH subjects
`on a stable regimen of Tyvaso switched to a corresponding dose of treprostinil inhalation powder
` TIP-PH-102: a phase 1, single-center, randomized, crossover study comparing systemic
`exposures of treprostinil inhalation powder and Tyvaso in healthy normal volunteers.
`
`On April 16, 2021, UTC submitted NDA 214324 for Tyvaso DPI (treprostinil) inhalation powder (for
`oral inhalation) for the treatment of 1) pulmonary arterial hypertension (PAH; WHO Group 1) to
`improve exercise ability and 2) pulmonary hypertension associated with interstitial lung disease (PH-
`ILD; WHO Group 3) to improve exercise ability. To support this NDA, UTC provided cross-
`reference to Tyvaso, Remodulin, and Orenitram NDAs in addition to conducting the above-
`referenced studies.
`
`The Applicant requested Priority Review and submitted a Rare Pediatric Disease Priority Review
`Voucher (PRV BLA 761171). This Application was filed on June 15, 2021 and deemed a priority
`review.
`
`On July 8, 2021, a Citizens Petition was submitted concerning the safety of excipient fumaryl
`diketopiperazine (FDKP). The review team addressed the impact of FDKP in its reviews as did the
`Division Director in his Memo dated October 14, 2021.
`
`On September 16, 2021, OPQ notified the Division that the Applicant’s drug substance analytical
`testing site,
` (
` was classified as Official Action Indicated
`(OAI) in 2020 and cGMP issues remain unresolved. The Division issued a Discipline Review Letter
`on September 24, 2021 notifying the Applicant of this facility issue and conveyed that “…per 21 CFR
`314.125, all manufacturing and testing processes must be adequate to preserve the identity, strength,
`quality, purity, and stability of the material produced and the proposed facilities must comply with the
`current good manufacturing practice regulations. This problem could impede approval.”
`
`This issue was not able to be resolved during the review cycle. See Facilities and Discipline Review
`sections for further details and recommendations.
`
` REGULATORY TIMELINE and APPLICATION DETAILS
`Pre-NDA Meeting (WRO):
`November 19, 2020
`
` NDA Stamp Date:
`April 16, 2021
`Filing Meeting:
`May 17, 2021
`
`Filing Date:
`June 15, 2021
`
`Filing Letter:
`June 15, 2021
`
` Mid-cycle Meeting:
`July 15, 2021
`
`Reference ID: 4873476
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 214324 – RPM Overview
`Page 4 of 7
`
`
`
`
`PeRC Meeting
`PDUFA Date:
`
`September 21, 2021
`October 16, 2021
`
`User Fee
`UTC submitted payment on April 15, 2021 (User Fee ID #3017970).
`
`Facilities
` is
` (FEI
`The drug substance analytical testing facility,
`currently classified as OAI; quality system and device deficiencies remain unresolved. All other sites
`were acceptable.
`
`Site Inspections
`The Clinical Pharmacology team requested Biopharmaceutical Inspections for the clinical and
`analytical sites for Study #TIP-PH-102 (Consult submitted May 26, 2021). The Office of Study
`Integrity and Surveillance (OSIS) stated that inspections were not warranted because the sites were
`recently inspected (2018) and found to be acceptable (Adeyemo, June 24, 2021).
`
`Proprietary Name
`The Applicant submitted a request for Proprietary Name review of Tyvaso DPI on April 22, 2021.
`DMEPA concluded that the Applicant’s proposed proprietary name was conditionally acceptable
`(Aidoo, June 17, 2021).
`
`Pediatric Review Committee (PeRC)
`This application triggered PREA. Since the Applicant received Orphan Drug Designation for the
`PAH indication, this indication was exempt from PREA requirements. For the PH-ILD indication, the
`Sponsor submitted a request for a full waiver for pediatric studies because the necessary studies are
`impossible or highly impracticable, as the number of pediatric patients with PH-ILD is extremely rare
`(Agreed iPSP, July 7, 2020; IND 134582). The Division and PeRC agreed with the Applicant’s
`request for waiver on September 21, 2021.
`
`Advisory Committee
`There was no Advisory Committee meeting for this NDA because this drug does not raise significant
`safety or efficacy issues.
`
`Review Status
`The Applicant submitted a Rare Pediatric Disease Priority Review Voucher (PRV BLA 761171). The
`Application was deemed a Priority Review.
`
` LABELING REVIEW
`The Division initiated labeling negotiations with the Applicant on September 24, 2021; the last
`version of the PI was submitted by the Applicant via email October 8, 2021 – the Division is in
`general agreement with this draft at the time of this action. The last version of the IFU was submitted
`on September 29, 2021; the Division had no further comments. Carton and containers comments were
`conveyed to UTC during the review cycle. There were no further comments after the Applicant’s
`October 1, 2021 response (SDN 12).
`
` DISCIPLINE REVIEWS
`Below are the conclusions reached by the primary review team. Please refer to DARRTS for
`complete reviews.
`
`Reference ID: 4873476
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 214324 – RPM Overview
`Page 5 of 7
`
`Divisional Memorandum (14Oct21 – Stockbridge)
`Recommended Action: Complete Response
`Dr. Stockbridge’s review addressed the impact of FDKP as an excipient. He stated that both he and
`the review team have “a low level of suspicion that FDKP will cause bronchospasm in patients with
`PAH, and this risk is not specifically named in proposed labeling of Tyvaso DPI”. Dr. Stockbridge
`concluded that the Division and OND concur with OPQ’s recommendation for a Complete Response
`due to
` OAI status.
`
`CDTL Memorandum (14Oct21 – Sapru)
`Recommended Action: Complete Response
`Dr. Sapru’s memo summarized each discipline’s review. He stated that after several inter-office
`meetings regarding the OAI status of
` he agreed with OPQ’s assessment to recommend a
`Complete Response.
`
`OPQ - Integrated Quality Review (30Sept21 – Multiple reviewers)
`Recommended Action: Complete Response
`OPQ provided an integrated review and concluded that all CMC information on this new drug
`product formulation is referenced in DMF #
` and found to be adequate to support approval. In
`addition, the review states