CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
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`
`
`
` APPLICATION NUMBER:
`
`
` 208276Orig1s000
`
`
`
`
` OTHER REVIEW(S)
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`
`

`

`
`
` DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`Public Health Service
`
`Division of Pediatric and Maternal Health
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Silver Spring, MD 20993
`Tel 301-796-2200
`
`FAX 301-796-9744
`
`
`Pregnancy and Lactation Labeling Rule (PLLR) Labeling Review
`
`Date:
`
`From:
`
`
`6-5-2017
`
`
`
`Leyla Sahin, M.D.
`Medical Officer, Maternal Health
`Division of Pediatric and Maternal Health
`
`Through:
`
`Tamara Johnson, M.D., M.S.
` Team Leader, Maternal Health
` Division of Pediatric and Maternal Health
`
`To:
`
`Division of Cardiovascular and Renal Products
`
`Drug:
`
`
`Implantable System for Remodulin (treprostinil); NDA 208276
`
`Proposed Indications: • Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1)
` to diminish symptoms associated with exercise
` • To diminish the rate of clinical deterioration in patients with
` pulmonary arterial hypertension requiring transition from Flolan®
` (epoprostenol sodium)
`
`Proposed route of administration:
`
`Subject:
`
`Implantable system
`
`Pregnancy and Lactation Labeling Rule (PLLR) conversion as part of NDA for
`new route of administration
`
`Applicant: United Therapeutics
`
`Materials Reviewed: • Applicant’s proposed labeling
` • Approved Remodulin labeling (12-2014)
` • Applicant’s pregnancy and lactation safety review
`• Literature review
`
`Consult Question: Please assist with Pregnancy and Lactation Labeling
`
`Reference ID: 4107175
`Reference ID: 4409052
`
`1
`
`

`

`INTRODUCTION
`
`The applicant submitted an NDA for a new delivery system for Remodulin (treprostinil) on
`December 15, 2016. Remodulin is currently approved as an injection for subcutaneous or
`
`intravenous use. The Division of Cardiovascular and Renal Products (DCRP) consulted the
`Division of Pediatric and Maternal Health (DPMH) on April 5, 2017 to assist with Pregnancy
`and Lactation Labeling Rule (PLLR) labeling.
`
`BACKGROUND
`
`Product Background
`Remodulin (treprostinil) is a prostacyclin vasodilator indicated for the treatment of pulmonary
`arterial hypertension (PAH) (WHO Group 1) to diminish symptoms associated with exercise.
`Studies establishing effectiveness of Remodulin included patients with NYHA Functional Class
`II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with
`congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue
`diseases (19%) (1.1).
`
`In patients with pulmonary arterial hypertension requiring transition from Flolan® (epoprostenol
`sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The major
`pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial
`vascular beds, and inhibition of platelet aggregation.
`
`Remodulin was approved in 2002 as an injection, for subcutaneous or intravenous use.
`Treprostinil is also marketed (by the same manufacturer) as an inhalation solution (Tyvaso) and
`an extended release tablet (Orenitram).
`
`The half-life is 4 hours.
`
`Reviewer comment
`The receptor level mechanism of action is not described in approved labeling, but the
`literature describes different activity at different receptors. Unlike other prostacyclins that cause
`uterine contractions, treprostinil binds to the EP2 receptors that mediate vasodilation in the
`
`pulmonary vasculature, whereas uterine receptors are F2 and E2.1
`
`Disease Background in Pregnancy
`Data on pregnant women with PAH are limited. Pregnancies resulting in delivery occur rarely in
`
`women with PAH, as illustrated by results from a large US health survey reporting only 182
`
`deliveries in patients with idiopathic PAH (IPAH) out of an estimated 11.2 million deliveries
`
`between 2002 and 2004.2 A publication that summarized data from the Registry Of Pregnancy
`
`1 Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial
` hypertension. Respiratory Medicine 2010; 104; 9-21.
`
`2 Chakravarty EF et al. Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell
`disease. Obstet Gynecol. 2008; 111(4): 927–9342008.
`
`2
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`Reference ID: 4107175
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`and Cardiac Disease (ROPAC) of the European Society of Cardiology, covering cases in Europe
`and Africa observed between 2008 and 2014, showed high maternal mortality (4/7) in patients
`with IPAH, while pregnancy outcomes in pulmonary hypertension due to left heart disease (most
`often affecting the mitral valve) appeared more favorable (3 maternal death cases in 112
`pregnancies).3 The 2015 Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension
`
`state that pregnancy is associated with a high risk of maternal and fetal mortality and that
`pregnancy should be discouraged.2
`
`
`Current state of Remodulin labeling
`Currently approved Remodulin labeling is in the Physician Labeling Rule format. Remodulin is
`labeled pregnancy category B, based on the lack of adverse developmental findings in animals at
`exposures 16 (rat) and 5 (rabbit) times the average rate used in clinical trials on a surface area
`basis. There is no information about human pregnancy in labeling.
`
`The Nursing Mothers subsection states that it is not known whether treprostinil is excreted in
`human milk or absorbed systemically after ingestion.
`
`Pregnancy and Lactation Labeling Rule (PLLR)
`The Pregnancy and Lactation Labeling Rule (PLLR) went into effect on June 30, 2015.4 The
`PLLR requirements include a change to the structure and content of labeling for human
`prescription drug and biologic products with regard to pregnancy and lactation. Additionally,
`information on pregnancy testing, contraception, and infertility that has been located in other
`sections of labeling are now presented in a new subsection, 8.3 Females and Males of
`Reproductive Potential, under Use in Specific Populations (8). Specifically, the pregnancy
`categories (A, B, C, D and X) will be removed from all prescription drug and biological product
`labeling and a new format will be required for all products that are subject to the 2006 Physicians
`Labeling Rule, to include information about the risks and benefits of using these products during
`pregnancy and lactation.
`
`REVIEW
`Pregnancy
`Nonclinical Experience
`No new nonclinical data were submitted with this NDA. The nonclinical PLLR revision is
`deferred to Dr. Belay Tesfamariam.
`
`Applicant’s Pregnancy Safety Review
`1. Safety database
`
`3 Sliwa K et al. ROPAC investigators. Pulmonary hypertension and pregnancy outcomes: data from the Registry of
`Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail. 2016;
`18(9):1119–28.
`
`4 Content and Format of Labeling for Human Prescription Drug and Biological Products, Requirements for
`Pregnancy and Lactation Labeling (79 FR 72063, December 4, 2014).
`
`3
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`Reference ID: 4107175
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`In the period since initial marketing (May 21, 2002 to May 16, 2017), there were 137 reports of
`exposure during pregnancy with Remodulin, Tyvaso, and Orenitram with the following
`outcomes:
`• normal newborn (n=42)
`• delivery occurred; no additional information provided (n=31)
`• unknown outcome (n=27)
`
`• outcome pending (n=15)
`
`spontaneous abortion (n=7)
`•
`• elective abortion (n=11)
`• maternal (and fetal) death (n=3)
`• congenital malformations (n=1)
`o abnormalities of heart, lung, and kidney (not described)
`
`The applicant concluded that these data do not indicate any new safety concerns.
`
`Reviewer comment
`
`Available case reports are not sufficient to inform the safety of treprostinil in pregnancy.
`
`
`2. Literature Review
`The applicant’s review of the published literature resulted in identification of 14 case reports in
`which pregnant women were exposed to treprostinil predominantly in the second and third
`trimesters of pregnancy (see Appendix A). All 14 cases resulted in live births, with some
`preterm deliveries reported. One patient was exposed to treprostinil in the first trimester,
`however the publication does not report on whether any congenital malformations were present
`in the neonate.
`
`Reviewer comment
`DPMH performed a search of published literature on the safety of treprostinil in pregnancy and
`did not identify any additional publications.
`
`Applicant’s Pregnancy Conclusion
`
`A review of all pregnancy cases did not reveal any patterns suggestive of a safety concern.
`
`
`Reviewer comment
`
`Available case reports are not sufficient to inform the safety of treprostinil in pregnancy.
`
`
`Lactation
`Nonclinical Experience
`
`No new nonclinical data were submitted with this NDA.
`
`
`Applicant’s Lactation Safety Review
`1. Safety database
`Two lactation cases were reported (no adverse reactions were reported).
`
`2. Literature Review
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`Reference ID: 4107175
`Reference ID: 4409052
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`There is a published report of a woman with PAH who was treated with intravenous
`treprostinil starting at 32 weeks gestation, and who breastfed for a year. The child was
`reported as being healthy at 2 years of age.5
`
`Reviewer comment
`DPMH performed a search of published literature on the safety of treprostinil in lactation
`and did not identify any additional publications. Medications and Mother’s Milk concludes that
`treprostinil is probably compatible with breastfeeding and states the following: “Although there
`are no data at this time about the transfer of treprostinil into human milk, the oral bioavailability
`of this product is low; therefore, systemic concentrations in breastfed infants would most likely
`be low.”6 LactMed (the Drugs and Lactation Database) states the following: “If treprostinil is
`required by the mother, it is not a reason to discontinue breastfeeding. However, until more data
`are available, treprostinil should only be used with careful monitoring during breastfeeding”.7
`
`Applicant’s Lactation Conclusion
`The applicant concluded that limited available data not indicate any safety signals with the use of
`treprostinil during lactation.
`
`Reviewer comment
`DPMH concurs.
`
`Infertility
`Nonclinical Experience
`
`No infertility effects were seen.
`
`
`Applicant’s Infertility Safety Review
`No infertility cases were reported.
`
`Reviewer comment
`DPMH performed a search of published literature and no reports on infertility effects were
`found.
`
`DISCUSSION
`
`Pregnancy
`There are only a limited number of published case reports of pregnancy exposure to treprostinil.
`The Risk Summary statement in Pregnancy labeling should reflect that there is insufficient data
`
`5 Franco V, Mueller J, Daniels CJ. Is the use of Remodulin safe for pregnant and breastfeeding patients with
`pulmonary arterial hypertension (PAH)? a case report. Heart Lung Transplant. 2012;31(Suppl. S):S71. [abstract]
`6 Hale, Thomas (2017) Medications and Mothers’ Milk. Amarillo, Texas Hale Publishing.
`
`7 https://www.toxnet nlm nih.gov/cgi-bin/sis/search2/f?./temp/~1A6TnQ:3
`The LactMed database is a National Library of Medicine database with information on drugs and lactation for
`healthcare practitioners and women. The LactMed database provides information when available on maternal levels
`in breast milk, infant blood levels, any potential effects in the breastfed infants if known, alternative drugs that can
`be considered.
`
`5
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`Reference ID: 4107175
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`to inform adverse developmental outcomes. PAH is associated with an increased risk of maternal
`and fetal mortality; it is appropriate to add this information under Clinical Considerations,
`Disease-associated maternal and embryo-fetal risk, per PLLR.
`
`Lactation
`There is only one published case report on treprostinil and lactation. This reported case did not
`identify adverse events; however this data is not sufficient to inform labeling. Inclusion of the
`risk-benefit statement, under PLLR, is appropriate for the Implantable System for Remodulin
`lactation labeling.
`
`Females and Males of Reproductive Potential
`Because there are no known infertility effects, this subsection is not needed.
`
`CONCLUSION
`The Pregnancy and Lactation subsections of labeling were structured to be consistent with
`PLLR, as follows:
`• 8.1 Pregnancy
` The “Pregnancy” subsection of the Implantable System for Remodulin labeling was
`formatted in the PLLR format to include “Risk Summary”, “Clinical Considerations”,
`and “Data” sections.
`• 8.2 Lactation
` The “Lactation” subsection of the Implantable System for Remodulin labeling was
`formatted in the PLLR format to include the “Risk Summary” section.
`
`DPMH LABELING RECOMMENDATIONS
`DPMH revised subsections 8.1 and 8.2 of the proposed Implantable System for Remodulin
`labeling for compliance with PLLR. DPMH recommendations are below.
`See final labeling for all of the labeling revisions negotiated with the applicant.
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug
`associated risk of adverse developmental outcomes. However, there are risks to the mother and
`the fetus associated with pulmonary arterial hypertension (see Clinical Considerations). In
`studies….. edits deferred to FDA Toxicology reviewers ….(see Data).
`animal
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`populations is unknown. All pregnancies have a background risk of birth defect, loss, or other
`adverse outcomes. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
`respectively.
`
`Reference ID: 4107175
`Reference ID: 4409052
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`6
`
`(b) (4)
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`

`

`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal
`mortality.
`
`Data
`Animal Data (edits deferred to FDA Toxicology reviewers)
`In pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late
`gestational development, at doses as high as 900 ng treprostinil/kg/min (about 117 times the
`starting human
`, on a ng/m2 basis and about 16 times the average
`achieved in clinical
`trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous
`subcutaneous infusions of treprostinil during organogenesis were limited to an increased
`incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1)
`associated with maternal toxicity (reduction in body weight and food consumption) at a dose of
`150 ng treprostinil/kg/min (about 41 times the starting human
`, on a ng/m2 basis, and 5
`times the average
`used in clinical trials). In rats, continuous subcutaneous infusion of
`treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min,
`did not affect the growth and development of offspring. No treprostinil treatment-related effects
`on labor and delivery were seen in animal studies. Animal reproduction studies are not always
`predictive of human response.
`
`8.2 Lactation
`Risk Summary
`There are no data on the presence of treprostinil in human milk, the effects on the breastfed
`infant, or the effects on milk production.
`
`
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`Reference ID: 4107175
`Reference ID: 4409052
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`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`APPENDIX A Published case reports of pregnant patients exposed to treprostinil (Applicant Table
`1-2)
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`Reference ID: 4107175
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`Reference ID: 4409052
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`8
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`

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`Reference List of Published Case Reports Reported in Appendix A
`
` Franco V, Mueller J, Daniels CJ. Is the use of Remodulin safe for pregnant and breastfeeding
`
`patients with pulmonary arterial hypertension (PAH)? a case report. Heart Lung Transplant.
`2012;31(Suppl. S):S71. [abstract]
`
`Smith JS, Mueller J, Daniels CJ. Pulmonary arterial hypertension in the setting of pregnancy:
`a case series and standard treatment approach. Lung. 2012;190(2):155-160.
`
`Preston IR, Feldman J, White J, et al. Safety and efficacy of transition from inhaled
`treprostinil to parenteral treprostinil in selected patients with pulmonary arterial hypertension.
`Pulm Circ. 2014;4(3):456-461.
`
`Sim H, Lee MJ, Lee JH, et al. Successful management in a pregnant woman with
`Eisenmenger’s syndrome undergoing emergency cesarean section under general anesthesia.
`Korean J Anesthesiol. 2014:67(Suppl):S69-S71.
`
`Rosengarten D, Kramer R. Pregnancy in a woman with pulmonary hypertension: favorable
`outcome with intravenous treprostinil. Clin Exp Obstet Gynecol. 2015;42(3):390-391.
`
`Kim GS, Yang M, Chang CH, et al. Management of cardiac arrest in a parturient with
`Eisenmenger’s syndrome and complete atrioventricular block during Cesarean section: a case
`report. Korean J Anesthesiol. 2015;68 (6):617-621.
`
`Liu B, Huang X, Zhang W, et al. Use of treprostinil in pregnant women with pulmonary
`arterial hypertension during peripartum period. Am J Respir Crit Care Med.
`2016;193:A7374. [abstract]
`
`Kaźnica-Wiatr M, Leśniak-Sobelga A, Kopeć G, et al. Pregnancy in pulmonary arterial
`hypertension. J Rare CV Dis. 2016;2 (7):215-219.
`
`Leovic MP, Robbins HN, Foley MR, et al. The “virtual” obstetrical intensive care unit:
`providing critical care for contemporary obstetrics in nontraditional locations. Am J Obstet
`Gynecol. 2016;215(6):736-738.
`
`Reference ID: 4107175
`Reference ID: 4409052
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`9
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`

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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/
`----------------------------------------------------
`LEYLA SAHIN
`06/05/2017
`
`TAMARA N JOHNSON
`06/05/2017
`
`Reference ID: 4107175
`Reference ID: 4409052
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisional Agency Information****
`
`Memorandum
`Date:
`October 26, 2016
`
`To:
`
`From:
`
`Wayne Amchin, RAC, MPA
`
`Regulatory Project Manager
`
`Division of Cardiovascular and Renal Products (DCaRP)
`
`
`Puja Shah, Pharm.D.
`
`Regulatory Review Officer
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`Subject:
`
`NDA 208276
`Remodulin Implantable System/Remodulin (treprostinil) injection
`
`OPDP acknowledges the receipt of your February 18, 2015, labeling consult request
`regarding the proposed Package Insert (PI), Carton/Container Labeling (CCL), and
`Instructions for Use (IFU) for Remodulin Implantable System/Remodulin (treprostinil)
`injection. Reference is made to the complete response (CR) letter issued by DCaRP to
`the Applicant on October 8, 2016. In the CR letter, DCaRP notes that on March 11,
`2016, FDA issued a Not Approvable letter on the device component in this drug-device
`combination product, which was submitted under a Premarket Approval Application.
`Additionally, DCaRP notes that there are insufficient data to evaluate the risk of potential
`patient exposure to microbial contaminants. As such, a substantially complete PI was not
`sent to OPDP for review. Therefore, OPDP defers comment on the Applicant’s PI, CCL,
`and IFU at this time.
`
`
`OPDP requests that DCaRP submit a new labeling consult request during the subsequent
`review cycle.
`
`If you have any questions, please contact Puja Shah 240-402-5040. Thank you.
`
`Reference ID: 4004399
`Reference ID: 4409052
`
`1
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`

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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/
`----------------------------------------------------
`PUJA J SHAH
`10/26/2016
`
`Reference ID: 4004399
`Reference ID: 4409052
`
`(
`
`
`
`