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Generic Medications in Pulmonary Arterial Hypertension - the Good, the Bad, and the Ugly

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Nathan Verlinden, PharmD, BCPS
Allegheny General Hospital
Pittsburgh, PA, USA

Pulmonary arterial hypertension (PAH) is a rare disease associated with a high burden of healthcare costs. In a recent analysis of costs in the United States, the average per-patient-per-month healthcare costs for patients with PAH were over $9,500 US dollars [1]. The average annual pharmacy costs in this study exceeded $50,000 per patient [1]. For patients requiring oral or parenteral prostacyclin therapy, medication costs can surpass $100,000 annually. The availability of generic medications to treat PAH might be expected to help reduce medication and overall healthcare costs. This article will discuss the current state of generic medications for PAH and some of the challenges for generic availability with a specific focus on issues in the US.

There are currently two Food and Drug Administration (FDA) approved PAH medications with generic availability in the US - sildenafil and non-thermostable epoprostenol (generic for Flolan®). The phosphodiesterase type V inhibitor, sildenafil, remains the only orally available generic medication in the US. Sildenafil is the least expensive medication for PAH and is available for less than $100 for a monthly supply [2]. Non-thermostable epoprostenol is the only available intravenous (IV) medication to treat PAH that is available as a generic.

One of the challenging cases for generic availability of PAH medications in the US has encompassed the endothelin receptor antagonist (ERA) class due to Risk Evaluation and Mitigation Strategies (REMS) regulations. In the case of bosentan, the branded manufacturer, Actelion Pharmaceuticals Ltd., pre-emptively took legal measures against several potential generic manufacturers in 2012 after declining to provide samples of bosentan to those generic companies [3]. Typically, generic manufacturers acquire medication samples from branded manufacturers for bioequivalence testing, which is required for filing abbreviated new drug applications (ANDAs) with the FDA. Actelion cited the REMS regulatory restrictions as justification for not supplying bosentan samples to generic competitors [3]. The generic manufacturers counterclaimed that Actelion's position violated antitrust laws [3]. During these proceedings, the Federal Trade Commission (FTC) filed an amicus brief regarding this case arguing that a branded manufacturer's refusal to provide samples to competitors can violate antitrust laws [4]. The FTC enforces antitrust laws and oversees areas of consumer protection. In addition, the FTC's brief explains that the current federal law framework cannot function as intended if generic manufacturers cannot access branded medication samples, which may threaten pharmaceutical competition and lead to increased drug costs [4]. The suit was eventually settled out of court in 2014 with the details remaining undisclosed to the public [5].

Where does all this legal background lead us now? In response to past court cases involving bosentan and other medications, FDA commissioner Scott Gottlieb announced a series of initiatives to enhance generic availability and lower drug costs in the US. In his June 2017 announcement, the FDA commissioner mentioned the past practice by branded manufacturers of limiting the availability of medication samples due to REMS program requirements [6]. He additionally discussed branded manufacturers using the requirement of a single, shared REMS system between brand-name and generic manufacturers to hinder generic access [6]. As a part of these initiatives, the FDA released a list of off-patent, off-exclusivity branded medications that do not have approved generics and a new policy to expedite review of generic medications where competition is limited [7]. Notably, bosentan was listed as a branded medication that is off-patent without an approved generic. Finally in November 2017, the FDA published new draft guidance on streamlining the process of a single, shared REMS program between brand-name and generic manufacturers [8].

Despite the challenges of generic availability for PAH medications, the year 2018 is expected to be a banner year for generics in the US. Table 1 lists PAH medications with expected or possible new generic availability in 2018. Currently, generic manufacturers have tentative ANDA approval by the FDA for parenteral treprostinil and tadalafil [9, 10]. As stated previously, bosentan is currently off-patent, but a timeline for generic availability remains uncertain. The patent for ambrisentan is set to expire in July 2018, so a generic may become available in the second half of 2018.

Table 1. Expected or possible new generic PAH medications in 2018


Anticipated Availability


Tadalafil (Adcirca®)

May 2018 [11]

Treprostinil injection (Remodulin®)

June 2018 [12]

Bosentan (Tracleer®)



Ambrisentan (Letairis®)


Patent expiration - July 2018 [13]

With the upcoming availability of several generic medications to treat PAH, the hope is that drug cost will subsequently decline over time. This is particularly relevant due to recent developments with non-profit assistance funds for patients with PAH in the US. Caring Voice Coalition (CVC) recently had its charity status revoked by the US Department of Health and Human Services [14]. CVC is no longer offering financial assistance for 2018. Several other non-profit organizations are no longer enrolling new patients, but will continue to cover patients already enrolled. In the past, pharmaceutical manufacturers of PAH medications have provided significant patient assistance for patients who have been unable to afford their medications. However, generic manufacturers typically do not have patient assistance programs. Thus, while generic availability may lead to overall lower drug prices from a payer perspective, it remains to be seen if this will translate into greater affordability for certain patients in the short term. In the long-term, generic medications for PAH are a welcome sight to reduce the high cost of these medications.

In conclusion, the road to generic availability for PAH medications has been difficult. Hopefully, with new FDA guidance the accessibility of generic medications with REMS programs will be easier in the future. Several new generic medications are expected to become available in 2018 for patients with PAH. In the long-term, these generics may help to lower drug costs. In the short term, it remains unclear how generic availability will affect affordability on a patient-specific basis. ■

Disclosure Statement: The author has no conflicts of interest.


  1. Dufour R, Pruett J, Hu N, et al. Healthcare resource utilization and costs for patients with pulmonary arterial hypertension: real-world documentation of functional class. J Med Econ. 2017;20:1178-86.
  2. GoodRx, Inc. GoodRx Website. https://www.goodrx.com/sildenafil. Accessed February 14th, 2018.
  3. Battaglia L. Risky conduct with risk mitigation strategies? The potential antitrust issues associated with REMS. Hogan Lovells Website. https://www.hlregulation.com/files/2013/10/Lauren-Battaglia-article1.pdf. Published March 2013. Accessed February 14, 2018.
  4. Federal Trade Commission. FTC amicus brief: improper use of restricted drug distribution programs may impede generic competition. FTC Website. https://www.ftc.gov/news-events/press-releases/2013/03/ftc-amicus-brief-improper-use-restricted-drug-distribution. Published March 12, 2013. Accessed February 14, 2018.
  5. Battaglia L, Leibenluft R. Actelion settles REMS dispute with generic drug manufacturers. Hogan Lovells Website. https://www.hlregulation.com/2014/03/06/actelion-settles-rems-dispute-with-generic-drug-manufacturers/. Published March 6, 2014. Accessed February 14, 2018.
  6. Gottlieb S. FDA working to lift barriers to generic drug competition. FDA Website. https://blogs.fda.gov/fdavoice/index.php/2017/06/fda-working-to-lift-barriers-to-generic-drug-competition/. Published June 21, 2017. Accessed February 14, 2018.
  7. Food and Drug Administration. List of off-patent, off-exclusivity drugs without an approved generic. FDA Website. https://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/UCM564441.pdf. Published June 27, 2017. Accessed February 14, 2018.
  8. Gottlieb S. Statement from FDA Commissioner Scott Gottlieb, M.D. on new steps to improve FDA review of shared Risk Evaluation and Mitigation Strategies to improve generic drug access. FDA Website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584259.htm. Published November 8, 2017. Accessed February 14, 2018.
  9. Food and Drug Administration. Tentative ANDA approval letter. ANDA 203649 - Sandoz generic Remodulin. FDA Website. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/203649Orig1s000ltr.pdf. Published October 31, 2014. Accessed February 14, 2018.
  10. Food and Drug Administration. Tentative ANDA approval letter. ANDA 206286 - Aurobindo generic Adcirca. FDA Website. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/206286orig1s000taltr.pdf. Published October 20, 2015. Accessed February 14, 2018.
  11. Reed T. United Therapeutics gets much-needed reprieve with drug patent. Washington Business Journal Website. https://www.bizjournals.com/washington/news/2017/11/21/united-therapeutics-gets-much-needed-reprieve-with.html. Published November 21, 2017. Accessed February 14, 2018.
  12. StreetInsider.com. United Therapeutics, Sandoz settle Remodulin-related litigation. https://www.streetinsider.com/Corporate+News/United+Therapeutics+%28UTHR%29%2C+Sandoz+Settle+Remodulin-Related+Litigation/10930817.html. Published September 30, 2015. Accessed February 14, 2018.
  13. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations Website. Patent and Exclusivity for: N022081. Ambrisentan (Letairis) tablets. https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001. Updated December 2017. Accessed February 14, 2018.
  14. Langreth R, Elgin B. Drug charity may shutter after US faults Pharma influence. Bloomberg Website. https://www.bloomberg.com/news/articles/2017-11-29/pharma-charity-may-shut-after-u-s-faults-drugmakers-influence. Updated November 29, 2017. Accessed February 14, 2018.

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