This document addresses intravenous, subcutaneous, and inhalation administration of prostacyclin analogues for the treatment of pulmonary arterial hypertension, (also referred to as idiopathic pulmonary arterial hypertension or IPAH), a life-threatening disease characterized by sustained elevations of pulmonary artery pressure with associated thickening of the pulmonary arteries and narrowing of the blood vessels.

Diagnostic Criteria for Pulmonary Arterial Hypertension (PAH):

• Right heart catheterization which shows a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units.

Criteria for Vasodilator Response:

• A favorable response is defined as a fall in mPAP of at least 10 mm Hg to an absolute mPAP of less than 40 mm Hg without a decrease in cardiac output, when challenged with inhaled nitric oxide, intravenous epoprostenol or intravenous adenosine. 

Medically Necessary:
Continuous intravenous infusion of epoprostenol sodium (prostacyclin, PGI2, Veletri^®_, Flolan^®) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

• Meets the diagnostic criteria for PAH (above); AND
• Demonstrates an unfavorable acute response to vasodilators; AND
• Meets one of the following selection criteria with New York Heart Association functional Class III or IV symptoms:
  • World Health Organization (WHO) Group I* idiopathic pulmonary arterial hypertension including all subtypes of WHO Group I PAH; or
  • Pulmonary hypertension associated with connective tissue disorders (e.g., scleroderma, systemic sclerosis, etc.); or
  • Pulmonary hypertension associated with congenital heart defects.

Continuous subcutaneous infusion of treprostinil sodium (Remodulin^®) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

• Meets the diagnostic criteria for PAH (above); AND
• Demonstrates an unfavorable acute response to vasodilators; AND
• Meets one of the following selection criteria with New York Heart Association functional Class II, III, or IV symptoms:
  • World Health Organization (WHO) Group I* idiopathic pulmonary arterial hypertension including all subtypes of WHO Group I PAH; or
  • Pulmonary hypertension associated with connective tissue disorders (e.g., scleroderma, systemic sclerosis, etc.); or
  • Pulmonary hypertension associated with congenital heart defects.

Continuous intravenous infusion of treprostinil sodium (Remodulin^®) is considered medically necessary for treatment of individuals who meet criteria for treprostinil treatment above when there is documented inability to tolerate treatment by subcutaneous infusion.

Inhalation therapy with iloprost (Ventavis^®) Inhalation Solution or TYVASO^™ Inhalation Solution* (treprostinil) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

• Meets the diagnostic criteria for PAH (see pg. 1); AND
• Demonstrates an unfavorable acute response to vasodilators; AND
• Meets one of the following selection criteria with New York Heart Association (NYHA) Functional Class III or IV symptoms: 
  • World Health Organization (WHO) Group I* idiopathic pulmonary arterial hypertension including all subtypes of WHO Group I PAH; or
  • Pulmonary hypertension associated with connective tissue disorders (e.g., scleroderma, systemic sclerosis, etc.); or
  • Pulmonary hypertension associated with congenital heart defects.

*FDA approved labeling for TYVASO (treprostinil) inhalation solution states for use in the treatment of pulmonary arterial hypertension (WHO Group I) in individuals with NYHA Class III symptoms, to increase walk distance (FDA, 2009). 

Continuous infusion of epoprostenol or treprostinil is considered medically necessary for individuals with severe PAH refractory to medical therapy with calcium channel blockers.

Not Medically Necessary:                                                                                    

Use of epoprostenol, treprostinil or iloprost is not medically necessary as a treatment for individuals appropriate for treatment with calcium channel blockers:

• Individuals who demonstrate a favorable acute hemodynamic response to vasodilators at cardiac catheterization who are deemed appropriate by the treating physician for a trial of calcium channel blocker treatment, or
• Individuals who demonstrated a favorable acute hemodynamic response to vasodilators but have not become refractory to, or unable to, tolerate therapeutic doses of calcium channel antagonists.

Continuous intravenous infusion of treprostinil sodium (Remodulin^®) is considered not medically necessary for treatment of individuals when inability to tolerate treatment by subcutaneous infusion has not been documented.

Investigational and Not Medically Necessary:

The use of epoprostenol, treprostinil, or iloprost is considered investigational and not medically necessary for all other applications in the absence of WHO Group I PAH including those with WHO Group II to V* pulmonary hypertension and for other causes of pulmonary hypertension, including, but not limited to, left ventricular failure, left sided valvular heart disease, chronic pulmonary diseases, and alveolar hypoventilation syndromes.

*See the Definitions section of this document for a description of the WHO Classification System.

The clinical effectiveness and safety of prostacyclin infusion therapy by continuous intravenous infusion of epoprostenol sodium (Flolan^®) (GlaxoSmithKline, London UK), continuous subcutaneous infusion of treprostinil sodium (Remodulin^®), and inhalation therapy with iloprost (Ventavis^®) inhalation solution for treatment of individuals with idiopathic pulmonary arterial hypertension (IPAH) or pulmonary hypertension associated with connective tissue disorders, such as scleroderma or congenital heart defects, is well documented in the peer-reviewed medical literature.  These therapies improve cardiopulmonary hemodynamics, exercise tolerance and quality of life in many individuals.  In addition, epoprostenol, has been shown to enhance survival for individuals who have been unresponsive to conventional medical therapy. 

In a retrospective study of 557 consecutive subjects with IPAH, it was observed that 70 individuals demonstrated an acute hemodynamic response to vasodilators at cardiac catheterization, defined in this study as at least a 20% decrease in both mPAP and PVR (Sitbon, 2005). Treatment with oral calcium channel blockers in this group of acute responders resulted in a long term response, (defined as subjects in NYHA Class I or II with a sustained hemodynamic improvement at one year without the addition of prostanoids or endothelin receptor antagonists) in only 54%, representing 6.8% of the total number of individuals studied. It is strongly recommended, therefore, that individuals treated with calcium channel antagonists are followed closely with reassessment at three months to ensure they have improved to NYHA Functional Class I or II. If this improvement is not observed, additional or alternative therapy should be instituted (Badesch, 2007).

Updated guidelines for the medical therapy of PAH from the American College of Chest Physicians (ACCP) clarify that an acute response to vasodilators is defined as a fall in mPAP of at least 10 mm Hg to 40 mm Hg or lower, with an unchanged or increased cardiac output when challenged with inhaled nitric oxide, intravenous epoprostenol or intravenous adenosine (Badesch, 2007).  In March 2009, the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA) 2009 Expert Consensus Document on Pulmonary Hypertension was released.  This document includes the following information:

In general, patients with poor prognostic indexes should be initiated on parenteral therapy, while patients with class II or early II symptoms commonly commence therapy with either endothelin receptor antagonists or PDE-5 inhibitors…Caution is recommended against widespread treatment of non-PAH PH until patient benefit has been proven in clinical trials. On the topic of combination therapy, while it is an attractive theoretical option in PAH, there are still ongoing trials investigating its safety and efficacy. Benefit of combination therapy has been suggested in several smaller, open label observational studies but randomized controlled trials are needed and in process…  (McLaughlin, 2009)

There is insufficient published evidence to support the use of epoprostenol, treprostinil, or iloprost for the treatment of PAH resulting from disorders other than those meeting the medical necessity criteria above. (This condition was formerly referred to as secondary pulmonary hypertension.)

For individuals with IPAH and a favorable response to acute vasodilator challenge, treatment with an appropriate oral calcium channel antagonist should be considered prior to the use of epoprostenol, treprostinil, or iloprost.  If a calcium channel antagonist is used, close follow up is recommended with reassessment after three months to verify that the person has improved to NYHA Functional Class I or II (Badesch, 2007).

On August 25, 2010 another epoprostenol sodium injectable agent, Veletri^® (manufactured by Hollister-Stier Laboratories, LLC, Spokane. WA for Actelion Pharmaceuticals US, Inc., South San Francisco, CA) was FDA approved for continuous intravenous infusion. The FDA approved indications are:

• "For the long-term intravenous treatment of primary pulmonary hypertension, and
• Pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy." (FDA, 2010)

Treprostinil (Remodulin^®) (United Therapeutics Corporation, Silver Spring, MD) was originally approved as a subcutaneous infusion.  However, in 2004, the Food and Drug Administration (FDA) approved intravenous use of treprostinil (Remodulin^®) "For those who are not able to tolerate a subcutaneous infusion for the treatment of PAH in patients with NYHA Class II, III, IV symptoms to diminish symptoms associated with exercise."  Although not part of the current FDA-approved labeling indications, the FDA reports that, "Remodulin is also indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolan; the risks and benefits of each drug should be carefully considered prior to transition." While local site reactions may be lessened by continuous IV infusion of epoprostenol, this route exposes the individual to intravenous catheter-related complications, such as sepsis and venous thromboembolism and, due to the shorter half-life of treprostinil, when given intravenously as compared to subcutaneously, may increase the risks related to abrupt cessation in the delivery of the medication, as occurs with pump malfunction.  Accordingly, Remodulin is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated, due to severe site pain or reaction.  An uncontrolled study demonstrated that transition from IV epoprostenol to subcutaneous Remodulin can be successfully achieved without major adverse side effects.

Iloprost (Ventavis^®) inhalation solution (Actelion Pharmaceuticals US, Inc., South San Francisco, CA) is a synthetic analogue of prostacyclin, which dilates systemic and pulmonary arterial vascular beds resulting in improvement in exercise capacity and the symptoms associated with PAH. Ventavis was FDA-approved under the *Orphan Drug designation on August 17, 2004 for, "The treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms." According to the FDA approval information, in controlled trials, it improved a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration (Olschewski, 2002). Ventavis is intended for inhalation administration only via either of two pulmonary drug delivery devices: the I-neb^® AAD^® System or the Prodose^® AAD^® System and has not been studied with any other nebulizers. The FDA labeling includes the following precautionary information: "Ventavis inhalation can induce bronchospasm, especially in susceptible patients with hyperreactive airways. Ventavis has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections. Such patients should be carefully monitored during therapy with Ventavis. Safety and efficacy in pediatric patients has not been established." (FDA, 2008)

On July 30, 2009, the FDA approved another inhalation drug form of treprostinil, TYVASO^™ Inhalation Solution for the treatment of PAH.  The approved FDA labeling states that, "TYVASO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III symptoms, to increase walk distance."  According to the FDA information, "While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration." (FDA, 2009)  The company, United Therapeutics Corporation (Silver Spring, MD) launched the drug in 2009 which is only available in the U.S. from three specialty pharmacy providers.  (See: http://tyvaso.com/getting_the_system.aspx.)

* The Orphan Drug designation stems from the Orphan Drug Act which offers a pharmaceutical company seven years' exclusivity for the treatment indication from the date FDA approves the marketing application; also tax breaks on clinical trial expenses and a waiver from some application fees. This designation is reserved for drugs that treat rare diseases and conditions for which there are either fewer than 200,000 individuals affected in the U.S. or that are more prevalent but for which there is no reasonable expectation that the cost of developing and marketing the drug in the U.S. would be recovered from U.S. sales (AHFS, 2008).

PAH is a life-threatening disease characterized by sustained elevations of the mean pulmonary arterial pressure (mPAP), thickening of the pulmonary arteries and narrowing of the blood vessels. As the disease progresses, the right side of the heart becomes enlarged and may fail.

PAH was classified as either primary (idiopathic) or secondary (see descriptions below), however, the World Health Organization (WHO) Classification System is now used to describe idiopathic pulmonary arterial hypertension (IPAH) and other causes of secondary pulmonary hypertension (PH). 

IPAH is characterized by a sustained level of mPAP without apparent cause.  The estimated incidence of IPAH is 1 to 2 cases per 1 million persons in the general population.  During childhood, the condition affects both genders equally; after puberty, it is more common in women than men and is most prevalent in persons 20 to 40 years of age.  If untreated, the median survival from time of diagnosis is less than 2.8 years.  Unexplained shortness of breath and fatigue are common early symptoms; angina and syncope are seen in advanced disease stages.

Secondary PH occurs as a complication of many pulmonary, cardiac and extrathoracic conditions. Common causes include scleroderma and its variants (i.e., the CREST syndrome), and various congenital heart defects.  In individuals with secondary PH, management is directed at early recognition and treatment of the underlying disease and may also include therapy of the hypertension itself.

The diagnosis and treatment of PAH is complex and continues to be refined.  Medical management consists of diuretics, supplemental oxygen, anticoagulants, calcium channel blockers, endothelin receptor antagonists (Bosentan [Tracleer]), and continuous infusion of prostacyclin (epoprostenol) or prostacyclin analog (treprostinil) or inhaled iloprost. Lung or heart-lung transplantation has been performed in individuals who are refractory to medical management.

Epoprostenol sodium is a naturally occurring prostacyclin that decreases PVR and increases cardiac output. Because of epoprostenol's short half-life, it must be administered intravenously with a portable infusion pump attached to a permanent indwelling central venous catheter.  Continuous intravenous epoprostenol infusions are reserved for those who are unresponsive to conventional therapy, and may be used either as long-term therapy or as a bridge to transplantation.  Epoprostenol is contraindicated in individuals with congestive heart failure due to severe left ventricular systolic dysfunction and those with hypersensitivity to epoprostenol or to structurally–related compounds.  It is not recommended for treatment in the following diagnoses: diseases of the left atrium or ventricle (e.g., cardiomyopathy, congestive heart failure), diseases of mitral or aortic valves, chronic lung disease (COPD) or disorders of alveolar hypoventilation.

Unlike epoprostenol, treprostinil (Remodulin^®) is administered by continuous subcutaneous infusion using an infusion pump designed for subcutaneous drug delivery.  Remodulin remains stable at room temperature, does not require reconstitution and is unlikely to cause serious infections, due to its subcutaneous method of delivery, (although continuous intravenous method of administering Remodulin is now FDA approved for those who are not able to tolerate the subcutaneous infusion of this drug).  Drugs, such as diuretics, antihypertensive agents, or vasodilators, that by themselves alter blood pressure, may exacerbate reductions in blood pressure caused by Remodulin.  Because Remodulin also inhibits platelet aggregation, there is potential for increased risk of bleeding, particularly among individuals maintained on anticoagulants.  During clinical trials, however, Remodulin was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, corticosteroids, and other medications.

New York Heart Association (NYHA) functional classification of angina pectoris:

Class I             No limitation with ordinary physical activity;
Class II            Slight limitation with fatigue, dyspnea, palpitations, or angina resulting from ordinary physical activity;
Class III           Marked limitation; symptomatic with less than ordinary activity;
Class IV           Symptoms present while at rest

Pulmonary Arterial Hypertension (PAH): A class of diseases categorized by persistently increased blood pressure in the pulmonary artery, which transports blood from the right ventricle of the heart to the lungs. This can lead to significant and potentially lethal damage to the heart, and may even require lung or heart-lung transplantation if not adequately controlled. PAH is defined by the 2009 ACCF/AHA Expert Consensus document as a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units.

World Health Organization (WHO) - functional classification for pulmonary arterial hypertension 
Class I:  no limitation of clinical activity; ordinary physical activity does not cause dyspnea or fatigue; 
Class II: slight limitation in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest; 
Class III: marked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest; 
Class IV: unable to perform any physical activity without symptoms; dyspnea and/or fatigue present at rest; discomfort increased by any physical activity.  (WHO, 2009).

Scleroderma: A systemic disorder of connective tissue characterized by induration and thickening of the skin, abnormalities of the blood vessels, and fibrotic degenerative changes in various body organs.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

When services are Not Medically Necessary or Investigational and Not Medically Necessary:
For the procedure codes listed above, when criteria are not met; for all other diagnoses, or when the code describes a procedure indicated in the Position Statement section as not medically necessary, or investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding.

Peer Reviewed Publications:

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3. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994; 121(6):409-415.
4. Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006; 28(6):1195-1203.
5. Bos AP, Tibboel D, Koot VC, et al. Persistent pulmonary hypertension in high-risk congenital diaphragmatic hernia patients: incidence and vasodilator therapy. J Pediatr Surg. 1993; 28(11):1463-1465. 
6. Budhiraja R, Hassoun PM. Portopulmonary hypertension: a tale of two circulations. Chest. 2003; 123(2):562-576.
7. Channick RN, Olschewski H, Seeger W, et al. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006; 48(7):1433-1437.
8. Channick R, Williamson TL. Diagnosis and treatment of pulmonary arterial hypertension. Cardiol Clin. 2004; 22(3):441-452.
9. Clapp LH, Finney P, Turcato S, et al. Differential effects of stable prostacyclin analogs on smooth muscles proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol. 2002; 26(2):194-202.
10. Forrest IA, Small T, Corris PA. Effect of nebulized epoprostenol (prostacyclin) on exhaled nitric oxide in patients with pulmonary hypertension due to congenital heart disease and in normal controls. Clin Sci (Lond). 1999; 97(1):99-102.
11. Hoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs. 2005; 65(10):1337-1354.
12. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006; 28(4):683-686.
13. Hunbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004; 351(14):1425-1436.
14. Lowson SM, Doctor A, Walsh BK, Doorley PA. Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac surgery. Crit Care Med. 2002; 30(12):2762-2764.
15. Maloney JP. Advances in the treatment of secondary pulmonary hypertension. Curr Opin Pul Med. 2003; 9(2):139-143.
16. McLaughlin VV, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacycline in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999; 130(9):740-743.
17. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002; 106(12):1477-1482.
18. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003; 41(2):293-299.
19. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174(11):1257-1263.
20. Nauser TD, Stites SW.  Diagnosis and treatment of pulmonary hypertension. Am Fam Physician. 2001; 63(9):1789-1798.
21. Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest. 2003; 124(4):1294-1304.
22. Olschewski H, Rose F, Grunig E, et al. Cellular pathophysiology and therapy of pulmonary hypertension. J Lab Clin Med. 2001; 138(6):367-377.
23. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002; 347(5):322-329.
24. Opitz, CF, Wensel, R, Bettmann, M, et al. Assessment of the vasodilator response in primary pulmonary hypertension: comparing prostacyclin and iloprost administered by either infusion or inhalation. Eur Heart J. 2003; 24(4),356-365.
25. Provencher S, Jais X, Yaici A, et al. Clinical challenges in pulmonary hypertension: Roger S. Mitchell Lecture.  Chest. 2005; 128(6 Suppl):622S-628S.
26. Rich S. The current treatment of pulmonary arterial hypertension: time to redefine success. Chest. 2006; 130(4):1198-1202.
27. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999; 99(14):1858-1865.
28. Rubenfire M, McLaughlin VV, Allen RP, et al. Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007; 132(3):757-763.
29. Rudarakanchana N, Trembath RC, Morrell NW. New insights into the pathogenesis and treatment of primary pulmonary hypertension. Thorax. 2001; 56(11):888-890.
30. Ruiz MJ, Escribano P, Delgado JF, et al. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids: 2-year experience. J Heart Lung Transplant. 2006; 25(11):1353-1357.
31. Ryerson CJ, Nayer S, Swiston JR, Sin DD. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir Res. 2010; 11:12.
32. Simonneau G, Barst RJ, Nazzareno G, et al. Continuous subcutaneous infusion of treprostinil a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165(6):800-804.
33. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004; 43(12 Suppl S):5S-12S.
34. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.  Circulation. 2005; 111(23):3105-3111.
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36. Vachiery JL, Hill N, Zwicke D, et al. Transitioning from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest. 2002; 121(5):1561-1565.
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Government Agency, Medical Society, and Other Authoritative Publications:

1. American Society of Health-System Pharmacists^® (AHFS) Hospital Formulary Service^® (AHFS). Epoprostenol sodium (Flolan^®). Treprostinil (Remodulin^®). Iloprost (Ventavis^®). AHFS Drug Information 2008^®. Bethesda, MD.  Available at: http://www.ashp.org/ahfs/  Accessed on January 12, 2011.
2. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. American College of Chest Physicians. Chest. 2004; 126(1 Suppl):35S-62S. Available at: http://www.chestjournal.org/cgi/content/full/126/1_suppl/35S. Accessed on January 12, 2011.
3. Badesch BD, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines.  Chest. 2007; 131(6):1917-1928.
4. The Canadian Agency for Drugs and Technologies in Health (CADTH). Health Technology Assessment Rapid Review: Drugs for pulmonary hypertension: a systematic review of the clinical effectiveness of combination therapy. April 2009. Available online at: http://www.cadth.ca/media/pdf/M0004_Drugs_for_Pulmonary_Arterial_Hypertension_tr_e.pdf.  Accessed on January 12, 2011.
5. Epoprostenol (Systemic) Monograph. December 1998. Revised February 26, 2007.  American Hospital Formulary Service. Available at: http://www.ashp.org/ahfs/. Accessed on January 12, 2011.
6. Epoprostenol sodium (Flolan^®). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/242B9E/DUPLICATIONSHIELDSYNC/B3181F/ND_PG/PRIH/ND_B/HCS/SBK/1/ND_P/Main/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/923429/ContentSetId/100/SearchTerm/Flolan/SearchOption/BeginWith.  Accessed on January 12, 2011.
7. Fleming T, Lindenfeld J, Lipicky R, et al. Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001. Circulation. 2001; 104(15):1742.
8. Gibbs J, Arneson C, Mottola D, Group UTCTS. Chronic infusion of treprostinil is safe and appears to prolong survival over a three-year period in patients with pulmonary arterial hypertension.  Abstract presented at the American Heart Association (AHA) Scientific Sessions, Chicago, IL.  November 17-20, 2002.
9. Iloprost inhalation solution (Ventavis^®). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/02218D/DUPLICATIONSHIELDSYNC/7A0885/ND_PG/PRIH/ND_B/HCS/SBK/2/ND_P/Main/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/1031/ContentSetId/31#therapeuticUsesSection.  Accessed on January 12, 2011.
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11. National Institutes of Health (NIH).  National Heart Lung and Blood Registry on Pulmonary Hypertension.  Ann Intern Med. 1987; 107:216-223; Ann Intern Med. 1991; 115:343-349. Available at: https://biolincc.nhlbi.nih.gov/studies/pphreg/?q=Pulmonary%20hypertension.  Accessed on January 12, 2011.
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14. Ruiz-Cano MJ, Escribano P, Cea-Calvo L, et al.  Continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, in primary pulmonary hypertension: a three year experience.  Abstract presented at the European Society of Cardiology Congress.  Vienna, Austria.  August 2003.
15. Simonneau G, Robbins IM, Beghetti M, et al. Updated classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54(1 suppl):S43-54.
16. Skoro-Sajer N, Lang I, Harja E, et al. A clinical comparison of slow and rapid-escalation treprostinil dosing regimen in patients with pulmonary arterial hypertension (PAH).  Abstract presented at the American Heart Association's 4^th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke.  Washington, DC.  October 12-14, 2002.
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18. United States Food and Drug Administration (FDA). Product Information: Remodulin^® (treprostinil sodium) injection.  Product information available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021272s009lbl.pdf.  Listing of FDA approvals available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed on January 12, 2011.
19. United States Food and Drug Administration (FDA). Product Information: Flolan^® (epoprostenol sodium) injection.  Labeling approval for March 12, 2008.    Available at:   http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020444s016lbl.pdf. Accessed on January 12, 2011.
20. United States Food and Drug Administration (FDA). Product Information: Ventavis^® (iloprost) inhalation solution. Approved labeling NDA#21-779/S-008. September 22, 2008. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021779s008lbl.pdf.  Accessed on January 12, 2011.
21. United States Food and Drug Administration (FDA). Product Information/Labeling:  TYVASO^™ (treprostinil) Inhalation Solution.  Approved labeling NDA#022387.  July 30, 2009.  Available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022387LBL.pdf.  Accessed on January 12, 2011.
22. United States Food and Drug Administration (FDA). Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. Available at: http://www.fda.gov/orphan/designat/list.htm.  Accessed on January 12, 2011.
23. United States Food and Drug Administration (FDA).  Product Information:  VELETRI^® (epoprostenol sodium) injection.  Approved labeling NDA#NDA022260.  August 25, 2010.  Available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022260s002lbl.pdf.  Accessed on January 12, 2011.

1. GlaxoSmithKline (London, UK) Flolan^® (epoprostenol injection) package insert. Research Triangle Park, NC. 2000; revised 07/2001.  Product information available at:  http://www.glaxowellcome.com.  Accessed on January 12, 2011.
2. United States Food and Drug Administration (FDA). Drug information available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/search/search.cfm   Accessed on January 12, 2011.

Epoprostenol Sodium
Flolan^®
Remodulin^® 
Treprostinil
Iloprost
VELETRI^® (epoprostenol sodium)
Ventavis^®
TYVASO^™

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.