*Documentation of pretreatment results from right heart catheterization and PEA required, as applicable

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1 DRUG POLICY BENEFIT APPLICATION Pulmonary Arterial Hypertension Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This policy may not apply to FEP. Benefits are determined by the Federal Employee Program. DESCRIPTION The intent of the Pulmonary Arterial Hypertension (PAH) drug policy is to ensure appropriate selection of patients for therapy based on product labeling, clinical guidelines and clinical studies. FDA-Approved Products and Indications Adcirca is an oral phosphodiesterase type 5 (PDE5) inhibitor approved for PAH, WHO Group 1 to improve exercise ability. Another oral PDE5 inhibitor, Revatio (available as generic sildenafil), is indicated for the treatment of adults with PAH, WHO Group 1, to improve exercise ability and delay clinical worsening. Tracleer is an oral endothelin receptor antagonist (ERA) indicated for the treatment of PAH, WHO Group 1 to improve exercise ability and to decrease clinical worsening. Other ERAs include Letairis, indicated for the treatment of PAH, WHO Group 1, to improve exercise ability and delay clinical worsening, and Opsumit, indicated for PAH, WHO Group 1, to delay disease progression. Prostanoids include intravenously (IV) infused products such as Flolan/Veletri (and their generic epoprostenol) and Remodulin, inhalation treatments including Tyvaso and Ventavis, and an oral formulation, Orenitram. Epoprostenol/Flolan/Veletri is indicated for the treatment of PAH, WHO Group 1, to improve exercise capacity. Remodulin is approved for PAH, WHO Group 1, to diminish symptoms associated with exercise. In patients requiring transition from Flolan (epoprostenol), Remodulin is indicated to decrease the rate of clinical deterioration. Tyvaso is indicated for the treatment of PAH, WHO Group 1, to improve exercise ability. Ventavis is indicated for the treatment of PAH, WHO Group 1, to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Orenitram is indicated for the treatment of PAH, WHO Group 1, to improve exercise capacity. Uptravi, an oral prostacyclin receptor agonist, is indicated to delay disease progression and reduce the risk of hospitalization in PAH WHO Group 1. Adempas, a soluble guanylate cyclase inhibitor, is approved for the treatment of adults with PAH, WHO Group 1, to improve exercise capacity, WHO functional class and to delay clinical worsening. Adempas is also indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), WHO Group 4, after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. POLICY Criteria for Approval I. Adempas may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member is 18 years of age or older Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 1

2 Member is not receiving concomitant treatment with a nitrate or nitric oxide donor medication, regardless of whether it is used on a regular or intermittent basis Member is not receiving concomitant treatment with a phosphodiesterase type 5 inhibitor Member s PAH fits one of the following scenarios (A or B): A) Pulmonary Arterial Hypertension PAH defined as WHO Group 1 class of pulmonary hypertension o For infants less than one year with any of the following conditions, PAH was confirmed by Doppler echocardiogram if right heart catheterization cannot be performed: Member has New York Heart Association (NYHA) functional Class II or III symptoms prior to the initiation of treatment B) Chronic Thromboembolic Pulmonary Hypertension (CTEPH) CTEPH define as WHO Group 4 class of pulmonary hypertension Member has one of the following: o Recurrent or persistent CTEPH after pulmonary endarterectomy (PEA)* o Inoperable CTEPH with diagnosis confirmed by BOTH of the following: Comuted tomography (CT)/magnetic resonance imaging (MRI) angiography or pulmonary angiography Pretreatment right heart catheterization with all of the following results: mpap 25 mmhg PCWP 15 mmhg PVR > 3 Wood units *Documentation of pretreatment results from right heart catheterization and PEA required, as applicable II. Adcirca or Revatio (and generic sildenafil) may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 2

3 Member has New York Heart Association (NYHA) functional Class II or III symptoms prior to the initiation of treatment Member is not receiving concomitant treatment with a nitrate or nitric oxide donor medication, regardless of whether it is used on a regular or intermittent basis Member is not receiving concomitant treatment with a guanylate cyclase simulator (e.g., Adempas) III. Remodulin or Tracleer may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Member has New York Heart Association (NYHA) functional Class II, III or IV symptoms prior to the initiation of treatment IV. Tyvaso may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Member has New York Heart Association (NYHA) functional Class III symptoms prior to the initiation of treatment V. Ventavis, epoprostenol, Flolan, or Veletri may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 3

4 Member has New York Heart Association (NYHA) functional Class III or IV symptoms prior to the initiation of treatment VI. Letairis or Opsumit may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Member has New York Heart Association (NYHA) functional Class II or III symptoms prior to the initiation of treatment VII. Orenitram or Uptravi may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH), when the following criteria are met: Member has PAH defined as WHO Group 1 class of pulmonary hypertension Member has New York Heart Association (NYHA) functional Class II or III symptoms prior to the initiation of treatment Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 4

5 Member is utilizing an endothelin receptor antagonist (e.g. Tracleer, Letairis or Opsumit) or phosphodiesterase type 5 inhibitor (e.g. Adcirca, Revatio/sildenafil), or has previously tried and failed one of these agents, or has contraindication to use these agents Member does not have severe hepatic impairment (Child Pugh Class C) Approval is for 12 months. Requests for continuation of therapy must meet ALL initial authorization criteria. The aforementioned drugs are considered not medically necessary for patients who do not meet the criteria set forth above. Prior approval is required. Submit a prior approval/treatment request now. Quantity limits apply. Adcirca: 60 tablets per 30 days Adempas: 90 tablets per 30 days Epoprostenol/Flolan/Veletri: Not applicable Letairis: 30 tablets per 30 days Opsumit: 30 tablets per 30 days Orenitram: Not applicable Remodulin: Not applicable Revatio (and generic sildenafil): 360 tablets per 30 days, 720 ml per 30 days Tracleer: 60 tablets per 30 days Tyvaso: 1 ampule per day Uptravi: 60 tablets per 30 days Ventavis: 9 ampules per day CLINICAL RATIONALE The goal of treatment in pulmonary arterial hypertension (PAH) is to improve symptoms, enhance functional capacity, lower pulmonary arterial pressure, normalize cardiac output, and ultimately to prevent progression of the disease and improve survival. The following is a brief synopsis of the approved PAH-specific therapies. Treatment selection is generally guided by the patient s WHO functional class. Several consensus guidelines are available, though treatment often requires individualization, as no single best approach has emerged from the evidence to date. Adcirca is approved for PAH, WHO Group 1 to improve exercise ability. Studies establishing effectiveness included predominantly patients with New York Heart Association (NYHA) Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue disease (23%). Revatio (and its generic, sildenafil) is indicated for the treatment of PAH, WHO Group 1 to improve exercise ability and delay clinical worsening in adults. The delay in clinical worsening was demonstrated when Revatio was added to background epoprostenol therapy. Studies establishing effectiveness were short -term (12 to 16 weeks), and included predominantly patients with NYHA Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (25%). Adding Revatio to Tracleer therapy did not result in any beneficial effect on exercise capacity. Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 5

6 Tracleer is an endothelin receptor antagonist (ERA) indicated for the treatment of PAH, WHO Group 1 to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts. Another ERA, Letairis is indicated for the treatment of PAH, WHO Group 1, to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue disease (32%). Opsumit, is another ERA indicated for PAH, WHO Group 1, to delay disease progression. Disease progression included: death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients with idiopathic or heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%). Tyvaso is indicated for the treatment of PAH, WHO Group 1, to improve exercise ability. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) of PAH associated connective tissue diseases (33%). Ventavis is indicated for the treatment of PAH, WHO Group 1, to improve composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%). Epoprostenol/Flolan/Veletri is indicated for the treatment of PAH, WHO Group 1, to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III - IV symptoms and etiologies or idiopathic or heritable PAH or PAH associated with connective tissue diseases. Orenitram is indicated for the treatment of PAH, WHO Group 1, to improve exercise capacity. The study that established effectiveness included predominantly patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%). When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit, and the effect, if any, on a background of another vasodilator is probably less than this. Given limited efficacy, it is not generally recommended as an initial treatment selection, nor as an initial add-on therapy. It may have a role when oral treatment is desired, when one or both of the other oral therapy options (PDE5 inhibitors or ERAs) are contraindicated. Orenitram is probably most useful to replace subcutaneous, intravenous, or inhaled treprostinil, but this use has not been studied. Remodulin is approved for PAH, WHO Group 1, to diminish symptoms associated with exercise. In patients requiring transition from Flolan (epoprostenol), Remodulin is indicated to decrease the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. Studies establishing effectiveness included predominantly patients with NYHA Functional class II-IV and etiologies of idiopathic or heritable PAH (58%) or PAH associated with congenital systemic -to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%). Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 6

7 Uptravi, an oral prostacyclin receptor agonist is indicated for the treatment of PAH, WHO Group 1, to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness was established in a longterm study in PAH patients with WHO Functional Class II-III symptoms (99%). Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%). The vast majority of patients utilized Uptravi as an adjunctive agent to an already stable regimen consisting of an ERA (16.4%), a PDE5 inhibitor (32.9%), or a combination of both (31.2%). Adempas is approved for the treatment of adults with PAH, WHO Group 1, to improve exercise capacity, WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Adempas monotherapy or in combination with ERAs or prostanoids. Studies establishing effectiveness included predominantly patients with NYHA Functional class II-III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). Adempas is also indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), WHO Group 4, after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. PROCEDURES AND BILLING CODES To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-CM diagnostic codes. J1325 Injection, epoprostenol, 0.5 mg J3285 Injection, treprostinil, 1 mg J7686 Treprostinil, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, 1.74 mg Q4074 Iloprost, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, up to 20 micrograms REFERENCES Drug Facts and Comparisons 4.0 [Internet database]. St. Louis: W olters Kluwer Health, Inc.; Available at: Accessed October, 7, Adcirca [prescribing information]. Indianapolis, IN: Eli Lilly and Company; April Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51(16): McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2009;53(17): Badesch DB, Champion HC, Gomez-Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54:S55-S66. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34-S41. Rubin LJ; American College of Chest Physicians. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):7S-10S. Barst RJ, Gibbs SR, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-S84. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults CHEST guideline and expert panel report. Chest 2014;46(2): Revatio [prescribing information]. New York, NY: Pfizer Inc.; March FDA Drug Safety Communication: FDA recommends against use of Revatio in children with pulmonary hypertension. Available at: Accessed April 28, Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 7

8 Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med. 2013;187(6): FDA Drug Safety Communication: FDA clarifies Warning about Pediatric Use of Revatio (sildenafil) for Pulmonary Arterial Hypertension. Available at: Accessed April 28, Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353: Rubin LJ, Badesch DB, Fleming RT, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension. Chest 2011;140(5): Tracleer [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; October Ventavis [prescribing information]. South San Francisco, CA. Actelion Pharmaceuticals US, Inc.; November Opsumit [prescribing information]. South San Francisco, CA. Actelion Pharmacueticals US, Inc.; February Letairis [prescribing information]. Foster City, CA. Gilead Sciences, Inc.; May Flolan [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; March Veletri [prescribing information]. South San Francisco, CA. Actelion Pharmacueticals US, Inc.; June Orenitram [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; October Adempas [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; September Jaff MR, McMurty MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16): Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(12): Jenkins D, Mayer E, Screaton N, Madani M. State-of-the-art chronic thromboembolic pulmonary hypertension diagnosis and management. Eur Respir Rev. 2012;21 (123): Remodulin [prescribing information]. Research Triangle Park, NC: United Therapeutics Corp; December Uptravi [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; December Sitbon O, Channick R, Chin K, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373: *Some content reprinted from CVSHealth POLICY HISTORY Policy #: Policy Creation: November 2015 Reviewed: February 2016 Revised: February 2016 Current Effective Date: May 30, 2016 Wellmark Blue Cross and Blue Shield is an independent licensee of the Blue Cross and Blue Shield Association. 8