CLINICAL POLICY Department: Medical Management Document Name: Pulmonary Arterial Hypertension Therapies

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1 Page: 1 of 15 IMPORTANT REMINDER This Clinical Policy has been developed by appropriately experienced and licensed health care professionals based on a thorough review and consideration of generally accepted standards of medical practice, peer-reviewed medical literature, government agency/program approval status, and other indicia of medical necessity. The purpose of this Clinical Policy is to provide a guide to medical necessity. Benefit determinations should be based in all cases on the applicable contract provisions governing plan benefits ( Benefit Plan Contract ) and applicable state and federal requirements, as well as applicable plan-level administrative policies and procedures. To the extent there are any conflicts between this Clinical Policy and the Benefit Plan Contract provisions, the Benefit Plan Contract provisions will control. Clinical policies are intended to be reflective of current scientific research and clinical thinking. This Clinical Policy is not intended to dictate to providers how to practice medicine, nor does it constitute a contract or guarantee regarding results or payment. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. Subject Medical necessity guidelines for the use of prostanoids, phosphodiesterase inhibitors, endothelin antagonists and soluble guanylate cyclase stimulators in the treatment of pulmonary arterial hypertension (PAH) Description The intent of the criteria is to ensure that patients follow selection elements established by Centene medical policy for PAH. Targeted drug therapies for this condition are listed in Table 1. Table 1. Targeted Drugs for PAH 1-9 Medication Generic Name FDA-Approved Indication(s) Prostanoids Flolan Veletri epoprostenol injection Treatment of PAH* to improve exercise capacity Remodulin Tyvaso Orenitram Ventavis treprostinil injection treprostinil inhalation solution Treprostinil extended release tablets iloprost inhalation solution Treatment of PAH* to diminish symptoms associated with exercise and to diminish the rate of clinical deterioration in patients with PAH requiring transition from Flolan Treatment of PAH* to improve exercise ability Treatment of PAH to improve exercise capacity Treatment of PAH* to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA

2 Page: 2 of 15 Medication Generic Name FDA-Approved Indication(s) Class), and lack of deterioration Phosphodiesterase Type-5 Inhibitors Adcirca tadalafil tablets Treatment of PAH* to improve exercise ability Revatio Treatment of PAH* to improve exercise ability and delay sildenafil tablets clinical worsening Endothelin Receptor Antagonists Letairis Treatment of PAH* to improve exercise ability and delay ambrisentan tablets clinical worsening Tracleer Treatment of PAH* to improve exercise ability and to bosentan tablets decrease clinical worsening Opsumit macitentan tablets Treatment of PAH* to delay disease progression Soluble Guanylate Cyclase Stimulator Adempas riociguat tablets Treatment of PAH* to improve exercise capacity, and to decrease clinical worsening. Treatment for persistent/ recurrent CTEPH + after surgical treatment or inoperable CTEPH + to improve exercise capacity. * World Health Organization Group 1 classification of pulmonary hypertension (Appendix B). + World Health Organization Group 4 classification of pulmonary hypertension (Appendix B). Abbreviations: NYHA = New York Heart Association, PAH = pulmonary arterial hypertension, CTEPH = chronic thromboembolic pulmonary hypertension. Management Challenge PAH is a progressive condition characterized by elevated pulmonary arterial pressures leading to right ventricular failure. 10 The prognosis is generally poor 11 ; however, treatment options have expanded significantly over the last decade, and eleven medications with various routes of administration are currently FDA-approved for this condition (Table 1). PAH can affect people of all ages, and women are more commonly affected than men. 10 Median survival among patients diagnosed with PAH in the United States between 1981 and 1985 was 2.8 years. 10 Since that time, prognosis has improved and the five-year survival for epoprostenol-treated patients is now 47% to 55%. 10 Despite the availability of multiple effective therapies, many patients remain symptomatic and new treatment approaches are needed. 10 As research in the area of PAH progresses, new therapeutics targets are likely to emerge and the management of PAH will continue to evolve. Policy/Criteria It is the policy of health plans affiliated with Centene Corporation that PAH therapy is medically necessary for members who meet the following algorithm criteria: Figure 1: PAH Diagnosis Algorithm

3 Page: 3 of 15 Figure 2: PAH Safety and Indication Algorithm Figure 3: PAH Safety and Indication Algorithm Cont d Figure 4: PAH Pediatric Algorithm Figure 5: Adcirca and Revatio Algorithm Figure 1: PAH Diagnosis Algorithm Diagnosis of PAH WHO Group 1? (See App B) Diagnosis WHO Group IV, CTEPH? (See App B) Figure 4 Age 18 years? Have persistent or recurrent CTEPH after surgery? PAH confirmed by right heart cath. (See App C) or 2D echo? Figure 2 Is the CTEPH inoperable?

4 Page: 4 of 15 Figure 2: PAH Safety and Indication Algorithm From Figure 1 What is the prescribed agent? Remodulin Tyvaso Ventavis Figure 3 Letairis Tracleer Opsumit If female, pregnant or planning pregnancy? Flolan Veletri Have CHF due to severe LV systolic dysfunction? Adempas, Adcirca, Revatio Taking a nitrate medication on a regular or intermittent basis? - Adcirca Revatio Orenitram Severe hepatic impairment (Child-Pugh C)? - Adempas Figure 5 Prescribed as monotherapy? - Tracleer Taking any PDE inhibitors? Approve for 3 months Currently taking glyburide or cyclosporine? Figure 3 - WHO Group IV If female, pregnant or planning pregnancy? WHO Group I - Letairis Diagnosis of idiopathic pulmonary fibrosis? Approve for 3 months Figure 3 - Opsumit Figure 3

5 Page: 5 of 15 From Figure 2 Currently receiving prescribed medication for PAH? Previously received any prostanoids, phosphodiesterase inhibitor, or endothelin antagonist for PAH? Figure 3: PAH Safety and Indication Algorithm (WHO Group I) Having/had a positive response to therapy? Approve for 6 months Had an inadequate response to vasoreactivity testing? Contraindication to vasoreactivity testing in Appendix G? Had a prior trial and failure of CCB? Any contraindication to CCBs per App E? Experience any NYHA Class IV symptoms per App F? Prescribed Flolan, Velentri, Ventavis, Tracleer or Remodulin? Contraindicated to Adcirca or generic Revatio therapy? Tried and failed a trial of Adcirca or generic Revatio? Approve for 3 months ; recommend trial of Adcirca or generic Revatio Experience any NYHA Class III symptoms per App F? Approve for 3 months Experience any NYHA Class II symptoms per App F? Prescribed agent, Letaris, Opsumit, Tracleer, Remodulin or Adempas

6 Page: 6 of 15 Figure 4: PAH Pediatric Algorithm Age < 18 years? Figure 1 Is prescribed agent sildenafil or tadalafil? PAH confirmed by right heart cath or cardiac ECHO? Therapy prescribed by a Ped. Cardiologist or Pulmonologist? Currently on prescribed therapy? Approve for 3 months Positive response to therapy? Approve for 6 months

7 Page: 7 of 15 Figure 5: Adcirca and Revatio From Figure 2 Experience any NYHA Class II or III symptoms per See App. F?, Adcirca, Revatio What is the prescribed dosage form? Tablets Approve for 3 months Injection Was taking oral Revatio but temporarily unable to take oral medication? Background PAH is defined as a resting mean pulmonary artery pressure 25 mm Hg and a pulmonary wedge pressure 15 mm Hg. 11,12 The clinical presentation in most patients consists of exertional dyspnea that progresses over months to years. 10 Exertional chest pain, syncope, and lower extremity edema are signs of severe PAH and impaired right heart function. 10 PAH may be idiopathic, inherited, or associated with other diseases or exposure to certain drugs or toxins. 10 Patients with connective tissue disease (eg, scleroderma), congenital heart disease, portal hypertension, and human immunodeficiency virus are at increased risk of developing PAH. 10 The use of certain appetite suppressants (eg, dexfenfluramine), cocaine, amphetamine, and methamphetamine can lead to PAH. 10 The classification of PAH was most recently updated in 2008 at the World Conference on Pulmonary Hypertension (Appendix A). 13 PAH can be further classified according to the New York Heart Association functional status of the patient (Appendix B). 14 In patients suspected of having PAH, complete right heart catheterization is required to confirm the diagnosis. 11 Doppler echocardiography can be used to estimate pulmonary arterial pressure, but

8 Page: 8 of 15 right heart catheterization remains the gold standard for diagnosis. 12 Acute vasodilator testing should be performed in all patients with idiopathic PAH who are potential candidates for long-term calcium channel blocker therapy. 11 Patients with PAH who respond to vasodilators acutely have an improved survival with the long-term use of a CCB. As such, unstable patients or those with severe right-heart failure, who should not be treated with CCBs, need not undergo vasodilator testing. Most recently a positive acute vasodilator response in a patient with PAH has been defined as a fall of mean PAP (mpap) of at least10mmhg to 40mmHg, with an increase or unchanged cardiac output (CO). Acute vasoreactivity testing with CCBs has been proven safer and more effective than testing with NO. The primary objective of acute vasodilator testing in patients with PAH is to delineate the subset of patients who might most effectively be treated with long term oral CCBs. 11 The goals of PAH treatment are to reduce symptoms, enhance quality of life, and increase survival. 11 Improvement in exercise capacity (i.e., six-minute walk test) and hemodynamics are objective measures of treatment response. 11 Several therapies for PAH are commonly used and generally accepted as effective, although not supported by randomized controlled trials (RCTs). 15 Examples include warfarin, diuretics, calcium channel blockers, digoxin, and supplemental oxygen. 15 Prostanoids Prostacyclin is a potent vasodilator that inhibits platelet activation and has antiproliferative properties. 11 In controlled clinical trials, treatment with continuous intravenous (IV) infusion of epoprostenol was shown to improve symptoms, exercise capacity, and hemodynamic status in patients with PAH, and to improve survival in idiopathic or heritable PAH. 15 Tyvasio, Remodulin and Orenitram are all trade names for different formulations of treprostinil. In RCTs of treprostinil administered by continuous subcutaneous infusion, improvements were reported in symptoms, exercise capacity, and hemodynamic status. 15 Continuous IV infusion of treprostinil also appears to be safe and effective. 15 Results from a RCT of inhaled iloprost showed an increase in exercise capacity and improvement in symptoms, pulmonary vascular resistance, and clinical events in patients with pulmonary hypertension. 15 Results from a RCT of inhaled treprostinil demonstrated improvement in exercise capacity. 16 During Orenitram studies, subjects with mild (n=8) hepatic impairment, administration of a single 1 mg dose of Orenitram resulted in a mean maximum concentration that was 1.6- and 2.1-fold, respectively values seen in healthy subjects. With moderate impairment (n=8), the corresponding ratios were 4.0- and 4.8-fold, and with severe impairment (n=6), they were 4.8- and 7.6-fold. For this reason, Orenitram is contraindicated in patients with severe liver damage. 16 Phosphodiesterase Type-5 (PDE-5) Inhibitors Nitric oxide (NO) is a vasodilator, platelet activation inhibitor, and inhibitor of vascular smooth muscle cell proliferation. 11 The vasodilator effects of NO rely on cyclic guanosine monophosphate

9 Page: 9 of 15 (cgmp), which is rapidly inactivated by phosphodiesterases. 11 PDE-5 inhibitors increase cgmp concentrations and enhance pulmonary vasodilation. 6,7 Sildenafil and tadalafil have been shown to improve exercise capacity and hemodynamic status in approximately 50% of patients enrolled in RCTs; tadalafil also improved clinical events. 15 An increased risk of mortality, however, was seen with increasing doses of Revatio (sildenafil) in a clinical trial investigating the use of Revatio in pediatric patients with pulmonary arterial hypertension. 17 This observation, coupled with a lack of efficacy seen with lower doses of Revatio with regard to improvement in exercise ability in this patient group, has resulted in a recommendation from the FDA against use of Revatio in pediatric patients. 17,18 Per the 2014 CHEST guidance We recognize there may be situations in which the benefit-risk profile of Revatio may be acceptable in individual children, for example, when other treatment options are limited and Revatio can be used with close monitoring, 21 Endothelin Receptor Antagonists Endothelin-1 is a potent vasoconstrictor that may contribute to the development of PAH. 11 RCTs have demonstrated that bosentan improves exercise capacity, functional class, hemodynamic status, echocardiographic and Doppler variables, and time to clinical worsening. 15 Results from RCTs of ambrisentan have shown improvements in exercise capacity and clinical events that seem comparable to those observed with bosentan. 15 Results from RCT of macitentan had shown reduction in clinical worsening events and improvements in exercise capacity. 19 Soluble Guanylate Cyclase (sgc) Stimulators Soluble guanylate cyclase is an enzyme in the cardiopulmonary system and the receptor for NO and when NO binds to sgc, the enzyme catalyzes the synthesis of signaling molecular cgmp. Adempas has a dual mode of action by sensitizes sgc to endogenous NO and also directly stimulating sgc via a different binding site, independently of NO. The stimulation leads to increased generation of cgmp with subsequent vasodilation. 20 For CTEPH, RCTs have demonstrated that Adempas improved exercise capacity from a placebo. For WHO Class I PAH, results from RCTS of Adempas shown improved in exercise capacity and where comparable to a placebo 20. Safety A major component of the Specialty Pharmacy Program for PAH is to ensure necessary safety concerns are addressed prior to initiating therapy with the targeted agents. Information from the product labeling, U.S. FDA MedWatches, and primary literature are considered. For a summary by medication refer to Table 2. Table 2. Safety Concerns Prior to Beginning Treatment 1-9

10 Flolan Veletri Remodulin Tyvaso Ventavis Adcirca Revatio Letairis Tracleer Opsumit Adempas Orenitram CLINICAL POLICY Page: 10 of 15 Safety Concern Contraindicated in patients with CHF due to severe LV systolic dysfunction Contraindicated in patients with pulmonary edema and/or PVOD during dose initiation Contraindicated in patients taking nitrates Contraindicated in patients taking any phopshodiesterase inhibitors Contraindicated in pregnancy pregnancy category Contraindicated in patients taking cyclosporine or glyburide Contraindicated in patients with idiopathic pulmonary fibrosis Avoid use in moderate and severe hepatic impairment Risk of liver injury and elevations of liver aminotransferases (ALT, AST) Withdrawal effects avoid abrupt withdrawal or large dose reductions Symptomatic hypotension Pulmonary venous hypertension consider in patients who develop acute pulmonary edema during treatment PVOD consider in patients who develop acute pulmonary edema during initiation of therapy Cardiovascular/vasodilator effects use with caution in patients with underlying cardiovascular conditions Fluid retention may require intervention Sepsis Chronic intravenous infusions associated with the risk of bloodstream infections and sepsis.

11 Flolan Veletri Remodulin Tyvaso Ventavis Adcirca Revatio Letairis Tracleer Opsumit Adempas Orenitram CLINICAL POLICY Page: 11 of 15 Safety Concern Decreases in hemoglobin and hematocrit Risk of bleeding, especially in patients receiving anticoagulants Safety and efficacy not established in patients with underlying pulmonary disease (eg, asthma or COPD) or pulmonary infections Bronchospasm Prolonged erection Decreased sperm counts Loss of vision or hearing impairment Drug interaction with CYP 2C8 inducers/inhibitors Drug interaction with CYP 3A inhibitors (eg, ritonavir) Drug interaction with CYP 3A inducers (eg, rifampin) Concomitant use with alpha-blockers may lower BP significantly Appendices Appendix A: Abbreviations BP = Blood pressure CHF = Congestive heart failure LV = Left ventricular PVOD = Pulmonary veno-occlusive disease ULN = Upper limit of normal LFT = Liver function test ULN = Upper limit of normal CCB = Calcium channel blocker NYHA = New York Heart Association PAH = Pulmonary Arterial Hypertension WHO = World Health Organization COPD = Chronic obstructive pulmonary disease Appendix B: WHO Classifications for Pulmonary Hypertension 16 WHO Group 1. Pulmonary Arterial Hypertension (PAH) 1.1 Idiopathic (IPAH) 1.2 Heritable PAH

12 Page: 12 of Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) Activin receptor-like kinase type 1 (ALK1), endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown 1.3 Drug- and toxin-induced 1.4. Associated with: Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases Schistosomiasis Chronic hemolytic anemia 1.5 Persistent pulmonary hypertension of the newborn 1. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) WHO Group 2. Pulmonary Hypertension Owing to Left Heart Disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease WHO Group 3. Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities WHO Group 4. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) WHO Group 5. Pulmonary Hypertension with Unclear Multifactorial Mechanisms 5.1 Hematologic disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis Appendix C: Definition of PAH

13 Page: 13 of 15 Mean pulmonary pressure >25 mmhg at rest or >30 mmhg with exercise confirmed by right heart catheterization Appendix D: Nitrate Therapy Examples Isosorbide dinitrate (eg, Isordil) Isosorbide mononitrate (eg, Imdur, Ismo) Nitroglycerin tablets/capsules, patch (eg, Nitro-Dur) Isosorbide dinitrate/hydralazine (BiDil) Appendix E: Contraindications to Calcium Channel Blockers Right sided heart failure Left ventricular dysfunction Appendix F: New York Heart Association Functional Classification 14 Class I: Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity. Appendix G: Contraindications to acute vasoreactivity testing 11,21 Low systemic blood pressure Low cardiac output Presence of NYHA Functional Class IV symptoms (See Appendix F) Overt right heart failure Hemodynamic instability References 1. Flolan [package insert]. Research Triangle Park, NC: GlaxoSmithKline; October Veletri [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; June 2012.

14 Page: 14 of Remodulin [package insert]. Research Triangle Park, NC: United Therapeutics Corp.; October Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corp.; August Ventavis [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; vember Adcirca [package insert]. Indianapolis, IN: Eli Lilly and Company; April Revatio [package insert]. New York, NY: Pfizer Inc.; March Letairis [package insert]. Foster City, CA: Gilead Sciences, Inc.; May Tracleer [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; October 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 developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension 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-S Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43-S 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. 15. Barst RJ, Gibbs SR, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-S McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55(18): Barst RJ, Ivy DD, Gaitan G et al. A randomized, double-blind, placebo-controlled, doseranging study of oral sildenafil citrate in treatment-naïve children with pulmonary arterial hypertension. Circulation. 2012;124: FDA Drug Safety Communication: FDA recommends against use of Revatio in children with pulmonary hypertension. Available at: Accessed August 30, Opsumit [package insert]. South San Francisco, CA: Actelion Pharmaceuticals, Inc.; October Adempas [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc, October

15 Page: 15 of Taichman D, Ornelas J, Chung L, et al, CHEST Guideline and Expert Panel Report: Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults, Chest. 2014;146(2): doi: /chest FDA Drug Safety Communication: FDA clarifies Warning about Pediatric Use of Revatio (sildenafil) for Pulmonary Arterial Hypertension. Available at: Accessed Feb 9, Orenitram [package insert]. Research Triangle, NC: United Therapeutics Corp. October 2014 Revision Log Date Converted to Centene embedded algorithm for authorization criteria 03/11 Revised initial duration of approval for sildenafil to two months 03/12 Revised duration of approval to 6 months 03/13 Converted to Centene policy template 05/13 Added medications Opsumit and Adempas to policy 02/14 Added Adcirca and Revatio to Pediatric algorithm with the requirement that treatment is 03/14 prescribed by a pediatric cardiologist Added approval timeframes to each algorithm Added Orenitram to the policy (Figure 2) 3/15 Renamed and reorganized Figures 2 and 3 Moved Pediatric indications to separate figure (Figure 4) Moved Adcirca and PAH indication questions to Figure 5 Added safety information about PDE-5 inhibitors in pediatric patients Added Appendix G: Contraindications to acute vasoreactivity testing Removed requirement to review the continuation of a drug based on serious adverse 08/15 event on page Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation.