Advances in

Pulmonary Hypertension Summer 09 Vol 8, No 2

Official Journal of the Pulmonary Hypertension Association

The 4th World Symposium on Pulmonary Hypertension: Perspectives for Practice

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Table of Contents

Guest Editor’s Memo

Guest Editor for this issue:

4th World Symposium Makes History

Myung H. Park, MD Assistant Professor of Medicine Director, Pulmonary Vascular Diseases Program Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland

The 4th World Symposium on Pulmonary Hypertension at Dana Point was a historical event. Composed of 11 working groups in areas of basic science, clinical science, and future perspectives, this 3-day event brought experts in pulmonary vascular disease from all over the world to review the past and current literature, update guidelines and recommendations, and discuss and debate issues regarding the controversies and the future directions in pulmonary arterial hypertension (PAH). What was singularly the most remarkable memory for me was witnessing the collective dedication of the group to reach that elusive, yet definite, goal —finding the cure for PAH, a disease that was recently considered “uniformly fatal.” Indeed, one only had to step into the room to feel the incredible energy and excitement of all the participants–we all felt the past, present, and future of PH converging in that moment. This meeting marked the 35th anniversary of the 1st World Health Organization Meeting on Pulmonary Hypertension held in Geneva in 1973, a meeting prompted by the outbreak of aminorex-induced PH. It is a testimony to the unflagging dedication of all involved that we now have 8 FDA-approved therapies with more treatments targeting novel pathways currently being developed. In putting this issue together, I have had the privilege of working closely with several key members of the working groups. In addition to bringing you a synopsis of several sections, our goals in this issue were to give you an insider’s view on the process of shaping the drafts, personal perspectives on some key controversial issues, and a taste of what we can and should expect at the next World Symposium in 2013. Furthermore, we present a lively roundtable discussion from Drs Robyn Barst, Marc Humbert, Ivan Robbins, and Lewis Rubin, in which they share their experiences and thoughts from the Dana Point meeting and place this symposium in context with the past ones. I hope you enjoy the journey from an insider’s look at the 4th World Symposium from Dana Point.

75 Advances in Pulmonary Hypertension CME Section 77 Epidemiology and Classification of Pulmonary Hypertension 78 Summary of Pulmonary Hypertension Genetics and Genomics 79 Diagnosis and Assessment of Pulmonary Arterial Hypertension 81 Updated Evidence-Based Treatment Algorithm in Pulmonary Arterial Hypertension 83 Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension 85 Future Perspectives for the Treatment of Pulmonary Arterial Hypertension 87 CME Self-Assessment Examination 89 Pulmonary Hypertension Roundtable: Messages from Dana Point 95 Ask the Expert 97 Article Reviews 99 Clinical Trials Update 100 PHRN Corner 102 International Corner Publisher Pulmonary Hypertension Association Carl Hicks, Board Chair Rino Aldrighetti, President Sherrie Borden, Vice President, Medical and Patient Education Publishing Staff Managing Editor Deborah L. McBride McBride Strategic Services [email protected] Design Director Michael McClain PHA Office Pulmonary Hypertension Association 801 Roeder Road., Ste 400 Silver Spring, MD 20910 301-565-3004, 301-565-3994 (fax) www.PHAssociation.org © 2009 by Pulmonary Hypertension Association. All rights reserved. None of the contents may be reproduced in any form whatsoever without the written permission of PHA. Advances in Pulmonary Hypertension is circulated to cardiologists, pulmonologists, rheumatologists and other selected physicians by the Pulmonary Hypertension Association. The contents of the articles are independently determined by the Editor and the Editorial Advisory Board. Cover Image Beach at Dana Point, California, USA, site of the 4th World Symposium on Pulmonary Hypertension, 2008. Photo credit: Lynn C. Kelly

Myung H. Park, MD Guest Editor

Editor’s Memo As a participant in the 4th World Symposium on Pulmonary Hypertension, held February 2008 in Dana Point, California, I was struck by several things—first was the beautiful setting. Although Southern California is no Venice, Italy (site of the 3rd World Symposium), the Pacific Ocean certainly holds its own as far as aesthetics are concerned. Secondly, I was amazed at how much new knowledge has been garnered since the 3rd World Symposium. Dedicated investigators have continued to help unravel the pathogenesis of pulmonary arterial hypertension (PAH) at the cellular and molecular levels. What happens inside the pulmonary vascular cells that drives the disease process is becoming increasingly clear. Although the complexities of this process are daunting, new “targets” for therapy are being identified in a classic demonstration of “bench-to-bedside” research. On the classification front, increased understanding of specific disease entities and drug exposures and their association with PAH have led to important changes in the classification system. On diagnosis, newer modalities such as biomarkers and advanced imaging (MRI) are gaining a foothold in the evaluation and follow-up of the pulmonary hypertension (PH) patient. Great advances have been made with treatment: at the 3rd World Symposium, 3 drugs were FDA-approved for PAH; at the time of the Dana Point meeting, 6 approved therapies were available. These new options lead to an expanded, evidence-based treatment algorithm. Perhaps most importantly, I was struck by the sheer number and diversity of (continued on page 63)

Editorial Advisory Board Editor-in-Chief Richard Channick, MD Professor of Clinical Medicine Pulmonary and Critical Care Division University of California, San Diego Medical Center San Diego, California Immediate Past Editor Ronald J. Oudiz, MD Associate Professor of Medicine The David Geffen School of Medicine at UCLA Director, Liu Center for Pulmonary Hypertension LA Biomedical Research Institute at Harbor-UCLA Medical Center Torrance, California Editor-in-Chief Elect Erika Berman Rosenzweig, MD Associate Professor of Clinical Pediatrics (in Medicine) Columbia University, College of Physicians and Surgeons Morgan Stanley Children's Hospital of New York New York, New York Associate Editors Kristin Highland, MD Assistant Professor of Medicine Division of Pulmonary, Critical Care, Allergy and Sleep Medicine Medical University of South Carolina Charleston, South Carolina Francisco Soto, MD, MS Director, Pulmonary Hypertension Program Pulmonary and Critical Care Medicine Medical College of Wisconsin Milwaukee, Wisconsin

The Scientific Leadership Council of the Pulmonary Hypertension Association The scientific program of the Pulmonary Hypertension Association is guided by the association’s Scientific Leadership Council. The Council includes the following health care professionals: Vallerie V. McLaughlin, MD Chair, SLC University of Michigan Health System Ann Arbor, Michigan David B. Badesch, MD SLC Immediate Past-Chair University of Colorado Health Sciences Center Aurora, Colorado John H. Newman, MD SLC Vice-Chair Vanderbilt Medical School Nashville, Tennessee Raymond L. Benza, MD Allegheny General Hospital Pittsburgh, Pennsylvania Todd Bull, MD University of Colorado Health Sciences Center Denver, Colorado Richard Channick, MD Editor-in Chief, Advances in Pulmonary Hypertension UCSD Medical Center La Jolla, California

Todd Bull, MD Associate Professor of Medicine Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Health Sciences Center Denver, Colorado Robert Schilz, DO, PhD Medical Director of Lung Transplantation and Pulmonary Vascular Disease University Hospital of Cleveland Case Western Reserve University Cleveland, Ohio Editorial Board Charles Burger, MD Chair, Pulmonary and Critical Care Medicine Associate Professor of Medicine Medical Director, PH Clinic Mayo Clinic Florida Jacksonville, Florida Karen Fagan, MD Chief, Division of Pulmonary and Critical Care Medicine University of South Alabama Mobile, Alabama Eli Gabbay, MD Lung Transplant Unit Royal Perth Hospital Western Australia, Australia Nick Kim, MD Associate Clinical Professor of Medicine University of California, San Diego La Jolla, California

Omar Minai, MD Dept of Pulmonary, Allergy and Critical Care Medicine Cleveland Clinic Cleveland, Ohio Myung Park, MD Assistant Professor of Medicine Director, Pulmonary Vascular Diseases Program Division of Cardiology University of Maryland School of Medicine Baltimore, Maryland Fernando Torres, MD Director, Pulmonary Hypertension Clinic University of Texas Southwestern Medical Center Dallas, Texas Glenna Traiger, RN, MSN Pulmonary & Critical Care Pulmonary Hypertension CNS University of California, Los Angeles Los Angeles, California R. James White, MD, PhD Assistant Professor of Medicine, Pharmacology & Physiology Division of Pulmonary and Critical Care Medicine University of Rochester Rochester, New York Roham Zamanian, MD Division of Pulmonary and Critical Care Medicine Stanford University Medical Center Stanford, California

Program Description The mission of Advances in Pulmonary Hypertension is to serve as the premiere forum for state of the art information regarding diagnosis, pathophysiology, and treatment of pulmonary hypertension. The 2003 Venice revision of the World Health Organization Classification serves as a guide to categories of pulmonary hypertension addressed by the Journal. While focusing on WHO Group I PAH, the other categories (Group II, Left heart disease; Group III, Associated with lung disease and/or hypoxemia; Group IV, Thrombotic and/or Embolic Disease; Group V, Miscellaneous) are also addressed. This mission is achieved by a combination of invited review articles, Roundtable discussions with panels consisting of international experts in PH, and original contributions. In addition, a special section in selected issues entitled “Profiles in Pulmonary Hypertension” recognizes major contributors to the field and serves as an inspiring reminder of the rich and collegial history of dedication to advancing the field. Objectives • Provide up-to-date information regarding diagnosis, pathophysiology, and treatment of pulmonary hypertension. • Serve as a forum for presentation and discussion of important issues in the field, including new paradigms of disease understanding and investigational trial design. • Recognize and preserve the rich history of individuals who have made major contributions to the field via dedication to patient care, innovative research, and furthering the mission of the PH community to cure pulmonary hypertension.

Deborah Jo Levine, MD University of Texas Health Science Center at San Antonio San Antonio, Texas

C. Gregory Elliott, MD University of Utah School of Medicine Murray, Utah Karen A. Fagan, MD University of South Alabama Mobile, Alabama Robert Frantz, MD Mayo Clinic College of Medicine Rochester, Minnesota John Granton, MD Toronto General Hospital Toronto, Canada Nicholas S. Hill, MD Tufts-New England Medical Center Boston, Massachusetts Marius Hoeper, MD University of Hanover Medical School Hanover, Germany Dunbar Ivy, MD University of Colorado Denver Health Sciences Center Denver, Colorado Zhi-Cheng Jing, MD Shanghai Pulmonary Hospital Shanghai, China Anne M. Keogh, MD St. Vincent’s Public Hospital Sydney, Australia Michael J. Krowka, MD Mayo Clinic Rochester, Minnesota James E. Loyd, MD Vanderbilt University Medical Center Nashville, Tennessee

Michael Mathier, MD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Richard Silver, MD Medical University of South Carolina Charleston, South Carolina Victor F. Tapson, MD Duke University Medical Center Durham, North Carolina

Michael D. McGoon, MD Immediate Past-Chair, PHA Board of Trustees Mayo Clinic Rochester, Minnesota

Jason Yuan, MD, PhD Chair, PHA Research Committee University of California, San Diego La Jolla, California

Srinivas Murali, MD Allegheny General Hospital Pittsburgh, Pennsylvania Ronald J. Oudiz, MD Immediate Past Editor-in-Chief, Advances in Pulmonary Hypertension Liu Center for Pulmonary Hypertension at Harbor – UCLA Medical Center Torrance, California Andrew Peacock, MD Western Infirmary Glasgow, Scotland, United Kingdom Erika Berman Rosenzweig, MD Editor-In-Chief Elect, Advances in Pulmonary Hypertension Columbia Presbyterian Medical Center New York, New York Ivan Robbins, MD Chair, Scientific Sessions Committee Vanderbilt University Nashville, Tennesee Julio Sandoval, MD National Institute of Cardiology of Mexico Tlalpan, Mexico

Liaisons Arlene Schiro, NP (voting) Chair, PH Resource Network Massachusetts General Hospital Boston, MA Harry Rozakis Board Liaison Emeritus Members Bruce H. Brundage, MD St. Charles Medical Center - Bend Bend, Oregon Alfred P. Fishman, MD University of Pennsylvania Health System Philadelphia, Pennsylvania The Mission of the Scientific Leadership Council is to provide medical and scientific guidance and support to the PHA by: • Developing and disseminating knowledge for diagnosing and treating pulmonary hypertension • Advocating for patients with pulmonary hypertension • Increasing involvement of basic and clinical researchers and practitioners More information on PHA’s Scientific Leadership Council and associated committees can be found at: www.PHAssociation.org/SLC/

Advances in Pulmonary Hypertension 59

Advances in Pulmonary Hypertension Author Guidelines 2009 Scope of Manuscripts Advances in Pulmonary Hypertension considers the following types of manuscripts for publication: • Reviews that summarize and synthesize peerreviewed literature to date on relevant topics in a scholarly fashion and format • Letters to the Editor • Clinical Case Studies Manuscript Submission Authors are required to submit their manuscripts in an electronic format, preferably by email to the Editor-in-Chief, Richard Channick, MD, [email protected]. Please provide manuscripts in a word processing program. Images should be submitted electronically as well. All material reproduced from previously published, copyrighted material should contain a full credit line acknowledging the original source. Authors are responsible for obtaining permission to reproduce such material. Contact Information: List all authors, including mailing address, titles and affiliations, phone, fax, and email. Please note corresponding author. Peer Review and Editing: Manuscripts will be peer reviewed. Accepted manuscripts will be edited for clarity, spelling, punctuation, grammar, and consistency with American Medical Association (AMA) style.

60 Advances in Pulmonary Hypertension

Manuscript Preparation Length: Full-length manuscripts should not exceed 4,000 words, including references. Please limit the reference list to 50 citations. Manuscripts should be accompanied by figures and/or tables. Generally, 4 to 5 figures and 2 to 3 tables are preferred for each manuscript. Please include a brief description to accompany these items, as well as a key for all abbreviated words. Spacing: One space after commas and periods. Manuscripts should be double spaced. Manuscripts should not contain an abstract but an introduction is recommended. References: All submissions should include numbered references that are referred to in the text by superscripts and that conform to AMA style. Example: Lewczuk J, Piszko P, Jagas J, et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest. 2001;119:818-823. Copyright: Manuscripts and accompanying material are accepted for exclusive publication in Advances in Pulmonary Hypertension. None of the contents may be reproduced without permission of the Pulmonary Hypertension Association. To request permission, please contact Donica Merhazion, PHA Associate Director of Medical Services, 240-485-0744 or [email protected]

S TA R T W I T H C O N F I D E N C E REVATIO: for patients with PAH as early as class II • REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability – WHO Group I

• A first-line treatment for class II and class III1 – Updated American College of Chest Physicians evidence-based clinical practice guidelines

• The lowest-priced oral PAH therapy* – REVATIO 20 mg tid *Based on wholesale acquisition cost: First DataBank Inc., 2008. Actual pharmacy or out-of-pocket costs may vary. Price comparisons do not imply comparable efficacy and safety. The pivotal trial for REVATIO included patients who were predominantly functional classes II and III, and the pivotal trial for Tracleer® included patients who were predominantly functional class III.

REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy. The use of REVATIO and organic nitrates in any form, at any time, is contraindicated. Co-administration of REVATIO with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, and ritonavir) is not recommended as serum concentrations of sildenafil substantially increase. Co-administration of REVATIO with CYP3A4 inducers, including bosentan; and more potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, and rifabutin, may alter plasma levels of either or both medications. Dosage adjustment may be necessary. Before starting REVATIO, physicians should carefully consider whether their patients with underlying conditions could be adversely affected by the mild and transient vasodilatory effects of REVATIO on blood pressure. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD) and administration of REVATIO to these patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered. The most common side effects of REVATIO (placebo-subtracted) were epistaxis (8%), headache (7%), dyspepsia (6%), flushing (6%), and insomnia (6%). Adverse events were generally transient and mild to moderate. Caution is advised when PDE5 inhibitors, such as REVATIO, are administered with ␣-blockers as both are vasodilators with blood pressure lowering effects. REVATIO should be used with caution in patients with anatomical deformation of the penis or patients who have conditions which may predispose them to priapism. In PAH patients, the concomitant use of vitamin K antagonists and REVATIO resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo. The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely post-marketing in temporal association with the use of PDE5 inhibitors for the treatment of erectile dysfunction, including sildenafil. It is not possible to determine if these events are related to PDE5 inhibitors or to other factors. Physicians should advise patients to seek immediate medical REVATIO contains sildenafil citrate, the attention in the event of sudden loss of vision while taking PDE5 inhibitors, including REVATIO. same active ingredient found in Viagra® Sudden decrease or loss of hearing has been reported in temporal association with the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO. Tracleer (bosentan) is a registered trademark of Actelion Pharmaceuticals.

Please see brief summary of prescribing information on adjacent page.

www.pfizerpro.com

Reference: 1. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-1928.

Brief summary of prescribing information

INDICATIONS AND USAGE REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability. The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy. CONTRAINDICATIONS Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated. REVATIO is contraindicated in patients with a known hypersensitivity to any component of the tablet. WARNINGS The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see Drug Interactions and DOSAGE AND ADMINISTRATION). REVATIO has vasodilator properties, resulting in mild and transient decreases in blood pressure (see PRECAUTIONS). Prior to prescribing REVATIO, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting hypotension (BP 170/110); • Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); • Patients currently on bosentan therapy. PRECAUTIONS General Before prescribing REVATIO, it is important to note the following: • Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha-blockers (see Drug Interactions), cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting were reported during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti-hypertensive drugs. • REVATIO should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erections greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. • In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans. • The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). The incidence of epistaxis was also higher in sildenafil-treated patients with concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). • The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration. Information for Patients Physicians should discuss with patients the contraindication of REVATIO with regular and/or intermittent use of organic nitrates. Sildenafil is also marketed as VIAGRA® for male erectile dysfunction. Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking all PDE5 inhibitors, including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors when used in the treatment of male erectile dysfunction. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see ADVERSE REACTIONS). Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking all PDE5 inhibitors, including REVATIO. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, Clinical Trials and Post-Marketing Experience). Drug Interactions In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo. Effects of Other Drugs on REVATIO In vitro studies: Sildenafil metabolism is principally mediated by the CYP3A4 (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. In vivo studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics. Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors. Sildenafil exposure without concomitant medication is shown to be 5-fold higher at a dose of 80 mg t.i.d. compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil was co-administered with erythromycin, a CYP3A4 inhibitor, at steady state (500 mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In a study performed in healthy volunteers, co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION). In another study in healthy volunteers, co-administration with the HIV protease inhibitor ritonavir, a potent CYP3A4 inhibitor, at steady state (500 mg b.i.d.) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates (see WARNINGS and DOSAGE AND ADMINISTRATION). Although the interaction between other protease inhibitors and REVATIO has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.), with the endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. The combination of both drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of potent CYP3A4 inducers is expected to cause greater decreases in plasma levels of sildenafil. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these

study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope (see PRECAUTIONS: General). Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg) did not affect the pharmacokinetics of sildenafil. Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin did not alter the pharmacokinetics of either sildenafil or atorvastatin. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil. Effects of REVATIO on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). In vivo studies: When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. In healthy subjects, co-administration of 125 mg b.i.d. bosentan and 80 mg t.i.d. sildenafil resulted in a 63% decrease in AUC of sildenafil and a 50% increase in AUC of bosentan. In a study of healthy volunteers, sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, both of which are CYP3A4 substrates. Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg). Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats, respectively, the human exposure at the Recommended Human Dose (RHD) of 20 mg t.i.d. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocyte and in vitro mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite 19 and 38 times, for males and females, respectively, the human exposure at the RHD of 20 mg t.i.d. Pregnancy Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). There are no adequate and well-controlled studies of sildenafil in pregnant women. Nursing Mothers It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in human milk, caution should be used when REVATIO is administered to nursing women. Pediatric Use Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established. Geriatric Use Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Clinical Trials Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg t.i.d. were studied. The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%) and the same as placebo (3%). In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were more frequent in REVATIO patients than placebo patients, are shown in Table 1. Adverse events were generally transient and mild to moderate in nature. Table 1. Sildenafil Adverse Events in ⱖ3% of Patients and More Frequent Than Placebo

ADVERSE EVENT % Epistaxis Headache Dyspepsia Flushing Insomnia Erythema Dyspnea exacerbated Rhinitis nos Diarrhea nos Myalgia Pyrexia Gastritis nos Sinusitis Paresthesia

Placebo (n=70) 1 39 7 4 1 1 3 0 6 4 3 0 0 0

Sildenafil 20 mg t.i.d. (n=69) Placebo Subtracted 9 8 46 7 13 6 10 6 7 6 6 5 7 4 4 4 9 3 7 3 6 3 3 3 3 3 3 3

At doses higher than the recommended 20 mg t.i.d. there was a greater incidence of some adverse events including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. In the pivotal study, the incidence of retinal hemorrhage at the recommended sildenafil 20 mg t.i.d. dose was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these events had risk factors for hemorrhage including concurrent anticoagulant therapy. Post-Marketing Experience In post-marketing experience with sildenafil citrate at doses indicated for male erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. When used to treat male-erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see PRECAUTIONS/ Information for Patients). Cases of sudden decrease or loss of hearing have been reported post-marketing in temporal association with the use of PDE5 inhibitors, including REVATIO. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of REVATIO, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (see PRECAUTIONS, Information for Patients). OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

October 2007

RVU00055

©2008 Pfizer Inc.

All rights reserved.

Printed in USA/August 2008

U.S. Pharmaceutical

Editor’s Memo (continued from inside front cover)

participants at the 4th World Symposium. In contrast, the prior 3rd World Symposium seemed somewhat more “exclusive,” with a relatively limited number of global experts meeting in small groups. I believe this expansion in the demographic of the meeting mirrors the disease itself. No longer is PH a rarefied condition treated in a handful of institutions by high-level experts. With the advent of widely available, effective therapy for PAH, we now have the “hot” disease, of interest to a wide-ranging group of healthcare providers. Educational initiatives and outreach, many generated by the Pulmonary Hyper-tension Association, have clearly taken hold, evidenced by the large and varied audience in Dana Point. This issue, I hope, will give you the “flavor” of this outstanding meeting. Dr Myung Park, the guest editor, has done a fabulous job gathering several authors, all a co-chair of their respective working groups at the 4th World Symposium. These contributors have provided overviews of their respective com-

mittees’ discussions and recommendations. For a complete summary of the symposium, read the supplement in the Journal of the American College of Cardiology, July 2009. I would also like to call your attention to another important, “must read” consensus document from June 2009, published jointly by the American College of Cardiology and American Heart Association, and endorsed by the American Thoracic Society and American College of Chest Physicians. This comprehensive document, edited by Dr Vallerie McLaughlin, summarizes the state of the art in PH. Finally, in this issue, I am pleased to introduce 4 new features: Article Reviews, Clinical Trials Update, PHRN Corner, and Ask the Expert. These new sections enhance the variety and scope of the journal. I look forward to your feedback, as we are always looking for ways to improve this unique publication. Enjoy. Richard N. Channick, MD Editor-in-Chief

a

PHA is Proud to Announce the 2009 Research Grant Award Winners! Recipients of the 2009 PHA Postdoctoral Fellowship Awards Revathi Rajkumar PhD University of Pittsburgh Research: “Genetic Mechanisms of Pulmonary Arterial Hypertension

Gregg Stashenko, MD Duke University, Durham Research: “Gene Expression Profiles in Patients with CTEPH Compared to Patients with IPAH”

Recipient of the 2009 Mentored Patient-Oriented Research Career Development Award (K23) Stephen Mathai, MD Johns Hopkins University, School of Medicine Research: “Neurohormonal Activation in Scleroderma-related Pulmonary Hypertension”

Recipients of the 2009 Pulmonary Hypertension Association/American Thoracic Society Partnership Grant for Pulmonary Hypertension Ari Zaiman, MD, PhD Johns Hopkins University School of Medicine Research: “Inhibition of TGF beta Signaling in Endothelial Cells: Role in Pulmonary Hypertension”

Lunyin Yu, MD Massachusetts General Hospital Research: “Role of NHE1 Gene in Development of Pulmonary Hypertension and Vascular Remodeling”

Empowered by hope

To read more about PHA’s research grant program and other research award winners, visit www.PHAssociation.org/support/ResearchFunding.asp

Advances in Pulmonary Hypertension 63

In the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1, Class II or III symptoms)

Living with PAH can be complicated...

Choosing a therapy should not be. Please see below for important safety information, including boxed WARNINGS on the possible risk of liver injury and the risk of serious birth defects.

INDICATION: LETAIRIS is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in patients with WHO Class II or III symptoms to improve exercise capacity and delay clinical worsening. Clinical worsening is defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape.1 Early escape criteria were two or more of the following after a minimum treatment period of 4 weeks: ≥20% decrease in 6-minute walk distance; worsening WHO functional class; worsening right ventricular failure; rapidly progressing cardiac, hepatic, or renal failure; and refractory systolic hypotension 5× ULN or if elevations are accompanied by bilirubin >2× ULN or by signs or symptoms of liver dysfunction • May cause fetal harm if taken during pregnancy • Must exclude pregnancy before the start of treatment • Prevent pregnancy thereafter by the use of two reliable methods of contraception

Important safety information regarding hepatotoxicity LETAIRIS is not recommended in patients with elevated aminotransferases (>3× ULN) at baseline because monitoring liver injury may be more difficult. If aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, itching, or jaundice) or increases in bilirubin >2× ULN, LETAIRIS treatment should be stopped. There is no experience with the reintroduction of LETAIRIS in these circumstances. Contraindication • Do not administer LETAIRIS to a pregnant woman because it can cause fetal harm Warnings and precautions • Decreases in hemoglobin have been observed within the first few weeks of treatment with LETAIRIS; measure hemoglobin prior to initiation, at 1 month, and periodically thereafter • Mild to moderate peripheral edema. Peripheral edema occurred more frequently in elderly patients (age ≥65 years) receiving LETAIRIS (29%; 16/56) compared to placebo (4%; 1/28) • Peripheral edema is a known class effect of endothelin receptor antagonists. In addition, there have been postmarketing reports of fluid retention occurring within weeks after starting LETAIRIS which required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure Drug interactions • Use caution when LETAIRIS is coadministered with cyclosporine A • Use caution when LETAIRIS is coadministered with strong CYP3A inhibitors (e.g., ketoconazole) or CYP2C19 inhibitors (e.g., omeprazole) • Use caution when LETAIRIS is coadministered with inducers of P-gp, CYPs, and UGTs

Letairis® (ambrisentan) is indicated for the treatment of PAH (WHO Group 1, Class II or III symptoms)

LETAIRIS offers Simple dosing One pill, once a day1 Two therapeutically effective doses1

Designed for everyday.

• Available in 5 mg and 10 mg tablets • Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg if 5 mg is tolerated

Reliable improvements Up to +59 m placebo-adjusted mean change from baseline in 6MWD* at 12 weeks with LETAIRIS†1

• LETAIRIS was studied in two 12-week, randomized, double-blind, placebo-controlled, multicenter studies (ARIES-1, N=201, and ARIES-2, N=192); 6MWD was the primary endpoint1 —ARIES-1: +51 m (10 mg, p3% incidence in the combined LETAIRIS treatment

group and more frequent than in the placebo group, with a difference of ≥1% between the LETAIRIS and placebo groups.

Please see the brief summary of full prescribing information on next page.

* 6MWD=6-minute walk distance; baseline mean 6MWD was 341 ± 76 m in ARIES-1 and 348 ± 84 m in ARIES-2.2 † Improvements in exercise capacity were greater for younger patients than for elderly patients (≥65 years), and greater for patients with idiopathic PAH (IPAH) than for those with associated PAH (APAH). Results of such subgroup analyses must be interpreted with caution. References: 1. LETAIRIS [Prescribing Information]. Foster City, Calif: Gilead Sciences, Inc; October 2008. 2. Data on file. Gilead Sciences, Inc. © 2008 Gilead Sciences, Inc. All rights reserved. ABS0130 December 2008 LETAIRIS is a registered trademark and Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.

LETAIRIS® (ambrisentan) 5 mg and 10 mg Tablets Brief summary of full prescribing information. See full prescribing information. Rx only. WARNING: POTENTIAL LIVER INJURY LETAIRIS (ambrisentan) can cause elevation of liver aminotransferases (ALT and AST) to at least 3 times the upper limit of normal (ULN). LETAIRIS treatment was associated with aminotransferase elevations >3× ULN in 0.8% of patients in 12-week trials and 2.8% of patients including long-term open-label trials out to one year. One case of aminotransferase elevations >3× ULN has been accompanied by bilirubin elevations >2× ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly. In the postmarketing period with another endothelin receptor antagonist (ERA), bosentan, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy. In at least one case with bosentan, a late presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of the suspect drug. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment. Elevations in aminotransferases require close attention. LETAIRIS should generally be avoided in patients with elevated aminotransferases (>3× ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin >2× ULN, treatment should be stopped. There is no experience with the re-introduction of LETAIRIS in these circumstances. CONTRAINDICATION: PREGNANCY LETAIRIS is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals [see Contraindications (4.1)]. Pregnancy must therefore be excluded before the initiation of treatment with LETAIRIS and prevented thereafter by the use of at least two reliable methods of contraception unless the patient has had a tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception is needed. Obtain monthly pregnancy tests. Because of the risks of liver injury and birth defects, LETAIRIS is available only through a special restricted distribution program called the LETAIRIS Education and Access Program (LEAP), by calling 1-866-664-LEAP (5327). Only prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS. In addition, LETAIRIS may be dispensed only to patients who are enrolled in and meet all conditions of LEAP [see WARNINGS, Prescribing and Distribution Program for LETAIRIS]. INDICATIONS AND USAGE: LETAIRIS is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. DOSAGE AND ADMINISTRATION: Adult Dosage: Initiate treatment at 5 mg once daily with or without food, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.Tablets may be administered with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH). Liver function tests should be measured prior to initiation and during treatment with LETAIRIS [see Warnings and Precautions (5.1)]. Women of Childbearing Potential: Pregnancy tests should be obtained monthly in women of childbearing potential taking LETAIRIS [see Contraindications (4.1)]. Pre-existing Hepatic Impairment: LETAIRIS is not recommended in patients with moderate or severe hepatic impairment [see Special Populations (8.7)]. CONTRAINDICATIONS: Pregnancy Category X: Teratogenicity is a class effect of endothelin receptor antagonists. There are no data on the use of LETAIRIS in pregnant women. LETAIRIS is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. WARNINGS AND PRECAUTIONS: Potential Liver Injury (see BOXED WARNING): Treatment with endothelin receptor antagonists has been associated with dose-dependent liver injury manifested primarily by elevation of serum aminotransferases (ALT or AST), but sometimes accompanied by abnormal liver function (elevated bilirubin). The combination of aminotransferases greater than 3-times the upper limit of normal (>3× ULN) and total bilirubin >2× ULN is a marker for potentially serious hepatic injury. Liver function tests were closely monitored in all clinical studies with LETAIRIS. For all LETAIRIS-treated patients (N=483), the 12-week incidence of aminotransferases >3× ULN was 0.8% and >8× ULN was 0.2%. Liver chemistries must be measured prior to initiation of LETAIRIS and at least every month thereafter. If there are aminotransferase elevations >3× ULN and ≤5× ULN, they should be re-measured. If the confirmed level is >3× ULN and ≤5× ULN, reduce the daily dose or interrupt treatment and continue to monitor every two weeks until the levels are 5× ULN and ≤8× ULN, LETAIRIS should be discontinued and monitoring should continue until the levels are 8× ULN, treatment should be stopped and re-initiation should not be considered. If aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, itching, or jaundice) or increases in bilirubin >2× ULN, LETAIRIS treatment should be stopped. Hematological Changes: Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with LETAIRIS. These decreases were observed within the first few weeks of treatment with LETAIRIS, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving LETAIRIS in the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving LETAIRIS (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis. Hemoglobin must be measured prior to initiation of LETAIRIS and should be measured at one month and periodically thereafter. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, discontinuation of treatment should be considered. Peripheral Edema: Peripheral edema is a known class effect of endothelin receptor antagonists. In addition, there have been post-marketing reports of fluid retention occurring within weeks after starting LETAIRIS which required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure. Co-administration of LETAIRIS and Cyclosporine A: Cyclosporine is a strong inhibitor of P-glycoprotein (P-gp), Organic Anion Transport Protein (OATP), and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-gp, OATP and CYP3A. Therefore, use caution when LETAIRIS is co-administered with cyclosporine A because cyclosporine A may cause increased exposure to LETAIRIS [see Drug Interactions (7)]. Coadministration of LETAIRIS and Strong CYP3A and 2C19 Inhibitors: Use caution when LETAIRIS is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) and CYP2C19-inhibitors (e.g., omeprazole) [see Drug Interactions (7)]. Prescribing and Distribution Program for LETAIRIS: Because of the risks of liver injury and birth defects, LETAIRIS is available only through a special restricted distribution program called the LETAIRIS Education and Access Program (LEAP). Only prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS. In addition,

LETAIRIS® (ambrisentan) may be dispensed only to patients who are enrolled in and meet all conditions of LEAP. To enroll or receive more information visit www.letairis.com or call 1-866-664-LEAP (5327). ADVERSE REACTIONS: Clinical Trials Experience: Safety data for LETAIRIS were obtained from two 12-week, placebo-controlled studies in patients with PAH (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to LETAIRIS in these studies ranged from 1 day to 4 years (N=418 for at least 6 months and N=343 for at least 1 year). In ARIES-1 and ARIES-2, a total of 261 patients received LETAIRIS at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse events that occurred in >3% of the patients receiving LETAIRIS and were more frequent on LETAIRIS than placebo are shown in Table 1. Table 1 Adverse Events in >3% of PAH Patients Receiving LETAIRIS and More Frequent than Placebo Placebo (N=132) LETAIRIS (N=261) Adverse event n (%) n (%) Placebo-adjusted (%) Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4 Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3 Palpitations 3 (2) 12 (5) 3 Nasopharyngitis 1 (1) 9 (3) 2 Abdominal pain 1 (1) 8 (3) 2 Constipation 2 (2) 10 (4) 2 Dyspnea 4 (3) 11 (4) 1 Headache 18 (14) 38 (15) 1 Note: This table includes all adverse events >3% incidence in the combined LETAIRIS treatment group and more frequent than in the placebo group, with a difference of ≥1% between the LETAIRIS and placebo groups. Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent. Fewer patients receiving LETAIRIS had adverse events related to liver function tests compared to placebo. Peripheral edema was similar in younger patients ( 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of Tracleer. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping Tracleer with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration]. Elevations in aminotransferases require close attention [see Dosage and Administration]. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment with Tracleer should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances. Teratogenicity Tracleer is likely to cause major birth defects if used by pregnant females based on animal data [see Contraindications]. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of childbearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving Tracleer [see Drug Interactions]. Monthly pregnancy tests should be obtained. INDICATIONS AND USAGE Pulmonary Arterial Hypertension Tracleer is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class II-IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. Considerations for use Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses. DOSAGE AND ADMINISTRATION Recommended Dosing Tracleer treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of liver injury. Tablets should be administered morning and evening with or without food. Required Monitoring Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. Dosage Adjustments for Patients Developing Aminotransferase Elevations The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment with Tracleer should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances. Table 1: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3 × ULN ALT/AST levels

Treatment and monitoring recommendations

> 3 and ≤ 5 × ULN

Confirm by another aminotransferase test; if confirmed, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pre-treatment values, continue or re-introduce the treatment as appropriate (see below).

> 5 and ≤ 8 × ULN

Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pre-treatment values, consider re-introduction of the treatment (see below).

> 8 × ULN

Treatment should be stopped and re-introduction of Tracleer should not be considered. There is no experience with re-introduction of Tracleer in these circumstances.

If Tracleer is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above. Use in Females of Childbearing Potential Initiate treatment in females of child-bearing potential only after a negative pregnancy test and only in females who are using two reliable methods of contraception. Females who have had a tubal sterilization or a Copper T 380A IUD or LNg 20 IUS inserted do not require other forms of contraception. Effective contraception must be practiced throughout treatment and for one month after stopping Tracleer. Females should seek contraceptive advice as needed from a gynecologist or similar expert. Urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer [see Boxed Warning, Contraindications, Drug Interactions]. Use in Patients with Pre-existing Hepatic Impairment Tracleer should generally be avoided in patients with moderate or severe liver impairment. There are no specific data to guide dosing in hepatically impaired patients; caution should be exercised in patients with mildly impaired liver function [see Warnings and Precautions]. Patients with Low Body Weight In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer in children between the ages of 12 and 18 years. Use with Ritonavir Co-administration of Tracleer in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see Drug Interactions]. Co-administration of Ritonavir in Patients on Tracleer Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon individual tolerability [see Dosage and Administration and Drug Interactions]. Treatment Discontinuation There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.

DOSAGE FORMS AND STRENGTHS Tracleer is available as 62.5 mg and 125 mg film-coated, unscored tablets for oral administration. 62.5 mg tablets: film-coated, round, biconvex, orange-white tablets, embossed with identification marking “62,5” 125 mg tablets: film-coated, oval, biconvex, orange-white tablets, embossed with identification marking “125” CONTRAINDICATIONS Pregnancy Category X [see BOXED WARNING] Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. In animal studies, bosentan caused teratogenic effects including malformations of the head, mouth, face, and large blood vessels. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of child bearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should also be obtained. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of Tracleer and cyclosporine A is contraindicated [see Drug Interactions]. Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and Tracleer is contraindicated [see Drug Interactions]. Hypersensitivity Tracleer is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include rash and angioedema [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Potential Liver Injury Elevations in ALT or AST by more than 3 × ULN were observed in 11% of bosentan-treated patients (N=658) compared to 2% of placebo-treated patients (N=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 3 × ULN) is a marker for potential serious liver injury. Elevations of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of Tracleer in these circumstances [see Dosage and Administration]. Patients with Pre-existing Hepatic Impairment Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Tracleer should generally be avoided in patients with moderate or severe liver impairment [see Dosage and Administration]. In addition, Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) because monitoring liver injury in these patients may be more difficult [see Boxed Warning]. Fluid Retention Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients [see Clinical Studies]. In addition, there have been numerous post-marketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Tracleer or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer therapy. Decreased Sperm Counts An open-label, single arm, multicenter, safety study evaluated the effect on testicular function of Tracleer 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with Tracleer. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Tracleer was discontinued and after two months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Tracleer have an adverse effect on spermatogenesis. Decreases in Hemoglobin and Hematocrit Treatment with Tracleer can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment. During the course of treatment the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur when Tracleer is administered, the possibility of associated pulmonary veno-occlusive disease should be considered and Tracleer should be discontinued. Prescribing and Distribution Program for Tracleer Because of the risks of liver injury and birth defects, Tracleer is available only through a special restricted distribution program called the Tracleer Access Program (T.A.P.). Only prescribers and

pharmacies registered with T.A.P. may prescribe and distribute Tracleer. In addition, Tracleer may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P. Information about Tracleer and T.A.P. can be obtained by calling 1-866-228-3546. To enroll in T.A.P., prescribers must complete the T.A.P. Tracleer (bosentan) Enrollment and Renewal Form (see T.A.P. Tracleer (bosentan) Enrollment and Renewal Form for full prescribing physician agreement) indicating agreement to: • Read and understand the communication and educational materials for prescribers regarding the risks of Tracleer. • Review and discuss the Tracleer Medication Guide and the risks of bosentan (including the risks of teratogenicity and hepatotoxicity) with every patient prior to prescribing Tracleer. • Review pretreatment liver function tests (ALT/AST/bilirubin) and, for females of childbearing potential, confirm that the patient is not pregnant. • Agree to order and monitor monthly liver function tests and, for females of childbearing potential, pregnancy tests. • Enroll all patients in T.A.P. and renew patients’ enrollment annually thereafter. • Educate and counsel females of childbearing potential to use reliable contraception, as defined on the Tracleer Enrollment and Renewal Form, during treatment with Tracleer and for one month after treatment discontinuation. • Counsel patients who fail to comply with the program requirements. • Notify Actelion Pharmaceuticals US, Inc. of any adverse events, including liver injury, and report any pregnancy during Tracleer treatment. Throughout treatment and for one month after stopping Tracleer, females of childbearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving Tracleer. ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: • Potential liver injury [see Boxed Warning and Warnings and Precautions] • Fluid retention [see Warnings and Precautions] Clinical Studies Experience Safety data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=94 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=328) to bosentan ranged from 1 day to 1.7 years (N=174 more than 6 months and N=28 more than 12 months). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on bosentan was abnormal liver function. The adverse drug events that occurred in ≥3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 2: Adverse events* occurring in ≥3% of patients treated with bosentan 125-250 mg twice daily and more common on bosentan in placebo-controlled studies in pulmonary arterial hypertension Adverse Event

Respiratory Tract Infection

Bosentan N=258

Placebo N=172

No.

%

No.

%

56

22%

30

17%

Headache

39

15%

25

14%

Edema

28

11%

16

9%

Chest Pain

13

5%

8

5%

Syncope

12

5%

7

4%

Flushing

10

4%

5

3%

Hypotension

10

4%

3

2%

Sinusitis

9

4%

4

2%

Arthralgia

9

4%

3

2%

Liver Function Test Abnormal

9

4%

3

2%

Palpitations

9

4%

3

2%

Anemia

8

3%

–

–

*Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Combined data from Study-351, BREATHE-1 and EARLY. Postmarketing Experience There have been several post-marketing reports of angioedema associated with the use of bosentan. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing Tracleer. The following additional adverse reactions have been reported during the post approval use of Tracleer. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Tracleer exposure: • Unexplained hepatic cirrhosis [see Boxed Warning] • Rash • Liver failure [see Boxed Warning] • Jaundice • Anemia requiring transfusion • Hypersensitivity [see Contraindications] • Thrombocytopenia • Neutropenia and leukopenia DRUG INTERACTIONS Cytochrome P450 Summary Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.

Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer [see Boxed Warning, Contraindications]. An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Cyclosporine A The concomitant administration of bosentan and cyclosporine A is contraindicated [see Contraindications]. During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A substrate) by approximately 50%. Glyburide An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of Tracleer and glyburide is contraindicated, and alternative hypoglycemic agents should be considered [see Contraindications]. Co-administration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A. The possibility of worsened glucose control in patients using these agents should be considered. Lopinavir/Ritonavir or Other Ritonavir-containing HIV Regimens In vitro data indicate that bosentan is a substrate of the Organic Anion Transport Protein (OATP), CYP3A and CYP2C9. Ritonavir inhibits OATP and inhibits and induces CYP3A. However, the impact of ritonavir on the pharmacokinetics of bosentan may largely result from its effect on OATP. In normal volunteers, co-administration of Tracleer 125 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily increased the trough concentrations of bosentan on Days 4 and 10 approximately 48-fold and 5-fold, respectively, compared with those measured after Tracleer administered alone. Therefore, adjust the dose of Tracleer when initiating lopinavir/ritonavir [see Dosage and Administration]. Co-administration of Tracleer 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily. Simvastatin and Other Statins Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A substrate), and its active ȕ-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins that are significantly metabolized by CYP3A, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A-metabolized statins should have cholesterol levels monitored after Tracleer is initiated to see whether the statin dose needs adjustment. Rifampin Co-administration of bosentan and rifampin in normal volunteers resulted in a mean 6-fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady-state. The effect of bosentan on rifampin levels has not been assessed. When consideration of the potential benefits and known and unknown risks leads to concomitant use, measure liver function weekly for the first 4 weeks before reverting to normal monitoring. Tacrolimus Co-administration of tacrolimus and bosentan has not been studied in humans. Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used together. Ketoconazole Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered. Warfarin Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers, decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary.This recommendation holds true when sildenafil is used for the treatment of pulmonary arterial hypertension or erectile dysfunction. Iloprost In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category X: Teratogenic Effects [see Contraindications] Use of Tracleer is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer. The prescriber should not dispense a prescription for Tracleer without documenting a negative urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse. Follow-up urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Tracleer. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. Drug interaction studies show that Tracleer reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer and should not be used as a patient’s only contraceptive method [see Drug Interactions]. Females of childbearing potential using Tracleer must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer therapy. Females of childbearing potential using Tracleer should seek contraception counseling from a gynecologist or other expert as needed.

Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose [MRHD] (on a mg/m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs [see Nonclinical Toxicology]. Nursing Mothers It is not known whether Tracleer is excreted into human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Tracleer, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and efficacy in pediatric patients have not been established. Geriatric Use Clinical studies of Tracleer did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised in dose selection for elderly patients given the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group. Hepatic Impairment Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. Mild liver impairment was shown not to impact the pharmacokinetics of bosentan. The influence of moderate or severe liver impairment on the pharmacokinetics of Tracleer has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients; caution should be exercised in patients with mildly impaired liver function. Tracleer should generally be avoided in patients with moderate or severe liver impairment [see Dosage and Administration, Warnings and Precautions]. Renal Impairment The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment. Patients with Low Body Weight [see Dosage and Administration]. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan. Reproductive and Developmental Toxicology Bosentan was teratogenic in rats given oral doses ≥60 mg/kg/day. In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of

60 and 300 mg/kg/day. Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. Impairment of Fertility/Testicular Function The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents. Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD). PATIENT COUNSELING INFORMATION Advise patients to consult the Medication Guide on the safe use of Tracleer. Important Information • Monthly monitoring of serum aminotransferases The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases. • Pregnancy testing and avoidance of pregnancy Patients should be advised that Tracleer is likely to cause birth defects based on animal studies. Tracleer treatment should only be initiated in females of childbearing potential following a negative pregnancy test. Females of childbearing potential must have monthly pregnancy tests and need to use two different forms of contraception while taking Tracleer and for one month after discontinuing Tracleer. Females who have a tubal ligation or a Copper T 380A IUD or LNg 20 IUS can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant and should seek contraceptive advice from a gynecologist or similar expert as needed. • Drug Interactions The physician should discuss with the patient possible drug interactions with Tracleer, and which medications should not be taken with Tracleer. The physician should discuss the importance of disclosing all concomitant or new medications. Distributed by: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA Revised August 2009 References for previous pages: 1. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. August 2009. 2. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100. 3. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-1123. 4. Data on fi le, Actelion Pharmaceuticals.

© 2009 Actelion Pharmaceuticals US, Inc. All rights reserved. 08 203 01 00 0909

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FOR PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) WITH NYHA CLASS II-IV SYMPTOMS

POSSIBILITIES

The first and only prostacyclin available for both SC and IV infusion t Improves symptoms associated with exercise1,2

t Multiple pump options

t Improves hemodynamics1

t No ice packs

t May be titrated to effect

t Up to 72 hours (SC) or 48 hours (IV) between reservoir changes

Indications: REMODULIN® (treprostinil sodium) Injection is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted. In patients with pulmonary arterial hypertension requiring transition from Flolan® (epoprostenol sodium), REMODULIN is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. Important Safety Information: Chronic intravenous infusions of REMODULIN are delivered using an indwelling central venous catheter. This route is associated with the risk of blood stream infections (BSI) and sepsis, which may be fatal. REMODULIN should be used only by clinicians experienced in the diagnosis and treatment of PAH. REMODULIN is a potent pulmonary and systemic vasodilator. Initiation of REMODULIN must be performed in a setting with adequate personnel and equipment for physiological monitoring and emergency care. Therapy with REMODULIN may be used for prolonged periods, and the patient’s ability to administer REMODULIN and care for an infusion system should be carefully considered. Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for excessive pharmacologic effects or for unacceptable infusion site symptoms. Abrupt withdrawal or sudden large reductions in dosage of REMODULIN may result in worsening of PAH symptoms and should be avoided. Caution should be used in patients with hepatic or renal insufficiency. The most common side effects of REMODULIN included those related to the method of infusion. For subcutaneous infusion, infusion site pain and infusion site reaction (redness and swelling) occurred in the majority of patients. These symptoms were often severe and could lead to treatment with narcotics or discontinuation of REMODULIN. For intravenous infusion, line infections, sepsis, arm swelling, tingling sensations, bruising, and pain were most common. General side effects (>5% more than placebo) were diarrhea, jaw pain, vasodilation, and edema. References: 1. Simonneau G, Barst RJ, Galie N, 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. 2. REMODULIN [package insert]. United Therapeutics Corporation; 2008. For important safety and other information, please see brief summary of full prescribing information on the back of this page.

REMODULIN is a registered trademark of United Therapeutics Corporation. Flolan is a registered trademark of GlaxoSmithKline. REM_JAd_NOV08v.5

Empowering Prostacyclin

REMODULIN® (treprostinil sodium) Injection BRIEF SUMMARY The following is a brief summary of the full prescribing information on Remodulin (treprostinil sodium) Injection. Please review the full prescribing information prior to prescribing Remodulin. INDICATIONS AND USAGE Pulmonary Arterial Hypertension In Patients With NYHA Class II-IV Symptoms Remodulin is indicated for the treatment of pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted. Pulmonary Arterial Hypertension In Patients Requiring Transition From Flolan® In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. WARNINGS AND PRECAUTIONS Risks Attributable To The Drug Delivery System Chronic intravenous infusions of Remodulin are delivered using an indwelling central venous catheter. This route is associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. In an open-label study of IV treprostinil (n=47), there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use. General Conditions Of Use Remodulin should be used only by clinicians experienced in the diagnosis and treatment of PAH. Remodulin is a potent pulmonary and systemic vasodilator. Initiation of Remodulin must be performed in a setting with adequate personnel and equipment for physiological monitoring and emergency care. Therapy with Remodulin may be used for prolonged periods, and the patient’s ability to administer Remodulin and care for an infusion system should be carefully considered. Dose Modification Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for excessive pharmacologic effects or for unacceptable infusion site symptoms. Abrupt Withdrawal Or Sudden Large Dose Reduction Abrupt withdrawal or sudden large reductions in dosage of Remodulin may result in worsening of PAH symptoms and should be avoided. Hepatic and Renal Insufficiency Caution should be used in patients with hepatic or renal insufficiency. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Events With Subcutaneously Administered Remodulin Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of Remodulin, infusion site pain and reaction were the most common adverse events among those treated with Remodulin. Infusion site reaction was defined as any local adverse event other than pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of treatment. Percentages of subjects reporting subcutaneous infusion site adverse events Reaction Pain Placebo Remodulin Placebo Remodulin Severe 1 38 2 39 Requiring narcotics* NA† NA† 1 32 Leading to discontinuation 0 3 0 7 * based on prescriptions for narcotics, not actual use † medications used to treat infusion site pain were not distinguished from those used to treat site reactions Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these are generally considered to be related to the pharmacologic effects of Remodulin, whether administered subcutaneously or intravenously. Adverse Events During Chronic Dosing The following table lists adverse events that occurred at a rate of at least 3% and were more frequent in patients treated with subcutaneous Remodulin than with placebo in controlled trials in PAH. Adverse Events in Controlled 12-Week Studies of Patients with PAH, Occurring with at Least 3% Incidence and More Common on Subcutaneous Remodulin than on Placebo Remodulin (N=236) Placebo (N=233) Percent of Patients Percent of Patients Infusion Site Pain 85 27 Infusion Site Reaction 83 27 Headache 27 23 Diarrhea 25 16 Nausea 22 18 Rash 14 11 Jaw Pain 13 5 Vasodilatation 11 5 Dizziness 9 8 Edema 9 3 Pruritus 8 6 Hypotension 4 2 Reported adverse events (at least 3%) are included except those too general to be informative, and those not plausibly attributable to the use of the drug, because they were associated with the condition being treated or are very common in the treated population. Adverse Events Attributable To The Drug Delivery System In controlled studies of Remodulin administered subcutaneously, there were no reports of infection related to the drug delivery system. There were 187 infusion system complications reported in 28% of patients (23% Remodulin, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 4 Placebo) reported nonAdverse Event

serious adverse events resulting from infusion system complications. Adverse events resulting from problems with the delivery systems were typically related to either symptoms of excess Remodulin (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were generally resolved by correcting the delivery system pump or infusion set problem such as replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration. In addition to these adverse events due to the drug delivery system during subcutaneous administration, the following adverse events may be attributable to the IV mode of infusion including arm swelling, paresthesias, hematoma and pain. Post-Marketing Experience In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Remodulin. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The following events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, and potential connection to Remodulin. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia and bone pain. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported. DRUG INTERACTIONS Reduction in blood pressure caused by Remodulin may be exacerbated by drugs that by themselves alter blood pressure, such as diuretics, antihypertensive agents, or vasodilators. Since Remodulin inhibits platelet aggregation, there is also a potential for increased risk of bleeding, particularly among patients maintained on anticoagulants. During clinical trials, Remodulin was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, corticosteroids, and other medications. Remodulin has not been studied in conjunction with Flolan or Tracleer® (bosentan). Effect Of Other Drugs On Remodulin In vivo studies: Acetaminophen - Analgesic doses of acetaminophen, 1000 mg every 6 hours for seven doses, did not affect the pharmacokinetics of Remodulin, at a subcutaneous infusion rate of 15 ng/kg/min. Effect Of Remodulin On Other Drugs In vitro studies: Remodulin did not significantly affect the plasma protein binding of normally observed concentrations of digoxin or warfarin. In vivo studies: Warfarin - Remodulin does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous Remodulin at an infusion rate of 10 ng/kg/min. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of treprostinil sodium during organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/ min (about 117 times the starting human rate of infusion, on a ng/m2 basis and about 16 times the average rate 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 an infusion rate of 150 ng treprostinil/kg/min (about 41 times the starting human rate of infusion, on a ng/m2 basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at rates of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. Because animal reproduction studies are not always predictive of human response, Remodulin should be used during pregnancy only if clearly needed. Labor And Delivery No treprostinil sodium treatment-related effects on labor and delivery were seen in animal studies. The effect of treprostinil sodium on labor and delivery in humans is unknown. Nursing Mothers It is not known whether treprostinil is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Remodulin is administered to nursing women. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Clinical studies of Remodulin did not include sufficient numbers of patients aged