1. Managing Multiple Medications in Patients with PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas

2. 2 Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: ̶ Describe the common medications used in the treatment of PAH and their interactions with one- another ̶ Describe common medications used in the management of patients’ other conditions – including underlying conditions leading to PAH ̶ Discuss how medications used to treat underlying medical conditions may interact with PAH-specific medications

3. Managing Multiple Medications in PAH

4. 4 Updated Definition of PAH Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66 Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294. Increased mean pulmonary arterial pressure (mPAP)* >25 mm Hg at rest Normal pulmonary capillary wedge pressure (PCWP) <15 mm Hg Increased pulmonary vascular resistance (PVR) † >3 Wood units Right Heart Catheterization Confirmed * Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.

5. 5 Issues in Managing PAH Drug-drug interactions — PAH-specific medications — Other medications given for the medical management of PAH — Drugs prescribed for co-morbid conditions Adverse effects Administration — Ability to comply with prescribing instructions Clinical experience and data evaluating use and order of multiple PAH-specific therapies

6. 6 PAH-specific Therapies Approved for Use in the US Endothelin Receptor Antagonists Phosphodiesterase- type 5 Inhibitors Prostanoids – Prostacyclin Analogs AmbrisentanSildenafilEpoprostenol (IV) BosentanTadalafilIloprost (inhaled) Treprostinil (IV, SC, and inhaled) FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction= Search.Search_Drug_Name. Accessed November 1, 2009.

7. 7 REVEAL Database: Overall PAH-specific Therapy at Time of Enrollment Adapted from: Badesch DB, et al. Chest. 2009. DOI 10.1378/chest.09-1140. E-pub ahead of print. N = 2438.

8. 8 REVEAL Database: Monotherapy vs Combination Therapy at Time of Enrollment Adapted from: Badesch DB, et al. Chest. 2009. DOI 10.1378/chest.09-1140. E-pub ahead of print. N = 2438.

9. 9 Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy Atrial septostomy and/or Lung transplantation Sequential Combination Therapy Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Failure to show improvement or deterioration with monotherapy

10. 10 PAH-specific Therapy Principles – Oral Therapy Drugs within a single class should not be combined Patients responding to but intolerant to drug within a class may benefit from a trial of an alternate drug within the same class — Sildenafil ↔ tadalafil — Bosentan ↔ ambrisentan Patients failing on monotherapy probably would not benefit from switching to alternative monotherapy within the same class — Expert-opinion recommends combination therapy Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78–S84.

11. 11 Pharmacokinetic Interactions Between PAH-specific Medications Drug 1Drug 2Action AmbrisentanNoneN/A BosentanSildenafilReduces sildenafil plasma concentrations 63% TadalafilReduces tadalafil Cmax 27% at steady state SildenafilBosentanIncreases bosentan concentrations 50% TadalafilBosentanIncreases bosentan AUC <20% EpoprostenolNoneN/A IloprostNoneN/A TreprostinilNoneN/A FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

12. 12 Bosentan-Sildenafil Pharmacokinetic Interactions Sildenafil With and Without BosentanBosentan With and Without Sildenafil Burgess G, et al. Eur J Clin Pharmacol. 2008;64(1):43–50. Plasma Concentration (ng/mL) 1600 1400 1200 1000 800 600 400 200 0 0123456789101112 Time (hr) Bosentan + Placebo Day 10 Bosentan + Placebo Day 16 Sildenafil + Bosentan Day 10 Sildenafil + Bosentan Day 16 Plasma Concentration (ng/mL) 600 0 024681012141618202224 Time (hr) Sildenafil + Placebo Day 6 Sildenafil + Placebo Day 16 Sildenafil + Bosentan Day 6 Sildenafil + Bosentan Day 16 100 200 300 400 500

13. 13 Bosentan-Tadalafil Pharmacokinetic Interactions Tadalafil With and Without BosentanBosentan With and Without Tadalafil Wrishko RE, et al. J Clin Pharmacol. 2008;48(5):610-618. Bosentan + placebo Bosentan + tadalafil Day 10 Steady State Pharmacokinetics in Healthy Volunteers Bosentan Plasma Concentration (ng/mL) 3000 036912 Time (hr) 2000 1000 0 Tadalafil + placebo Tadalafil + bosentan Tadalafil Plasma Concentration (ng/mL) 1000 024487296 0 Time (hr) 500

14. 14 No Pharmacokinetic Interactions Between Ambrisentan and Tadalafil Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. N = 26, healthy volunteers. AmbrisentanTadalafil

15. Clinical Trial Data: Combination PAH Therapy

16. 16 PACES: Sildenafil Added to Epoprostenol: Change from Baseline in 6-Minute Walk Distance N=267; *P<0.01 versus placebo (ITT population). Mean Change From Baseline (m) Weeks 0 48 12 16 * Placebo Sildenafil -10 0 10 20 30 40 50 Simonneau G, et al. Ann Intern Med. 2008;149(8):521-530.

17. 17 STEP: Add-on Inhaled Iloprost to Stable Bosentan Monotherapy Patients (%) Improved 1 Class 34.4% Clinical Deterioration 6.0% 62.5% N=67. Inhaled iloprost added to stable bosentan monotherapy for a mean of 17.6 to 18.8 months. 94% of patients were NYHA class III at baseline. Iloprost Placebo McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174(11):1257-1263. 0% 15.2% No Change Change From Baseline in NYHA Class 91.0% Worsened 1 Class 3% 0%

18. 18 Efficacy of Prostanoid Add-on to Failing Oral PAH Therapy Jacobs W, et al. J Heart Lung Transplant. 2009;28(3):280-284. N=18. End observations completers only. 4 patients had died or were unable to perform 6-minute walk distance at study end. Start Prostanoid 6MWD 500 450 400 300 4m4m PrEnd obs 350 Baseline + 64 m P=0.003 PrePost

19. 19 Lack of Efficacy of Bosentan + Epoprostenol Combination Therapy (BREATHE-2) Adapted from Humbert M, et al. Eur Respir J. 2004;24(3):353–359. Placebo/epoprostenol (n=10) Baseline Bosentan/epoprostenol (n=19) Baseline Placebo/epoprostenol 16 Weeks Bosentan/epoprostenol 16 Weeks -4004080120 6MWD m

20. 20 Tadalafil in PAH Associated with Collagen Vascular Disease Girgis R. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #9099 6MWD at 16 Weeks * P<0.05 vs placebo. Placebo (n = 16) vs 40 mg tadalafil (n = 17). From randomized dose-ranging trial, including 2.5, 10, 20, and 40 mg tadalafil. Baseline 4816 -30 -20 0 20 40 30 10 -10 12 Placebo Tadalafil 40 mg Weeks Change from baseline 6MWD (m) * * ^

21. 21 Tadalafil in PAH – Change in 6MWD Girgis R. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #9099 * P<0.05 vs placebo. Placebo (n = 56) vs 40 mg tadalafil (n = 50) of patients with IPAH/HPAH. From randomized dose-ranging trial, including 2.5, 10, 20, and 40 mg tadalafil. ^ 481216 Placebo Tadalafil 40 mg Change From Baseline 6MWD (m) Weeks IPAH * * * 40 35 30 25 20 15 10 5 0 Baseline

22. Additional Pharmacotherapeutic Considerations with PAH

23. 23 General Medical Care for PH Diuretics — Drug choice is based on physician experience Oral anticoagulants — Generally recommended for patients with IPAH in absence of contraindications Maintain INR of 1.5 to 2.5 (US guidelines) Digoxin — Short-term IV therapy increases cardiac output; no long-term data demonstrating efficacy in PAH — Slows ventricular rate in patients with atrial fibrillation/flutter Barst RJ et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

24. 24 Anticoagulation in PAH: Role of Thrombotic Arteriopathy Adapted from Johnson SR, et al. Chest. 2006;130(2);545-552. Prothrombotic state Pulmonary arterial hypertension Thrombotic arteriopathy Abnormal hematologic parameters

25. 25 Known Interactions of PAH-specific Medications with Oral Anticoagulants DrugInteraction AmbrisentanNone BosentanDecreased the plasma concentrations of S-warfarin and R-warfarin by 29% and 38%, respectively SildenafilNone TadalafilNone EpoprostenolInhibits platelet aggregation. Potential to increase bleeding risk. IloprostInhibits platelet function. Potential to increase bleeding risk. TreprostinilInhibits platelet aggregation. Potential to increase bleeding risk. FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

26. 26 Effects of Bosentan on Warfarin Pharmacokinetics Weber C, et al. J Clin Pharmacol. 1999;39(8):847-854. R-warfarin S-warfarin N = 12 healthy male volunteers. Two-way crossover design. Placebo Concentration (µg\L) 2000 024487296120 Time (hr) Bosentan 1500 1000 500 0 Placebo Concentration (µg\L) 2000 024487296120 Time (hr) Bosentan 1500 1000 500 0

27. 27 Interactions of PAH-specific Medications with Digoxin DrugInteraction AmbrisentanNone BosentanNone EpoprostenolDecreased digoxin oral clearance 15% IloprostNone SildenafilNone reported TadalafilNone TreprostinilNone reported FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

28. 28 PDE-5 Inhibitors: Comparison of Sildenafil and Tadalafil Both agents act at same PDE5 binding site — Comparable mechanism of action, potencies, adverse effect profiles Tadalafil has longer elimination half-life — Once-daily versus three-times-daily dosing TadalafilSildenafil FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/scripts/ cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009. N H H H N N CH 3 O O O O HN N N HOOC N N N CH 3 CH 3 CO 2 H CO 2 H OH CO 2 H O 2 S CH 2 CH 2 CH 3 CH 3 CH 2 O O

29. 29 PDE-5 Inhibitors: Important Class-related Drug-drug Interactions Organic nitrates — Contraindicated in any form, due to risk of life- threatening systemic hypotension Alpha blockers — Potential for increased effects of alpha blockers used for systemic hypertension May result in dizziness or syncope Ritonavir and other CYP3A inhibitors — Not recommended due to increased exposure to PDE5 inhibitor FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

30. 30 PDE-5 Inhibitor Interaction with CYP3A4 Inhibitor Example of PDE-5 inhibitor interaction with CYP3A4 inhibitors Co-administration dramatically increases plasma concentration and AUC Muirhead GJ, et al. Br J Clin Pharmacol. 2002;53(suppl 1):37S-43S. Sildenafil Plasma Concentration (ng/mL -1 ) 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 04812162024 Time Post Dose (h)

31. 31 ERAs: Comparison of Bosentan and Ambrisentan Bosentan is sulfonamide — Metabolism is dependent on CYP450 enzyme system Inhibitors and inducers of CYP3A can impact bosentan clearance Ambrisentan is propanoic acid derivative — Multiple clearance pathways Not CYP3A dependent — Ambrisentan has longer half-life Once-daily dosing BosentanAmbrisentan NH S N N N N H 2 O H 3 C H 3 C CH CH 3 O O OO O N COOH N H 3 CO CH 3 CH 3 O

32. 32 Endothelin Receptor Antagonist Class Effects Teratogenicity — Pregnancy is contraindicated with both ambrisentan and bosentan Use of bosentan requires non-hormonal contraceptives to prevent pregnancy Peripheral edema

33. 33 Bosentan Contraindications Due to Drug-drug Interactions Cyclosporin A — Steady-state bosentan concentrations increased 3- to 4-fold Glyburide — Increased risk of elevated liver aminotransferases — Use alternative glucose control agents Bosentan full prescribing information. 2009.

34. 34 Bosentan Important Drug-drug Interactions Hormonal contraceptives — Exposures decreased by bosentan — Nonhormonal birth control mandatory Modest reduction in warfarin concentrations Ketoconazole increases bosentan concentrations by 2-fold — No dose adjustment required, but potential for increased adverse effects Rifampicin — 6-fold increase in initial bosentan trough levels, followed by 60% decrease in steady-state levels Tacrolimus — Animal studies suggest increased bosentan levels. Use with caution Bosentan full prescribing information. 2009. Wrishco RE, et al. J Clin Pharmacol. 2008;48(5):610-618.

35. 35 Ambrisentan: Important Drug-drug Interactions Cyclosporin A, rifampin, ritonavir — All may cause increase in ambrisentan exposure Ambrisentan full prescribing information. 2007.

36. Managing PAH Co-morbid Conditions

37. 37 REVEAL: Co-Morbidities in Patients With PAH Badesch DB, et al. Chest. 2009. DOI 10.1378/chest.09-1140. E-pub ahead of print. Dilated cardiomyopathy History of DVT History of PE Renal insufficiency Cirrhosis Valvular heart disease Non-skin cancer Ischemic cardiovascular event Diabetes mellitus (I and II) Thyroid disease Sleep apnea Obstructive airway disease Clinical depression Rheumatoid arthritis Lupus Other Scleroderma CVD/CTD Obesity (BMI ≥ 30) Hypertension

38. 38 REVEAL Registry: Commonly Used Medications in Patients With PAH Badesch DB et al. Chest. 2009. DOI 10.1378/chest.09-1140. E-pub ahead of print. Clopidogrel ACE inhibitor Corticosteroids Psychotropics Beta blocker Statin Other anti-inflammatory Aspirin Other antidepressant SSRI Calcium channel blocker Synthetic thyroid Digoxin Oxygen Warfarin Diuretic

39. 39 Medical Management of PAH Associated with Systemic Sclerosis No disease modifying therapy is approved for the treatment of systemic sclerosis — Immunosuppressants may be prescribed, but have not been proven in clinical trials — Imatinib is currently being evaluated in clinical trials A wide range of medications are used to manage symptoms of systemic sclerosis Zandman-Goddard G, et al. Clin Dev Immunol. 2005;12(3):165-173.

40. 40 Therapeutic Approaches to Systemic Sclerosis OrganMechanismTreatment Examples SkinImmunosuppressionMethotrexate Cyclosporin Raynaud phenomenon VasodilationCCBs Fibrosing alveolitisImmunosuppressionCyclophosphamide GIMotility enhancers PPIs Octreotide Omeprazole Renal crisisVasodilationACE inhibitors Zandman-Goddard G, et al. Clin Dev Immunol. 2005;12(3):165-173.

41. 41 Raynaud Phenomenon Therapeutic Approaches And Their Potential Interaction with PAH Therapy Drug/Drug Class Potential Interaction with PAH Therapy CCBsAmlodipine-sildenafil co-administration results in additional decrease in supine BP Alpha blockersUse with caution with PDE5 inhibitors Glyceryl trinitrate PDE5 inhibitor use contraindicated with all forms of nitrates ACE inhibitorsNone noted Serotonin antagonists SSRIs may interfere with anticoagulation (warfarin) kinetics Adapted from: Riemekasten G, et al. Rheumatology. 2006;45(suppl 3):iii49–iii51. Package Inserts.

42. 42 Ambrisentan Does Not Interfere With Pharmacokinetics of Omeprazole Harrison B, et al. Am J Respir Crit Care Med. 2009;179:A3348. 0 Ethinyl Estradiol Plasma Concentration (pg/mL) 160 140 120 100 60 0 20 80 40 122436 Ambrisentan, n=26 Ambrisentan + Omeprazole, n=7 180 Time (hours) 48 ^

43. 43 PAH and Co-morbid Diabetes No data published on management of diabetes in patients with PAH Bosentan and glyburide co-administration contraindicated due to increased risk of elevated liver transaminases — Use alternate forms of glycemic control Bosentan full prescribing information. 2009.

44. 44 SSRI Use in PAH and Co-morbid Clinical Depression: Antidepressant AND PAH Therapy? Shah SJ, et al. Chest. 2009;136(3):694-700. Cumulative hazard of death by SSRI use. Patients enrolled in PH observational database. Cumulative Hazard 0.60 0246802468 Time (years) 0.40 0.20 0.00 No SSRI SSRI No SSRI47330621213571 SSRI693523148 Number at Risk:

45. 45 Body Mass Index in PAH Varies by Etiology: Comparison of REVEAL and NHANES Waxman AB. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8573 N = 2,141 REVEAL subjects compared with age- and gender- matched controls from NHANES REVEAL BMI, kg/m 2 NHANES BMI, kg/m 2 P value 28.328.20.37 29.128.1<0.001 27.826.90.18 24.626.8<0.001 27.528.7<0.001 32.628.7<0.001 26.728.70.045 29.228.90.70 Overall IPAH FPAH CDH CTD Drugs & Toxins HIV PortoPH REVEAL pts have lower BMI REVEAL pts have higher BMI REVEAL BMI – NHANES BMI -6-5-4-3-20123456

46. 46 Pathophysiology of Obesity-related Cardiomyopathy In: Dela Cruz CS, et al. Clin Chest Med. 2009;30(3):509–523. Excessive Adipose Tissue OSA/OHS Hypoxemia/Acidosis Pulmonary Arterial Hypertension Pulmonary venous Hypertension RV Failure RV Hypertrophy and Enlargement No Change in HR Decreased SVR LV Failure Increase Circulating Blood Volume Increase LV Stroke Volume Increased CO LV Enlargement Increased LV Wall Stress Eccentric LV Hypertrophy LV Diastolic & Systolic Dysfunction

47. 47 Therapy of PAH Related to Obesity- hypoventilation Syndrome Obesity-hypoventilation syndrome (OHS) usually related to BMI >34 and daytime hypercapnia (PCO2 of ≥45 mm Hg) Tracheostomy should be offered along with chronic outpatient mechanical ventilation — Nocturnal O2 supplementation, CPAP not adequate therapy Additional PAH-specific therapy may be added as needed Alam S, et al. Clin Chest Med. 2007;28(1):91–115.

48. 48 Modafinil Use in PAH Related to Obstructive Sleep Apnea Indicated for reducing excessive sleepiness in narcolepsy, obstructive sleep apnea/hypoventilation syndrome (OSA/OHS), and shift work sleep disorder (SWSD) Metabolism is via hepatic enzymes — Potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2 — Potential to interfere with S-warfarin metabolism Modafinil prescribing information. 2007.

49. 49 Use of PAH-specific Therapy in Patients with Portopulmonary Hypertension (PoPH) Bosentan, but not iloprost, associated with improved clinical outcomes Hoeper MM, et al. Eur Respir J. 2007;30(6):1096–1102. 31 consecutive patients with Child class A or B cirrhosis and severe PoPH treated for up to 3 yrs with either inhaled iloprost or bosentan 1.0 0.8 0.6 0.4 0.2 0.0 Overall Survival

50. 50 Use of PAH-specific Therapy in PoPH ERAs (ambrisentan and bosentan) recommended only in patients with mild liver disease — Avoid with moderate or severe liver disease PDE5 inhibitors (tadalafil and sildenafil) may be used in mild-to-moderate liver disease — Neither has been studied in severe liver disease Riley TR 3rd, et al. Am Fam Physician. 2001;64(10):1735-1740. FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

51. 51 Use of Beta-blockers in PoPH Nonselective beta blockers or isosorbide mononitrate may be provided to prevent variceal bleeding in patients with cirrhosis — Beta blockers worsen hemodynamics and exercise capacity in PoPH Beta blockers + CYP3A4 inhibitors may increase AUC or decrease clearance of PDE5 inhibitors — All nitrates are contraindicated with PDE5 inhibitors Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. FDA. Package inserts for above products. Accessed at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

52. Adherence to Therapy* * Note: Heart failure literature accessed as surrogate for PAH. PAH-specific data on adherence to therapy is lacking.

53. 53 Managing Polypharmacy: Adherence to Therapy Nonadherence to medication regimens is common, even in severe illness In heart failure patients, >88% adherence rates associated with better outcomes Lack of adherence to cyclosporin regimen associated with late acute organ rejection Riegel B, et al. Circulation. 2009;120(12):1141-1163.

54. 54 Three-times Daily vs Once-daily Dosing Intervals and Adherence to Chronic Therapy Adapted from: Saini SD, et al. Am J Manag Care. 2009;15(6):e22-e33. Diabetes Migraine Chronic Diseases Hypertension Epilepsy Heart Failure Adherence (%) TID QD 0102030405060708090100

55. 55 Depression as Barrier to Self-care in Heart Failure Depression and depressive symptoms are independently associated with hospitalization and mortality in persons with heart failure Depressive symptoms predict worse health status, and physical and social functioning, symptom burden, and QOL Depression is associated with nonadherence to medications, decreased participation in exercise, lower adherence to diet recommendations, and lower rates of smoking cessation in patients with coronary disease Riegel B, et al. Circulation. 2009;120(12):1141-1163.

56. 56 Clinical Anxiety and Self-care in Heart Failure Riegel B, et al. Circulation. 2009;120(12):1141-1163. Taking all medications as prescribed Daily monitoring of weight as recommended Daily monitoring of symptoms of heart failure as recommended

57. Complementary Alternative Medicine (CAM)

58. 58 Use of Complementary/Alternative Medical Regimens National Health Interview Survey (2002) N = 10,572 with cardiovascular disease 36% had used CAM (excluding prayer) in the previous 12 months Most common types of CAM — Herbal products (18%) — Mind-body therapies (17%) Yeh GY, et al. Am J Cardiol. 2006;98(5):673-680.

59. 59 Commonly Used Herbal/Complementary Medications in Cardiovascular Disease Yeh GY, et al. Am J Cardiol. 2006;98(5):673-680. n = 1816 Soy supplements Peppermint Ginger supplements Fish oils/omega fatty acids St. John’s wort Glucosamine Ginkgo biloba Ginseng Garlic supplements Echinacea

60. 60 Summary/Conclusions PAH is rarely an isolated condition Managing patients with PAH must be considered within the context of managing other co-morbid conditions Drug-drug interactions should be considered when initiating or altering PAH-specific therapy Adherence to medication regimens and barriers to adherence should also be considered Patients may self-medicate with herbal products and should be appropriately counseled