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Managing Multiple Medications in Patients with PAH

Managing Multiple Medications in Patients with PAH. ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas. Learning Objectives (CME, CE, CPE). At the completion of this educational activity, participants should be able to:

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Managing Multiple Medications in Patients with PAH

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  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. 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. Updated Definition of PAH 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. 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.

  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. PAH-specific Therapies Approved for Use in the US FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

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

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

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

  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. Pharmacokinetic Interactions Between PAH-specific Medications 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. Bosentan-Sildenafil Pharmacokinetic Interactions Sildenafil With and Without Bosentan Bosentan With and Without Sildenafil 600 1600 Sildenafil + Placebo Day 6 Sildenafil + Placebo Day 16 Sildenafil + Bosentan Day 6 Sildenafil + Bosentan Day 16 Bosentan + Placebo Day 10 Bosentan + Placebo Day 16 Sildenafil + Bosentan Day 10 Sildenafil + Bosentan Day 16 1400 500 1200 400 1000 Plasma Concentration (ng/mL) Plasma Concentration (ng/mL) 300 800 600 200 400 100 200 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) Time (hr) Burgess G, et al. Eur J Clin Pharmacol. 2008;64(1):43–50.

  13. Bosentan-Tadalafil Pharmacokinetic Interactions Day 10 Steady State Pharmacokinetics in Healthy Volunteers 1000 3000 Tadalafil + placebo Bosentan + tadalafil Tadalafil + bosentan Bosentan + placebo 2000 500 Tadalafil Plasma Concentration (ng/mL) Bosentan Plasma Concentration (ng/mL) 1000 0 0 0 24 48 72 96 0 3 6 9 12 Time (hr) Time (hr) Tadalafil With and Without Bosentan Bosentan With and Without Tadalafil Wrishko RE, et al. J Clin Pharmacol. 2008;48(5):610-618.

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

  15. Clinical Trial Data: Combination PAH Therapy

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

  17. STEP: Add-on Inhaled Iloprost to Stable Bosentan Monotherapy Change From Baseline in NYHA Class 91.0% Iloprost Placebo 62.5% Patients (%) 34.4% 15.2% 6.0% 3% 0% 0% Clinical Deterioration Improved 1 Class Worsened 1 Class No Change 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. McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174(11):1257-1263.

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

  19. Lack of Efficacy of Bosentan + Epoprostenol Combination Therapy (BREATHE-2) Placebo/epoprostenol (n=10) Baseline Placebo/epoprostenol 16 Weeks Bosentan/epoprostenol (n=19) Baseline Bosentan/epoprostenol 16 Weeks -40 0 40 80 120 6MWD m Adapted from Humbert M, et al.Eur Respir J. 2004;24(3):353–359.

  20. * Placebo Tadalafil 40 mg 40 * 30 20 Change from baseline6MWD (m) 10 0 -10 -20 4 8 12 16 Baseline -30 Weeks ^ Tadalafil in PAH Associated with Collagen Vascular Disease 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. Girgis R. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #9099

  21. Tadalafil in PAH – Change in 6MWD ^ IPAH Change From Baseline 6MWD (m) * * 40 35 30 25 20 15 10 5 0 * Placebo Tadalafil 40 mg Baseline 48 12 16 Weeks * 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. Girgis R. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #9099

  22. Additional Pharmacotherapeutic Considerations with PAH

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

  25. Known Interactions of PAH-specific Medications with Oral Anticoagulants 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. Effects of Bosentan on Warfarin Pharmacokinetics R-warfarin S-warfarin 2000 2000 Placebo Placebo Bosentan Bosentan 1500 1500 1000 1000 Concentration (µg\L) Concentration (µg\L) 500 500 0 0 0 24 48 72 96 120 0 24 48 72 96 120 Time (hr) Time (hr) N = 12 healthy male volunteers. Two-way crossover design. Weber C, et al. J Clin Pharmacol. 1999;39(8):847-854.

  27. Interactions of PAH-specific Medications with Digoxin 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. 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 O O C H H 3 C H 3 N N H N C H C H O 3 2 N H C O H N 2 N N H C H C H C H 2 2 3 O O S C O H 2 2 N H O O C O H O N C H C O H 3 2 O Tadalafil Sildenafil 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.

  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. PDE-5 Inhibitor Interaction with CYP3A4 Inhibitor 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 Sildenafil Plasma Concentration (ng/mL-1) 0 4 8 12 16 20 24 Time Post Dose (h) • Example of PDE-5 inhibitor interaction with CYP3A4 inhibitors • Co-administration dramatically increases plasma concentration and AUC Muirhead GJ, et al. BrJ Clin Pharmacol. 2002;53(suppl 1):37S-43S.

  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 O O S N H O C H C O O H H C 3 3 O N H C O N 3 H C H O 3 2 C H 3 O N N O N C H N C H 3 Bosentan Ambrisentan

  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. 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. 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. 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. REVEAL: Co-Morbidities in Patients With PAH 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 Badesch DB, et al. Chest. 2009. DOI 10.1378/chest.09-1140. E-pub ahead of print.

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

  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. Therapeutic Approaches to Systemic Sclerosis Zandman-Goddard G, et al. Clin Dev Immunol. 2005;12(3):165-173.

  41. Raynaud Phenomenon Therapeutic Approaches And Their Potential Interaction with PAH Therapy Adapted from: Riemekasten G, et al. Rheumatology. 2006;45(suppl 3):iii49–iii51. Package Inserts.

  42. Ambrisentan Does Not Interfere With Pharmacokinetics of Omeprazole ^ 180 160 140 Ambrisentan, n=26 Ambrisentan + Omeprazole, n=7 120 Ethinyl Estradiol Plasma Concentration (pg/mL) 100 80 60 40 20 0 0 12 24 36 48 Time (hours) Harrison B, et al. Am J Respir Crit Care Med. 2009;179:A3348.

  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. SSRI Use in PAH and Co-morbid Clinical Depression: Antidepressant AND PAH Therapy? No SSRI 0.60 0.40 Cumulative Hazard 0.20 SSRI 0.00 0 2 4 6 8 Time (years) Number at Risk: No SSRI 473 306 212 135 71 SSRI 69 35 23 14 8 Cumulative hazard of death by SSRI use. Patients enrolled in PH observational database. Shah SJ, et al. Chest. 2009;136(3):694-700.

  45. Body Mass Index in PAH Varies by Etiology: Comparison of REVEAL and NHANES Overall IPAH FPAH CDH CTD Drugs & Toxins HIV PortoPH -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 REVEAL pts have lower BMI REVEAL pts have higher BMI REVEAL BMI – NHANES BMI N = 2,141 REVEAL subjects compared with age- and gender- matched controls from NHANES Waxman AB. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8573

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

  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. 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. Use of PAH-specific Therapy in Patients with Portopulmonary Hypertension (PoPH) Bosentan, but not iloprost, associated with improved clinical outcomes 1.0 0.8 0.6 Overall Survival 0.4 0.2 0.0 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 Hoeper MM, et al. Eur Respir J. 2007;30(6):1096–1102.

  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.

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