a CMe-Certified enduring Material M I anaG nG PatIentS wIth Pah: what you need to know about drug interactions Harrison W. Farber, MD Program Chair Professor of Medicine Director, Pulmonary Hypertension Center Boston University School of Medicine Boston, MA healthA CONTINUINGmatters MEDICAL EDUCATIONcme COMPANY This activity is jointly sponsored by the University of Kentucky This program is supported by an independent College of Medicine and HealthmattersCME. educational grant from Gilead Sciences Medical Affairs. a CMe-Certified enduring Material Letter from the Chair ManaGInG PatIentS wIth Pah: what you need to know about Dear Health Care Professional: drug Pulmonary arterial hypertension (PAH) is a rare but serious disease with severe and often interactions disabling symptoms. When left untreated, PAH is rapidly fatal, and late diagnosis is associ- ated with an increased risk of death, even with treatment. PAH most frequently affects patients in their 40s and 50s, a time in their lives when the symptoms can cause significant disruption in their capacity to work and participate in family and social activities. Until recently, the options for PAH patients were limited to general treatments, such as Harrison W. Farber, MD Program Chair Professor of Medicine Director, Pulmonary Hypertension Center diuretics, anticoagulants, and calcium channel blockers, or PAH-specific therapies, such Boston University School of Medicine Boston, MA as intravenous epoprostenol, that were invasive and involved complex administration. healthmatterscme A CONTINUING MEDICAL EDUCATION COMPANY However, the advent of new therapies within the past several years has provided physi- This activity is jointly sponsored by the University of Kentucky This program is supported by an independent College of Medicine and HealthmattersCME. educational grant from Gilead Sciences Medical Affairs. cians with a greater range of treatments that not only improve symptoms and are easier to administer but also seem to prolong survival. These PAH-specific therapies include subcutaneous and inhaled prostacyclin analogues, endothelin receptor antagonists, and tabLe of phosphodiesterase-5 inhibitors. These medications target the different pathophysiologic Contents pathways that lead to the vascular remodeling that is characteristic of the disease. As discussed in this monograph, patients are often treated with more than one medication INTRODUCTION ............................................................................. 3 for PAH and regimens usually include both general treatments and one or more PAH-spe- cific therapies. As with all diseases requiring multiple medications, the potential for drug- Key Learnings .....................................................................................................6 drug interactions exists between PAH-specific medications, general treatments, and other drugs given to treat comorbidities. Although data are lacking from randomized trials on TREATMENT OVERVIEW ...........................................7 the clinical significance of drug interactions with PAH medications, physicians may want to take into consideration the potential for drug interactions when selecting therapies for Combination Therapy for PAH ...................................9 their PAH patients. In addition, because PAH requires long-term treatment, the potential Key Learnings ................................................................................................10 for drug interactions may become more important as the patient ages and the possibility of developing comorbid conditions increases. This monograph summarizes known and clinically relevant drug-drug interactions between PAH and non-PAH agents and presents DRUG-DRUG INTERACTIONS case studies that highlight the challenges physicians often confront when treating PAH IN THE MANAGEMENT patients who require multiple medications or who have other serious conditions. OF PAH ....................................................................................................................11 This CME activity will benefit clinicians by informing them about known and clinically Review of the Cytochrome relevant drug interactions associated with PAH-specific medications. It will also provide P450 Enzyme System ................................................................13 them with a basic understanding of the role drug metabolism plays in the potential for Key Learnings ................................................................................................16 drug interactions. In turn, this CME activity will benefit PAH patients by increasing aware- ness among clinicians of the potential for PAH medications to cause drug interactions with other PAH-specific medications, general treatments, and medications used to treat other INTERACTIVE CASE STUDIES conditions, and may thereby reduce the risk of clinically relevant interactions. C ASE 1: An interaction between 2 different I hope that you will find this monograph to be a useful part of your continuing education PAH-specific medications...................................................18 about this multifaceted disease. C ASE 2: An interaction between a PAH-specific medication and a general PAH treatment ....................................20 Sincerely, Harrison W. Farber, MD C ASE 3: Program Chair An interaction between a Professor of Medicine PAH-specific medication and Director, Pulmonary Hypertension Center non-PAH medications ................................................................23 Boston University School of Medicine Boston, MA REFERENCES ........................................................................................27 introDUCtion Table 1: 2008 Clinical Classification of Pulmonary Hypertension Group Type of Pulmonary Hypertension ulmonary arterial hypertension (PAH) is a serious, progres- 1 Pulmonary arterial hypertension (PAH) sive disorder associated with vascular remodeling that P 1.1 Idiopathic (IPAH) leads to right ventricular dysfunction and functional impair- ment, culminating in right-heart failure and death.1-3 PAH is 1.2 Heritable 1.2.1: BMPR2 defined as a mean pulmonary artery pressure (mPAP) ≥25 mm 1.2.2: ALK1, endoglin (with or without hereditary hemorrhagic Hg with a mean pulmonary capillary wedge pressure (mPCWP) telangiectasia) (or left ventricular end-diastolic pressure) ≤15 mm Hg.2 1.2.3: Unknown Late diagnosis is common, at which point functionality is 1.3 Drug- and toxin-induced 1,2 already seriously impaired. According to data collected by a 1.4 Associated with (APAH): national PAH registry in France, 75% of patients are diagnosed 1.4.1: Connective tissue disease at stage functional class (FC) III and IV, approximately 2 years af- 1.4.2: Human immunodeficiency virus (HIV) infection ter the onset of symptoms.4,5 Despite a range of available treat- 1.4.3: Portal hypertension ments, long-term survival is generally poor,6 although some 1.4.4: Congenital heart disease (CHD) 1.4.5: Schistosomiasis evidence suggests the survival rate may be improving with 1.4.6: Chronic hemolytic anemia newer PAH-specific medications.7,8 Evidence demonstrating a 1.5 Persistent pulmonary hypertension of the newborn clear survival benefit with PAH treatment is lacking because there are no placebo-controlled survival studies, none will be 1.6 Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) attempted, and the only available mortality data are based on 2 Pulmonary hypertension owing to left-heart disease the use of historical controls. 2.1: Systolic dysfunction 2.2: Diastolic dysfunction Clinical classification and functional class staging 2.3: Valvular disease PAH is just one form of pulmonary hypertension, which 3 Pulmonary hypertension owing to lung diseases and/or hypoxia includes numerous conditions that affect pulmonary vascular 3.1: Chronic obstructive pulmonary disease pressure. The most recent system for classification of types 3.2: Interstitial lung disease of pulmonary hypertension was developed at the 4th World 3.3: Other pulmonary diseases with mixed restrictive and obstructive pattern Symposium on Pulmonary Hypertension, held in Dana Point, 3.4: Sleep-disordered breathing 9 California, in 2008. 3.5: Alveolar hypoventilation disorders 3.6: Chronic exposure to high altitude 4th World Symposium on Pulmonary Hypertension 3.7: Developmental abnormalities 3 Classification System. As shown in Table 1, pulmonary 4 Chronic thromboembolic pulmonary hypertension (CTEPH) hypertension is classified into 5 main groups based on underly- 5 Pulmonary hypertension with unclear multifactorial ing mechanisms or pathology. Group 1 includes all forms of mechanisms PAH: idiopathic PAH (IPAH), heritable (formerly called familial) 5.1: Hematologic disorders: myeloproliferative disorders, PAH, PAH associated with drug and toxin exposure, PAH associ- splenectomy 5.2: Systemic disorders: sarcoidosis, pulmonary Langerhans cell ated with specific systemic disorders, PAH of the newborn, and histiocytosis lymphangioleiomyomatosis, neurofibromatosis, PAH associated with veno-occlusive disease and/or pulmonary vasculitis capillary hemangiomatosis. 5.3: Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Functional class. PAH is further described according to the 5.4: Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis World Health Organization (WHO) FC staging system, which was modified from the New York Heart Association