Updates on Pulmonary Hypertension Treatment Dane Mellgren, PharmD PGY-1 Pharmacy Practice Resident Hennepin County Medical Center 04/27/18
Disclosure • I have no disclosures to be made regarding the content of this presentation. 4/19/2018
Objectives • Distinguish the differences between pharmacological agents used in treatment of pulmonary hypertension including pharmacology, drug interactions, and adverse events. • Design a pharmacotherapy plan for treating patients with pulmonary hypertension using current practice guidelines. • Develop approaches to management of complications associated with pulmonary hypertension therapies. • Determine the role of anticoagulation in treatment of pulmonary hypertension. 4/19/2018
Guideline Review 4/19/2018
World Health Organization Classifications • Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. • Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. • Class III: Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. • Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-sided heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. 4/19/2018
CHEST Guidelines 2013 4/19/2018
Initial Management • 8. We suggest that patients with PAH who, in the, absence of right-sided heart failure or contraindications to CCB therapy, demonstrate acute vaso- reactivity according to consensus definition, should be considered candidates for a trial of therapy with an oral CCB 4/19/2018
What’s Next WHO Functional Class II • For treatment-naive patients with PAH with WHO FC II symptoms who are not candidates for, or who have failed, CCB therapy, we advise monotherapy be initiated with a currently approved ETRA, PDE5 inhibitor, or the soluble guanylate cyclase stimulator riociguat. • Endothelin Receptor Antagonists • Ambrisentan • Bosentan • Macitentan • Phosphodiesterase-5 Inhibitors • Sildenafil • Tadalafil • Soluble Guanylate Cyclase Inhibitors • Riociguat 4/19/2018
WHO Functional Class III • For treatment-naive PAH patients with WHO FC III symptoms who are not candidates for, or who have failed CCB therapy, we advise monotherapy be initiated with a currently approved ETRA, a PDE5 inhibitor, or the soluble guanylate cyclase stimulator riociguat. • For PAH patients in WHO FC III who have evidence of progression of their disease, and/or markers of poor clinical prognosis despite treatment with one or two classes of oral agents, we advise consideration of the addition of a parenteral or inhaled prostanoid. • Parenteral Prostanoids • Epoprostenol • Treprostinil • Inhaled Prostanoids • Treprostinil 4/19/2018
WHO Functional Class IV • For treatment naive PAH patients in WHO FC IV, we advise initiation of monotherapy with a parenteral prostanoid agent. • For treatment naive PAH patients in WHO FC IV who are unable or do not desire to manage parenteral prostanoid therapy, we advise treatment with an inhaled prostanoid in combination with an ETRA. 4/19/2018
Drug Class-Specific Information 4/19/2018
Oral Calcium Channel Blockers (CCB’s) 4/19/2018
Oral Calcium Channel Blockers • Dosing of calcium channel blockers in pulmonary arterial hypertension is far removed from those doses used in other disease states • Diltiazem: 720 - 960mg per day • Amlodipine: 20 - 30mg per day • Nifedipine: 180 - 240mg per day 4/19/2018
Common Side and Management • Side Effect • Management • Edema • Diuretic therapy • Bradycardia (diltiazem) • Frequent assessment of HR • Hypotension • Repeat BP monitoring • Elevated liver enzymes/hepatic • Repeat LFT testing injury • Dizziness • Orthostatic testing • Flushing • Active cooling techniques • Headache • Pain Management 4/19/2018
Warnings/Precautions and Drug Interactions • • Warnings Drug-Drug Interactions • • Diltiazem Diltiazem • • Do not use in patient with congestive Benzodiazepines heart failure • Beta-Blockers • Is excreted in breastmilk, use in lactation • Buspirone in not recommended • Carbamazepine • Amlodipine • Cimetidine • Caution in use with severe hepatic • impairment Clonidine • • Nifedipine Cyclosporine • • Caution in use with severe hepatic Digoxin impairment • Quinidine • Rifampin • Statins • Amlodipine • Azole antifungals • Carbamazepine • Nifedipine • Azole antifungals • Certain antiretrovirals • Rifampin • Phenytoin • Carbamazepine 4/19/2018
Endothelin Receptor Antagonists (ERTA’s) 4/19/2018
How they work (abridged) 4/19/2018
Ambrisentan (Letairis) • 10, 24. We recommend ambrisentan to improve 6MWD • Dosing: 5mg by mouth once daily, increasing to goal of 10mg daily at 4-week intervals 4/19/2018
Common Side Effects and Management • Side Effects • Management • Edema • Fluid Restriction, Diuretic Therapy • Repeated discussion with men of • Reduced Sperm Counts in males child-bearing age regarding reproductive goals • Nasal congestion • Decongestant therapy • Flushing • Active cooling measures • Hepatotoxicity • Repeat LFT’s following initiation, discontinue if LFT’s >5x ULN 4/19/2018
Warnings/Precautions and Drug Interactions • Warnings • Drug Interactions • Contraindicated in pregnancy • Cyclosporine • Contraindicated in patients with idiopathic pulmonary fibrosis 4/19/2018
Risk Evaluation and Mitigation Program • http://letairisrems.com/ 4/19/2018
Bosentan (Tracleer) • 11-12. We suggest bosentan to delay time to clinical worsening and improve cardiopulmonary hemodynamics. • 22-23. We suggest the use of bosentan to decrease hospitalizations related to PAH in the short-term, and to improve cardiopulmonary hemodynamics. • We recommend the use of bosentan to improve 6MWD • Dosing: Patients >12 y.o. and >40kg-62.5mg by mouth twice daily for 4 weeks then increase to 125mg twice daily • Patients >12 y.o. who weigh <40kg-62.5mg twice daily • Patient’s <12 y.o. - 16-64mg twice daily incrementally from 4-40kg 4/19/2018
Common Side Effects and Management • Side Effects • Management • Edema • Fluid Restriction, Diuretic Therapy • Repeated discussion with men of • Reduced Sperm Counts in males child-bearing age regarding reproductive goals • Hepatotoxicity • Repeat LFT’s in patients if clinically indicated, discontinue if bilirubin levels reach >2 x ULN • Repeat hemoglobin checks after • Decreased Hemoglobin and initiation of therapy Hematocrit • Decongestant Therapies • Nasopharyngitis/bronchitis 4/19/2018
Warnings/Precautions and Drug Interactions • Warnings • Drug Interactions • Contraindicated in pregnancy • Cyclosporine • No benefit in patients with CHF • Ritonavir with reduced LVEF • Glyburide • Rifampin 4/19/2018
Risk Evaluation and Mitigation Program • http://www.tracleerrems.com/ 4/19/2018
Macitentan (Opsumit) • 13. We suggest macitentan to delay the time to clinical worsening • 25-26. We suggest macitentan to improve WHO FC and delay the time to clinical worsening • Dose: 10mg by mouth once daily 4/19/2018
Common Side Effects and Management • Side Effects • Management • Edema • Fluid Restriction, Diuretic Therapy • Repeated discussion with men of • Reduced Sperm Counts in males child-bearing age regarding reproductive goals • Hepatotoxicity • Repeat LFT’s following initiation, discontinue if LFT’s >5x ULN • Decreased Hemoglobin and Hematocrit 4/19/2018
Warnings/Precautions and Drug Interactions • Warnings • Drug Interactions • Contraindicated in pregnancy • Cyclosporine • Contraindicated in patients with idiopathic pulmonary fibrosis 4/19/2018
Risk Evaluation and Mitigation Program • http://www.opsumitrems.com/ 4/19/2018
Phosphodiesterase-5 Inhibitors (PDE- 5’s) 4/19/2018
How They Work 4/19/2018
Sildenafil • 14. We recommend sildenafil to improve 6MWD • 27-29. We recommend the use of sildenafil to improve 6MWD and to improve WHO FC. We suggest the use of sildenafil to improve cardiopulmonary hemodynamics. • Dosing: 5mg three times daily titrated to maximum dosing of 20mg three times daily 4/19/2018
Common Side Effects and Management • Side Effects • Management • Hypotension • Frequent blood pressure monitoring • Baseline vision testing with • Vision loss repeat at dose changes • Baseline hearing exams • Hearing loss • Priapism • Acute emergency management • Vaso-occlusive crisis 4/19/2018
Warnings/Precautions and Drug Interactions • Warnings • Drug Interactions • Not to be used in pediatric • Ritonavir patients due to increased • Antihypertensives mortality • Pregnancy 4/19/2018
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