Updates on Pulmonary Hypertension Treatment

Transcription

1 Updates on Pulmonary Hypertension Treatment Dane Mellgren, PharmD PGY-1 Pharmacy Practice Resident Hennepin County Medical Center 04/27/18

2 Disclosure I have no disclosures to be made regarding the content of this presentation.

3 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 Guideline Review

5 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.

6 CHEST Guidelines 2013

7 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 vasoreactivity according to consensus definition, should be considered candidates for a trial of therapy with an oral CCB

8 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

9 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

10 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.

11 Drug Class-Specific Information

12 Oral Calcium Channel Blockers (CCB s)

13 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: mg per day Amlodipine: 20-30mg per day Nifedipine: mg per day

14 Common Side and Management Side Effect Edema Bradycardia (diltiazem) Hypotension Elevated liver enzymes/hepatic injury Dizziness Flushing Headache Management Diuretic therapy Frequent assessment of HR Repeat BP monitoring Repeat LFT testing Orthostatic testing Active cooling techniques Pain Management

15 Warnings/Precautions and Drug Interactions Warnings Diltiazem Do not use in patient with congestive heart failure Is excreted in breastmilk, use in lactation in not recommended Amlodipine Caution in use with severe hepatic impairment Nifedipine Caution in use with severe hepatic impairment Drug-Drug Interactions Diltiazem Benzodiazepines Beta-Blockers Buspirone Carbamazepine Cimetidine Clonidine Cyclosporine Digoxin Quinidine Rifampin Statins Amlodipine Azole antifungals Carbamazepine Nifedipine Azole antifungals Certain antiretrovirals Rifampin Phenytoin Carbamazepine

16 Endothelin Receptor Antagonists (ERTA s)

17 How they work (abridged)

18 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

19 Common Side Effects and Management Side Effects Edema Reduced Sperm Counts in males Nasal congestion Flushing Hepatotoxicity Management Fluid Restriction, Diuretic Therapy Repeated discussion with men of child-bearing age regarding reproductive goals Decongestant therapy Active cooling measures Repeat LFT s following initiation, discontinue if LFT s >5x ULN

20 Warnings/Precautions and Drug Interactions Warnings Contraindicated in pregnancy Contraindicated in patients with idiopathic pulmonary fibrosis Drug Interactions Cyclosporine

21 Risk Evaluation and Mitigation Program

22 Bosentan (Tracleer) We suggest bosentan to delay time to clinical worsening and improve cardiopulmonary hemodynamics 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 mg twice daily incrementally from 4-40kg

23 Common Side Effects and Management Side Effects Edema Reduced Sperm Counts in males Hepatotoxicity Decreased Hemoglobin and Hematocrit Nasopharyngitis/bronchitis Management Fluid Restriction, Diuretic Therapy Repeated discussion with men of child-bearing age regarding reproductive goals Repeat LFT s in patients if clinically indicated, discontinue if bilirubin levels reach >2 x ULN Repeat hemoglobin checks after initiation of therapy Decongestant Therapies

24 Warnings/Precautions and Drug Interactions Warnings Contraindicated in pregnancy No benefit in patients with CHF with reduced LVEF Drug Interactions Cyclosporine Ritonavir Glyburide Rifampin

25 Risk Evaluation and Mitigation Program

26 Macitentan (Opsumit) 13. We suggest macitentan to delay the time to clinical worsening We suggest macitentan to improve WHO FC and delay the time to clinical worsening Dose: 10mg by mouth once daily

27 Common Side Effects and Management Side Effects Edema Reduced Sperm Counts in males Hepatotoxicity Decreased Hemoglobin and Hematocrit Management Fluid Restriction, Diuretic Therapy Repeated discussion with men of child-bearing age regarding reproductive goals Repeat LFT s following initiation, discontinue if LFT s >5x ULN

28 Warnings/Precautions and Drug Interactions Warnings Contraindicated in pregnancy Contraindicated in patients with idiopathic pulmonary fibrosis Drug Interactions Cyclosporine

29 Risk Evaluation and Mitigation Program

30 Phosphodiesterase-5 Inhibitors (PDE-5 s)

31 How They Work

32 Sildenafil 14. We recommend sildenafil to improve 6MWD 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

33 Common Side Effects and Management Side Effects Hypotension Vision loss Hearing loss Priapism Vaso-occlusive crisis Management Frequent blood pressure monitoring Baseline vision testing with repeat at dose changes Baseline hearing exams Acute emergency management

34 Warnings/Precautions and Drug Interactions Warnings Not to be used in pediatric patients due to increased mortality Pregnancy Drug Interactions Ritonavir Antihypertensives

35 Tadalafil (Adcirca) 15. We suggest tadalafil to improve 6MWD We suggest the use of tadalafil to improve 6MWD, to improve WHO FC, to delay time to clinical worsening and to improve cardiopulmonary hemodynamics. Dosing: 40mg once daily

36 Common Side Effects and Management Side Effects Hypotension Vision loss Hearing loss Management Frequent blood pressure monitoring Baseline vision testing with repeat at dose changes Baseline hearing exams Priapism

37 Warnings/Precautions and Drug Interactions Warnings Contraindicated for use with nitrates Contraindicated to be used with guanylate cyclase stimulators Careful use of these medications in patients with underlying cardiovascular disease Drug Interactions Ritonavir Azole antifungals Rifampin

38 Soluble Guanylate- Cyclase Stimulators

39 How They Work

40 Riociguat (Adempas) We suggest riociguat to improve 6MWD, improve WHO FC, delay the time to clinical worsening and improve cardiopulmonary hemodynamics We suggest riociguat to improve 6MWD, improve WHO FC, delay the time to clinical worsening and improve cardiopulmonary hemodynamics. Dosing: Initial dose of 1mg three times daily, increased by 0.5mg three times daily every 2 weeks as tolerated to a maximum dose of 2.5mg

41 Common Side Effects and Management Side Effects Hypotension Increased Risk of Bleed GI discomfort Management Frequent blood pressure monitoring Counseling regarding signs and symptoms of bleed, increased hemoglobin monitoring

42 Warnings/Precautions and Drug Interactions Warnings Contraindicated in pregnancy Smoking Drug Interactions Azole antifungals Ritonavir Nitrates PDE-5 Inhibitors Rifampin Phenytoin

43 Risk Evaluation and Mitigation Strategy www. AdempasREMS.com

44 Parenteral and Inhaled Prostanoids

45 How They Work

46 Epoprostenol (Flolan, Veletri) We suggest continuous IV epoprostenol to improve FC, improve 6MWD, and improve cardiopulmonary hemodynamics We suggest continuous IV epoprostenol to improve WHO FC, improve 6MWD, and improve cardiopulmonary hemodynamics Dosing: Intravenous: 2ng/kg/min initial dose, increase by 2ng/kg/min every 15 minutes until a tolerance is reached

47 Common Side Effects and Management Side Effects Flushing Headache Nausea/vomiting Hypotension Chest pain Jaw Pain Management Active cooling measures Pain management Antiemetic's as needed Frequent blood pressure monitoring Pain management strategies

48 Warnings/Precautions and Drug Interactions Warnings Contraindicated for use in patients with congestive heart failure due to left ventricular dysfunction Avoid abrupt withdrawal of therapy Drug Interactions Digoxin Furosemide Antiplatelets/anticoagulants

49 Stability Instructions-Flolan

50 Stability Instructions-Veletri

51 Treptrostinil (Remodulin-IV) (Tyvaso-Inhaled) 41. We suggest continuous IV treprostinil to improve 6MWD We suggest continuous subcutaneous treprostinil to improve 6MWD and improve cardiopulmonary hemodynamics. 49. In patients with PAH who remain symptomatic on stable and appropriate doses of an endothelin receptor antagonist (ETRA ) or a PDE5 inhibitor, we suggest the addition of inhaled treprostinil to improve 6MWD. 55. We suggest continuous IV treprostinil to improve 6MWD We suggest continuous subcutaneous treprostinil to improve 6MWD and improve cardiopulmonary hemodynamics. Dosing: Intravenous/intramuscular injection (continuous)-1.25 ng/kg/min initial dose, increase by 1.25ng/kg/min per week for first 4 weeks, then increase by 2.5ng/kg/min weekly thereafter as tolerated Inhaled: 3 breaths (18mcg treprostinil) inhaled 4 times daily separated by at least 4 hours, if not tolerated initially, 1-2 breaths may be taken and titrated to goal of 3 breaths per treatment

52 Common Side Effects and Management Side Effects Infusion site pain and reaction Nausea/Diarrhea Jaw Pain Edema Cough (inhaled) Throat Irritation Management Icing of the affected area, effective main management Antiemetic's, antidiarrheals Diuretic therapy if warranted Topical anesthetics

53 Warnings/Precautions and Drug Interactions Warnings Use if IV infusion increases risk of bloodstream infections Do not abruptly withdraw therapy Drug Interactions Gemfibrozil Rifampin Anticoagulants

54 Prostacyclin Receptor Antagonists

55 How They Work

56 Selexipag (Uptravi) Selexipag is indicated for the treatment of pulmonary arterial hypertension to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms. Dosing: 200mcg by mouth twice daily, increase by 200mcg twice daily weekly as tolerated up to 1600mcg twice daily

57 Common Side Effects and Management Side Effects Headache Nausea/Vomiting/Diarrhea Jaw Pain Myalgia's Extremity Pain Management Pain management Antiemetic's/antidiarrheals Neuropathic pain management

58 Warnings and Drug Interactions Warnings Dose reductions are necessary in severe hepatic dysfunction Drug Interactions Gemfibrozil Rifampin

59 Anticoagulation

60 Warfarin (Coumadin) Warfarin is the only anticoagulant that has been studied for use in patients with pulmonary arterial hypertension. There is, however, conflicting data on what the appropriate INR goal for these patients is.

61 Questions?

62 References Ambrisentan. Package Insert. Gilead Pharmaceuticals. Revised 10/2015. Amlodipine Besylate. Package Insert. Caraco Pharmeuticals. Revised 12/2008. Bapat, A. Anticoagulation in the Management of Pulmonary Hypertension. American College of Cardiology. Feb. 05, Bosentan. Package Insert. Actelion Pharmaceuticals. Revised Diltiazem Hydrochloride. Package Insert. Teva Pharmaceuticals. Revised 02/2011. Endothelin Receptor Antagonists. General Pharmacology. Epoprostenol. Package Insert. Actelion Pharmaceuticals. Revised 11/2017. Epoprostenol. Package Insert. GlaxoSmithKline Pharmaceuticals. Revised Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119: Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo- Controlled, Multicenter, Efficacy (ARIES) study 1 and 2. Circulation 2008;117: Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371: Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:

63 References Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369: Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24: Macitentan. Package Insert. Actelion Pharmaceuticals. Issued 03/2017. Nifedipine Extended-Release tablets. Package Insert. Par Pharmaceuticals. Revised 09/2012. Phsophodiesterase Inhibitors. General Pharmacology. Remodulin. Package Insert. United Therapeutics Corp. Revised 10/2017 Riociguat. Package Insert. Bayer HealthCare Pharmaceuitcals Inc. Revised 01/2017. Sastry BKS, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: Selexipag. Package Insert. Actelioin Pharmaceuticals. Issued 12/2017. Sildenafil. Package Insert. Pfizer Labs. Revised 01/2014. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165: Tadalafil. Packge Insert. Eli Lilly and Company. Revised 08/2017. Taichman DB, Ornelas J, Chung L, et. al. Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. CHEST Guideline and Expert Panel Report. CHEST 2014; 146 ( 2 ): Tyvaso. Package Insert. United Therapeutics Corporation. Revised 10/2017.