updates on pulmonary hypertension treatment · • phosphodiesterase-5 inhibitors ... • hearing...

Updates on Pulmonary Hypertension TreatmentDane 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.

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Guideline Review

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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.

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CHEST Guidelines 2013

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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

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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

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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

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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.

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Drug Class-Specific Information

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Oral Calcium Channel Blockers (CCB’s)

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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

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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

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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


• Certain antiretrovirals

• Rifampin

• Phenytoin

• Carbamazepine

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Endothelin Receptor Antagonists (ERTA’s)

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How they work (abridged)

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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

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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

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• Warnings

• Contraindicated in pregnancy

• Contraindicated in patients with idiopathic pulmonary fibrosis

• Drug Interactions

• Cyclosporine

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Risk Evaluation and Mitigation Program

• http://letairisrems.com/

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http://letairisrems.com/

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

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• Side Effects

• Edema


• Hepatotoxicity

• Decreased Hemoglobin and Hematocrit

• Nasopharyngitis/bronchitis

• Management



• 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

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• Warnings


• No benefit in patients with CHF with reduced LVEF


• Cyclosporine

• Ritonavir

• Glyburide

• Rifampin

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• http://www.tracleerrems.com/

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http://www.tracleerrems.com/

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

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• Side Effects

• Edema


• Hepatotoxicity

• Decreased Hemoglobin and Hematocrit

• Management



• Repeat LFT’s following initiation, discontinue if LFT’s >5x ULN

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• Warnings


• Contraindicated in patients with idiopathic pulmonary fibrosis


• Cyclosporine

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• http://www.opsumitrems.com/

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http://www.opsumitrems.com/

Phosphodiesterase-5 Inhibitors (PDE-5’s)

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How They Work

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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

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• 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

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• Warnings

• Not to be used in pediatric patients due to increased mortality

• Pregnancy


• Ritonavir

• Antihypertensives

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Tadalafil (Adcirca)

• 15. We suggest tadalafil to improve 6MWD

• 30-33. 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

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• Side Effects

• Hypotension

• Vision loss

• Hearing loss

• Priapism

• Management


• Baseline vision testing with repeat at dose changes

• Baseline hearing exams

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• 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


• Ritonavir


• Rifampin

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Soluble Guanylate-Cyclase Stimulators

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How They Work

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Riociguat (Adempas)

• 16-19. We suggest riociguat to improve 6MWD, improve WHO FC, delay the time to clinical worsening and improve cardiopulmonary hemodynamics.

• 34-37. 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

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• Side Effects

• Hypotension

• Increased Risk of Bleed

• GI discomfort

• Management


• Counseling regarding signs and symptoms of bleed, increased hemoglobin monitoring

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• Warnings


• Smoking



• Ritonavir

• Nitrates

• PDE-5 Inhibitors

• Rifampin

• Phenytoin

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Risk Evaluation and Mitigation Strategy

• www. AdempasREMS.com

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Parenteral and Inhaled Prostanoids

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How They Work

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Epoprostenol (Flolan, Veletri)

• 38-40. We suggest continuous IV epoprostenol to improve FC, improve 6MWD, and improve cardiopulmonary hemodynamics.

• 52-54. 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

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• Side Effects

• Flushing

• Headache

• Nausea/vomiting

• Hypotension

• Chest pain

• Jaw Pain

• Management

• Active cooling measures

• Pain management

• Antiemetic's as needed


• Pain management strategies

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• Warnings

• Contraindicated for use in patients with congestive heart failure due to left ventricular dysfunction

• Avoid abrupt withdrawal of therapy


• Digoxin

• Furosemide

• Antiplatelets/anticoagulants

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Stability Instructions-Flolan

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Stability Instructions-Veletri

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Treptrostinil (Remodulin-IV) (Tyvaso-Inhaled)

• 41. We suggest continuous IV treprostinil to improve 6MWD

• 42-43. We suggest continuous subcutaneous treprostinil to improve 6MWDand 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

• 56-57. We suggest continuous subcutaneous treprostinil to improve 6MWDand 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

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• 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

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• Warnings

• Use if IV infusion increases risk of bloodstream infections

• Do not abruptly withdraw therapy


• Gemfibrozil

• Rifampin

• Anticoagulants

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Prostacyclin Receptor Antagonists

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How They Work

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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

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• Side Effects

• Headache

• Nausea/Vomiting/Diarrhea

• Jaw Pain

• Myalgia's

• Extremity Pain

• Management

• Pain management

• Antiemetic's/antidiarrheals

• Neuropathic pain management

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Warnings and Drug Interactions

• Warnings

• Dose reductions are necessary in severe hepatic dysfunction


• Gemfibrozil

• Rifampin

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Anticoagulation

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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.

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Questions?

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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, 2016. http://www.acc.org/latest-in-cardiology/articles/2016/02/04/14/53/anticoagulation-in-the-management-of-pulmonary-arterial-hypertension.

• Bosentan. Package Insert. Actelion Pharmaceuticals. Revised 09.2017.

• Diltiazem Hydrochloride. Package Insert. Teva Pharmaceuticals. Revised 02/2011.

• Endothelin Receptor Antagonists. General Pharmacology. http://www.cvpharmacology.com/vasodilator/ETblockers

• Epoprostenol. Package Insert. Actelion Pharmaceuticals. Revised 11/2017.

• Epoprostenol. Package Insert. GlaxoSmithKline Pharmaceuticals. Revised 04.2016.

• Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–903.

• 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;117:3010–9.

• 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: 2093–100.

• Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353: 2148–57.

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http://www.cvpharmacology.com/vasodilator/ETblockers

References

• Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369: 330–4.0

• Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353–9.

• Macitentan. Package Insert. Actelion Pharmaceuticals. Issued 03/2017.

• Nifedipine Extended-Release tablets. Package Insert. Par Pharmaceuticals. Revised 09/2012.

• Phsophodiesterase Inhibitors. General Pharmacology. http://www.cvpharmacology.com/vasodilator/PDEI

• 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; 43:1149–53.

• 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: 800–4.

• 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 ): 449 – 475.

• Tyvaso. Package Insert. United Therapeutics Corporation. Revised 10/2017.

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http://www.cvpharmacology.com/vasodilator/PDEI

updates on pulmonary hypertension treatment · • phosphodiesterase-5 inhibitors ... • hearing...

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