Hypertension Treatment Dane Mellgren, PharmD PGY-1 Pharmacy - - PowerPoint PPT Presentation

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Hypertension Treatment Dane Mellgren, PharmD PGY-1 Pharmacy - - PowerPoint PPT Presentation

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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

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SLIDE 1

Updates on Pulmonary Hypertension Treatment

Dane Mellgren, PharmD PGY-1 Pharmacy Practice Resident Hennepin County Medical Center

04/27/18

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SLIDE 2

Disclosure

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

4/19/2018

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SLIDE 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.

4/19/2018

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SLIDE 4

Guideline Review

4/19/2018

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SLIDE 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.

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SLIDE 6

CHEST Guidelines 2013

4/19/2018

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SLIDE 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 vaso- reactivity according to consensus definition, should be considered candidates for a trial of therapy with an oral CCB

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 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

  • ne 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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SLIDE 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.

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SLIDE 11

Drug Class-Specific Information

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SLIDE 12

Oral Calcium Channel Blockers (CCB’s)

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SLIDE 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: 720 - 960mg per day
  • Amlodipine: 20 - 30mg per day
  • Nifedipine: 180 - 240mg per day

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SLIDE 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

4/19/2018

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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
  • Azole antifungals
  • Certain antiretrovirals
  • Rifampin
  • Phenytoin
  • Carbamazepine

4/19/2018

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SLIDE 16

Endothelin Receptor Antagonists (ERTA’s)

4/19/2018

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SLIDE 17

How they work (abridged)

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SLIDE 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

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SLIDE 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

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Warnings/Precautions and Drug Interactions

  • Warnings
  • Contraindicated in pregnancy
  • Contraindicated in patients with

idiopathic pulmonary fibrosis

  • Drug Interactions
  • Cyclosporine

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SLIDE 21

Risk Evaluation and Mitigation Program

  • http://letairisrems.com/

4/19/2018

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SLIDE 22

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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SLIDE 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

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SLIDE 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

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SLIDE 25

Risk Evaluation and Mitigation Program

  • http://www.tracleerrems.com/

4/19/2018

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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

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SLIDE 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

4/19/2018

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SLIDE 28

Warnings/Precautions and Drug Interactions

  • Warnings
  • Contraindicated in pregnancy
  • Contraindicated in patients with

idiopathic pulmonary fibrosis

  • Drug Interactions
  • Cyclosporine

4/19/2018

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SLIDE 29

Risk Evaluation and Mitigation Program

  • http://www.opsumitrems.com/

4/19/2018

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SLIDE 30

Phosphodiesterase-5 Inhibitors (PDE-5’s)

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SLIDE 31

How They Work

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SLIDE 32

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

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SLIDE 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

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SLIDE 34

Warnings/Precautions and Drug Interactions

  • Warnings
  • Not to be used in pediatric

patients due to increased mortality

  • Pregnancy
  • Drug Interactions
  • Ritonavir
  • Antihypertensives

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SLIDE 35

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

4/19/2018

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SLIDE 36

Common Side Effects and Management

  • Side Effects
  • Hypotension
  • Vision loss
  • Hearing loss
  • Priapism
  • Management
  • Frequent blood pressure

monitoring

  • Baseline vision testing with

repeat at dose changes

  • Baseline hearing exams

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SLIDE 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

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SLIDE 38

Soluble Guanylate- Cyclase Stimulators

4/19/2018

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SLIDE 39

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

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 42

Warnings/Precautions and Drug Interactions

  • Warnings
  • Contraindicated in pregnancy
  • Smoking
  • Drug Interactions
  • Azole antifungals
  • Ritonavir
  • Nitrates
  • PDE-5 Inhibitors
  • Rifampin
  • Phenytoin

4/19/2018

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SLIDE 43

Risk Evaluation and Mitigation Strategy

  • www. AdempasREMS.com

4/19/2018

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SLIDE 44

Parenteral and Inhaled Prostanoids

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SLIDE 45

How They Work

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SLIDE 46

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

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 49

Stability Instructions-Flolan

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SLIDE 50

Stability Instructions-Veletri

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SLIDE 51

Treptrostinil (Remodulin-IV) (Tyvaso-Inhaled)

  • 41. We suggest continuous IV treprostinil to improve 6MWD
  • 42-43. 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
  • 56-57. 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

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 53

Warnings/Precautions and Drug Interactions

  • Warnings
  • Use if IV infusion increases risk
  • f bloodstream infections
  • Do not abruptly withdraw therapy
  • Drug Interactions
  • Gemfibrozil
  • Rifampin
  • Anticoagulants

4/19/2018

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SLIDE 54

Prostacyclin Receptor Antagonists

4/19/2018

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SLIDE 55

How They Work

4/19/2018

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SLIDE 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

4/19/2018

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SLIDE 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

4/19/2018

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Warnings and Drug Interactions

  • Warnings
  • Dose reductions are necessary in

severe hepatic dysfunction

  • Drug Interactions
  • Gemfibrozil
  • Rifampin

4/19/2018

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SLIDE 59

Anticoagulation

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SLIDE 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.

4/19/2018

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SLIDE 61

Questions?

4/19/2018

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SLIDE 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, 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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SLIDE 63

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.

4/19/2018