ph-9991063
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Oral Pulmonary Arterial Hypertension Agents Prior Authorization with Quantity Limit

Policy Number: PH-9991063

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.

Oral Pulmonary Arterial Hypertension Agents Prior Authorization with Quantity Limit

TARGET AGENT(S)

Adcirca (tadalafil)a

Adempas (riociguat)

Letairis (ambrisentan)a

Opsumit® (macitentan)

Orenitram® (treprostinil)

Revatio (sildenafil)a

Tracleer® (bosentan)a

Tyvaso® (treprostinil)

Uptravi® (selexipag)

Ventavis® (iloprost)

a- generic available, subject to prior authorization with quantity limit

Brand (generic)

GPI (NDC)

Multisource Code

Quantity Limit (per day or as listed)

Adcirca (tadalafil)a

20 mg tablet

40143080000320

M, N, O, or Y

2 tablets

Adempas (riociguat)

0.5 mg tablet

4013405000****

M, N, O, or Y

3 tablets

1 mg tablet

4013405000****

M, N, O, or Y

3 tablets

1.5 mg tablet

4013405000****

M, N, O, or Y

3 tablets

2.0 mg tablet

4013405000****

M, N, O, or Y

3 tablets

2.5 mg tablet

4013405000****

M, N, O, or Y

3 tablets

Letairis (ambrisentan)a

5 mg tablet

4016000700****

M, N, O, or Y

1 tablet

10 mg tablet

4016000700****

M, N, O, or Y

1 tablet

Opsumit (macitentan)

  10 mg tablet

4016005000****

M, N, O, or Y

1 tablet

Orenitram (treprostinil)

  0.125 mg tablet

4017008005****

M, N, O, or Y

N/A

  0.25 mg tablet

4017008005****

M, N, O, or Y

N/A

  1 mg tablet

4017008005****

M, N, O, or Y

N/A

  2.5 mg tablet

4017008005****

M, N, O, or Y

N/A

5 mg tablet

4017008005****

M, N, O, or Y

N/A

Revatio (sildenafil)a

20 mg tablet

40143060100320

M, N, O, or Y

3 tablets

10 mg/mL oral suspension

40143060101920

M, N, O, or Y

2 bottles (224 mL)/30 days

Tracleer (bosentan)

32 mg tablet

40160015007320

M, N, O, or Y

4 tablets

62.5 mg tableta

40160015000320

M, N, O, or Y

2 tablets

125 mg tableta

40160015000330

M, N, O, or Y

2 tablets

Tyvaso (treprostinil)

0.6 mg/mL System Starter Kit inhalation solution

40170080002020

(66302-206-01)

M, N, O, or Y

1 kit/180 days

0.6 mg/mL System Refill kit inhalation solution

40170080002020

(66302-206-02)

M, N, O, or Y

1 package of 28 ampules/28 days

0.6 mg/mL 4 pack Carton inhalation solution

40170080002020

(66302-206-03)

M, N, O, or Y

7 packages of 4 ampules/28 days

Institutional starter kit inhalation solution

40170080002020

(66302-206-04)

M, N, O, or Y

1 kit/180 days

Uptravi (selexipag)

Titration pack

4012007000B720

M, N, O, or Y

1 pack/180 days

200 mcg tablet

40120070000310

(66215-0602-06)

M, N, O, or Y

2 tablets

Titration Bottle

200 mcg tablet

40120070000310

(66215-0602-14)

M, N, O, or Y

140 tablets/180 days

400 mcg tablet

40120070000315

M, N, O, or Y

2 tablets

600 mcg tablet

40120070000320

M, N, O, or Y

2 tablets

800 mcg tablet

40120070000325

M, N, O, or Y

2 tablets

1000 mcg tablet

40120070000330

M, N, O, or Y

2 tablets

1200 mcg tablet

40120070000335

M, N, O, or Y

2 tablets

1400 mcg tablet

40120070000340

M, N, O, or Y

2 tablets

1600 mcg tablet

40120070000345

M, N, O, or Y

2 tablets

Ventavis (iloprost)

10 mcg/mL inhalation solution

40170060002020

M, N, O, or Y

9 packages of 30 ampules/30 days

20 mcg/mL inhalation solution

40170060002040

M, N, O, or Y

9 packages of 30 ampules/30 days

a- generic available, subject to prior authorization with quantity limit

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met: 

  1. ONE of the following:
    1. BOTH of the following:
      1. ONE of the following:
        1. Information has been provided that indicates the patient is currently being treated with the requested agent within the past 90 days

OR

        1. The prescriber states that the patient is currently being treated with the requested agent within the past 90 days AND is at risk if therapy is changed

AND

      1. The patient has an FDA labeled indication for the requested agent

OR

    1. The patient has a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), WHO Group 4 and ALL of the following:
      1. The requested agent is Adempas

AND

      1. The patient’s diagnosis has been confirmed by a ventilation-perfusion scan and a confirmatory selective pulmonary angiography

AND

      1. The patient has a mean pulmonary artery pressure of >20 mmHg

AND

      1. The patient has a pulmonary capillary wedge pressure ≤15 mmHg

AND

      1. The patient has a pulmonary vascular resistance ≥3 Wood units

AND

      1. ONE of the following:
        1. The patient is NOT a candidate for surgery

OR

        1. The patient has had a pulmonary endarterectomy AND has persistent or recurrent disease

AND

      1. The patient will NOT be using the requested agent in combination with a PDE5 inhibitor (e.g., tadalafil [Adcirca or Cialis] or sildenafil [Revatio or Viagra])

OR

    1. The patient has a diagnosis of pulmonary arterial hypertension (PAH), WHO Group 1 and ALL of the following:
      1. The patient’s diagnosis has been confirmed by right heart catheterization (chart notes required)

AND

      1. The patient’s mean pulmonary arterial pressure is >20 mmHg

AND

      1. The patient has a pulmonary capillary wedge pressure ≤15 mmHg

AND

      1. The patient has a pulmonary vascular resistance ≥3 Wood units

AND

      1. The patient’s World Health Organization (WHO) functional class is II or greater

AND

      1. If the requested agent is Adcirca, Adempas, Revatio, sildenafil, or tadalafil, the patient will NOT be using the requested agent in combination with a PDE5 inhibitor (e.g., tadalafil [Adcirca or Cialis] or sildenafil [Revatio or Viagra])

AND

      1. ONE of the following:
        1. The request is for Adcirca (tadalafil) for use in combination with Letairis (ambrisentan) for dual therapy ONLY

OR

        1. The requested agent will be utilized as monotherapy

OR

        1. The requested agent will be utilized for add-on therapy to existing monotherapy (dual-therapy) [except combo requests for Adcirca with Letairis for dual therapy], and BOTH of following:
          1. The patient has unacceptable or deteriorating clinical status despite established PAH pharmacotherapy

AND

          1. The requested agent is in a different therapeutic class

OR

        1. The requested agent will be utilized for add-on therapy to existing dual therapy (triple therapy) and ALL of the following:
          1. The patient is WHO functional class III or IV

AND

          1. ONE of the following:
            1. A prostanoid has been started as one of the agents in the triple therapy

OR

            1. The patient has an intolerance, FDA labeled contraindication, or hypersensitivity to ALL prostanoids

AND

          1. The patient has unacceptable or deteriorating clinical status despite established PAH pharmacotherapy

AND

          1. All three agents in the triple therapy are from a different therapeutic class

AND

      1. If the request is for ONE of the following brand agents with an available generic equivalent (listed below), then ONE of the following:
        1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent

            OR

        1. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent

            OR

        1. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent

Brand

Generic Equivalent

Revatio (tablet, oral solution)

sildenafil (tablet, oral solution)

Adcirca

tadalafil

Tracleer 62.5 mg and 125 mg tablets

bosentan 62.5 mg and 125 mg tablets

Letairis

ambrisentan

OR

    1. The patient has another FDA approved indication for the requested agent

AND

  1. ONE of the following:
    1. The patient’s age is within FDA labeling for the requested indication for the requested agent

OR

    1. The prescriber has provided information in support of using the requested agent for the patient’s age

AND

  1. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis

AND

  1. The patient does not have any FDA labeled contraindications to the requested agent

AND

  1. For all agents except Orenitram, ONE of the following:
    1. The requested quantity (dose) does NOT exceed the program quantity limit

OR

    1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

  AND

      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication

  AND

      1. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit

OR

    1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

AND

      1. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication

AND

      1. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval:  12 months

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

  1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process

AND

  1. The patient has had clinical benefit with the requested agent (e.g., stabilization, decreased disease progression) (chart notes required)

AND

  1. If the request is for ONE of the following brand agents with an available generic equivalent (listed below), then ONE of the following:
    1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent

OR

    1. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent

OR

    1. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent

Brand

Generic Equivalent

Revatio (tablet, oral solution)

sildenafil (tablet, oral solution)

Adcirca

tadalafil

Tracleer 62.5 mg and 125 mg tablets

bosentan 62.5 mg and 125 mg tablets

Letairis

ambrisentan

AND

  1. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., cardiologist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis

AND

  1. The patient does not have any FDA labeled contraindications to the requested agent

AND

  1. For all agents except Orenitram, ONE of the following:
    1. The requested quantity (dose) does NOT exceed the program quantity limit

OR

    1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

  AND

      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication

  AND

      1. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit

OR

    1. ALL of the following:
      1. The requested quantity (dose) is greater than the program quantity limit

AND

      1. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication

AND

      1. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval:  12 months

FDA APPROVED INDICATIONS AND DOSAGE1-10

Agent(s)

Indication(s)

Dosage

Adcirca (tadalafil)a

Tablets

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group I) to improve exercise ability.  Studies establishing effectiveness included predominately patients with NYHA Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%)

40 mg (two 20 mg tablets) orally once daily; dividing the dose over the course of the day is not recommended

Adempas

(riociguat)

Tablets

Treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (*WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class

1 mg orally three times daily.  Initial doses may be started at 0.5 mg three times daily for those who may not tolerate the hypotensive effects.  Up-titrate the dose by 0.5 mg three times daily according to blood pressure up to a maximum dose of 2.5 mg three times daily. Dose increases should be no sooner than 2 weeks apart.

Treatment of adults with pulmonary arterial hypertension (PAH), (*WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.  Efficacy was shown in patients on monotherapy or in combination with endothelin receptor antagonists or prostanoids.  Studies establishing effectiveness included predominately patients with WHO functional class II-III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%)

Letairis

(ambrisentan)a

Tablets

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group 1):

  • To improve exercise capacity and delay clinical worsening.
  • In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability

Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%)

5 mg orally once daily, with or without tadalafil 20mg once daily; At 4-week intervals, either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10mg or tadalafil 40 mg.

Opsumit® (macitentan)

Tablets

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group 1) to reduce the risks of disease progression and hospitalization for PAH.  

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%)

10 mg orally once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

Orenitram (treprostinil)

Tablets

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group 1) to delay disease progression and to improve exercise capacity. 

The study that established effectiveness included predominately WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%). 

Starting dose is 0.25 mg orally twice daily 12 hours apart OR 0.125 mg three times daily taken approximately 8 hours apart. 

Titrate by 0.25 or 0.5 mg twice daily or 0.125 mg three times daily, not more than every 3-4 days as tolerated.  Max dose based on tolerability.

Revatio (sildenafil citrate)a

Tablets

Oral solution Injection solution

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group I) in adults to improve exercise ability and delay clinical worsening.  The delay in clinical worsening was demonstrated when Revatio was added to background epoprostenol therapy.

Studies establishing effectiveness were short-term (12 to 16 weeks) and included predominately patients with NYHA Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).

Limitation of use:  Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity.

Oral tablets:

5 mg or 20 mg orally three times daily 4-6 hours apart;

no greater efficacy seen with higher doses in clinical trial

IV bolus injection:

2.5 mg or 10 mg IV bolus three times daily; IV injection is for patients temporarily unable to take oral medication

Powder for oral suspension: 5 mg or 20 mg orally three times daily 4-6 hours apart; no greater efficacy seen with higher doses in clinical trial

Tracleer®

(bosentan)

Tablets film coateda

Tablets soluble

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group I):

  • in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%).
  • in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.

Patients >12 y.o. and >40 kg: 62.5 mg orally twice daily for 4 weeks, then increase to 125 mg twice daily.  Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.

Patients >12 y.o. and <40 kg: Initial and maintenance dose is 62.5 mg orally twice daily

Patients ≤12 years of age and:

≥4-8 kg: 16 mg orally twice daily for both initial and maintenance dose

>8-16 kg: 32 mg orally twice daily for both initial and maintenance dose

>16-24 kg: 48 mg orally twice daily for both initial and maintenance dose

>24-40 kg: 64 mg orally twice daily for both initial and maintenance dose

Tyvaso®

(treprostinil)

Inhalation solution

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on background of bosentan (an endothelin receptor antagonist) or sildenafil (a PDE 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

Administer in 4 separate treatment sessions each day approximately four hours apart, during waking hours.

Initial dosage: 3 breaths [18 mcg] inhaled per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths. 

Dosage should be increased by an additional 3 breaths per treatment session at approximately 1 to 2-week intervals, if tolerated.

Titrate to target maintenance dosage of 9 breaths (54 mcg) per treatment session as tolerated.

Max dose is 9 breaths per treatment session four times daily

Uptravi® (selexipag)

Tablets

Treatment of pulmonary arterial hypertension (PAH, *WHO Group I) 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.

Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%)

Starting dose: 200 mcg orally twice daily. 

Increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily.

Ventavis® (iloprost)

Inhalation solution

Treatment of pulmonary arterial hypertension (PAH) (*WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%)

The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5.0 mcg and maintained at that dose; otherwise maintain the dose at 2.5 mcg. Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).

* – WHO = World Health Organization

a-generic available

CLINICAL RATIONALE

The World Health Organization (WHO) has classified pulmonary hypertension (PH) based upon etiology into the following five groups:15

  • Group 1 - Pulmonary arterial hypertension (PAH)
  • Group 2 – PH due to left heart disease
  • Group 3 – PH due to chronic lung disease and/or hypoxemia
  • Group 4 – PH due to chronic thromboembolic pulmonary hypertension
  • Group 5 – PH due to unclear multifactorial mechanisms

Group 1, also known as pulmonary arterial hypertension (PAH), is defined by a pre-capillary pattern in the invasive hemodynamic evaluation, characterized by a mPAP >20 mmHg with a normal pulmonary capillary wedge pressure (i.e., ≤15 mmHg) and a pulmonary vascular resistance ≥3 Wood units, in the absence of pulmonary parenchymal or thromboembolic disease. Group 1 can occur in isolation or in association with clinical conditions, as noted in the following subcategories: idiopathic, heritable, drug/toxin induced, association with other diseases (i.e., connective tissue disease, HIV infection, portal hypertension, congenital heart diseases, schistosomiasis), long-term responders to calcium channel blockers, with overt features of venous/capillaries (pulmonary veno-occlusive disease [PVOD]/pulmonary capillary haemangiomatosis [PCH]), and persistent PH of the newborn syndrome. 15 

Group 4 is due to chronic thrombotic and/or embolic disease including chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is characterized pathologically by organized thromboembolic material and altered by vascular remodeling initiated or potentiated by a combination of defective angiogenesis, impaired fibrinolysis and endothelial dysfunction. These changes lead to PH, defined as a mean pulmonary arterial pressure >20 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, and pulmonary vascular resistance ≥3 Woods units. The hemodynamic changes occur in the presence of multiple chronic/organized occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental) after at least 3 months of effective anticoagulation. Ventilation/perfusion scan planar images combined with a confirmatory CT pulmonary angiography remain the preferred diagnostic tests for CTEPH despite advances in computed tomography (CT) and magnetic resonance (MR). CT and MR can be used in conjunction with the preferred diagnostic tests to identify complications of the disease but should not be solely relied upon due to concerns of false-positive cases mimicking CTEPH.12,17 The 6th World Symposium on Pulmonary Hypertension (WSPH) recommends all patients diagnosed with CTEPH start with lifelong anticoagulation therapy. WSPH notes that antiplatelet therapy is not an alternative to anticoagulation in patients with CTEPH. Pulmonary endarterectomy (PEA) remains the first line treatment option for CTEPH. WSPH notes that the best treatment is uncertain for patients that may be technically operable but may not benefit from endarterectomy due to comorbidities. Targeted medical therapy is initiated in those patients that are inoperable or those with persistent/recurrent PH following PEA.

The diagnosis of PAH requires right heart catheterization (RHC) to demonstrate a mean pulmonary artery pressure >20 mmHg at rest and a pulmonary vascular resistance ≥3 Wood units. Several additional criteria to exclude the remaining categories of PH must also be met:14,15,19

  • Mean pulmonary capillary wedge pressure ≤15 mmHg (to exclude PH due to left heart disease [i.e., group 2 PH])
  • Chronic lung diseases and other causes of hypoxemia are mild or absent (to exclude PH owing to chronic lung disease or hypoxemia [i.e., group 3 PH])
  • Venous thromboembolic disease is absent (to exclude chronic thromboembolic PH [i.e., group 4 PH])
  • Certain miscellaneous disorders are absent, including systemic disorders (e.g., sarcoidosis), hematologic disorders (e.g., myeloproliferative diseases), and metabolic disorders (e.g., glycogen storage disease). The purpose is to exclude PH with unclear multifactorial mechanisms (group 5 PH).

World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension are:20

  • Class I: Patients with PH without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope.
  • Class II: Patients with PH having slight limitation of physical activity. No discomfort at rest, but ordinary physical activity causes increased dyspnea, fatigue, chest pain, or near syncope.
  • Class III: Patients with PH having marked limitation of physical activity. No discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or near syncope.
  • Class IV: Patients with PH unable to carry out any physical activity without symptoms and may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest, with increased discomfort by any physical activity.

The 6th symposium on PAH also included recommendations for pediatric patients with PH. The 2019 guidelines and the 2015 American Heart Association and American Thoracic Society guidelines note that the definition of PAH in pediatric patients mirrors the adult definition. The guidelines also recommend the same diagnostic testing and algorithm as adult patients, with the inclusion of a full shunt evaluation during RHC to rule out congenital heart disease.13,18

Treatment Guidelines

Guidelines recommend that patients be referred to a PAH expert center for diagnosis confirmation and management. Current treatment strategies are based on the severity of newly diagnosed patients, assessed by a risk stratification approach. The risk stratification takes clinical, exercise, right ventricular function, and hemodynamic parameters, and combines them to define a low, intermediate, or high-risk status according to patients expected 1-year mortality. The risk stratification includes the following factors:11,13,14,20

Determinates of prognosis (estimated 1-year mortality)

Low Risk

<5%

Intermediate Risk

5-10%

High Risk

>10%

Clinical signs of right heart failure

Absent

Absent

Present

Progression of symptoms

No

Slow

Rapid

Syncope

No

Occasional during brisk or heavy exercise, or occasional orthostatic in an otherwise stable patient

Repeated with little or regular physical activity

WHO functional class

I-II

III

IV

6-minute walking distance

>440 meters

165-440 meters

<165 meters

Cardiopulmonary exercise testing

Peak VO2 >15 ml/min/kg

(>65% pred.)

VE/VCO2 slope <36

Peak VO2 11–15 ml/min/kg (35–65% pred.)

VE/VCO2 slope 36–44.9

Peak VO2 <11 ml/min/kg

(<35% pred.)

VE/VCO2 slope ≥45

N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels

BNP <50 ng/l

NT-proBNP <300 ng/l

BNP 50–300 ng/l

NT-proBNP 300–1400 ng/l

BNP >300 ng/l

NT-proBNP >1400 ng/l

Imaging (echocardiography, CMR imaging)

RA area <18 cm2

No pericardial effusion

RA area 18–26 cm2

No or minimal, pericardial

effusion

RA area >26 cm2

Pericardial effusion

Hemodynamics

RAP <8 mmHg

CI ≥2.5 L/min/m2

SvO2 >65%

RAP 8–14 mmHg

CI 2.0–2.4 L/min/m2

SvO2 60–65%

RAP >14 mmHg

CI <2.0 L/min/m2

SvO2 <60%

BNP: brain natriuretic peptide; CI: cardiac index; CMR: cardiac magnetic resonance; pred.: predicted; RA: right atrium; RAP: right atrial pressure; SvO2: mixed venous oxygen saturation; VE/VCO2: ventilatory equivalents for carbon dioxide; VO2: oxygen consumption

The 6th World Symposium on Pulmonary Hypertension evidence-based treatment algorithm for adults:11,16

  • Treatment Naïve patients:
    • Head-to-head comparisons among different compounds are not available, no evidence-based first line treatment can be proposed for initial monotherapy, if monotherapy is chosen.
    • Vasoreactive patients (only idiopathic PAH, heritable PAH, or drug induced PAH):
      • High dose calcium channel blockers (CCB) that have been progressively titrated
      • Response should be evaluated after 3 to 6 months
      • Adequate treatment response is defined as WHO-FC I/II with sustained hemodynamic improvement after at least 1 year on CCBs alone
      • Patients without an adequate response to high dose CCBs should be treated with approved PAH medications according to non-vasoreactive treatment strategy
    • Non-vasoreactive patients:
      • Low or intermediate risk: Treat with initial oral combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor (listed in sequence by recommendation rating)
        • WHO-FC II: ambrisentan plus tadalafil, or other ERA and PDE5 combination
        • WHO-FC III: ambrisentan plus tadalafil, or other ERA and PDE5 combination
      • High risk: Initial combination therapy (an ERA and a PDE5 inhibitor) plus IV prostacyclin (listed in sequence by recommendation rating)
        • Epoprostenol has the strongest recommendation
        • WHO-FC III/IV: bosentan plus sildenafil plus IV epoprostenol, bosentan plus IV epoprostenol, other ERA/PDE5 plus SC treprostinil, other ERA/PDE5 plus other IV prostacyclin
  • Response should be evaluated after 3 to 6 months:
    • Low risk at follow up: continue therapy with structured follow up until risk progression
    • Intermediate risk: Triple sequential combination therapy or double combination therapy in case initial monotherapy was chosen (listed in sequence by recommendation rating and alphabetical order)
      • WHO-FC II: macitentan added to sildenafil, riociguat added to bosentan, selexipag added to ERA and/or PDE5, treprostinil inhaled added to sildenafil or bosentan, iloprost inhaled added to bosentan, tadalafil added to bosentan, ambrisentan added to sildenafil, bosentan added to sildenafil, other double combinations, other triple combinations
      • WHO-FC III/IV: macitentan added to sildenafil, riociguat added to bosentan, selexipag added to ERA and/or PDE5, sildenafil added to epoprostenol, treprostinil inhaled added to sildenafil or bosentan, iloprost inhaled added to bosentan, tadalafil added to bosentan, ambrisentan added to sildenafil, bosentan added to epoprostenol, bosentan added to sildenafil, other double combinations, other triple combinations
      • Macitentan plus sildenafil, riociguat plus bosentan, selexipag plus ERA and/or PDE5 have the highest levels of recommendations and evidence
      • Referral for lung transplant should also be considered
    • High risk: maximal medical therapy including an IV prostacyclin is recommended and listing for lung transplant
      • Bosentan plus sildenafil plus IV epoprostenol, bosentan plus IV epoprostenol, other ERA/PDE5 plus SC treprostinil, other ERA/PDE5 plus other IV prostacyclin
    • If still at intermediate or high risk after second treatment step (3 to 6 months after change in therapy), maximal medical therapy (triple therapy including a SC or IV prostacyclin [IV preferred for high risk]) is recommended and listing for lung transplant
      • Intermediate-risk status on double combination therapy with an ERA and a PDE5 or riociguat, the addition of selexipag should be considered
      • Triple combination therapy including selexipag who remain in the intermediate-risk group or progress to high risk, substitution with SC or IV prostacyclin should be considered
  • Transitioning patients from one PAH-specific therapy to another might be considered for a number of reasons, but transitioning patients that have an extraordinary response to therapy and desire to transition to less invasive therapy is not recommended except in rare circumstances and under close expert care

The 6th World Symposium on Pulmonary Hypertension pragmatic treatment algorithm in pediatrics:11,18

  • Treatment with targeted PAH therapies in children is almost exclusively based on experience and data from adult studies, due to the lack of pediatric clinical trials
  • Patients with a positive vasoreactive response should be initiated on oral CCBs and continued if there is sustained and improved response.
  • Recommend vasoreactive patients remain on CCBs in addition to targeted PAH therapies
  • Non-vasoreactive patients or those with failed or non-sustained response should undergo risk stratification to determine therapy. Pediatric risk stratification is as follows:

Determinates of Risk

Low Risk

High Risk

Clinical signs of right heart failure

No

Yes

Progression of symptoms

No

Yes

6-minute walking distance (>6 years of age)

>350 meters

<350 meters

Growth

Normal

Failure to thrive

WHO functional class

I, II

III, IV

N-terminal pro-brain natriuretic peptide plasma levels

Minimally elevated

Significantly elevated,

Rising level

Echocardiography

NA

RA/RV enlargement

Reduced LV size

Increased RV/LV ratio

Reduced TAPSE

Low RV FAC

Pericardial effusion

Hemodynamics

Systemic CI >3.0 L/min/m2

Systemic venous saturation >65%

Acute vasoreactivity

Systemic CI <2.5 L/min/m2

mRAP >10 mmHg

PVRI >20 WU/m2

Systemic venous saturation <60%

PACI <0.85 ml/mmHg/m2

RV: right ventricle; WHO: World Health Organization; RA: right atrium; LV: left ventricle; FAC: fractional area change; TAPSE: tricuspid annular plane systolic excursion; CI: cardiac index; mRAP: mean right atrial pressure; PVRI: pulmonary vascular resistance index; WU: Wood Units; PACI: pulmonary arterial compliance index.

  • Low risk: oral monotherapy with either an ERA (i.e., bosentan, ambrisentan) or a PDE5 inhibitor (i.e., sildenafil, tadalafil) is recommended
  • Early combination therapy should be considered in children that deteriorate on either ERA or PDE5 therapy
      • Remain low risk despite deterioration: addition of inhaled prostacyclin may be beneficial
    • High risk: IV epoprostenol or treprostinil are recommended, with early consideration of lung transplantation in patients with deteriorating high-risk features

The American College of Chest Physicians (CHEST) guidelines (2019) state20:

  • WHO FC II [treatment naïve and not a candidate for or failure to calcium channel blocker (CCB) therapy]:
    • Combination with ambrisentan and tadalafil
    • Patients unable to tolerate or unwilling to take combination therapy: monotherapy with an ERA or PDE5 inhibitor (listed in order of recommendation level and alphabetically)
      • Ambrisentan, sildenafil, bosentan, macitentan, tadalafil, riociguat
    • Parenteral or inhaled prostanoids should not be used as initial or second line therapy
  • WHO FC III [treatment naïve, not a candidate for or failure to calcium channel blocker (CCB) therapy, and no evidence of rapid progression of their disease or poor prognosis]:
    • Combination with ambrisentan and tadalafil
    • Patients unable to tolerate or unwilling to take combination therapy: monotherapy with an ERA or PDE5 inhibitor (listed in order of recommendation level and alphabetically)
      • Ambrisentan, bosentan, sildenafil, macitentan, tadalafil, riociguat
  • WHO FC III [treatment naïve with evidence of rapid progression of their disease, or other markers of a poor clinical prognosis]:
    • Initial treatment with IV or SC prostanoid
    • Suggest the addition of inhaled prostanoid (i.e., treprostinil, iloprost) in patients that remain symptomatic on stable and appropriate doses of an ERA or PDE5 inhibitor
    • There is no recommendation for patients unwilling to manage PAH with IV or SC prostanoid, so may consider addition of inhaled or oral prostanoid,
  • 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]: addition of a parenteral or inhaled prostanoid
  • WHO FC IV [treatment naïve]: monotherapy with a parenteral prostanoid agent
  • WHO FC IV [treatment naïve and unable/or do not desire parenteral prostanoid therapy]: an inhaled prostanoid in combination with an ERA or PDE5 inhibitor
  • WHO FC III or IV [with unacceptable or deteriorating clinical status despite established PAH pharmacotherapy]: a second or third class of PAH therapy should be started
  • Due to insufficient evidence, recommendations cannot be made for or against the use of selexipag
  • There is no evidence to support the use of oral treprostinil as add-on or combination therapy 

The AHA/ATS guidelines for the treatment of pediatric pulmonary hypertension state16:

  • Oral therapy in children with lower-risk PAH is recommended and should include either a PDE5 inhibitor or an ERA
  • A goal-targeted therapy approach in which PAH-specific drugs are added progressively to achieve specified therapeutic targets can be useful
  • Intravenous and subcutaneous prostacyclin or its analogs should be initiated without delay for patients with higher-risk PAH

The Chest guidelines recognize that there is still a lack of head-to-head comparisons of pharmacologic agents for the treatment of PAH, and because of their differing burdens and risks to patients, it is recommended that drug therapy be chosen on the basis of a methodical evaluation of disease severity and the risk for further short-term deterioration.  The optimal method of evaluation has not been studied.  No one agent can be definitively recommended preferentially. Additionally, it notes that adding a second class of PAH therapy for patients whose clinical status remains unacceptable despite established PAH-specific monotherapy requires that the clinician assess whether the patient has received an adequate trial of the initial monotherapy. At present, this assessment combines evaluation of the duration of monotherapy, the expected response to the monotherapy, the observed response to the monotherapy, and the patient’s severity of illness and pace of decline. Unacceptable clinical status will vary for individual patients and clinicians, but symptomatic limitation of desired physical activities usually guides these decisions.20

Safety

Adcirca2

Tadalafil has the following contraindications:

  • Concurrent use (regular or intermittent) of organic nitrates in any form
  • Do not use Adcirca in patients who are using a Guanylate Cyclase (GC) stimulator, such as riociguat
  • History of known serious hypersensitivity reaction to tadalafil (Adcirca or Cialis)

Adempas6

Riociguat has the following contraindications:

  • Pregnancy
  • Co-administration with nitrates or nitric oxide donors (e.g., amyl nitrite) in any form
  • Concomitant use with specific phosphodiesterase (PDE) inhibitors (e.g., sildenafil, tadalafil, vardenafil) or nonspecific PDE inhibitors (e.g., dipyridamole, theophylline)
  • Pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP)

Black box warnings include:

  • Do not administer Adempas to a pregnant female because it may cause fetal harm. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • Females of reproductive potential: exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for one month after stopping treatment.

Letairis3

Ambrisentan has the following contraindications:

  • Pregnancy
  • Idiopathic pulmonary fibrosis (including IPF patients with pulmonary hypertension [WHO group 3])

Black box warnings include:

  • Do not administer Letairis to a pregnant female because it may cause fetal harm. Letairis is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • Exclude pregnancy before the initiation of treatment with Letairis. Females of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after dis continuation of treatment.

Opsumit5

Macitentan has the following contraindication:

  • Pregnancy

Black box warnings include:

  • Do not administer Opsumit to a pregnant female because it may cause fetal harm. Opsumit was consistently shown to have teratogenic effects when administered to animals. If Opsumit is used during pregnancy, advise the patient of the potential risk to a fetus. 
  • Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception.

Orenitram7

Treprostinil tablets have the following contraindication:

  • Severe hepatic impairment (Child-Pugh Class C)

Revatio1

Sildenafil has the following contraindications:

  • Concomitant use of organic nitrates in any form, either regularly or intermittently
  • Concomitant use of riociguat
  • Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension

Tracleer4

Bosentan has the following contraindications:

  • Pregnancy
  • Use with cyclosporine A
  • Use with glyburide
  • Hypersensitivity to bosentan or any component of the product

Black box warnings include:

Hepatotoxicity

In clinical studies, Tracleer caused at least 3-fold upper limit of normal (ULN) elevation of

liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated

bilirubin in a small number of cases. Because these changes are a marker for potential

serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation

of treatment and then monthly.

In the post marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with Tracleer in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of Tracleer in these cases could not be excluded. In at least one case, the initial presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by nonspecific symptoms, all of which resolved slowly over time after discontinuation of Tracleer. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping Tracleer with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction.

Elevations in aminotransferases require close attention. Tracleer should generally be avoided in patients with elevated aminotransferases (>3 × ULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2 × ULN, treatment with Tracleer should be stopped. There is no experience with the reintroduction of Tracleer in these circumstances.

Embryo-Fetal Toxicity

Tracleer is likely to cause major birth defects if used by pregnant females based on animal

data. Therefore, pregnancy must be excluded before the start of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective.

Uptravi10

Selexipag has the following contraindication:

  • Concomitant use of a strong CYP2C8 inhibitor (e.g., gemfibrozil)

REFERENCES

  1. Adcirca prescribing information. Eli Lilly and Company. September 2020.
  2. Adempas prescribing information. Bayer HealthCare.  January 2018.
  3. Letairis prescribing information. Gilead. August 2019.
  4. Opsumit prescribing information.  Actelion Pharmaceuticals, Inc. January 2021.
  5. Orenitram prescribing information.  United Therapeutics Corporation. October 2019.
  6. Revatio prescribing information. Pfizer. February 2018.
  7. Tracleer prescribing information. Actelion Pharmaceuticals, Inc. May 2019.
  8. Tyvaso Prescribing Information. United Therapeutics Corp. October 2017.
  9. Uptravi Prescribing Information. Actelion Pharmaceuticals, Inc.  September 2019.
  10. Ventavis Prescribing Information. Actelion Pharmaceuticals, Inc. December 2019.
  11. Galiè, Nazzareno, et. al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal. 37(1): 67–119. https://doi.org/10.1093/eurheartj/ehv317.
  12. Irene Lang, MD and Michael Madani, MD. Contemporary Reviews in Cardiovascular Medicine: Update on Chronic Thromboembolic Pulmonary Hypertension. Circulation. 2014;130:508-518.
  13. Abman SH, Hansmann G, et al. Pediatric pulmonary hypertension – guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037-2099.
  14. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62 Suppl: D42–50.
  15. Simonneau, G., Montani, D., Celermajer, D. S., Denton, C. P., Gatzoulis, M. A., Krowka, M., … Souza, R. (2019). Haemodynamic definitions and updated clinical classification of pulmonary hypertension. The European respiratory journal53(1), 1801913. doi:10.1183/13993003.01913-2018.
  16. Galiè, N., Channick, R. N., Frantz, R. P., Grünig, E., Jing, Z. C., Moiseeva, O., … McLaughlin, V. V. (2019). Risk stratification and medical therapy of pulmonary arterial hypertension. The European respiratory journal53(1), 1801889. doi:10.1183/13993003.01889-2018.
  17. Kim, N. H., Delcroix, M., Jais, X., Madani, M. M., Matsubara, H., Mayer, E., … Jenkins, D. P. (2019). Chronic thromboembolic pulmonary hypertension. The European respiratory journal53(1), 1801915. doi:10.1183/13993003.01915-2018.
  18. Rosenzweig, E. B., Abman, S. H., Adatia, I., Beghetti, M., Bonnet, D., Haworth, S., … Berger, R. (2019). Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. The European respiratory journal53(1), 1801916. doi:10.1183/13993003.01916-2018.
  19. Frost, A., Badesch, D., Gibbs, J., Gopalan, D., Khanna, D., Manes, A., … Torbicki, A. (2019). Diagnosis of pulmonary hypertension. The European respiratory journal53(1), 1801904. doi:10.1183/13993003.01904-2018.
  20. Klinger, James R. et al. (2019). Therapy for Pulmonary Arterial Hypertension in Adults. CHEST, 155(3):565 - 586.

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
 
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