Effective Date

Date of Origin 

7/1/2023

Adcirca®

(tadalafil)

Tablets^

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

* – WHO = World Health Organization

^- generic available

1

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

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%)

* – WHO = World Health Organization

2

Letairis® 

(ambrisentan)

Tablets^

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

• To improve exercise ability 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%)

* – WHO = World Health Organization

^- generic available

3

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%)

* – WHO = World Health Organization

4

Orenitram®

(treprostinil)

Tablets

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

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

* – WHO = World Health Organization

5

Revatio®

(sildenafil citrate)

Tablets^

Oral solution^

Injection solution

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

Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in pediatric patients 1 to 17 years of age to improve exercise ability and, in pediatric patients too young to perform standard exercise testing, pulmonary hemodynamics thought to underly improvements in exercise.

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.

* – WHO = World Health Organization

^- generic available

6

Tadliq®

(tadalafil)

Oral suspension

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

* – WHO = World Health Organization

23

Tracleer®

(bosentan)

Tablets film coated^

Tablets soluble

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

• 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.

* – WHO = World Health Organization

^- generic available

7

Tyvaso®, Tyvaso DPI™

(treprostinil)

Inhalation solution

Inhalation powder

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 a background of bosentan (an endothelin receptor antagonist) or sildenafil (a PDE 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

Treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO group 3) to improve exercise ability. The study establishing effectiveness included patients with etiologies of idiopathic interstitial pneumonia (IIP) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE), and WHO group 3 connective tissue disease.

* – WHO = World Health Organization

8,22

Uptravi^®

(selexipag)

Tablets

Powder for injection

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

* – WHO = World Health Organization

9

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%)

* – WHO = World Health Organization

10

Pulmonary Hypertension

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 mean pulmonary arterial pressure (mPAP) greater than 20 mmHg with a normal pulmonary capillary wedge pressure (i.e., less than or equal to 15 mmHg) and a pulmonary vascular resistance greater than or equal to 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 3 is pulmonary hypertension (PH) due to lung disease and/or hypoxia. PH associated with chronic lung disease is linked with reduced functional status and worse outcomes. There are seven subgroups within WHO group 3, one of which is ILD associated PH (WHO group 3.2). Right heart catheterization (RHC) is the gold standard for the diagnosis of PH associated with lung disease. WHO group 3 PH is distinguished from WHO group 1 based on the presence of an FVC less than 70% predicted and extensive parenchymal changes on CT. Prior to starting PAH therapy for the treatment of PH associated with lung disease, the patient’s underlying lung disease should be optimally treated according to current guidelines.(21)

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 greater than 20 mmHg, pulmonary capillary wedge pressure less than or equal to 15 mmHg, and pulmonary vascular resistance greater than or equal to 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. The 6^th 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. (12,17)

The diagnosis of PAH requires right heart catheterization (RHC) to demonstrate a mPAP greater than 20 mmHg at rest and a pulmonary vascular resistance greater than or equal to 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 less than or equal to 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 include the following:(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 6^th 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)

Initial Assessment Tool:

6MWD, 6-minute walking distance; BNP, brain natriuretic peptide; CI, cardiac index; cMRI, cardiac magnetic resonance imaging; CPET, cardiopulmonary exercise testing; HF, heart failure; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAH, pulmonary arterial hypertension; pred., predicted; RA, right atrium; RAP, right atrial pressure; sPAP, systolic pulmonary arterial pressure; SvO2, mixed venous oxygen saturation; RVESVI, right ventricular end-systolic volume index; RVEF, right ventricular ejection fraction; SVI, stroke volume index; TAPSE, tricuspid annular plane systolic excursion; VE/VCO2, ventilatory equivalents for carbon dioxide; VO2, oxygen uptake; WHO-FC, World Health Organization functional class.

Follow-up Assessment Tool:

6MWD, 6-minute walking distance; BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro-brain natriuretic peptide; WHO-FC, World Health Organization functional class.
Risk is calculated by dividing the sum of all grades by the number of variables and rounding to the next integer.
aWHO-FC I and II are assigned 1 point as both are associated with good long-term survival.

The 6^th World Symposium on Pulmonary Hypertension evidence-based treatment algorithm for adults includes the following recommendations:(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. In some cases, the combination of CCB with approved PAH is required.
  • 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: ambrisartan plus tadalafil, macitentan plus tadalafil, or other ERA and PDE5 inhibitor
    • High risk: Initial combination therapy (an ERA and a PDE5 inhibitor) plus IV prostacyclin with epoprostenol having the strongest recommendation
• 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
    • 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 (epoprostenol or treprostinil) is recommended and listing for lung transplant
  • 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 2022 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines recommend a risk-based, goal-orientated treatment approach in patients with PAH. Risk stratification at diagnosis is done using a three-strata model and follow-up a four strata model. The recommended treatment algorithm for non-vasoreactive patients or patients unresponsive to CCB is as follows: (11)

• Initial treatment:
  • Patients without cardiopulmonary comorbidities (e.g., obesity, hypertension, diabetes):
    • Low or intermediate prognosis risk: Treat with oral combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor: ambrisentan plus tadalafil, macitentan plus tadalafil, or other ERA and PDE5 combination
    • High prognosis risk: Treat with oral combination therapy with an endothelin receptor antagonist (ERA) plus a phosphodiesterase type-5 (PDE5) inhibitor and IV/SC prostacyclin analogue 
  • Patients with cardiopulmonary comorbidities (all prognosis risk categories)
    • Oral monotherapy with PDE5 inhibitors or ERA
• Response should be evaluated after 3 to 6 months:
  • Patients without cardiopulmonary comorbidities:
    • Low risk at follow up: continue therapy
    • Intermediate to low risk: add prostacyclin receptor agonist (PRA) (selexipag), OR, switch from PDE5 inhibitor to soluble guanylate cyclase stimulator(sGCs) (riociguat)
    • Intermediate to high or high risk: add IV/SC prostacyclin analogue (epoprostenol or treprostinil) and/or evaluate for lung transplant.  If adding IV/SC prostacyclin analogue is unfeasible, adding selexipag or switching from PDE5 inhibitor to riociguat may be considered
  • Patients with cardiopulmonary comorbidities:
    • Individualized therapy. Patients that present at intermediate or high risk of death while receiving PDE5 inhibitors or ERA monotherapy, treatment based on individual basis

The 6^th World Symposium on Pulmonary Hypertension pragmatic treatment algorithm in pediatrics includes the following recommendations:(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
• Therapeutic strategy is based on risk stratification and treatment response, extrapolated from that in adults, but adapted for age
• Patients with a positive vasoreactive response should be initiated on high-dose 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:

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 prognosis 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 prognosis risk: IV epoprostenol or treprostinil are recommended, with early consideration of lung transplantation in patients with deteriorating high-risk features
• In cases of insufficient response to recommended therapy or when drugs are not available, a Potts shunt, balloon atrial septostomy (BAS) or lung transplant may be considered in patients with severe pulmonary hypertension

The American College of Chest Physicians (CHEST) guideline (2019) states:(20)

• 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 state:(13)

• 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 guideline recognizes 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

Adcirca(1), Tadliq(23)

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, Cialis, or Tadliq)

Adempas(2)

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)
• Concomitant use with other soluble guanylate cyclase (sGC) stimulators
• 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.

Letairis(3)

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 discontinuation of treatment.

Opsumit(4)

Macitentan has the following contraindications:

• Pregnancy
• History of hypersensitivity reaction to macitentan or any component of the product

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.

Orenitram(5)

Treprostinil tablets have the following contraindication:

• Severe hepatic impairment (Child-Pugh Class C)

Revatio(6)

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

Tracleer(7)

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 (greater than 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 greater than 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 (greater than 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 greater than or equal to 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.

Uptravi(9)

Selexipag has the following contraindications:

• Hypersensitivity to the active substance or to any of the excipients
• Concomitant use of a strong CYP2C8 inhibitor (e.g., gemfibrozil)

1

Adcirca prescribing information. Eli Lilly and Company. September 2020.

2

Adempas prescribing information. Bayer HealthCare. September 2021.

3

Letairis prescribing information. Gilead. August 2019.

4

Opsumit prescribing information.  Actelion Pharmaceuticals, Inc. October 2021.

5

Orenitram prescribing information.  United Therapeutics Corporation. November 2020.

6

Revatio prescribing information. Pfizer. January 2023.

7

Tracleer prescribing information. Actelion Pharmaceuticals, Inc. July 2022.

8

Tyvaso Prescribing Information. United Therapeutics Corp. May 2022.

9

Uptravi Prescribing Information. Actelion Pharmaceuticals, Inc.  October 2021.

10

Ventavis Prescribing Information. Actelion Pharmaceuticals, Inc. March 2022.

11

Humbert, Marc, et. al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the 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: International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on Rare Respiratory Diseases (ERN-LUNG).  European Heart Journal, Volume 43, Issue 38, 7 October 2022, Pages 3618–3731, https://doi.org/10.1093/eurheartj/ehac237.

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 journal, 53(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 journal, 53(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 journal, 53(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 journal, 53(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 journal, 53(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.

21

Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J 2019; 53: 1801914.

22

Tyvaso DPI prescribing information. United Therapeutics Corp. May 2022. 

23

Tadliq prescribing information. CMP Pharma, Inc. June 2022. 

Letairis

ambrisentan tab

10 MG ; 5 MG

M ; N ; O ; Y

O ; Y

Tracleer

bosentan tab  ; bosentan tab for oral susp

125 MG ; 32 MG ; 62.5 MG

M ; N ; O ; Y

N ; O ; Y

Ventavis

iloprost inhalation solution

10 MCG/ML ; 20 MCG/ML

M ; N ; O ; Y

N

Opsumit

macitentan tab

10 MG

M ; N ; O ; Y

N

Adempas

riociguat tab

0.5 MG ; 1 MG ; 1.5 MG ; 2 MG ; 2.5 MG

M ; N ; O ; Y

N

Revatio

sildenafil citrate for suspension

10 MG/ML

M ; N ; O ; Y

O ; Y

Revatio

sildenafil citrate tab

20 MG

M ; N ; O ; Y

O ; Y

Tadliq

tadalafil oral susp

20 MG/5ML

M ; N ; O ; Y

N

01-01-2023

Adcirca ; Alyq

tadalafil tab

20 MG

M ; N ; O ; Y

O ; Y

Orenitram ; Orenitram titration kit m

treprostinil diolamine tab er  ; treprostinil tab er titr pk (mo ; treprostinil tab er titr pk(mo

0.125 MG ; 0.25 MG ; 1 MG ; 2.5 MG ; 5 MG

M ; N ; O ; Y

N

Tyvaso dpi maintenance ki ; Tyvaso dpi titration kit

treprostinil inh powd  ; treprostinil inh powder

112 112 x48MCG ; 112 84 x 32MCG ; 16 MCG ; 32 MCG ; 48 MCG ; 64 MCG

M ; N ; O ; Y

N

10-01-2022

Tyvaso ; Tyvaso refill ; Tyvaso starter

Treprostinil Inhalation Solution 0.6 MG/ML

0.6 MG/ML

M ; N ; O ; Y

N

Uptravi

selexipag tab

1000 MCG ; 1200 MCG ; 1400 MCG ; 1600 MCG ; 200 MCG ; 400 MCG ; 600 MCG ; 800 MCG

M ; N ; O ; Y

N

Uptravi titration pack

selexipag tab therapy pack

200 MCG

M ; N ; O ; Y

N

Adcirca ; Alyq

tadalafil tab

20 MG

60

TABS

30

DAYS

Adempas

riociguat tab

0.5 MG ; 1 MG ; 1.5 MG ; 2 MG ; 2.5 MG

90

TABS

30

DAYS

Letairis

ambrisentan tab

10 MG ; 5 MG

30

TABS

30

DAYS

Opsumit

macitentan tab

10 MG

30

TABS

30

DAYS

Orenitram titration kit m

treprostinil tab er titr pk (mo

0.125 MG

1

PACK

180

DAYS

Orenitram titration kit m

treprostinil tab er titr pk (mo

0.125 MG

1

PACK

180

DAYS

Orenitram titration kit m

treprostinil tab er titr pk(mo

0.125 MG

1

PACK

180

DAYS

Revatio

sildenafil citrate for suspension

10 MG/ML

2

BOTTS

30

Revatio

sildenafil citrate tab

20 MG

90

TABS

30

DAYS

Tadliq

Tadalafil Oral Susp

20 MG/5ML

300

MLS

30

DAYS

01-01-2023

Tracleer

bosentan tab

125 MG ; 62.5 MG

60

TABS

30

DAYS

Tracleer

bosentan tab for oral susp

32 MG

120

TABS

30

DAYS

Tyvaso

treprostinil inhalation solution

0.6 MG/ML

7

PKGS

28

DAYS

66302-0206-03

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

112 112 x48MCG

224

CARTS

28

DAYS

10-01-2022

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

32 MCG

112

CARTS

28

DAYS

10-01-2022

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

48 MCG

112

CARTS

28

DAYS

10-01-2022

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

64 MCG

112

CARTS

28

DAYS

10-01-2022

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

16 MCG

112

CARTS

28

DAYS

10-01-2022

Tyvaso dpi titration kit

Treprostinil Inh Powd

16 MCG

252

CARTS

180

DAYS

10-01-2022

Tyvaso dpi titration kit

Treprostinil Inh Powder

112 84 x 32MCG

196

CARTS

180

DAYS

10-01-2022

Tyvaso refill

treprostinil inhalation solution

0.6 MG/ML

28

PKGS

28

DAYS

66302-0206-02

Tyvaso starter

treprostinil inhalation solution

0.6 MG/ML

1

KIT

180

DAYS

66302-0206-04

Tyvaso starter

treprostinil inhalation solution

0.6 MG/ML

1

KIT

180

DAYS

66302-0206-01

Uptravi

selexipag tab

200 MCG

60

TABS

30

DAYS

66215-0602-06

Uptravi

selexipag tab

200 MCG

140

TABS

180

DAYS

66215-0602-14

Uptravi

selexipag tab

1000 MCG ; 1200 MCG ; 1400 MCG ; 1600 MCG ; 200 MCG ; 400 MCG ; 600 MCG ; 800 MCG

60

TABS

30

DAYS

Uptravi titration pack

selexipag tab therapy pack

200 MCG

1

PKG

180

DAYS

Ventavis

iloprost inhalation solution

10 MCG/ML ; 20 MCG/ML

270

AMPULS

30

DAYS

Adcirca ; Alyq

tadalafil tab

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Adempas

riociguat tab

0.5 MG ; 1 MG ; 1.5 MG ; 2 MG ; 2.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Letairis

ambrisentan tab

10 MG ; 5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Opsumit

macitentan tab

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Orenitram ; Orenitram titration kit m

treprostinil diolamine tab er  ; treprostinil tab er titr pk (mo ; treprostinil tab er titr pk(mo

0.125 MG ; 0.25 MG ; 1 MG ; 2.5 MG ; 5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Revatio

sildenafil citrate for suspension

10 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Revatio

sildenafil citrate tab

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tadliq

tadalafil oral susp

20 MG/5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tracleer

bosentan tab  ; bosentan tab for oral susp

125 MG ; 32 MG ; 62.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso ; Tyvaso refill ; Tyvaso starter

Treprostinil Inhalation Solution 0.6 MG/ML

0.6 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki ; Tyvaso dpi titration kit

treprostinil inh powd  ; treprostinil inh powder

112 112 x48MCG ; 112 84 x 32MCG ; 16 MCG ; 32 MCG ; 48 MCG ; 64 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi

selexipag tab

1000 MCG ; 1200 MCG ; 1400 MCG ; 1600 MCG ; 200 MCG ; 400 MCG ; 600 MCG ; 800 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi titration pack

selexipag tab therapy pack

200 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ventavis

iloprost inhalation solution

10 MCG/ML ; 20 MCG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Adcirca ; Alyq

tadalafil tab

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Adempas

riociguat tab

0.5 MG ; 1 MG ; 1.5 MG ; 2 MG ; 2.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Letairis

ambrisentan tab

10 MG ; 5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Opsumit

macitentan tab

10 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Orenitram titration kit m

treprostinil tab er titr pk (mo

0.125 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Orenitram titration kit m

treprostinil tab er titr pk (mo

0.125 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Orenitram titration kit m

treprostinil tab er titr pk(mo

0.125 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Revatio

sildenafil citrate for suspension

10 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Revatio

sildenafil citrate tab

20 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tadliq

Tadalafil Oral Susp

20 MG/5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tracleer

bosentan tab

125 MG ; 62.5 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tracleer

bosentan tab for oral susp

32 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso

treprostinil inhalation solution

0.6 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

112 112 x48MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

32 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

48 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

64 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi maintenance ki

Treprostinil Inh Powder

16 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi titration kit

Treprostinil Inh Powd

16 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso dpi titration kit

Treprostinil Inh Powder

112 84 x 32MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso refill

treprostinil inhalation solution

0.6 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso starter

treprostinil inhalation solution

0.6 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Tyvaso starter

treprostinil inhalation solution

0.6 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi

selexipag tab

200 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi

selexipag tab

200 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi

selexipag tab

1000 MCG ; 1200 MCG ; 1400 MCG ; 1600 MCG ; 200 MCG ; 400 MCG ; 600 MCG ; 800 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Uptravi titration pack

selexipag tab therapy pack

200 MCG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ventavis

iloprost inhalation solution

10 MCG/ML ; 20 MCG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

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. The requested agent is eligible for continuation of therapy AND ONE of the following:

1. 1. 1. 1. Information has been provided that indicates the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
         2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed AND
      2. The patient has an FDA approved indication for the requested agent OR
   2. 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
      2. The patient’s diagnosis has been confirmed by a ventilation-perfusion scan and a confirmatory selective pulmonary angiography AND
      3. The patient has a mean pulmonary artery pressure of greater than 20 mmHg AND
      4. The patient has a pulmonary capillary wedge pressure less than or equal to 15 mmHg AND
      5. The patient has a pulmonary vascular resistance greater than or equal to 3 Wood units AND
      6. ONE of the following:
         1. The patient is NOT a candidate for surgery OR
         2. The patient has had a pulmonary endarterectomy AND has persistent or recurrent disease AND
      7. 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
   3. 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 (medical records required) AND
      2. The patient’s mean pulmonary arterial pressure is greater than 20 mmHg AND
      3. The patient has a pulmonary capillary wedge pressure less than or equal to 15 mmHg AND
      4. The patient has a pulmonary vascular resistance greater than or equal to 3 Wood units AND
      5. The patient’s World Health Organization (WHO) functional class is II or greater AND
      6. 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
      7. ONE of the following:
         1. The requested agent will be utilized as monotherapy OR
         2. The requested agent will be utilized as dual therapy that consists of an endothelin receptor antagonist (ERA) plus phosphodiesterase 5 inhibitor (PDE5i) as initial therapy OR
         3. The requested agent will be utilized for add-on therapy to existing monotherapy (dual therapy) [except combo requests for endothelin receptor antagonist (ERA) plus phosphodiesterase 5 inhibitor (PDE5i) for dual therapy], and BOTH of following:
            1. The patient has unacceptable or deteriorating clinical status despite established PAH pharmacotherapy AND
            2. The requested agent is in a different therapeutic class OR
         4. 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
            2. ONE of the following:
               1. A prostanoid has been started as one of the agents in the triple therapy OR
               2. The patient has an intolerance, FDA labeled contraindication, or hypersensitivity to ALL prostanoids AND
            3. The patient has unacceptable or deteriorating clinical status despite established PAH pharmacotherapy AND
            4. All three agents in the triple therapy are from a different therapeutic class OR
   4. The patient has a diagnosis of pulmonary hypertension associated with interstitial lung disease (PH-ILD, WHO group 3) AND ALL of the following:
      1. The requested agent is Tyvaso AND
      2. The patient’s diagnosis has been confirmed by right heart catheterization (medical records required) AND
      3. The patient’s mean pulmonary arterial pressure is greater than 20 mmHg AND
      4. The patient has a pulmonary capillary wedge pressure less than or equal to 15 mmHg AND
      5. The patient has a pulmonary vascular resistance greater than or equal to 3 Wood units AND
      6. The patient has an FVC less than 70% of predicted AND
      7. The patient has extensive parenchymal changes on computed tomography (CT) AND
      8. BOTH of the following:
         1. The patient is currently treated with standard of care therapy for ILD (e.g., Ofev) AND
         2. The patient will continue standard of care therapy for ILD (e.g., Ofev) OR
   5. The patient has another FDA approved indication for the requested agent AND
2. If the patient has an FDA approved indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. The prescriber has provided information in support of using the requested agent for the patient’s age for the requested indication AND
3. If the request is for ONE of the following brand agents with an available generic equivalent (listed below), then ONE of the following:

3. 1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
   2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
   3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND
4. If the request is for Tadliq, then one of the following:​​​​​​
   1. The patient has tried and had an inadequate response to generic tadalafil tablets OR
   2. The patient has an in intolerance or hypersensitivity to generic tadalafil tablets that is not expected to occur with the requested agent OR
   3. The patient had an FDA labeled contraindication to generic tadalafil tablets that is not expected to occur with the requested agent AND
5. 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
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

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
2. The patient has had clinical benefit with the requested agent (e.g., stabilization, decreased disease progression) (medical records required) AND
3. If the requested agent is Tyvaso for a diagnosis of pulmonary hypertension associated with interstitial lung disease (PH-ILD, WHO group 3), then the patient will continue standard of care therapy for ILD (e.g., Ofev) AND
4. If the request is for ONE of the following brand agents with an available generic equivalent (listed below), then ONE of the following: 

4. 1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
   2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
   3. The prescriber has provided information to support the use of the requested brand agent over the generic equivalent AND
5. If the request is for Tadliq, then one of the following:​
   1. The patient has tried and had an inadequate response to generic tadalafil tablets OR
   2. The patient has an in intolerance or hypersensitivity to generic tadalafil tablets that is not expected to occur with the requested agent OR
   3. The patient had an FDA labeled contraindication to generic tadalafil tablets that is not expected to occur with the requested agent AND
6. 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
7. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. The requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit OR
3. ALL of the following:
   1. The requested quantity (dose) is greater than the program quantity limit AND
   2. The requested quantity (dose) is greater than the maximum FDA labeled dose for the requested indication AND
   3. The prescriber has provided information in support of therapy with a higher dose for the requested indication

Length of Approval: 12 months