**Criteria for Non-Formulary Use: Endothelin Receptor Antagonists (ERAs)
in Pulmonary Arterial Hypertension (PAH)**

**VHA Pharmacy Benefits Management Services and the Medical Advisory
Panel**

*The following recommendations are based on current medical evidence.
The content of the document is dynamic and will be revised as new
clinical data become available. The purpose of this document is to
assist practitioners in clinical decision making, to standardize and
improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician, however, must make the ultimate judgment
regarding the propriety of any course of treatment in light on
individual patient situations*

Refer to the Ambrisentan Monograph at
[www.pbm.va.gov](http://www.pbm.va.gov/) or
[http://vaww.pbm.va.gov](http://vaww.pbm.va.gov/)

+-----------------------------------------------------------------------+
| **FDA APPROVED INDICATIONS FOR USE**                                  |
+-----------------------------------------------------------------------+
| -   **Ambrisentan:** Treatment of PAH (World Health Organization      |
|     \[WHO\] Group 1^1^) in patients with WHO functional class II or   |
|     III symptoms^2^; may be considered in patients who experienced    |
|     asymptomatic aminotransferase elevations on other ERAs after      |
|     aminotransferase levels return to normal.                         |
|                                                                       |
| -   **Bosentan:** Treatment of PAH (WHO Group 1^1^) in patients with  |
|     WHO functional class III or IV symptoms^2^                        |
+-----------------------------------------------------------------------+
| **EXCLUSION CRITERIA (If one is selected, patient is NOT eligible)**  |
+-----------------------------------------------------------------------+
| -   Pregnancy (FDA Category X)                                        |
|                                                                       |
| -   Women of childbearing potential not using adequate contraception  |
|     in accordance with prescribing information                        |
|                                                                       |
| -   Moderate or severe liver impairment or baseline liver function    |
|     test (LFT) abnormalities (aminotransferase elevations \>3x upper  |
|     limit of normal \[ULN\])                                          |
|                                                                       |
| -   History of LFT elevations on previous ERA therapy accompanied by  |
|     symptoms of liver toxicity or increases in bilirubin \>2x ULN     |
+-----------------------------------------------------------------------+
| **INCLUSION CRITERIA**                                                |
+-----------------------------------------------------------------------+
| *All of the following must be selected for patient to be eligible:*   |
|                                                                       |
| -   Definitive diagnosis of PAH confirmed by right-heart              |
|     catheterization including hemodynamic diagnosis: mean pulmonary   |
|     artery pressure \[mPAP\] \>25 mmHg and pulmonary capillary wedge  |
|     pressure \[PCWP\] or left ventricular end diastolic pressure      |
|     \[LVEDP\] ≤15 mm Hg                                               |
|                                                                       |
| -   WHO Group 1 PAH^1,3^                                              |
|                                                                       |
| -   Under the care of an experienced provider in the management of    |
|     PAH                                                               |
|                                                                       |
| -   Patient is treated with or has been assessed for adjunct          |
|     therapies such as oxygen, diuretics, digoxin and warfarin         |
|                                                                       |
| *If applicable, the following must be selected for patient to be      |
| eligible:*                                                            |
|                                                                       |
| -   If acute vasoreactivity test positive, calcium channel antagonist |
|     therapy has been tried unless right heart failure is present^4^   |
|                                                                       |
| -   Contraindication (relative or absolute), intolerance, or          |
|     inadequate response to sildenafil, or other compelling reason not |
|     to use sildenafil for patients with WHO functional class II or    |
|     III symptoms^2^                                                   |
|                                                                       |
| *One of the following must be selected for patient to be eligible:*   |
|                                                                       |
| -   For **ambrisentan** only: WHO functional class II or III^2^       |
|                                                                       |
| -   For **bosentan** only: WHO functional class II, III or IV^2^      |
+-----------------------------------------------------------------------+
| **DOSAGE AND ADMINISTRATION**                                         |
+-----------------------------------------------------------------------+
| -   **Ambrisentan:** 5 mg orally once daily, consider increasing to   |
|     10 mg orally once daily if tolerated                              |
|                                                                       |
| -   **Bosentan:** 62.5 mg orally twice daily x4 weeks, then increase  |
|     to 125 mg orally twice daily                                      |
+-----------------------------------------------------------------------+
| **REQUIRED AND RECOMMENDED MONITORING**                               |
+-----------------------------------------------------------------------+
| In addition to standard monitoring in a patient with PAH, the         |
| following is **[required]{.underline}**:                              |
|                                                                       |
| -   Baseline and monthly monitoring of pregnancy tests (if            |
|     appropriate) and LFTs                                             |
|                                                                       |
| -   Baseline, one month, and periodic monitoring of hemoglobin        |
|                                                                       |
| Additional recommended monitoring:                                    |
|                                                                       |
| -   [Fluid status]{.underline}: ERAs have been associated with        |
|     peripheral edema and fluid retention requiring intervention,      |
|     particularly in the first few weeks after starting therapy        |
+-----------------------------------------------------------------------+
| **ISSUES FOR CONSIDERATION (See prescribing information for further   |
| details)**                                                            |
+-----------------------------------------------------------------------+
| -   ERAs are associated with hepatotoxicity. LFT abnormalities appear |
|     to be dose related, may occur at any time during treatment, and   |
|     are generally asymptomatic. Should LFT elevations occur,          |
|     management may include dose reduction, temporary or permanent     |
|     discontinuation of therapy, and closer monitoring, as outlined in |
|     the prescribing information for each agent.                       |
|                                                                       |
| -   ERAs are available only through restricted access programs.       |
|     Ambrisentan is available through the Letairis Education and       |
|     Access Program (LEAP) --                                          |
|     [www.letairis.com](http://www.letairis.com/) or 1-866-664-LEAP;   |
|     Bosentan is available through the Tracleer Access Program (TAP)   |
|     -- [www.tracleer.com](http://www.tracleer.com/) or                |
|     1-866-228-3546. For additional information on VA specific         |
|     processes, see                                                    |
|     [http://vaww.national.cmop.va                                     |
| .gov/PBM/Special%20Handling%20Drugs/Forms/AllItems.aspx](http://vaww. |
| national.cmop.va.gov/PBM/Special Handling Drugs/Forms/AllItems.aspx). |
|                                                                       |
| -   Combination therapy: Evidence from randomized controlled trials   |
|     is currently too limited to fully evaluate the efficacy and       |
|     safety of combination therapy (e.g., with a prostanoid or         |
|     sildenafil), although several trials are currently ongoing. At    |
|     this time, if combination therapy is considered, enrollment into  |
|     a clinical trial is strongly encouraged. Outside of a clinical    |
|     trial setting, combination therapy may be considered on a         |
|     case-by-case basis.                                               |
|                                                                       |
| -   **Ambrisentan:** Drug interactions have not been well studied     |
|     with ambrisentan; however, caution is recommended with            |
|     co-administration of cyclosporine or strong inhibitors or         |
|     inducers of CYP3A or CYP2C19.                                     |
|                                                                       |
| -   **Bosentan:** Co-administration of glyburide or cyclosporine with |
|     bosentan is **[contraindicated]{.underline}** due to significant  |
|     drug interactions. Hormonal contraceptives are not recommended as |
|     a sole means of preventing pregnancy with bosentan, as decreased  |
|     effectiveness may occur. Additional interactions with drugs       |
|     affecting CYP3A4 or CYP2C9 pathways are likely given the          |
|     metabolism of bosentan.                                           |
+-----------------------------------------------------------------------+

1\. The WHO classification of PH divides the disease into 5 groups
(Rubin. Chest.2004;126:7S-10S):

  ------- -----------------------------------------------------------------
  Group   Classification

  1       Pulmonary arterial hypertension (PAH): including idiopathic
          (IPAH), familial (FPAH), associated (\[APAH\]: collagen vascular
          disease, congenital systemic-to-pulmonary shunts, portal
          hypertension, HIV infection, drugs and toxins (see Ambrisentan
          Monograph for complete listing)

  2       Pulmonary venous hypertension (PH due to left heart disease)

  3       Pulmonary hypertension associated with disorders of the
          respiratory system or hypoxemia

  4       Pulmonary hypertension due to chronic thrombotic or embolic
          disease

  5       Miscellaneous pulmonary hypertension (inflammation or
          nonthrombotic obstruction)
  ------- -----------------------------------------------------------------

2\. WHO Functional Classes for PH (Rubin. Chest. 2004;126:7S-10S):

  ----- --------------------------------------------------------------------
  I     No limitation in physical activity; ordinary physical activity does
        not cause dyspnea or fatigue

  II    Slight limitations in physical activity; ordinary physical activity
        produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms
        at rest

  III   Marked limitation of physical activity; less than ordinary physical
        activity produces dyspnea, fatigue, chest pain, or near-syncope; no
        symptoms at rest

  IV    Unable to perform any physical activity without symptoms; dyspnea
        and/or fatigue present at rest; discomfort increased by any physical
        activity
  ----- --------------------------------------------------------------------

3\. Treatment of non-WHO Group 1 pulmonary hypertension is aimed at the
underlying disease. Evidence for the use of endothelin receptor
antagonists in non-WHO Group 1 PAH is limited and use is generally not
recommended; any exceptions should be considered on a case-by-case
basis.

4\. Positive acute vasodilator response defined as a fall in mPAP of ≥10
mm Hg to ≤40 mm Hg with an increase or no change in cardiac output. A
small percentage of patients (6.8%) have been shown to have a long term
response to calcium-channel antagonists as predicted by acute
vasodilator testing (Sitbon et al. Circulation. 2005;111:3105-11).