EPOPROSTENOL FLOLAN  - WHAT IS IT ?

Primary pulmonary hypertension is a rare disorder that presents most commonly in women 20 to 40 years of age. The etiology is unknown but may be associated with autoimmune disorders, toxic substances, and specific genetic determinants. The patient?s pulmonary vasculature undergoes extensive remodeling that results in increased pulmonary artery pressure and pulmonary vascular resistance. Primary pulmonary hypertension typically results in right-sided heart failure and death within years of the onset of symptoms.

Patients with these disorders have historically been treated with heart-lung or lung transplants, high-dose calcium channel blockers (nifedipine up to 240 mg/day and diltiazem up to 720 mg/day), and nitric oxide. Other agents that have been used with variable success include anticoagulants, acetylcholine, tolazoline, prazosin, isoproterenol, hydralazine, nitrates, nitroprusside and captopril. The overall goal of treatment is to improve pulmonary function and the quality of life, while serving as a bridge to successful heart or heart-lung transplants in those patients who are considered candidates for such surgery.

Pulmonary hypertension secondary to congenital heart disease, or other diseases such as scleroderma, Crest syndrome, Raynaud's phenomenon, systemic lupus erythematosus, and polymyositis (mixed connective tissue disease) may also present with pulmonary vasculature and connective tissue remodeling, causing increased vascular resistance and decreased pulmonary function, potentially leading to right-sided heart failure.

The patient's response to vasodilators is typically tested in a cardiac catheterization lab using oral calcium channel blockers, IV prostacyclin and/or other vasodilators. Baseline pulmonary artery pressures and pulmonary vascular resistances are compared to post-vasodilatory treatment values to assess the patient's responsiveness to the medication.

Epoprostenol, also known as prostacyclin and prostaglandin I2, is a strong vasodilator of all vascular beds. The beneficial effects of epoprostenol are a result of both relaxation of vascular smooth muscle cells and an inhibition of platelet aggregation.

Policy/Criteria
Epoprostenol may be considered medically necessary for the following conditions:

1. Patients with primary pulmonary hypertension or secondary pulmonary hypertension, due to congenital heart disease, or systemic sclerosis/scleroderma. *Refer to Appendix I for classification of systemic sclerosis/scleroderma.

AND

a. Exhibit New York Heart Association (NYHA) Class III or IV symptoms. *Refer to Appendix I for listing of NYHA Classification.

b. Are unresponsive to other forms of therapy (e.g., calcium channel blockers, nitric oxide) or who are not candidates for these medications.

Administration Considerations:
Epoprostenol is indicated for administration by continuous IV infusion via a central venous catheter. Administration via inhalation is another option that has been shown to be efficacious in small studies and may be considered medically necessary for the short-term treatment of primary pulmonary hypertension and pulmonary hypertension secondary to systemic sclerotic diseases. Drug delivery via inhalation may require higher doses than continuous IV infusion and may not be appropriate for long term use; therefore, this method should be reserved for patients who cannot tolerate IV infusion or patients for whom infusion is contraindicated (e.g. local infections, sepsis from IV catheter.

Availability Considerations:
Epoprostenol is an orphan drug with limited availability and can only be administered through a hospital or home infusion company. If Epoprostenol is to be administered on an outpatient basis, it must be done through home infusion for both IV and inhalation administration methods.

Epoprostenol is considered investigational for other applications, including but not limited to:

1. Ischemic vascular diseases
2. Congestive heart failure
3. Chronic obstructive pulmonary disease

Appendix I: Classification of Scleroderma/Systemic Sclerosis

a. Limited cutaneous scleroderma defined by a symmetric skin thickening limited to distal extremities and face. This subset has features of the CREST syndrome (e.g. Calcinosis, Raynaud?s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia).

b. Diffuse cutaneous scleroderma defined as the rapid development of symmetric skin thickening of proximal/distal extremities, face, and trunk. These patients are at greater risk for development of kidney and other visceral disease in the early course.

c. Sine scleroderma is the systemic sclerosis of visceral organs, which may occur in the absence of any skin involvement.

d. Undifferentiated connective tissue disease is designated for patients who do not meet a diagnostic criteria for any one connective tissue disease.

e. Overlap syndromes defines patients with systemic sclerosis in association with features of other connective tissue diseases, such as systemic lupus erythematosus, polymyositis, and rheumatoid arthritis.

Appendix II: NYHA Class I-IV PH CLASSIFICATIONS

NYHA Class I      No limitation. Ordinary activity does not cause problems.
NYHA Class II     Slight limitation in physical activity. Ordinary physical activity will result in symptoms.
NYHA Class III    Marked limitation of physical activity. Less than ordinary activity leads to symptoms.
NYHA Class IV    Inability to carry on any activity without symptoms. Symptoms may be present at rest.

Scientific Background
Therapy for secondary pulmonary hypertension focuses on treatment of the underlying etiology, but may also include therapy of the hypertension itself, similar to primary pulmonary hypertension. (1-3)

Treatment of secondary pulmonary hypertension associated with scleroderma is based on the following studies. In a case series, 17 patients with pulmonary hypertension associated with either scleroderma, CREST syndrome, systemic lupus erythematosus (SLE) or Sjogren?s syndrome, were treated with epoprostenol. (4) Patients were observed from 14 to 154 weeks. After 6 weeks, improved exercise capacity was seen in 15 of 17 patients. The remaining 2 patients died of pulmonary edema or sepsis. During long-term follow-up, an additional 5 patients died, 2 patients underwent successful lung transplantation, and 7 of the remaining 8 patients had a persistent clinical improvement. Badesch et al 2000, conducted a randomized study in 111 patient with pulmonary hypertension related to scleroderma. Patients were randomized to receive either conventional therapy or conventional therapy in addition to epoprostenol therapy. (5) The primary endpoint was measurement of exercise capacity. Exercise capacity was significantly improved in the epoprostenol treated group compared to the control group, where exercise capacity actually decreased. A total of 38% of patients in the treatment group reported improvements in the NYHA classification, compared to none in the control group.

Rosenzweig et al 1999, reported a case series of 20 patients with pulmonary hypertension secondary to congenital heart disease, who failed conventional therapy.(6) Although none of the patients experienced a decrease in pulmonary artery pressure, in response to epoprostenol, long-term therapy was associated with a 21% reduction in pulmonary artery pressure. Additionally, the NYHA classification in these patients improved from a mean of 3.2 to 2.0. There was no significant increase in exercise capacity.

Epoprostenol via inhalation is an alternative administration route that has been studied to a limited extent. (7) In a small study of 6 patients, the effects of aerosolized prostacyclin was compared to nasal oxygen, and inhaled nitric oxide, in patients with severe pulmonary hypertension. Results indicated aerosolized epoprostenol caused selective pulmonary vasodilatation, increases cardiac output, and improves venous and arterial oxygenation in these patients.

There is little to no evidence supporting the use of epoprostenol in the treatment of ischemic vascular disease, congestive heart failure (8), and chronic obstructive pulmonary disease.(9)

Rationale for Benefit Administration
This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.