Last updated Feb. 7, 2023, by Lindsey Shapiro, PhD
Fact-checked by José Lopes, PhD
What is Flolan for PH?
Flolan (epoprostenol GM), approved more than 25 years ago in the U.S., was the first therapy for pulmonary arterial hypertension (PAH). It is indicated as an into-the-vein (intravenous) treatment to improve exercise ability for people with PAH.
The therapy is marketed by GlaxoSmithKline, with a generic version available.
How does Flolan work?
PAH is caused by a narrowing of the pulmonary arteries that send blood from the heart to the lungs. This narrowing makes it harder to pump blood to the lungs, and as a consequence, the heart has to work too hard. Blood pressure is raised, and oxygen transport throughout the body is limited as a result.
Flolan’s active ingredient, epoprostenol, is a synthetic version of prostacyclin, a molecule in the body that promotes vasodilation, or the relaxation and widening of blood vessels.
The actions of epoprostenol are twofold: it binds to cells on artery walls to active signaling pathways that drive vasodilation, but also inhibits activation of platelets (involved in blood clotting) and prevents them from building up and blocking vessels.
By mimicking the activities of prostacyclin, Flolan is thought to make it easier for the heart to pump blood to the lungs, and in turn, for the lungs to provide oxygen to the rest of the body.
Janssen markets another formulation of epoprostenol called Veletri, that works similarly but is designed to be more stable at room temperature.
Flolan’s mechanism also is similar to that of Remodulin, another injectable, synthetic version of prostacyclin that’s marketed by United Therapeutics.
Who can take Flolan?
The U.S. Food and Drug Administration approved Flolan in 1995 to improve exercise capacity in PAH patients from the World Health Organization (WHO) group 1.
Studies establishing its effectiveness mostly included patients with a New York Heart Association (NYHA) functional classification III-IV, or those with marked to severe symptoms during physical activity.
Flolan is approved in several countries worldwide, including Japan, and also is available in the European Union.
Who should not use Flolan?
Patients who have heart failure caused by a reduced left ventricular ejection fraction — the percentage of blood leaving the heart each time it contracts — or those who have a hypersensitivity to Flolan or any of its ingredients should not use the medication.
How is Flolan administered?
Flolan is supplied as a white to off-white powder in single-use vials (0.5 or 1.5 mg epoprostenol) that must be reconstituted in a supplied diluent before use.
The treatment is administered as a continuous intravenous infusion via a tube called a catheter that a doctor inserts into a vein. The infusion is controlled by an external, battery-operated pump.
Flolan is started at a dose of 2 nanograms per kilogram per minute (ng/kg/min), which is increased in 1 to 2 ng/kg/min increments, with at least 15 minutes in between doses. The increase is based on a person’s clinical response, including persistence of symptoms and side effects.
Treatment should always be initiated with a healthcare professional and blood pressure monitoring. Patients will be educated on catheter care, use of the infusion pump, and medication preparation and administration.
Large, sudden dose reductions of Flolan should be avoided. A backup infusion pump and extra intravenous infusion supplies should be provided to avoid interruptions in drug delivery.
Flolan in clinical trials
A number of randomized clinical trials, observational studies, and registries have evaluated Flolan as a potential treatment for PAH over the past few decades.
Flolan in idiopathic and heritable PAH
Flolan’s approval was based on the findings from two randomized clinical trials, which compared the treatment against conventional therapies in PAH patients with idiopathic (no known cause) or heritable PAH.
In the first trial, 24 PAH patients were randomly assigned to receive Flolan or conventional PAH therapies for eight weeks, or about two months.
Flolan led to a significant and sustained decrease in pulmonary vascular resistance (PVR), which measures the resistance to blood flow in the pulmonary arteries. Treatment also led to a decrease in pulmonary arterial pressure (PAP) compared with patients on conventional therapy. Both are indicators of PAH severity.
Participants were able to continue treatment post-trial in an open-label extension for up to 18 months. Flolan continued to demonstrate sustained benefits in key hemodynamic or blood circulation measurements.
The second trial enrolled 41 patients with severe primary pulmonary hypertension who were treated with Flolan plus conventional therapy, and 40 others who used conventional therapy only, for 12 weeks, or about three months.
The results of this study showed that Flolan led to significant improvements in exercise capacity, as measured by the six-minute walk distance test. Reductions in PAP, PVR, and improvements in other hemodynamics and lung parameters compared with conventional therapy were observed.
Flolan also significantly decreased mortality rate.
Flolan in PAH with systemic sclerosis
Another clinical trial evaluated the effects of continuous Flolan infusion in patients with PAH associated with systemic sclerosis (SSc), supporting the expansion of the therapy’s label to include these patients. SSc is a type of connective tissue disorder commonly accompanied by PAH.
A total of 111 patients were randomly assigned to receive Flolan plus conventional therapy or conventional therapy alone for 12 weeks, or about three months. Similar to findings in other PAH patients, Flolan was associated with significant improvements in exercise capacity compared with the conventional therapy group.
Hemodynamic measures also were significantly improved, including decreases in PAP and PVR. Improvements in NYHA functional classification were observed for 21 people using Flolan, and no patients using conventional therapy.
Following that study, 102 patients continued in the trial’s open-label extension study, in which all received Flolan for up to three years. Results showed that survival was improved with Flolan compared with the natural history of SSc-PAH.
Flolan in combination with other therapies
A number of trials have evaluated Flolan’s efficacy when used in combination with other therapies.
The 16-week BREATHE-2 study compared the effects of Flolan alone or in combination with Tracleer (bosentan) among 33 PAH patients. A non-significant trend toward clinical and hemodynamic improvements was found with the combination as compared with Flolan alone.
Another randomized, controlled study (NCT00159861) involving 267 patients found that Flolan combined with Revatio (sildenafil) led to improvements in exercise capacity and a longer time to clinical worsening than Flolan alone.
A retrospective registry study later found that a combination of all three therapies led to major improvements in exercise capacity and PVR after four months, which were sustained over the long term.
The Flolan International Randomized Survival Trial (FIRST) evaluated the effects of Flolan on survival among 471 NYHA class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction. This condition is marked by the inability of the heart’s left ventricle to pump blood to the body efficiently.
The trial was stopped after an interim analysis showed a significantly higher mortality rate in patients receiving Flolan compared with those receiving conventional treatment alone. This finding led to the contraindication of Flolan’s use for patients with heart failure due to left ventricular dysfunction.
Common side effects of Flolan
The most common side effects associated with Flolan include:
- jaw pain
- musculoskeletal pain
These side effects are generally associated with vasodilation.
Pulmonary edema — fluid buildup in the lungs — may occur with Flolan treatment. Flolan should be discontinued if this side effect occurs and should not be readministered.
Worsening PAH when stopping treatment
If Flolan is abruptly discontinued or the dose is lowered quickly, patients may experience rebound PAH symptoms. Instead, any dose of Flolan should be gradually decreased under the supervision of a healthcare professional.
Side effects due to vasodilation may occur when using Flolan. These include a drop in systemic blood pressure and associated symptoms including flushing, nausea, vomiting, dizziness, and headache. Blood pressure should be monitored during treatment initiation and anytime the dose is changed.
Because Flolan inhibits platelets, patients using the treatment may be at an increased risk for bleeding events, particularly if they have other risk factors for bleeding.
Limited data are available on the use of Flolan during pregnancy. Animal studies have not demonstrated adverse effects on a developing fetus at doses larger than the maximum recommended human dose. There are no data on the presence of Flolan during breastmilk.
Patients who are pregnant or wish to become pregnant while using Flolan, and those nursing or planning to breastfeed should discuss the matter with their doctors.
Pulmonary Hypertension News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.