TRISTAR STONECREST MEDICAL CENTER

PHARMACY & THERAPEUTICS COMMITTEE– FORMULARY REVIEW

July 2020

GENERIC NAME: Aerosolized Epoprostenol Sodium

BRAND NAME: Flolan®
MANUFACTURER: GlaxoSmithKline (GSK)
DATE OF APPROVAL: September 1995

Dosage Form(s)/How Supplied1, 2

Solution Reconstituted, Intravenous: 0.5 mg; 1.5 mg

Indication(s) and Contraindications1,2

 Indications:
o FDA approved: Treatment of pulmonary arterial hypertension (PAH) in patients with NYHA Class III or IV symptoms to
improve exercise capacity.
o Off-Label: Acute respiratory distress syndrome, refractory moderate to severe; Acute vasodilator testing in pulmonary
arterial hypertension; Post-cardiothoracic surgery complicated by pulmonary hypertension, right ventricular dysfunction,
or refractory hypoxemia
 Contraindications: hypersensitivity to Flolan or any of its ingredients; heart failure with reduced ejection fraction; patients
who develop pulmonary edema during dose initiation.
Dosage and Administration1

 Fixed-dose: Initial: Use a 20,000 ng/mL solution and nebulize at a rate of 8 mL/hour; titrate down based on clinical response by
reducing the concentration to 10,000 ng/mL while continuing to nebulize at a rate of 8 mL/hour; discontinue within 4 to 6 hours
as tolerated.
 Weight-based: Initial: 10 or 50 ng/kg/minute based on ideal body weight; titrate by increasing or decreasing dose in increments
of 10 ng/kg/minute every 30 minutes to 2 hours as tolerated based on clinical response; maximum dose: 50 ng/kg/minute).

Mechanism of Action and Pharmacokinetics1

Flolan is composed of epoprostenol which is a prostacyclin and PGI 2; both of which are strong vasodilator. In
Mechanism addition, it is a potent endogenous inhibitor of platelet aggregation. The reduction in platelet aggregation results
of Action from epoprostenol's activation of intracellular adenylate cyclase and the resultant increase in cyclic adenosine
monophosphate concentrations within the platelets. Additionally, it is capable of decreasing thrombogenesis and
platelet clumping in the lungs by inhibiting platelet aggregation.
Absorption Bioavailability IV: ~100%
Half-life: ~6 minutes
Distribution Vdss: 357 mL/kg (based on animal studies)
Metabolism 2 active metabolites: 6-keto-PGF (1 alpha) and 6,15-diketo-13,14-dihydro-PGF (1 alpha). 14 inactive metabolites
Excretion Fecal: 4%
Renal: 82%
*all data provided is for intravenous formulations as the nebulized formula is still being studied.

Warnings/Precautions2
Warnings:
 Pulmonary edema: Some patients with PAH have developed pulmonary edema during dosing adjustment and acute
vasodilator testing. If pulmonary edema develops during therapy initiation, discontinue and do not re-administer.
 Rebound pulmonary hypertension: Avoid abrupt interruptions or large sudden reductions in dosage; may result in
rebound pulmonary hypertension

Prepared by: Sierra Munoz, PharmD Candidate 2021

Reviewed/Revised by: Maegan Wilson. PharmD, BCPS
  Vasodilation: Systemic epoprostenol is a potent pulmonary and systemic vasodilator and can cause hypotension.
Inhaled administration may result in minimal systemic absorption and potentially decrease risk of vasodilation when
compared to systemic therapy. Monitor BP and symptoms regularly during initiation and after dose change.
 Conditions that increase bleeding risk: Use with caution in patients with other risk factors for bleeding due to platelet
aggregation inhibition of epoprostenol.
 Infection: Chronic continuous IV infusion of epoprostenol via a chronic indwelling central venous catheter (CVC) has
been associated with local infections and serious blood stream infections.

Adverse Effects2

Headache (46% to 83%), dizziness (8% to 83%), Flushing (23% to 58%), tachycardia (1% to 43%), fever (≤25%), chills (≤25%),
hypotension (13% to 27%), chest pain (11%), anxiety (≤21%), nervousness (≤21%), hyperesthesia (≤12%), hypoesthesia (≤12%),
paresthesia (≤12%), Dermal ulcer (39%), eczema (≤10% to ≤25%), skin rash (≤10% to ≤25%), urticaria (≤10% to ≤25%), Nausea and
vomiting (32% to 67%), anorexia (25% to 66%), diarrhea (37% to 50%), Sepsis (≤25%), Musculoskeletal pain (3% to 84%), arthralgia
(≤84%), neck pain (≤84%), jaw pain (54% to 75%), myalgia (44%), hyperkinesia (≤21%), tremor (≤21%), Flu-like symptoms (≤25%)

Drug/Food Interactions1,2

 Anticoagulants: increased risk of bleeding

 Antihypertensive Agents: additive hypotensive effects

 Antiplatelet Agents: May enhance antiplatelet effects leading to increased bleed risk
 Digoxin: oral clearance of digoxin was reduced by 15%
 Diuretics: additive hypotensive effects
 Furosemide: oral clearance of furosemide was reduced by 13%. Not likely clinically significant
 Vasodilating Agents: additive hypotensive effects
Storage Requirements2

 Unopened vials of Flolan and sterile diluent: store at 15° - 25°C (59° - 77°F) and protected from light in the carton.
 Reconstituted Flolan: Store at 2° - 8°C (36° - 46°F), do not freeze, protect from light. Discard reconstituted solution after 48 hrs
Pharmacoeconomics3

Drug Dose Price

Flolan® 0.5mg $22.43
Flolan® 1.5mg $54.17
Epoprostenol Sodium 0.5mg $19.44
Epoprostenol Sodium 1.5mg $46.94

Discussion / Recommendations4,5,6,7,8,9

Acute respiratory distress syndrome is associated with a severe hypoxemia, systemic inflammatory response, and high
hospital mortality. Despite this, viable treatment options have remained limited. Use of prostaglandin analogs, such as Flolan®, have
grown in popularity as a potential treatment option for ARDS, but there is limited efficacy data and no studies have yet to study
mortality as a primary endpoint.4 There have been three studies comparing the use of inhaled epoprostenol (IEPO) and inhaled nitric
oxide (INO). The first, a retrospective cohort analysis compared the efficacy of iEPO with iNO in 105 patients with refractory
hypoxemia, a symptoms of ARDS. The study concluded no change in the PFR at 1 hour, duration of iPVD therapy, duration of
mechanical ventilation, ICU and hospital LOS, adverse events, and in-hospital mortality between the IEPO and INO groups. This trial
showed that that inhaled epoprostenol was as effective as inhaled nitric oxide for the treatment of ARDS. 6 Another retrospective
study was conducted to access the time between the development of hypoxia and the initiation of iEPO. The study consisted of only
36 patients of which they received iEPO for a mean of 5.9 days after developing hypoxia. By 12 hours the PFR improved from a mean
of 67 to 142 at 12. At 48 hours the PFR improved to 202 at 48 hours (P = 0.001). Within 48 hours, more than 90% of patients had a
decrease in their FiO2 to 60% or less. The authors concluded that the use of iEPO as salvage therapy can be effective in improving
PFR but its effect on mortality could not be determined. 7 The last study was a retrospective, noninterventional, propensity-matched,
noninferiority cohort study compared the use of iNO and iEPO for the treatment of ARDS. The study concluded there was no

Prepared by: Sierra Munoz, PharmD Candidate 2021

Reviewed/Revised by: Maegan Wilson. PharmD, BCPS
difference in ICU-free days, death at ICU discharge, and changes in PFR. 8 While these studies showed that IEPO was as effective as
INO for the treatment of ARDS, but the efficacy of INO is still unproven for ARDS.

One study was conducted to study the effects of iEPO on oxygenation improvement in patients diagnosed with ARDS. It
consisted of a small retrospective observational study of 16 patients. The study findings indicated that 62.5% of patients receiving
iEPO demonstrated a response to therapy, defined as at least a 10% increase in the PFR within 4 hours of treatment initiation. Only
40% of patients who had a response survived to discharge. Their results showed no increase in survival benefit using iEPO in critically
ill patients with severe ARDS.9 The majority of the published literature is composed of small sample sizes and varied methods
including different doses, length of treatment, methods of delivery and variable definitions of ARDS. This makes this data difficult to
extrapolate to a larger population. At this time, there is limited evidence on the use of Flolan® via inhalation for the treatment of
acute respiratory distress syndrome and it should not be added to formulary until greater efficacy can be demonstrated.

References

1. Flolan. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc.
http://online.lexi.com. Updated May 12, 2020. Accessed June 26, 2020.
2. GlaxoSmithKline. Flolan® (epoprostenol sodium for injection) prescribing information. Research Triangle Park, NC; 2011 Mar.
3. Red Book Online [database online]. Greenwood Village, CO: IBM Corporation. http://www.micromedexsolutions.com/.
Updated March 25, 2009. Accessed March 27, 2020.
4. Schroeder, Nicole M. PharmD, BCPS, BCCCP; Castiello, Danielle R. BSN, RN, CCRN; Siemianowski, Laura A. PharmD, BCPS,
BCCCP Inhaled epoprostenol for acute respiratory distress syndrome, Nursing Critical Care: July 2018 - Volume 13 - Issue 4 -
p 6-13 doi: 10.1097/01.CCN.0000534919.47806.75
5. Hawn JM, Bauer SR, Wanek MR, et al. Effectiveness, Safety, and Economic Comparison of Inhaled Epoprostenol Brands,
Flolan and Veletri, in Acute Respiratory Distress Syndrome. Ann Pharmacother. 2020;54(5):434-441.
doi:10.1177/1060028019888853
6. Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S, Weinhouse GInhaled epoprostenol vs inhaled nitric oxide for
refractory hypoxemia in critically ill patients☆. Journal of Critical Care. 2013;28(5):844–848. doi:
10.1016/j.jcrc.2013.03.006.
7. Tabrizi MB, Schinco MA, Tepas JJ 3rd, Hwang J, Spiwak E, Kerwin AJ. Inhaled epoprostenol improves oxygenation in severe
hypoxemia. J Trauma Acute Care Surg. 2012;73(2):503–506.
8. Ammar MA, Bauer SR, Bass SN, Sasidhar M, Mullin R, Lam SW. Noninferiority of inhaled epoprostenol to inhaled nitric
oxide for the treatment of ARDS. Ann Pharmacother. 2015;49(10):1105–1112.
9. Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and medication errors associated with the use of
inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. Ann Pharmacother.
2013;47(6):790–796.

Prepared by: Sierra Munoz, PharmD Candidate 2021

Reviewed/Revised by: Maegan Wilson. PharmD, BCPS