Epoprostenol (Flolan) is a prostaglandin analog, a prostacyclin (PGI-2) used in the treatment of idiopathic pulmonary arterial hypertension (WHO Class 1). It is a potent vasodilator and antiplatelet drug.

Epoprostenol (Flolan) Uses:

• Pulmonary arterial hypertension:

  • Used to increase exercise tolerance in patients with NYHA Class III or IV symptoms who have pulmonary arterial hypertension (PAH) (WHO Group I).

Note:

• Continuous IV epoprostenol is advised as first-line therapy in PAH patients having WHO-FC IV symptoms, according the Fifth World Symposium on Pulmonary Hypertension (WSPH) and American College of Chest Physicians (ACCP) treatment recommendations.

• Off Label Use of Epoprostenol in Adults:

  • Used in acute vasodilator testing in pulmonary arterial hypertension
  • Used in hypoxia secondary to acute respiratory distress syndrome
  • Used in pulmonary arterial hypertension related to cardiopulmonary bypass

Epoprostenol (Flolan) Dose in Adults

Epoprostenol (Flolan) Dose in the treatment of pulmonary arterial hypertension (PAH):

• IV: Initial: 2 ng per kg per minute;
• a lower initial dose may be used if the patient is intolerant of the starting dose.
• Increase dose in increments of 1 to 2 ng per kg per minute at intervals of  15 minutes or more than 15 minutes until dose-limiting side effects (eg, headache, hypotension, nausea, flushing, jaw pain) are noted or response to epoprostenol plateaus.
• The dose may also be lowered by 1 to 2 ng per kg per minute every 15 minutes to a dose that is tolerated.
• The usual optimal dose (monotherapy):
  • 25 to 40 ng per kg per minute;
  • significant patient variability in optimal dose exists.
  • The maximum dose with chronic therapy has not been defined; however, doses as high as 195 ng per kg per minute have been described in children.

• Epoprostenol (Flolan) Dose adjustment during the chronic phase of treatment:

  • If PAH symptoms persist or recur following improvement, increase the dose in 1 to 2 ng per kg per minute increments at intervals of 15 minutes or more than 15 minutes.
  • May also increase the dose at intervals of 24 to 48 hours or longer (eg, every 1 to 2 weeks).
  • Note:
    • The need for increased doses should be expected with chronic use; incremental increases occur more frequently during the first few months after the drug is initiated.
    • In the case of dose-limiting pharmacologic events (eg, vomiting, hypotension, severe nausea), decrease dose in 2 ng per kg per minute decrements at intervals of ≥15 minutes until dose-limiting effects resolve.
    • Avoid abrupt withdrawal or sudden large dose reductions.
  • Note:
    • Adverse events may resolve without dosage adjustment.
  • Lung transplant:
    • In patients receiving lung transplants, epoprostenol may be tapered after sequential lung transplantation once the allografts have been reperfused.
    • If cardiopulmonary bypass utilized, epoprostenol may be tapered after pump perfusion has been initiated.

Epoprostenol (Flolan) Dose in the treatment of Acute vasodilator testing in patients with PAH (off-label):

Note: Only patients who might be considered candidates for calcium channel blocker medication should undergo acute vasodilator testing.

• IV: Initial:
  • 2 ng per kg per minute;
  • Increase dose in increments of 2 ng per kg per minute every 10 to 15 minutes;
• Dosing range during testing:
  • 2 to 12 ng per kg per minute.

Epoprostenol (Flolan) Dose in the treatment of Hypoxia secondary to acute respiratory distress syndrome (off-label):

• Inhalation (off-label): Initial:
  • 0.01 to 0.05 mcg per kg per minute;
  • Increase the dose in a stepwise fashion based on efficacy and tolerability.
  • Wean by reducing the dose by 0.01 mcg per kg per minute every 1 to 2 hours as tolerated.

Epoprostenol (Flolan) Dose in the treatment of Intraoperative pulmonary hypertension during cardiac surgery with cardiopulmonary bypass (CPB) (off-label):

• Inhalation (off-label route):

Note:

• Institution-specific protocols vary.
• Studies included utilized Flolan brand; however, the formulary status of epoprostenol formulations may vary with some institutions utilizing Veletri, the more thermostable formulation.
  • Administration after induction of anesthesia before incision:
    • 60 mcg (4 mL of 15,000 ng/mL concentration) via jet nebulizer; effect persists for ~25 minutes.
  • OR
  • Intraoperative administration:
    • Nebulization via ventilator circuit: Using a 15,000 ng/mL concentration and an oxygen flow of 8 L/minute, begin administration via jet nebulizer

Epoprostenol (Flolan) Dose in the treatment of Post-cardiothoracic surgery pulmonary hypertension, right ventricular dysfunction, or refractory hypoxemia (off-label):

• Inhalation (off-label route):
  • Study utilized Flolan brand; however, the formulary status of epoprostenol formulations may vary with some institutions utilizing Veletri, the more thermostable formulation.
  • If using Flolan, may need to change the ventilator filter every 2 hours due to glycine buffer diluent; may cause ventilator valve malfunction.
  • The tidal volume delivered by ventilator may require adjustment.
  • Nebulization via ventilator circuit:
    • Using a 20,000 ng per mL concentration, prime nebulizer chamber with 15 mL; administer remainder at a constant rate of 8 mL per hour; delivers ~38 ng per kg per minute (based on a 70 kg patient);
    • set oxygen flow at 2 to 3 L/minute; wean as tolerated.
  • Note:
    • Although not achieved with this regimen, in general, doses more than 50 ng per kg per minute do not provide additional benefit, may increase the risk of hypotension and should be avoided.
• OR
  • Nebulization via a facemask with Venturi attachment:
    • Using a 20,000 ng per mL concentration, prime nebulizer chamber with 15 mL;
    • set oxygen flow at 2 to 3 L/minute; 8 mL per hour will be nebulized;
    • wean as tolerated.
  • Weaning procedure:
    • Reduce dose by 50 percent every 2 to 4 hours (ie, 20,000 ng per mL to 10,000 ng per mL to 5,000 ng per mL) until a concentration of 2,500 ng/mL is reached;
    • Carefully discontinue once the patient remains stable on this concentration for at least 4 hours.

Epoprostenol (Flolan) Dose in Children

Epoprostenol (Flolan) Dose in the treatment of pulmonary hypertension:

• Infants, Children, and Adolescents:

  • Continuous IV infusion:
    • Initial: 1 to 2 nanograms per kg per minute; titrate to clinical effect (eg, improvement in pulmonary pressures or right ventricular mechanics) or dose-limiting side effects (eg,  bone pain, headache nausea, diarrhea, jaw pain);
    • average effective dose: 80 nanograms per kg per minute;
    • Dose range: 40 to more than 150 nanograms per kg per minute in some patients.
    • Note: Excessive epoprostenol can lead to a high-output state (hyperdynamic right ventricle with an impact on cardiac output) and require a decrease in dose.
  • Inhalation:
    • Very limited data available;
    • efficacy results vary with patient age and etiology of pulmonary hypertension.
    • Other factors that may impact efficacy include product formulation (e.g, dilution, stability, pH) and the drug delivery system (eg, type of nebulizer, placement in the ventilator circuit, ventilator settings).
  • Continuous nebulization:
    • 20 to 50 nanograms per kg per minute;
    • dosing based on a small prospective trial of 14 children (median age: 54 months) with acute lung injury who received either aerosolized saline or inhaled epoprostenol administered in incremental doses (10, 20, 30, 40, and 50 nanograms per kg per minute);
    • significant improvement of the oxygenation index was observed at the 30 nanograms per kg per minute dose level and values close to significant at the 20, 40, and 50 nanograms per kg per minute dose were observed;
    • eight of the 14 children were considered responders to therapy with an improvement in oxygenation, and the calculated number needed to treat was 1.8 (95% chlorine, 1.2 to 3.2);
    • during the trial, no significant changes in respiratory or systemic cardiovascular variables (eg, HR, MAP, arterial pH) or ventilator settings were reported.

Epoprostenol (Flolan) Pregnancy Risk Category: B

• The information available on epoprostenol use in pregnancy is not complete.
• However, the manufacturer states that adverse maternal and fetal outcomes have not yet been linked to its use.
• Bad pregnancy outcomes are associated with pulmonary arterial hypertension (PAH). PAH women should avoid pregnancy.

Epoprostenol use during breastfeeding:

• It is unknown if breast milk contains epoprostenol.
• According to the manufacturer breastfeeding during therapy is a decision that should be made after considering the risks to infants and the benefits to mothers.

Epoprostenol (Flolan) Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments.

Epoprostenol (Flolan) Dose in Liver disease:

The manufacturer's labeling doesn't provide any dosage adjustments.

Common Side Effects of Epoprostenol (Flolan):

• Cardiovascular:

  • Flushing
  • Tachycardia
  • Hypotension
  • Chest Pain

• Central Nervous System:

  • Headache
  • Dizziness
  • Chills
  • Anxiety
  • Nervousness
  • Hyperesthesia
  • Hypoesthesia
  • Paresthesia
  • Agitation

• Dermatologic:

  • Dermal Ulcer
  • Eczema
  • Skin Rash
  • Urticaria

• Gastrointestinal:

  • Nausea And Vomiting
  • Anorexia
  • Diarrhea

• Infection:

  • Sepsis

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain
  • Arthralgia
  • Neck Pain
  • Jaw Pain
  • Myalgia
  • Hyperkinesia
  • Tremor

• Respiratory:

  • Flu-Like Symptoms

• Miscellaneous:

  • Fever

Less Common Side Effects Of Epoprostenol (Flolan):

• Cardiovascular:

  • Bradycardia

• Dermatologic:

  • Diaphoresis

• Gastrointestinal:

  • Abdominal Pain
  • Dyspepsia

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Dyspnea

Contraindications to Epoprostenol (Flolan):

• Hypersensitivity to epoprostenol, any chemical with a similar structure, or any ingredient in the mixture
• Chronically ill patients with significant left ventricular dysfunction and cardiac failure
• Patients who have pulmonary edema after dose initiation may continue to use chronically.

Warnings and precautions

• Pulmonary edema

  • Stop therapy immediately if pulmonary edema occurs during treatment initiation.
  • Patients with PAH may develop pulmonary edema from dosing adjustment or acute vasodilator test (an off-label usage), which can be linked to concomitant heart disease (LV systolic dysfunction and significantly elevated left-heart filling pressures) as well as pulmonary venoocclusive disease/pulmonary hemangiomatosis.

• Rebound pulmonary hypertension

  • Avoid abrupt interruptions and sudden drops in dosage. This could lead to rebound pulmonary hypertension (eg asthenia, dyspnea or dizziness).
  • After treatment interruption, a fatal case occurred.
  • To avoid treatment interruptions, it is important to have immediate access to medications or pumps and infusion sets.

• Vasodilation

  • Epoprostenol, a powerful pulmonary and systemic vasodilator, can cause hypotension, flushing, dizziness and nausea.
  • Monitor blood pressure and other symptoms during and after dose changes.

• Conditions that increase bleeding risk

  • Epoprostenol acts as a powerful inhibitor against platelet aggregation.
  • Patients with bleeding risk factors should be treated with caution

Epoprostenol: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Keep an eye on your pulmonary function, your level of weariness, your risk of syncope and chest pain, your blood pressure, your pulmonary vascular resistance, your pulmonary arterial pressure, and your general level of well-being.
• Following the establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours.
• In addition, the pump device and catheters should be monitored frequently to avoid “system” related failure.
• Monitor arterial pressure; assess all vital functions. Hypoxia, flushing, and tachycardia may indicate an overdose.

How to administer Epoprostenol (Flolan)?

IV:

• For IV use via an infusion pump.
• Use infusion sets with an in-line 0.22-micron filter.
• When administered on an ongoing basis, must be infused through a central venous catheter.
• The peripheral infusion may be used temporarily until the central line is established.
• Do not administer as a bolus injection.
• Avoid abrupt withdrawal (including interruptions in delivery) or sudden large reductions in dosing.
• The ambulatory infusion pump should be small and lightweight, be able to adjust infusion rates in 2 ng per kg per minute increments, have occlusion, end of infusion, and low battery alarms, have ± 6 percent accuracy of the programmed rate, and have positive continuous or pulsatile pressure with intervals of 3 minutes or less than 3 minutes between pulses.
• The reservoir should be made of polyvinyl chloride, polypropylene, or glass.
• Immediate access to back up pumps, infusion sets, and medication is essential to prevent treatment interruptions.
• Consult manufacturer’s labeling for infusion rate example calculations.

Flolan-specific administration considerations:

• If Flolan reconstituted using pH 12 sterile diluent for Flolan, then avoid administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG);
• consult administration set manufacturer to confirm compatibility with highly alkaline solutions (eg, pH 12 sterile diluent for Flolan).

Epoprostenol (Flolan) Inhalation (off-label route):

Intraoperative administration:

• Administer via jet nebulizer connected to the inspiratory limb of the ventilator near the endotracheal tube with a bypass oxygen flow of 8 L/minute to achieve administration of a high proportion of small particles.

Post-cardiothoracic surgery:

• May also be administered via a jet nebulizer connected to the inspiratory limb of the ventilator near the endotracheal tube or via a face mask with a Venturi attachment for aerosolization with a bypass oxygen flow of 2 to 3 L per minute.

Note:

• Glycine buffer diluent may cause ventilator valve malfunction; it has been recommended that filters be changed on the ventilator every 2 hours; may also use a ventilator heating coil.

Mechanism of action of Epoprostenol (Flolan):

• Prostacyclin is another name for Epoprostenol. 
• It acts as a strong vasodilator in all vascular beds.
• It is also a powerful endogenous inhibitor against platelet aggregation. 
• Epoprostenol activates intracellular adenylate cyclase, resulting in a reduction in platelet aggregation.
• It is also capable of decreasing thrombogenesis, platelet clumping and pulmonary inflammation by inhibiting platelet accumulation.

Metabolism

• Rapidly hydrolyzed; subject to some enzymatic degradation; forms two active metabolites (6-keto-prostaglandin F a and 6,15-diketo-13,14-dihydro-prostaglandin F a) with minimal activity and 14 inactive metabolites

Half-life elimination:

• ~6 minutes

Excretion:

• Urine (84 percent );
• feces (4 percent )

International Brand Names of Epoprostenol:

• Veletri
• Caripul
• Flolan
• Dynovase

Epoprostenol Brand Names in Pakistan:

There is no brand available in Pakistan.