Epoprostenol

>10%

Flushing (58%)

Jaw pain (54%)

Headache (49%)

Myalgia (44%)

Diarrhea (37%)

Nausea (32%)

Vomiting (32%)

Flu-like symptoms (25%)

Eczema (25%)

Rash (25%)

Urticaria (25%)

Hypotension (16%)

Anxiety (11%)

Nervousness (11%)

1-10%

Musculoskeletal pain (2%)

Hyperesthesia (1%)

Tachycardia (1%)

Frequency Not Defined

Hemorrhage

Thrombocytopenia

Serious side effects have been reported with epoprostenol including the following:

• Worsening symptoms of pulmonary arterial hypertension (PAH) with a sudden decrease in the dose of this medication. Epoprostenol can cause serious withdrawal side effects. To avoid withdrawal side effects, do not suddenly stop taking this medication. Your doctor will slowly decrease your dose before stopping this medicine altogether. Sudden and dramatic changes in dose may lead to unstable blood pressure, a return of pulmonary hypertension symptoms, or fatal low blood pressure.
• Sepsis. Epoprostenol may cause a serious complication resulting from an infection in your bloodstream. Tell your doctor immediately if you develop signs of symptoms of a severe infection, such as fever, chills, low blood pressure, difficulty breathing, or fast heart rate. To reduce the risk of infection in the bloodstream, it is important to know how to properly care for the catheter and infusion pump.
• Fluid in your lungs (pulmonary edema). If you develop pulmonary edema after starting epoprostenol, your healthcare provider will stop your treatment and you should not receive epoprostenol again.
• Widening of your blood vessels (vasodilation). Vasodilation reactions can happen after you start epoprostenol. These reactions are common and may cause low blood pressure (hypotension), flushing, nausea, vomiting, dizziness, and headache. Your healthcare provider should check your blood pressure regularly during treatment with epoprostenol, especially when you start epoprostenol and after your dose is changed.
• Increased risk for bleeding. Epoprostenol affects how well your blood clots, so your risk for bleeding is increased. This is especially true if you have other risk factors for bleeding. Tell your healthcare provider if you develop any unusual bruising or bleeding.

Epoprostenol can cause dizziness. Do not drive or operate heavy machinery until you know how epoprostenol affects you.

Do not take epoprostenol if you:

• are allergic to epoprostenol or to any of its ingredients
• have heart failure due to severe left heart disease
• have pulmonary edema (fluid in your lungs)

If you suspect you have received too much epoprostenol, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If epoprostenol is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Epoprostenol can increase your risk of bleeding. This effect is increased when you also use medicines to prevent blood clots, such as:

• heparin or warfarin (Coumadin, Jantoven);

• alteplase (Activase), tenecteplase (TNKase), urokinase (Abbokinase);

• dalteparin (Fragmin), enoxaparin (Lovenox), fondaparinux (Arixtra), tinzaparin (Innohep); or

• abciximab (ReoPro), anagrelide (Agrylin), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), eptifibatide (Integrelin), prasugrel (Effient), ticlopidine (Ticlid), tirofiban (Aggrastat).

Tell your doctor about all other medications you use, especially:

• digoxin (digitalis, Lanoxin);

• a diuretic (water pill);

• heart or blood pressure medications;

• aspirin or an NSAID (nonsteroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.

This list is not complete and other drugs may interact with epoprostenol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

• It is used to treat high blood pressure in the lungs.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Shortness of breath.
• Very bad dizziness or passing out.
• Very bad headache.
• Dark urine.
• Chest pain or pressure or a fast heartbeat.
• Slow heartbeat.
• A heartbeat that does not feel normal.
• Pale skin.
• Shakiness.
• Feeling very tired or weak.
• A burning, numbness, or tingling feeling that is not normal.
• Swelling of belly.
• Redness or swelling where the shot is given.
• Skin sores.
• Very bad irritation where the shot was given.

Epoprostenol sodium for injection is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Trials establishing effectiveness included predominantly (97%) patients with New York Heart Association (NYHA) Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH associated with connective tissue diseases (51%).

Mechanism of Action

Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation.

Pharmacodynamics

Acute Hemodynamic Effects

Acute intravenous infusions of Epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH/SSD produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of Epoprostenol on mean pulmonary artery pressure (PAPm) were variable and minor.

In humans, hemodynamic changes due to Epoprostenol (e.g., increased heart rate, facial flushing) returned to baseline within 10 minutes of termination of 60-minute infusions of 1 to 16 ng/kg/min. This pharmacodynamic behavior is consistent with a short in vivo half-life and rapid clearance in man, as suggested by the results of animal and in vitro studies.

In animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac output and stroke volume. The effect of Epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally-mediated bradycardia, but at higher doses, Epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of Epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.

Drug Interactions

Additional reductions in blood pressure may occur when Epoprostenol is administered with diuretics, antihypertensive agents, or other vasodilators.

When other antiplatelet agents or anticoagulants are used concomitantly, there is a potential for Epoprostenol to increase the risk of bleeding. However, patients receiving infusions of Epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding.

Pharmacokinetics

Absorption/Distribution

Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of Epoprostenol. Animal studies using tritium-labeled Epoprostenol have indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled Epoprostenol were reached within 15 minutes and were proportional to infusion rates.

Metabolism

Tritium-labeled Epoprostenol has been administered to humans in order to identify the metabolic products of Epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than Epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that Epoprostenol is extensively metabolized in humans.

Elimination

The in vitro half-life of Epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of Epoprostenol in humans is expected to be no greater than 6 minutes.

Drug Interactions

In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide in whom therapy with Epoprostenol was initiated, apparent oral clearance values for furosemide (n = 23) were decreased by 13% on the second day of therapy and returned to baseline values by Day 87. The change in furosemide clearance value is not likely to be clinically significant.

In a pharmacokinetic substudy in patients with congestive heart failure receiving digoxin in whom therapy with Epoprostenol was initiated, apparent oral clearance values for digoxin (n = 30) were decreased by 15% on the second day of therapy and returned to baseline values by Day 87. Clinical significance of this interaction is not known.

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Flolan: 0.5 mg (1 ea); 1.5 mg (1 ea)

Veletri: 0.5 mg (1 ea); 1.5 mg (1 ea)

Generic: 0.5 mg (1 ea); 1.5 mg (1 ea)

• Prostacyclin
• Prostaglandin
• Vasodilator

Epoprostenol is also known as prostacyclin and PGI2. It is a strong vasodilator of all vascular beds. In addition, it is a potent endogenous inhibitor of platelet aggregation. The reduction in platelet aggregation results 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.

Metabolism

Rapidly hydrolyzed; subject to some enzymatic degradation; forms two active metabolites (6-keto-prostaglandin F1α and 6,15-diketo-13,14-dihydro-prostaglandin F1α) with minimal activity and 14 inactive metabolites

Excretion

Urine (84%); feces (4%)

Half-Life Elimination

~6 minutes

Refer to adult dosing.

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Prostacyclin Analogues may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anticoagulants: Prostacyclin Analogues may enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: Prostacyclin Analogues may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Digoxin: Epoprostenol may increase the serum concentration of Digoxin. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Thrombolytic Agents: May enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

Concerns related to adverse effects:

• Pulmonary edema: Some patients with PAH have developed pulmonary edema during dosing adjustment and acute vasodilator testing (an off-label use), which may be associated with concomitant heart failure (LV systolic dysfunction with significantly elevated left heart filling pressures) or pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. If pulmonary edema develops during therapy initiation, discontinue and do not readminister.

• Rebound pulmonary hypertension: Avoid abrupt interruptions or large sudden reductions in dosage; may result in rebound pulmonary hypertension (eg, dyspnea, dizziness, asthenia). A fatal case occurred following interruption. Immediate access to medication or pump and infusion sets is essential to prevent treatment interruptions.

• Vasodilation: Epoprostenol is a potent pulmonary and systemic vasodilator and can cause hypotension and other reactions such as flushing, nausea, vomiting, dizziness, and headache. Monitor blood pressure and symptoms regularly during initiation and after dose change.

Disease-related concerns:

• Conditions that increase bleeding risk: Epoprostenol is a potent inhibitor of platelet aggregation. Use with caution in patients with other risk factors for bleeding.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate Use: Initiation or transition to epoprostenol requires specialized cardiopulmonary monitoring in a critical care setting where clinicians are experienced in advanced management of pulmonary arterial hypertension. To reduce the risk of thromboembolism during chronic use, anticoagulants should be coadministered unless contraindicated.

• 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 events have not been observed in animal reproduction studies. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).

Caution is recommended. -According to some manufacturers, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Unknown Comments: The effects in the nursing infant are unknown.